TITRE DE LA THESE THESE par
Transcripción
TITRE DE LA THESE THESE par
FACULTÉ des SCIENCES DOCTORAT EN NEUROSCIENCES des Universités de Genève et de Lausanne UNIVERSITÉ DE GENEVE FACULTÉ DE MÉDECINE Professeur M. PELIZZONE, directeur de thèse TITRE DE LA THESE Minimum Requirements for a Retinal Prosthesis to Restore Useful Vision THESE Présentée à la Faculté des Sciences de l’Université de Genève pour obtenir le grade de Docteure en Neurosciences par Angélica PÉREZ FORNOS de México D.F., Mexique Thèse N° 3737 Genève Editeur: Université de Genève 2006 ANGÉLICA PÉREZ FORNOS Chemin de Saule 39 CH-1233 Bernex Geneva, Switzerland +41(22)348-3959 +41(76)564-3959 [email protected] OBJECTIVE To occupy a position where challenging ideas and projects are proposed and developed; thus demanding constant effort, creativity, research, and actualization. OVERVIEW • • • • • • • Strong interests in research and emerging technologies. Dedicated, organized, and detail-oriented person. Good problem solving abilities through analysis and synthesis. Creative, material and human resources integrator. Leadership, excellent multidisciplinary team worker. Interested on continuous education and both person and team improvement. Self-demanding and perfectionist. AREAS OF EFFECTIVENESS • • • • • • • • Project planning and supervision. Team management. Custom system design and development. Programming. Computer simulations. Real time and off-line signal processing. Design, configuration, and customization of data acquisition systems. Computer-aided dynamic system simulation (CACSD). EXPERIENCE Feb/1999 – Jul/1999 NEURAL REHABILITATION ENGINEERING LABORATORY, Brussels, Belgium. Recording and Analysis of Visual Evoked Potentials Obtained by Electrical Stimulation Design and development of a custom VEP (Visual Evoked Potentials) recording system. This system was designed to register and analyze the electroencephalographic (EEG) activity resulting of electrical stimulation of the visual pathways with surface electrodes on healthy volunteers, as well as that resulting of direct stimulation of the optic nerve on a blind volunteer. Apr/2000 - Mar/2001 marchFIRST Switzerland – Consultant Project Management. Design and development of custom desktop and web applications. Specialized group and personal tutoring. Project management. Apr/2001 – to date Geneva University - HCUGE, Ophthalmology Clinic, Switzerland - Research Assistant Within the framework of the CMOS-retina project, design and development of computer and analysis tools for research in psychophysics of vision. Participation in the conception and execution of research experiments. ADDITIONAL SKILLS • • • • EDUCATION 1994 - 1999 LANGUAGES General knowledge on natural sciences and mathematics (calculus, physics, anatomy, physiology, and chemistry). Expertise in the use of several software tools (MS Word, MS Excel, MS Power Point, MS Access, MS Works, MS SQL Server AutoCad, PSpice). Programming languages and environments: Turbo Pascal, Turbo C, LabView, MatLab, Assembler, Visual Basic, ASP, Visual Interdev, Visual Studio, VB Script, JavaScript, HTML, XML, Visual C++. Good knowledge of other applied technology systems (microprocessors, microcontrollers, classic control systems, power electronics). UNIVERSIDAD IBEROAMERICANA, A.C., México D.F., México Biomedical Engineering (equivalence of a Physics Bachelor from the University of Geneva) • • • Spanish English French PUBLICATIONS • • • • • • • • • • • Pérez Fornos, A. (1999). Recording and Analysis of Visual Evoked Potentials Obtained by Electrical Stimulation. Universidad Iberoamericana, Plantel Santa Fe, México City, Mexico. Pérez Fornos, A., Rappaz B., Sommerhalder, J., Safran, A.B., Pelizzone, M. (2002). Simulation of Artificial Vision: Effects of dynamic versus static spatial quantization of the stimulus on reading. Experimental Eye Research; 72(S2): 127. Varsori, M., Pérez Fornos, A., Safran, A.B., Whatham, A. (2002). Changes in viewing strategy in normal subjects during adaptation to artificial central scotomas. Experimental Eye Research; 72(S2): 129. Pérez Fornos, A., Sommerhalder, J., Chanderli, K., Pittard, A., Baumberger, B., Fluckiger, M., Safran, A.B., & Pelizzone, M. (2004). Minimum requirements for mobility in known environments and perceptual learning of this task in eccentric vision. ARVO Meeting Abstracts, 45, 5445 (abstract). Sommerhalder, J., Rappaz, B., de Haller, R., Pérez Fornos, A., Safran, A.B., & Pelizzone, M. (2004). Simulation of artificial vision: II. Eccentric reading of full-page text and the learning of this task. Vision Research, 44(14), 1693-1706. Varsori, M., Pérez Fornos, A., Safran, A.B., & Whatham, A. (2004). Development of a viewing strategy during adaptation to an artificial central scotoma. Vision Research, 44(23), 2691-2705. Pérez Fornos, A., Sommerhalder, J., Rappaz, B., Safran, A.B., & Pelizzone, M. (2004). Changes in eye movement strategy during the process of learning eccentric reading. Neuro-ophthalmology, 28(3), 99 (abstract). Pérez Fornos, A., Sommerhalder, J., Pittard, A., Safran, A.B., & Pelizzone, M. (2005). Minimum requirements for visuomotor coordination and learning of this task in eccentric vision. ARVO Meeting Abstracts, 46, 1533 (abstract). Pérez Fornos, A., Sommerhalder, J., Rappaz, B., Safran, A.B., & Pelizzone, M. (2005). Simulation of Artificial Vision, III: Do the spatial or temporal characteristics of stimulus pixelization really matter? Investigative Ophthalmology & Visual Science, 46(10), 3906-3912. Pérez Fornos, A., Sommerhalder, J., Rappaz, B., Pelizzone, M., & Safran, A.B. (2006). Processes involved in oculomotor adaptation to eccentric reading. Investigative Ophthalmology & Visual Science, 47(4), 1439-1447. Sommerhalder, J., Pérez Fornos, A., Chanderli, K., Colin, L., Schaer, X., Mauler, F., Safran, A.B., & Pelizzone, M. (2006). Minimum requirements for mobility in unpredictable environments. ARVO Meeting Abstracts, 47, 3204 (abstract). Acknowledgements This dissertation is the conclusion of 5 amazing years of work. It is also the fruit of the joint effort of several people, and I would like to thank them all: Dr. Jörg R. Sommerhalder for his enormous human and scientific support through all these years of close collaboration. Dr. Karim Chanderli for all the laughs and for his fundamental contribution to this project. Prof. Marco Pelizzone for his guidance and for always forcing me to give the best of myself. Prof. Avinoam B. Safran for his continous interest in my work, and for his unconditional trust and support. Prof. Daniel Bertrand, Prof. Dominique Muller, and Prof. Nelson Y. Kiang for making time in their busy agendas and accepting to take part in the jury of this thesis. Benjamin Rappaz, Raoul de Haller, Alexandre Pittard, Flavien Mauler, Lise Colin, and Xavier Schaer for their active collaboration in the different experiments. All the volunteers that participated in the experiments; I know that it was not always easy... And to all the people that I forgot to mention but that made this project a reality… It is never easy to summarize 5 years of work in one “thank you” page… Agradecimientos Para Mateo, el otro cerebrito escondido detrás de esta tesis Una etapa más completada... Y al volver la vista atrás me sigo sorprendiendo al darme cuenta del inmenso apoyo que traigo detrás. Hay mucha gente sin la que esto no hubiera sido posible. Gracias: A Roberto, el amor de mi vida, por formar parte de mis sueños... A mi Papá y a mi Mamá, por enseñarme que nada es imposible y por hacer todos mis sueños realidad... A Jingle, por obligarme a seguir mis sueños y a no dejar de soñar... Al Pato, por enseñarme todos los días que en la diversidad está la riqueza... A Belita, mi eterna incondicional, la única capaz de transformar mis errores en aciertos... A mis abuelos David y Lola, por maravillarse siempre de todos mis logros, grandes y pequeños... A Rocío, por su apoyo moral y lingüístico, y por enseñarme a reírme de mi misma y de mi mamertez... A mi tía Lelia, el colchoncito donde siempre puedo apoyarme, reponerme y descansar... A mi tía Encarna, por estar siempre presente, aún a larga distancia... A mis primos: Güera, Paquito, Javier, Ángel, Andrea, Robi, Tani, David, Manuel V., Alex, Vanesa, Manuel P., Danny... por ser los espejos donde aprendí a mirarme a mí misma... Al resto de mi familia, que no menciono explícitamente por falta de espacio, no por falta de ganas y reconocimiento... A mis amigos: Flais, La Maru, Pete, Anik, Christian, Stephan, Sandra, María, Martha, Adris, Salustia... gracias a quienes puedo enfrentar la vida a carcajadas... A los que ya no están… Siempre los llevo dentro de la cabeza y cerquita del corazón. Table of Contents Summary.............................................................................................................i Résumé............................................................................................................ vii Resumen .......................................................................................................... xv 1 Introduction .................................................................................................1 1.1 Anatomy and Physiology of Vision ...........................................................1 1.1.1 The Eye .............................................................................................2 1.1.2 The Optic Nerve and Optic Tract ..........................................................6 1.1.3 The Visual Cortex................................................................................7 1.2 Blindness and Low Vision........................................................................8 1.3 Visual prostheses as a means to rehabilitate blindness ............................ 10 1.3.1 Cortical Stimulation ........................................................................... 12 1.3.2 Optic Nerve Stimulation..................................................................... 14 1.3.3 Retinal Stimulation ............................................................................ 17 1.3.4 Alternative approaches ...................................................................... 23 1.3.5 Comparison of the different approaches.............................................. 23 1.4 Minimum requirements for useful artificial vision..................................... 25 1.5 Scope of this thesis .............................................................................. 28 1.5.1 Significance ...................................................................................... 29 2 General Methods ........................................................................................ 31 2.1 Basic principles of the simulation methodologies..................................... 31 2.2 Image processing................................................................................. 32 2.2.1 Square pixelization............................................................................ 32 2.2.2 Gaussian pixelization ......................................................................... 33 2.2.3 Off-line/Real-time pixelization ............................................................ 34 2.3 Experimental setup .............................................................................. 34 2.3.1 Stationary system ............................................................................. 38 2.3.2 Mobile system .................................................................................. 38 2.4 Data analysis and statistics ................................................................... 39 2.4.1 Percentage scores ............................................................................ 39 2.5 3 Ethical considerations........................................................................... 40 Experiments on Reading ............................................................................. 41 3.1 Foreword ............................................................................................ 41 3.2 Introduction ........................................................................................ 41 3.2.1 Reading in the context of artificial vision............................................. 43 3.3 Specific methods for the reading experiments ........................................ 45 3.3.1 Subjects........................................................................................... 45 3.3.2 Experimental setup ........................................................................... 45 3.4 Pilot experiment: Reading of isolated 4-letter words ............................... 46 3.4.1 Stimuli ............................................................................................ 46 3.4.2 Acute experiments with 4-letter words................................................ 47 3.4.3 Habituation to reading 4-letter words in eccentric vision ...................... 51 3.5 Full-page reading................................................................................. 58 3.5.1 Stimuli ............................................................................................ 59 3.5.2 Analysis methodology ....................................................................... 59 3.5.3 Experimental protocol ....................................................................... 61 3.5.4 Experiment 1: Full-page reading in central vision................................. 62 3.5.5 Experiment 2: Full-page reading in eccentric vision.............................. 63 3.6 Discussion........................................................................................... 71 3.6.1 Main outcome of these experiments ................................................... 71 3.6.2 Analysis of the learning process ......................................................... 73 3.6.3 Additional considerations................................................................... 76 4 3.7 Conclusions ......................................................................................... 77 3.8 Publications resulting from this research ................................................ 78 Experiments on Visuomotor Coordination ..................................................... 79 4.1 Foreword ............................................................................................ 79 4.2 Introduction ........................................................................................ 79 4.2.1 Vision and visuomotor coordination .................................................... 80 4.2.2 Visuomotor coordination in the context of artificial vision ..................... 83 4.3 Specific methods for the experiments on visuomotor coordination............ 84 4.3.1 Subjects........................................................................................... 84 4.3.2 Visuomotor tasks .............................................................................. 84 4.3.3 Effective field of view ........................................................................ 86 4.3.4 Experimental setup ........................................................................... 87 4.4 Acute experiments on visuomotor coordination....................................... 88 4.4.1 Experimental protocol ....................................................................... 88 4.4.2 Experiment 3: Manipulation – The chips task....................................... 89 4.4.3 Experiment 4: Pointing – The LEDs task.............................................. 91 4.4.4 Summary of the results of these experiments...................................... 92 4.5 Habituation experiments on visuomotor coordination .............................. 93 4.5.1 Experimental protocol ....................................................................... 93 4.5.2 Preparatory experiment: Learning in central vision............................... 94 4.5.3 Experiment 5: Learning in eccentric vision .......................................... 96 5 4.6 Discussion ........................................................................................... 98 4.7 Conclusions ....................................................................................... 101 4.8 Publications resulting from this research .............................................. 101 Experiments on Mobility ............................................................................ 103 5.1 Foreword........................................................................................... 103 5.2 Introduction ...................................................................................... 103 5.2.1 What have we learned from low vision patients? ............................... 104 5.2.2 Mobility in the context of artificial vision............................................ 106 5.3 Specific methods for the experiments on mobility ................................. 106 5.3.1 Subjects......................................................................................... 106 5.3.2 Effective field of view ...................................................................... 106 5.3.3 Experimental setup ......................................................................... 107 5.4 Acute experiments on mobility ............................................................ 107 5.4.1 Experiment 6: Laboratory maze ....................................................... 107 5.4.2 Experiment 7: Random forest .......................................................... 111 5.4.3 Experiment 8: Real street crossing ................................................... 114 5.4.4 Summary of the results of these experiments.................................... 118 5.5 Habituation experiments on mobility .................................................... 119 5.5.1 Experimental protocol ..................................................................... 119 5.5.2 Preparatory experiment: Learning in central vision............................. 120 5.5.3 Experiment 9: Learning in eccentric vision ........................................ 121 6 5.6 Discussion......................................................................................... 122 5.7 Conclusion ........................................................................................ 124 5.8 Publications resulting from this research .............................................. 125 Towards Better Simulations of Artificial Vision ............................................. 127 6.1 Foreword .......................................................................................... 127 6.2 Introduction ...................................................................................... 128 6.3 Specific methods for these simulations ................................................ 129 6.3.1 Subjects......................................................................................... 129 6.3.2 Experimental Setup......................................................................... 129 6.4 Experiment 10: Real-time Square vs. Off-line Square Pixelization ........... 130 6.4.1 Experimental protocol ..................................................................... 130 6.4.2 Results .......................................................................................... 130 6.5 Experiment 11: Off-line Gaussian vs. Off-line Square Pixelization ........... 132 6.5.1 Experimental protocol ..................................................................... 132 6.5.2 Results .......................................................................................... 132 6.6 Experiment 12: Real-time Gaussian vs. Real-time Square Pixelization ..... 133 6.6.1 Experimental protocol ..................................................................... 133 6.6.2 Results .......................................................................................... 134 6.7 Discussion......................................................................................... 134 6.7.1 Implications of these results for simulations of artificial vision ............ 136 7 8 6.8 Conclusion ........................................................................................ 137 6.9 Publications resulting from this research .............................................. 137 General Conclusions ................................................................................. 139 7.1 Summary of the results ...................................................................... 139 7.2 Implication of these results for the development of visual prostheses..... 140 7.3 Future work ...................................................................................... 142 7.4 Closing remarks ................................................................................. 143 References .............................................................................................. 145 Appendix A..................................................................................................... 165 Appendix B..................................................................................................... 167 Appendix C..................................................................................................... 169 Appendix D..................................................................................................... 171 Appendix E ..................................................................................................... 183 Publications .................................................................................................... 185 Summary Blindness is a severe handicap because vision is one of the most important sensory modalities underlying human activity. Certain forms of retinal degeneration can lead to complete blindness. Some can occur early in life, like RP, and the resulting visual impairment usually increases with age. Other forms of blindness are mostly age related with higher incidence in elderly people. Thus, the impact of blindness will become more and more important as life expectancy increases. Today, technological advances have opened new perspectives and it is possible to envision neural prostheses to restore some useful vision to totally blind patients. Such devices aim to restore function by direct electrical stimulation of neural tissue. This kind of approach has proven to be very successful with cochlear implants in the case of deafness (NIH Consensus Statement, 1995). Several research groups have initiated projects aiming at the development of various visual prostheses and a huge effort is presently going on in this field. The implantation of the first basic prototypes of visual prostheses demonstrate that the hope for a useful aid is not so far away (Dobelle, 2000; Chow et al., 2002; Veraart et al., 2003; Humayun et al., 2003). There is increasing evidence that, some day, visual prostheses could bring similar benefits to blind people as those provided by cochlear implants to deaf patients. To this date, most efforts in the field appear to be concentrated on the development of technical solutions for visual prostheses (microelectronics, biocompatibility, electrophysiology, etc…). One key issue seems however to attract very little attention: What are the minimum requirements for useful artificial vision? In other words, what is the minimal visual information, necessary to perform common daily tasks? Rationale The goal of the research presented here was to determine minimum requirements to achieve useful artificial vision. To design visual prostheses, the knowledge of the minimum information to be transmitted to the brain in order to restore useful function is essential, theoretically and practically. The history of cochlear implant development clearly illustrates the importance of modeling studies. Breakthroughs like the advent of multi-channel cochlear implants, allowing for adequate speech recognition, were only possible as a result of psychophysical studies (Tong et al., 1983; Eddington et al., 1998a; Eddington et al., 1998b). Therefore, the research effort presented in this dissertation is to provide this type of information to the artificial vision research community in time, hoping to prevent large-scale use of prototype retinal implants with insufficient numbers of stimulation contacts. i General methods The experimental approach used in these studies was designed to mimic, as realistically as possible, visual perceptions provided by retinal implants. Such devices present certain features that lead to several major constraints about the visual percepts that can be elicited. Retinal prostheses will consist of a finite number of discrete stimulation contacts (limited resolution), will be implanted at a fixed location in the eye, and will subtend only a fraction of the entire visual field. Furthermore, highly eccentric implantation areas will probably have to be envisioned since the anatomo-physiology of the retina does not favor a foveal location for a visual prosthesis (Sjöstrand et al., 1999a; Sjöstrand et al., 1999b). The best sites, potentially preserving retinotopic activation without major distortion, are located at an eccentricity of 10° and more. This means that the vision of future users of retinal prosthesis will probably be restricted to small peripheral areas of their visual field. An experimental setup designed to simulate conditions of artificial vision on normal volunteers was developed. This setup allows for presentation of pixelized images, stabilized on visual field areas of a given eccentricity. Therefore, it is capable of mimicking the type of visual information transmitted by a retinal prosthesis and to make parametric changes in the amount or nature of such information. The minimum requirements for three classes of basic visual functions were investigated: the identification of small objects as in reading and the localization of objects and body in space for adequate visuomotor coordination and whole-body mobility. Experiments on reading Reading is an extremely important activity in our modern societies and represents one of the main goals of low vision patients seeking rehabilitation. The thorough analysis of this task is, thus, fundamental for the evaluation of the rehabilitation prospects of visual prostheses for blind patients. A first series of experiments using isolated 4-letter words showed that performance drops abruptly when the information content of the target is reduced below a certain threshold (expressed in number of pixels). For central reading, a viewing window containing at least 250 pixels is necessary to code 4-letter words. At eccentricities beyond 10°, reading performance decreases rapidly even if more than 250 pixels are used. A second study was dedicated to respond the question of whether the task of eccentric reading under such specific conditions could be improved by training. Two subjects, naive to this task, were trained to read isolated 4-letter words under conditions of simulated artificial vision at 15° eccentricity (in the lower visual field). Reading performance of both subjects increased impressively throughout this experiment. Reading scores of 6% and 23% correct were observed at the beginning of the experiment; by the end of the experiment (about one month of daily training; 1 hour/day), reading scores improved to 64% and 85%. Control tests demonstrated that the learning process consisted essentially in the adaptation to use an eccentric area of the retina for the reading task. ii A second set of experiments addressed the more realistic task of full-page reading, which included the control of the subjects’ eye movements to achieve page navigation in similar conditions of artificial vision, mimicking an eccentric retinal implant. Three subjects, naïve to the task, were trained for almost two months (about 1 hour/day) to read full-page texts. Subjects had to use their own eye movements to displace a 10° x 7° viewing window stabilized at 15° eccentricity in their lower visual field. Initial reading scores were very low for two subjects (about 13% correctly read words), and astonishingly high for the third subject (86% correctly read words). However, all of them significantly improved their performance with time, reaching close to perfect reading scores (ranging from 86% to 98%) at the end of training. Initial reading rates were as low as 1 to 5 words/min and increased significantly with time to 14 to 28 words/min. Qualitative text understanding was also estimated. A score of at least 85% correct was necessary to achieve ‘good’ text understanding. Gaze position recordings, made during the experimental sessions, demonstrated that the control of eye movements, especially the suppression of reflexive vertical saccades, constituted an important part of the overall adaptive learning process. Experiments on visuomotor coordination The lack of resolution might affect visuomotor tasks requiring detailed vision, such as those involving object identification. Furthermore, difficulties with visuomotor coordination may also result from defects in the peripheral visual field and available field of view, which affect localization/orientation abilities. Encoding spatial information and using it to direct a particular motor response might, therefore, impose various constraints (in terms of information requirements) to a visual prosthesis. Two tests were especially developed to examine these tasks. In the first configuration, the chips task, subjects had to recognize simple figures (drawn on wooden chips) and place them in the adequate position and orientation on randomized templates. In the second test, the LEDs task, subjects had to point with the finger, as precisely as possible, on spots marked by light points (LEDs) displayed underneath a touch screen. Similar to the reading experiments, artificial vision was simulated by projecting images of limited resolution (pixelization level) on a 10° x 7° viewing window, stabilized at a fixed position in the visual field. For these experiments the size of the effective field of view projected in this 10° x 7° visual area (portion of the environment visible at glance) could also be varied. In a first experiment, the minimum requirements needed to reach optimum performance were established using central vision. Both the number of pixels contained in the viewing window, as well as the effective field of view projected inside it, selectively affected visuomotor performance; various combinations of these parameters allowed good performance on these tasks. Nevertheless, the results revealed a fundamental limit for visuomotor performance: a minimum effective resolution of approximately 2 pixels/deg2 of the environmental space was necessary to achieve both tasks with reasonable accuracy and speed (i.e. approximately 100 pixels with a 8° x 6° field of view; about 400 pixels with a 16° x 12° field of view; or iii around 1600 pixels with a 33° x 23° field of view). A field of view of approximately 16° x 12° represented the best resolution/performance compromise and subjects spontaneously reported preferring it to the others. In a second experiment, 3 normal volunteers, naïve to eccentric viewing, were trained to perform the visuomotor tasks using a viewing window stabilized at 15° of eccentricity in the lower visual field. An effective field of view of 16° x 12° was chosen for this second experiment. To be consistent with our previous experiments on reading, a resolution of 498 pixels in the viewing window was judged to be the most adequate for learning the task in eccentric vision (effective resolution of 2.6 pixels/deg2). For the chips task, one subject achieved excellent %-correct scores immediately, while the other 2 subjects consistently obtained scores above 95% after 4 to 15 sessions. Average time required to correctly place a chip asymptoted at around 9 s after 8, 13, and 38 sessions. For the leds task, pointing precision converged around 0.7 cm but results were very variable. Pointing rates stabilized within 8 sessions at 5.8 s/target. Experiments on mobility Mobility essentially requires the capacity to judge egocentric and exocentric distances for solving issues such as localization of body in space, perception of movement, distance estimation, and speed estimation. These tasks might, therefore, impose different constraints to an artificial vision system than those found in the previous tasks. As in the previous experiments, artificial vision was simulated by projecting images of limited resolution on a 10° x 7° viewing window, subtending different fractions of the environment, and stabilized at a fixed position in the visual field. First, we determined the minimum requirements for useful mobility in central vision. Since the minimum information required for achieving satisfactory performance varies according to the type of environment in which the task is to be performed, a series of tasks involving different realistic situations were evaluated. The first configuration, the laboratory maze task, was conceived to assess mobility performance in familiar, randomized indoor environments. This task consisted in walking through an indoor course consisting of 6 obstacles frequently encountered in daily life. The second setting, the random forest task, was designed to assess mobility performance in randomized, unfamiliar indoor environments including some dynamic elements. Subjects had to walk through an ‘artificial forest’ composed of 52 randomly positioned obstacles or ‘trees’, from a random starting position to a random end position. The last task, the real street crossing, was intended to assess the visual requirements for mobility in a real-life, dynamic environment. In this case, the capacity of estimating speed and distance of approaching objects (cars) was investigated. Results of these experiments confirmed that minimum information requirements were closely linked to the type of environment on which the tasks were to be performed. Mobility in well-known indoor environments required relatively little visual information: approximately 0.2 pixels/deg2 (i.e. 150 pixels with a 33° x 23° field of view or 600 pixels with a 66° x 46° field of view). Large fields of view did not seem to be of particular advantage in these settings. Mobility in less predictable iv environments incorporating some dynamic elements, such as that of the random forest task, was more sensitive to the number of pixels available on the viewing window, requiring approximately 500 pixels. A 33° x 23° field of view tended to yield the best performance. Finally, approximately 1000 pixels seem to be required for subjects to feel safe while performing mobility tasks in unknown, dynamic environments such as that of the real street crossing task. As fewer pixels were available in the viewing window, subjects needed to compensate with additional information sources (i.e. hearing); smaller visual, fields providing more detailed visual information, seem to be advantageous in these settings. Second, we evaluated possible learning effects when performing mobility tasks in eccentric vision (15° in the lower visual field). According to the first mobility experiments, an effective field of view of 33° x 23° seems to be the best compromise between a large enough field of view while still maintaining reasonable image resolution and was, thus, chosen for this second experiment. To be consistent with our previous experiments on reading, a resolution of 498 pixels in the viewing window was judged to be the most adequate for learning the task in eccentric vision (effective resolution of 0.65 pixels/deg2). Mobility performance in eccentric vision was explored using the laboratory maze task. Error counts asymptoted within the first 10 training sessions. The time to accomplish the mobility task stabilized after about 40 sessions. Interestingly, under similar experimental conditions, subjects could achieve the task more rapidly in eccentric vision than in central vision after training. Experiments exploring more realistic simulations of artificial vision In our previously mentioned studies, we used simplified simulations of artificial vision to determine the basic parameters for visual prostheses to restore useful function. In a final series of experiments we explored the effect of such simplifications on the most ‘information-demanding’ task: full page reading. Normal volunteers had to read full-pages of text using a 10° x 7° viewing window stabilized in central vision. In a first study, we measured reading performance comparing off-line and real-time square pixelizations at different resolutions. Results showed that real-time square pixelization required about 30% less information (pixels) than its off-line counterpart. In a second experiment, off-line square pixelization was compared to off-line gaussian pixelization with various degrees of overlap (σ). Results from this experiment revealed a restricted range of gaussian widths (0.143 < σ < 0.571) for which performance was equivalent or significantly better than that obtained with square pixelization. Finally, in a third experiment, realtime square pixelization was compared to real-time gaussian pixelization. This experiment demonstrated, however, that reading performance was similar in both real-time pixelization conditions. This investigation revealed that real-time stimulus pixelization favors reading performance. Performance gains were, however, relatively moderate and did not v allow for a significant (e.g. two-fold) reduction of the minimum resolution (400-500 pixels) needed to achieve useful reading abilities. Conclusion Taken together, these results suggest that, about 500 phosphenes retinotopically arranged over a 10° x 7° retinal area (corresponding to an implant surface of 3 x 2 mm2), is the minimum visual information required to restore useful function. If this minimum criterion is fulfilled, retinal implants might restore some full-page reading abilities to blind patients. Visuomotor coordination and whole-body mobility seem to be less demanding, in terms of information content, than the reading task. In addition, the effective field of view represented by the active area of the implant will have to be optimized for each task. A highly magnified effective field of view simultaneously containing strings of 4-6 characters and about two lines of text (about 2° x 1.4° for a typical newspaper) is required for efficient reading, an effective field of view of about 16° x 12° seems to allow for efficient visuomotor coordination, and an effective field of view of 33° x 23° appears to be necessary for tasks involving whole-body mobility. A significant learning process will be required to reach optimal performance with such devices, especially if the implant has to be placed outside the fovea. Visual prostheses should aim to meet these criteria in order to provide efficient functional rehabilitation to blind patients. vi Résumé La vision est l’une des modalités sensorielles la plus importante pour l’activité humaine. Sa perte engendre un handicap lourd. Certaines formes de dégénérescences rétiniennes peuvent conduire à la cécité. Dans la rétinite pigmentaire, par exemple, la perte de vision peut survenir à un âge relativement précoce. D'autres maladies sont principalement dues au vieillissement, ayant par conséquent une incidence plus élevée chez les personnes d’un âge avancé. Ainsi, au vu de l’augmentation de l’espérance de vie, la cécité est amenée à devenir un problème de plus en plus important. Aujourd'hui, les progrès technologiques ont ouvert de nouvelles perspectives, offrant la possibilité d'envisager des prothèses neurales pour restituer une vision utile à des patients aveugles. Ces dispositifs tentent de restituer une fonction visuelle par stimulation électrique directe du tissu neural. Une approche similaire approche s'est avérée très réussie avec la mise au point d’implants cochléaires dans le cas de problèmes de surdité (NIH Consensus Statement, 1995). Plusieurs groupes ont entamé des recherches visant au développement de diverses prothèses visuelles. L'implantation des premiers prototypes de ces dispositifs montre que l'espoir d’une aide utile n'est pas loin (Dobelle, 2000; Chow et al., 2002; Veraart et al., 2003; Humayun et al., 2003). Il y a de plus en plus d’évidence qu’un jour les prothèses visuelles pourraient apporter aux patients aveugles des bénéfices semblables à ceux procurés aux patients sourds par les implants cochléaires. Jusqu’à aujourd’hui, la plupart des efforts dans le domaine sont concentrés sur le développement de solutions à des problèmes techniques des prothèses visuelles (microélectronique, biocompatibilité, électrophysiologie, etc...). Cependant, une question semble attirer très peu d’attention bien que fondamentale: Quel est l’information minimale pour une vision artificielle utile ? En d'autres termes, quel est le minimum d'information visuelle nécessaire pour accomplir les tâches quotidiennes? Buts Le but de ce projet est de déterminer les caractéristiques minimales pour qu’un implant rétinien permette une vision utile. La connaissance du minimum d'information qui doit être transmis au cerveau pour restituer une fonction utile est essentielle, théoriquement et pratiquement, pour la conception de prothèses visuelles. L'histoire du développement des implants cochléaires illustre clairement l'importance de telles études. Des avancées, comme le développement des implants cochléaires multicanaux permettant la reconnaissance de la parole, ont été rendues possibles grâce à des études psychophysiques (Tong et al., 1983; Eddington et al., 1998a; Eddington et al., 1998b). Ainsi, la recherche menée dans le cadre de cette thèse a pour objectif principal de fournir ce type d'information, dans l’espoir d’éviter vii l'utilisation à grande échelle d’implants rétiniens comportant un nombre insuffisant d’électrodes de stimulation. Méthodes générales L'approche expérimentale utilisée pour ces études a été conçue pour reproduire, de la façon la plus réaliste possible, la perception visuelle telle qu’elle sera produite par les implants rétiniens. Ces dispositifs auront certaines caractéristiques impliquant différentes contraintes fondamentales sur la perception visuelle qui pourra être évoquée. Les prothèses rétiniennes consisteront en un nombre fini d’électrodes de stimulation (résolution limitée), qui seront implantées à un endroit fixe dans l’œil et couvriront seulement une fraction du champ visuel. En outre, des zones d'implantation très excentrées devront probablement être envisagées puisque les caractéristiques anatomiques et physiologiques de la rétine ne favorisent pas l’implantation d’une prothèse visuelle proche de la fovéa. Les meilleurs sites pour l’implantation, permettant potentiellement de préserver une bonne rétinotopie sans déformation majeure de l’image, sont situés à des excentricités supérieures à 10°. Ceci signifie que la vision des futurs utilisateurs de prothèses rétiniennes sera vraisemblablement limitée à de petits secteurs périphériques de leur champ visuel. Un simulateur de vision artificielle a été développé pour réaliser les tests psychophysiques. Ce système permet de présenter des images de résolution limitée (pixelisées), stabilisées sur des régions déterminées du champ visuel (à une excentricité donnée). Il est capable d'imiter l'information visuelle transmise par une prothèse rétinienne et permet de faire des changements paramétriques de la quantité ou de la nature de cette information. Les conditions minimales pour trois tâches visuelles fondamentales ont été étudiées : l'identification de petits objets comme par exemple dans la lecture, la localisation du corps et la localisation d’objets dans l'espace permettant une coordination visuomotrice et une mobilité adéquate. Études sur la lecture La lecture est une activité extrêmement importante dans la société moderne et est un des buts principaux de la rééducation en basse vision. L'analyse exhaustive de cette tâche est donc essentielle pour l'évaluation des perspectives de réadaptation des futurs porteurs de prothèses visuelles. Une première étude sur la lecture de mots isolés de 4 lettres a démontré que les performances des sujets chutaient abruptement lorsque l’information représentant la cible était réduite en dessous d'un certain seuil (exprimé en nombre de pixels). Ainsi, la lecture en vision centrale nécessite une aire de stimulation contenant au moins 250 pixels pour coder les mots de 4 lettres. À des excentricités supérieures à 10°, les performances diminuaient rapidement même pour des résolutions supérieures à 250 pixels. Dans les mêmes conditions expérimentales une deuxième étude a été consacrée à l’évaluation de possibles effets d’apprentissage dans la lecture de mots de 4 lettres. Deux sujets, naïfs à la tâche, se sont entraînés à lire des mots pixélisés de 4 lettres (250 pixels) dans des conditions simulées de vision artificielle à une viii excentricité de 15° (dans le champ visuel inférieur). Les performances de lecture des 2 sujets ont augmenté considérablement tout au long de l’expérience. Au début de l’étude les sujets identifiaient correctement seulement 6% et 23% des mots. À la fin de la période d’apprentissage (environ 1 h/jour pendant un mois), les mêmes sujets arrivaient à lire 64% et 85% des mots correctement. Des expériences contrôles ont démontré que, pour cette tâche, l'apprentissage a essentiellement consisté en l’adaptation du sujet à l’utilisation d’une aire excentrée de la rétine pour lire. Un deuxième ensemble d'expériences a été conduit sur la tâche plus réaliste de lecture de textes en pleine page, comprenant le contrôle des mouvements oculaires du sujet lors de la navigation sur la page de texte, dans des conditions similaires de vision artificielle excentrée. Trois sujets, naïfs à la tâche, se sont entraînés pendant presque deux mois (environ 1 h/jour) à lire des pages entières de texte. Les sujets devaient employer leurs propres mouvements oculaires pour déplacer une fenêtre de stimulation de 10° x 7°, stabilisée à 15° dans le champ visuel inférieur. Au début des expériences, les scores de lecture1 étaient très bas pour deux sujets (environ 13%), et étonnamment hauts pour le troisième sujet (86%). Cependant, les 3 sujets se sont améliorés de manière significative pendant la période d’apprentissage, atteignant des scores presque parfaits à la fin de l’expérience (de 86% à 98%). Les vitesses de lecture initiales étaient très basses, de 1 a 5 mots/min, et ont sensiblement augmenté avec le temps pour atteindre de 14 à 28 mots/min. Une analyse qualitative de la compréhension des textes a aussi été réalisée. Un minimum de 85% de mots correctement lus s’est avéré nécessaire à une bonne compréhension des textes. Les enregistrements des mouvements oculaires obtenus pendant les séances expérimentales ont clairement démontré que le contrôle de ces mouvements, plus particulièrement la suppression des saccades réflexes verticales, a constitué une partie très importante de l’apprentissage global de la lecture en excentricité. Études sur la coordination visuomotrice La résolution réduite des images générées par une prothèse visuelle pourrait affecter sérieusement les tâches de coordination visuomotrice exigeant une vision détaillée, comme l’identification d’objets ou cibles potentielles. De plus, des défauts de la vision périphérique limitant le champ visuel disponible affectent les capacités de localisation/orientation dans l’espace, et pourraient engendrer des difficultés dans la coordination visuomotrice. Par conséquent, la codification de l’information spatiale pertinente à ces tâches et l’utilisation de cette même information dans le but de diriger une réponse motrice particulière, peuvent imposer différentes contraintes à une prothèse visuelle. Deux tests ont été développés pour évaluer les capacités de coordination visuomotrice en simulant une vision artificielle sur des sujets normaux. Dans la première tâche, la tâche des jetons, le sujet devait reconnaître des objets (motifs dessinés sur des jetons en bois) et les poser par la suite sur des motifs identiques 1 % de mots correctement lus. ix situés sur un plan de travail arrangé aléatoirement. Les différents objets ne pouvaient être reconnus que visuellement (et non par le toucher). Dans le deuxième test, la tâche des LEDs, les sujets devaient pointer avec un doigt, aussi précisément que possible, à des endroits déterminés d’un plan de travail (touch screen) représentés par des points lumineux (LEDs) s’allumant aléatoirement. Comme dans les études sur la lecture, la vision artificielle était simulée en projetant des images de résolution réduite (pixelisées) dans une fenêtre de stimulation de 10° x 7°, stabilisée à un endroit fixe du champ visuel. De plus, pour ces expériences la taille du champ visuel réel projeté dans la fenêtre de 10° x 7° (portion de l’environnement visible simultanément dans la fenêtre de stimulation) pouvait être aussi modifiée, ce qui n’était pas le cas dans les expériences de lecture. Dans une première étape, l’information minimale requise pour atteindre une performance visuomotrice efficace en vision centrale a été déterminée. Tant le nombre de pixels contenus dans la fenêtre de stimulation que la taille du champ visuel effectif projeté dans cette fenêtre semblent avoir un effet sur la performance visuomotrice. Cependant, chacun des deux paramètres a une influence différente. Plusieurs combinaisons de ces paramètres ont permis d’obtenir une bonne performance pour la tâche des jetons et la tâche des LEDs. Néanmoins, les résultats ont révélé un seuil minimal de résolution pour la performance visuomotrice. Une résolution effective minimale de 2 pixels/deg2 (par exemple, environ 100 pixels avec un champ visuel effectif de 8° x 6°, autour de 400 pixels avec un champ visuel effectif de 16° x 12° ou aux alentours de 1600 pixels avec un champ visuel effectif de 33° x 23°) s’est, en effet, avérée nécessaire à l’accomplissement des deux tâches avec une précision adéquate. Un champ visuel effectif de 16° x 12° semble être le meilleur compromis entre performance et résolution pour obtenir une vitesse raisonnable. De plus, les sujets l’ont spontanément identifié comme étant leur préféré. Dans une deuxième étape, 3 volontaires normaux, naïfs à la vision excentrée, se sont entraînés à réaliser les deux tâches en utilisant une fenêtre de stimulation stabilisée à 15° d’excentricité dans le champ visuel inférieur. Suite aux résultats de la première série d’expériences, un champ visuel effectif de 16° x 12° à été choisi. En accord avec nos premières études sur la lecture, une résolution de 498 pixels à été jugée comme la plus adéquate pour l’apprentissage en vision excentrée (résolution effective de 2.6 pixels/deg2). Pour la tâche des jetons, un sujet a immédiatement atteint des scores2 excellents, alors que les 2 autres sujets ont obtenu des scores supérieurs à 95% après 4 et 15 séances. La vitesse de placement des jetons3 s’est stabilisée, pour tous les sujets, à environ 9 s/jeton après 8, 13, et 38 séances. Pour la tâche des LEDs, l’erreur de pointage4 a convergé autour de 0.7 cm. Cependant, les résultats des 3 sujets étaient très variables. Les vitesses de pointage5 se sont stabilisées autour de 5.8 s/LED pour tous les sujets en moins de 8 séances. 2 3 4 5 % de jetons correctement placés (bonne position et orientation). Temps nécessaire en moyenne pour placer un jeton correctement. Distance absolue entre la position réelle du LED et l’endroit pointé par le sujet. Temps moyen nécessaire pour localiser et pointer sur un LED. x Études sur la mobilité La mobilité dépend essentiellement de la capacité à juger les distances égocentriques et exocentriques, de façon à pouvoir localiser son corps dans l'espace, percevoir les mouvements, estimer les distances, et estimer la vitesse. Ce type de tâche pourrait donc imposer des contraintes différentes aux prothèses visuelles que celles préalablement identifiés lors des deux études précédentes. Les méthodes de simulation utilisées pour cette série d’expériences sont similaires a celles employées précédemment. La vision artificielle a été simulée en projetant des images de résolution limitée, comprenant différentes portions de l’environnement, et stabilisées à un endroit fixe du champ visuel. Dans un premier temps, les conditions minimales nécessaires à une mobilité efficace ont été déterminées en vision centrale. Il est connu que pour des tâches de mobilité le minimum d’information nécessaire pour avoir une bonne performance varie en fonction de l’environnement où la tâche est accomplie. Par conséquent, l’évaluation du minimum d’information nécessaire à la mobilité a été évaluée sur une série de tâches dans différentes situations réalistes. Le premier test, le parcours de laboratoire, a été conçu pour étudier la mobilité dans des environnements intérieurs, familiers mais aléatoirement arrangés. Cette tâche consistait à réaliser un parcours comprenant 6 obstacles de la vie quotidienne (une table, une porte, une table avec une chaise, un passage entre 2 poteaux, et un slalom de 3 poteaux). Le deuxième test, la forêt aléatoire, a été conçu pour l’évaluation de la mobilité dans un environnement intérieur, aléatoire et imprédictible, incluant quelques éléments dynamiques. Pour cette tâche, les sujets devaient traverser d’un point de départ à un point d’arrivé aléatoires une «forêt artificielle» constituée de 52 obstacles («arbres») accommodés aléatoirement. Pendant cette traversée, un nombre variable de personnes (0, 1 ou 2) pouvaient traverser la forêt. Le sujet devait alors les éviter. Le dernier test, la traversée d’une route réelle, a été conçu pour évaluer les exigences de la mobilité dans des environnements réels et dynamiques. La capacité des sujets à estimer la vitesse et la distance d’objets en approche (voitures) a été plus particulièrement étudiée. La tâche consistait à juger la possibilité de traverser une route réelle en fonction de la « qualité/quantité » de l’information visuelle fournie par le simulateur de vision artificielle6. Les résultats de cet ensemble d’expériences sur la mobilité ont confirmé que les besoins en information varient selon le type d’environnement dans lequel la tâche est accomplie. La mobilité dans des environnements connus requiert relativement peu d’information visuelle: approximativement 0.2 pixels/deg2 (par exemple, 150 pixels avec un champ visuel effectif de 33° x 23° ou 600 pixels avec un champ visuel effectif de 66° x 46°). Dans de tels environnements aucun avantage n’a été constaté avec des champs visuels plus larges. La capacité de mobilité dans des environnements moins prévisibles s’est avérée plus sensible au nombre de pixels contenus dans l’aire de stimulation. Pour de telles tâches, environ 500 pixels sont nécessaires. Une tendance à une meilleure performance a été observée avec un champ visuel effectif de 33° x 23°. Enfin, autour de 1000 pixels étaient nécessaires pour se sentir en sécurité pendant des tâches de mobilité dans des environnements dynamiques, comme celui de la 6 Pour des raisons évidentes de sécurité, les sujets ne devaient pas réellement accomplir la traversée. xi traversée d’une route. Dans cette dernière tâche, au fur et a mesure que le nombre de pixels disponibles dans l’aire de stimulation diminuait, les sujets devaient compenser la manque de résolution par une autre sources d’information (l’audition). Des champs visuels plus restreints, offrant une information visuelle plus détaillée, semblaient, de plus, être avantageux dans ces environnements inconnus et dynamiques. Dans un deuxième temps, nous avons évalué les éventuels effets d'apprentissage lors des tâches de mobilité exécutées en vision excentrée (15° dans le champ visuel inférieur). Selon les premières expériences de mobilité, un champ visuel effectif de 33° x 23° apparaît comme le meilleur compromis entre un champ visuel assez grand tout en maintenant une résolution d'image raisonnable. Un tel champ visuel a donc été choisi pour cette étude. Suivant les résultats des études sur la lecture, une résolution de 498 pixels à été jugée comme la plus adéquate pour l’apprentissage en vision excentrée (résolution effective de 0.65 pixels/deg2). La tâche utilisée pour cette évaluation fut le parcours de laboratoire. Le nombre d’erreurs lors des parcours s’est stabilisé en moins de 10 séances d’apprentissage. Le temps nécessaire pour compléter le parcours s’est stabilisé après environ 40 séances. A la fin de l’étude, les sujets pouvaient accomplir la tâche même plus rapidement en vision excentrée qu’en vision centrale, dans les mêmes conditions expérimentales. Études explorant des simulations plus réalistes de la vision artificielle Dans les études précédentes, certaines simplifications ont été effectuées lors des simulations de vision artificielle. D’une part, la pixélisation a été réalisée avec un algorithme décomposant les images en une matrice de pixels carrés et d’intensité lumineuse uniforme. Ce type de traitement ne correspond certainement pas a ce que pourrait être une réponse physiologique évoquée par une prothèse visuelle. D’autre part, pour les études sur la lecture un algorithme de pixélisation statique a été appliqué. Dans le but d’évaluer les éventuels avantages/désavantages liés a des stimuli plus réalistes, une dernière série d’expériences a donc été réalisée, lors de laquelle les caractéristiques temporelles et spatiales de l’algorithme de réduction de l’information étaient modifiées. Nous avons exploré l'effet de telles simplifications sur la tâche la plus «exigeante» en termes d’information: la lecture de textes pleine page. Tout d’abord, un algorithme de pixélisation statique (images pré-pixélisées) a été comparé avec un autre algorithme de pixélisation dynamique (pixélisation en temps réel de l’image dans la fenêtre de stimulation), à différentes résolutions. Les performances de lecture (score et vitesse de lecture) mesurées pour 5 sujets normaux ont montré qu’une pixélisation en temps réel présente un avantage par rapport à une pixélisation statique équivalente car, en bougeant leurs yeux, les sujets peuvent intégrer plusieurs images pixélisées légèrement différemment pour reconnaître les mots plus facilement. Dans un deuxième temps, des performances de lecture obtenues lors des simulations utilisant des pixels carrés d’intensité uniforme ont été comparées avec celles obtenues lors des simulations utilisant pixels avec une xii distribution d’intensité gaussienne de plusieurs largeurs (σ). Les résultats ont révélé que, pour certaines gaussiennes de largeurs optimales (0.143 < σ < 0.571), la performance était très similaire, ou même très légèrement supérieure, à celle obtenue avec la pixélisation carrée. Ces expériences démontrent qu’une simulation plus réaliste (pixélisation du stimulus en temps réel) induit une amélioration des performances de lecture d’environ 30%. Néanmoins, l’amélioration constatée avec des algorithmes dynamiques n’est pas suffisante pour diminuer le nombre de pixels nécessaires pour la lecture de façon significative (par exemple, à la moitié). En outre, pour arriver à de bonnes performances, il serait souhaitable d’utiliser des paramètres de stimulation produisant des phosphènes7 avec des largeurs (dispersions) dans la zone de nos valeurs optimales. Les résultats de futures études électrophysiologiques indiqueront ce qui sera réellement possible. Conclusion L’ensemble des résultats obtenus suggère que 400-500 phosphènes, arrangés rétinotopiquement sur une surface rétinienne de 10° x 7° (correspondant à une surface d’implant de 3 x 2 mm2), constituent l’information minimale requise pour restituer une fonction visuelle utile. Si ce critère minimum est respecté, nous pouvons espérer rétablir certaines capacités de lecture aux futurs porteurs de ces prothèses rétiniennes. La coordination visuomotrice et la mobilité dans des environements familiers sont des tâches moins exigeantes en termes de contenu d’information que la lecture. De plus, le champ visuel effectif représenté par la surface active de l’implant devra probablement être optimisé pour chaque tâche. Un champ visuel effectif avec beaucoup d’agrandissement, contenant de 4 a 6 lettres et une hauteur d’environ deux lignes de texte (ce qui correspond à un champ visuel de 2° x 1.4° pour un journal typique), est nécessaire pour permettre une lecture efficace. Un champ visuel effectif d’environ 16° x 12° permet une performance efficace (lente mais assez précise) pour les tâches de coordination visuomotrice. Enfin, les tâches de mobilité requièrent un champ visuel effectif d’environ 33° x 23°. Une période d’apprentissage relativement longue sera également nécessaire à l’obtention des performances optimales si ces implants doivent être placés loin de la fovéa. Toutes les prothèses visuelles devraient viser à satisfaire ces critères afin de pouvoir fournir une réadaptation considérée comme « fonctionnelle » aux patients aveugles. 7 Perception visuelle isolée évoqué par un moyen de stimulation autre que la lumière (e.g. avec des courants électriques). xiii Resumen La ceguera es una discapacidad importante ya que la visión constituye una de las principales modalidades sensoriales y es fundamental para la actividad humana. Ciertas formas de degeneración de retina pueden conducir a una ceguera absoluta. Algunas, como la retinitis pigmentosa, pueden ocurrir a una edad relativamente precoz. Otras causas de ceguera están relacionadas con el envejecimiento y, en consecuencia, tienen mayor incidencia en personas de edad avanzada. Por lo tanto, el impacto global de la ceguera se vuelve más importante a medida que la esperanza de vida aumenta. Los avances tecnológicos recientes han abierto nuevas perspectivas y hoy en día es posible imaginar prótesis neuronales que permitan regenerar algún tipo de visión útil a pacientes completamente ciegos. Dichos dispositivos intentan restituir la sensación visual mediante estimulación eléctrica directa del tejido nervioso. Este concepto ha sido muy exitoso en el caso de los implantes cocleares para la rehabilitación de los pacientes sordos (NIH Consensus Statement, 1995). Varios grupos de investigación han lanzado proyectos ambiciosos con el objetivo de desarrollar diferentes tipos de prótesis visuales, que interactúan con el sistema nervioso a diferentes niveles (retina, nervio óptico o corteza cerebral visual). Los primeros prototipos de dichas prótesis han sido implantados recientemente (Dobelle, 2000; Chow et al., 2002; Veraart et al., 2003; Humayun et al., 2003), lo que sugiere que el sueño de una ayuda visual útil podría volverse realidad en un futuro no tan lejano. Cada día hay más evidencia que sugiere que en un futuro cercano las prótesis visuales podrían traer a los pacientes ciegos beneficios semejantes a los que ya proporcionan los implantes cocleares a los pacientes sordos. La mayoría de los esfuerzos parecen estar concentrados en el desarrollo de soluciones técnicas para las prótesis visuales (microelectrónica, biocompatibilidad, electrofisiología, etc…). Sin embargo, un aspecto clave de este desarrollo parece atraer muy poca atención: ¿Cuáles son los requerimientos de base para obtener una visión artificial útil? En otras palabras: ¿Cuál es la información visual mínima que debe ser transmitida al sistema nervioso para poder realizar las tareas básicas de la vida cotidiana? Justificación El objetivo de los estudios presentados en esta tesis es delinear los requerimientos visuales mínimos para lograr una rehabilitación funcional adecuada mediante un dispositivo de visión artificial. El conocimiento del mínimo de información que debe ser transmitida al cerebro para restaurar una función visual “útil” es esencial, teórica y prácticamente, para el diseño de prótesis visuales. La historia del desarrollo de los implantes cocleares subraya la importancia de este tipo de estudios. Adelantos como el desarrollo de los implantes cocleares multicanal, que permiten la discriminación adecuada del habla, son el resultado de estudios xv psicofísicos (Tong et al., 1983; Eddington et al., 1998a; Eddington et al., 1998b). Esta tesis pretende, por consiguiente, determinar este tipo de parámetros anticipadamente para evitar el uso a gran escala de prótesis que tengan una cantidad insuficiente de contactos de estimulación. Métodos generales Los métodos experimentales utilizados durante este estudio se diseñaron para imitar, de la manera más realista posible, las percepciones visuales que producirán las prótesis retinales. Estos dispositivos presentan ciertas características que restringirán importantemente el tipo de percepciones visuales que podrán ser evocadas. Las prótesis retinales consistirán en una cantidad finita de contactos de estimulación (resolución de la imagen limitada), estarán implantadas en un lugar fijo de la retina y cubrirán solo una fracción del campo visual natural (limitado por el tamaño del área activa del implante). Por otra parte, probablemente deberán considerarse áreas de implantación muy excéntricas ya que la anatomo-fisiología de la retina no favorece una localización foveal para estas prótesis (Sjöstrand et al., 1999a; Sjöstrand et al., 1999b). Las mejores ubicaciones para, potencialmente, preservar una activación retinotópica sin mayor distorsión de la imagen se encuentran a más de 10° de excentricidad. Esto quiere decir que las percepciones visuales de los futuros portadores de las prótesis retinales estarán limitadas a pequeñas áreas periféricas del campo visual. Se diseñó un dispositivo experimental para simular dichas condiciones de visión artificial en voluntarios con visión normal. Este sistema permite la presentación de imágenes de resolución limitada (pixeladas) estabilizadas en áreas del campo visual de determinada excentricidad. Por lo tanto, este simulador permite imitar el tipo de información visual trasmitido por una prótesis retinal y, al mismo tiempo, permite efectuar cambios paramétricos en la cantidad y naturaleza de dicha información. Se evaluaron los requerimientos de las funciones visuales básicas: la identificación de objetos/símbolos pequeños como se requiere durante la lectura, y la localización de objetos y del propio cuerpo en el espacio como se requiere durante las tareas de coordinación visuomotriz y de movilidad. Experimentos sobre la lectura La lectura es una actividad extremadamente importante en las sociedades modernas y constituye la meta principal de la rehabilitación de los pacientes de baja visión. El análisis sistemático de esta tarea es fundamental para la evaluación de las perspectivas de rehabilitación que podrán ofrecerse a los futuros portadores de prótesis visuales. El estímulo visual que se utilizó para la primera serie de experimentos sobre la lectura fueron palabras de cuatro letras (por ejemplo, “alto”). Los resultados revelaron que el rendimiento de lectura disminuye abruptamente cuando la información que representa la palabra se reduce más allá de cierto límite (expresado en número de píxeles): Se requiere un mínimo de 250 píxeles contenidos en un área xvi de visión de 10° x 3.5° (3 x 1 mm2 en la retina) para codificar correctamente las palabras de cuatro letras. A excentricidades más allá de 10° el rendimiento de lectura decae rápidamente aún con resoluciones de imagen mayores a 250 píxeles. Un segundo estudio fue dedicado a investigar si el rendimiento de lectura excéntrica puede mejorarse mediante el entrenamiento. Dos voluntarios con visión normal, sin previa experiencia en tareas involucrando la visión excéntrica, fueron entrenados para leer palabras de cuatro letras bajo condiciones simuladas de visión artificial, a 15° de excentricidad (en el campo visual inferior). El rendimiento de lectura de ambos sujetos mejoró notablemente durante el periodo de entrenamiento (aproximadamente un mes de entrenamiento diario; 1 hora/día). Durante las primeras sesiones experimentales los sujetos lograban leer correctamente solo 6% y 23% de las palabras presentadas; al final del experimento, su rendimiento mejoró hasta alcanzar un 64% y 85% de palabras correctamente identificadas. Algunos experimentos de control demostraron que el proceso de aprendizaje consistió, principalmente, en adaptarse a utilizar un área excéntrica de la retina para realizar la tarea de lectura. Una segunda serie de experimentos fue diseñada para investigar una tarea más realista: la lectura de páginas de texto, incluyendo el uso de los movimientos oculares para la navegación sobre la misma, en condiciones similares de visión artificial imitando una prótesis de retina excéntrica. Tres voluntarios sin experiencia previa en la tarea fueron entrenados durante casi dos meses (aproximadamente 1 hora/día) para leer textos de esta manera. Los sujetos debían usar sus propios movimientos oculares para desplazar una ventana de visión de 10° x 7° que contenía 572 píxeles8, estabilizada a 15° de excentricidad en su campo visual inferior. Las tasas de lectura9 iniciales fueron muy bajas en dos sujetos, y extraordinariamente altas en el caso del tercero (alrededor de 86%). Sin embargo, los tres voluntarios mejoraron su rendimiento con el tiempo, alcanzando tasas de lectura casi perfectas (entre 86% y 98%) al final del experimento. Las velocidades de lectura10 iniciales fueron muy bajas, de 1 a 5 palabras/min, y con el entrenamiento aumentaron significativamente a 14-28 palabras/min. También se llevó a cabo un análisis cualitativo de la comprensión general de los textos leídos. Este análisis reveló que se requieren tasas de lectura de al menos 85% de palabras correctamente identificadas para alcanzar una “buena” comprensión de los textos. El análisis posición de los ojos con respecto a las páginas de texto demostró que una parte importante del aprendizaje consistió en la mejora del control de los movimientos oculares excéntricos, especialmente la supresión de los sacádicos verticales reflejos (intentando centrar la ventana de visión en la fovea). 8 Resolución de imagen equivalente al mínimo obtenido en los primeros experimentos con las palabras de 4 letras. El lector debe tener en cuenta que para los experimentos de lectura de páginas enteras de texto, la ventana de visión medía el doble que en los experimentos de lectura de palabras de 4 letras, por lo cual también se duplicó el número de píxeles. 9 % de palabras correctamente identificadas. 10 Número de palabras correctamente identificadas por unidad de tiempo. xvii Experimentos sobre la coordinación visuomotriz La falta de resolución puede afectar seriamente la coordinación visuomotriz, esencialmente aquellas actividades que requieren la identificación de objetos. Por otro lado, se sabe que los defectos de la visión periférica afectan las capacidades básicas de localización y orientación, lo que también puede tener un impacto en las tareas de coordinación visuomotriz. La codificación de la información espacial y la utilización de dicha información con el objetivo de dirigir una respuesta motora particular puede, por lo tanto, imponer ciertas condiciones (con respecto a los requerimientos de información) a una prótesis visual. Se diseñaron dos pruebas para explorar los aspectos principales de la coordinación visuomotriz. La primera de ellas, la prueba de las fichas, consistía en reconocer figuras simples dibujadas en fichas de madera para luego colocarlas en la posición y orientación adecuadas sobre patrones aleatorios. La segunda configuración, la prueba de los LEDs, consistía en señalar con el dedo, tan precisamente como fuera posible, puntos luminosos (LED) que se encendían al azar bajo una pantalla sensible al tacto (touch screen. De manera similar a los experimentos sobre la lectura, se simularon las condiciones de visión artificial proyectando imágenes de resolución limitada en una ventana de visión de 10° x 7°, estabilizada en posiciones determinadas del campo visual. Durante estos experimentos también se investigó la importancia del tamaño del campo visual efectivo11 representado por la imagen proyectada en la ventana de visión. En un primer experimento se evaluaron las condiciones visuales mínimas necesarias para alcanzar un rendimiento óptimo en visión central. Tanto el número de píxeles contenidos en la ventana de visión como el tamaño del campo visual efectivo proyectado a su interior afectaron el rendimiento visuomotriz; varias combinaciones de estos dos parámetros permitieron un buen desempeño en ambas pruebas. Sin embargo, los resultados revelaron un límite fundamental para el rendimiento visuomotriz: una resolución efectiva de 2 píxeles/deg2 (es decir: 100 píxeles con un campo visual efectivo de 8° x de 6°, 400 píxeles con un campo visual efectivo de 16° x de 12° ó 1600 píxeles con un campo visual efectivo de 33° x de 23°). Un campo visual efectivo de aproximadamente 16° x 12° resultó ser el mejor compromiso entre una resolución suficientemente detallada y un campo visual suficientemente grande para estas actividades; además, los voluntarios expresaron espontáneamente su preferencia por este campo visual. En un segundo experimento se entrenó a tres voluntarios con visión normal, sin experiencia previa de visión excéntrica, a realizar las dos pruebas de coordinación visuomotriz utilizando una ventana de visión estabilizada a 15° de excentricidad en el campo visual inferior. Para este experimento se utilizó un campo visual efectivo de 16° x 12°. Dados los resultados de los experimentos sobre la lectura, se eligió una resolución de imagen de 498 píxeles para aprender a realizar las tareas en visión excéntrica (resolución efectiva de 2.6 píxeles/deg2). Durante la prueba de las fichas, 11 Porción del espacio visible simultáneamente en la imagen representada en la ventana de visión. xviii uno de los sujetos logró tasas de posicionamiento12 excelentes de manera inmediata. Los otros dos sujetos necesitaron entre 4 y 15 sesiones para obtener sistemáticamente tasas superiores a 95%. El tiempo promedio para colocar una ficha correctamente se estabilizó alrededor de 9 s/ficha tras 8, 13 y 38 sesiones. Durante la prueba de los LEDs, la precisión de localización13 convergió alrededor de 0.7 cm, pero los resultados fueron muy variables. La velocidad de señalización se estabilizó en 8 sesiones alrededor de 5 s/LED. Experimentos sobre la movilidad De manera general, la movilidad requiere la capacidad de juzgar distancias egocéntricas y exocéntricas para poder resolver cuestiones como la localización del propio cuerpo en el espacio, la percepción del movimiento, la estimación de distancias y la estimación de velocidades. Por lo tanto, estas tareas pueden tener requerimientos de información diferentes a los ya delineados para las tareas estudiadas con anterioridad. Al igual que en los experimentos previos, se simularon las condiciones de visión artificial proyectando imágenes de resolución limitada en una ventana de visión de 10° x 7°, que estaba estabilizada en posiciones fijas del campo visual y que contenía diferentes fracciones del entorno visual. Primero se determinaron los requerimientos mínimos para la movilidad en visión central. Dichos requerimientos parecen depender de las condiciones en la que la actividad debe llevarse a cabo. Por lo tanto, se realizaron varias pruebas en distintos contextos. La primera prueba, el recorrido de laboratorio, fue diseñada para evaluar el desempeño en entornos interiores, aleatorios pero familiares. Esta prueba consistía en completar un recorrido de laboratorio compuesto de 6 obstáculos comunes colocados al azar: una mesa con una silla, una serie de marcas en el piso, una puerta, tres escalones, el paso entre dos postes y el zigzagueo alrededor de 3 columnas). La segunda prueba, el bosque aleatorio, fue dirigida a evaluar la movilidad en entornos interiores, aleatorios y desconocidos incluyendo algunos elementos dinámicos. Los sujetos, desde una posición inicial aleatoria, debían cruzar un “bosque artificial” compuesto de 52 “árboles” colocados al azar hasta una posición final aleatoria. Durante este recorrido, un número variable de personas (0, 1 ó 2) podía cruzar el bosque perpendicularmente a la trayectoria de los sujetos, y todo choque con estas personas debía evitarse. La última prueba, el cruce de una calle real, fue diseñada para estudiar los requerimientos visuales de la movilidad en un entorno real y dinámico. En este caso, se evaluó la capacidad de estimar la velocidad y la distancia de objetos (automóviles) en acercamiento. La prueba consistía en juzgar la posibilidad de cruzar una calle de tránsito regular (sentido único) en función de la cantidad/calidad de información visual proporcionada por el simulador de visión artificial14. Los resultados de esta serie de experimentos confirmaron que la cantidad mínima de información requerida durante las tareas de movilidad varía de acuerdo al contexto en que éstas deben realizarse. La movilidad en entornos interiores y 12 % de fichas correctamente colocadas (posición y orientación adecuadas). Calculada como el promedio de los errores en la señalización (distancia absoluta entre la ubicación real del LED y la posición indicada por los sujetos). 14 Por razones obvias de seguridad los sujetos no debían cruzar la calle realmente. 13 xix conocidos requiere relativamente poca información: aproximadamente 0.2 píxeles/deg2 (es decir 150 píxeles con un campo visual efectivo de 33° x 23° ó 600 píxeles con un campo visual efectivo de 66° x 46°). Los campos de visión amplios no parecen representar ninguna ventaja en estas circunstancias. Las tareas de movilidad en entornos menos previsibles que incluyen ciertos elementos dinámicos, como en la tarea del bosque aleatorio, parecen ser más sensibles a la cantidad de información disponible en la ventana de visión, requiriendo alrededor de 500 píxeles. Los campos de visión de alrededor de 33° x 23° parecen favorecer el desempeño en este caso. Finalmente, se necesitan aproximadamente 1000 píxeles para sentirse seguro durante las tareas de movilidad en entornos reales, desconocidos y dinámicos, como en la prueba del cruce de una calle real. A medida que se reducía la cantidad de píxeles disponibles en la ventana de visión, los sujetos debían buscar alternativas para compensar la falta de información (por ejemplo, utilizando más la audición). Los campos visuales más reducidos, que proporcionan una información más detallada del entorno, parecen constituir una ventaja en estos contextos. En segundo lugar se evaluaron los posibles efectos de aprendizaje cuando las tareas de movilidad deben realizarse en visión excéntrica (15° en el campo visual inferior). De acuerdo a los resultados de los primeros experimentos de movilidad, un campo visual efectivo de 33° x 23° parece representar el mejor compromiso para el desempeño. Dicha condición proporciona una visión global del entorno lo suficientemente amplia mientras mantiene un nivel de resolución de imagen razonable. Por consiguiente, se eligió esta condición para el segundo estudio. Para ser consistente con los resultados de los experimentos sobre la lectura, se eligió una resolución de imagen de 498 píxeles para este experimento (es decir, una resolución efectiva de 0.65 píxeles/deg2). En este caso se evaluó la movilidad utilizando la prueba del recorrido de laboratorio descrita anteriormente. La cantidad de errores por recorrido disminuyó con el tiempo, y alcanzó una asíntota en 10 sesiones. El tiempo necesario para completar el recorrido disminuyó de forma considerable con el entrenamiento y alcanzó valores estables en alrededor de 40 sesiones. Sorprendentemente, después del entrenamiento los sujetos lograron un mejor desempeño en visión excéntrica que en visión central. Experimentos explorando simulaciones más realistas de la visión artificial En los estudios anteriores se hicieron ciertas simplificaciones en las simulaciones de visión artificial. Por una parte, la pixelización (reducción de resolución de la imagen) se llevó a cabo con un algoritmo que descompone las imágenes en matrices de píxeles cuadrados y de intensidad uniforme (pixelización cuadrada). Dicho algoritmo es adecuado para simular los estímulos a resolución reducida transmitidos por un implante retinal ya que, en teoría, la forma de los píxeles no altera el contenido de información global presente en la imagen. Sin embargo, este tipo de procesamiento no corresponde a lo que podría ser la respuesta fisiológica evocada por una prótesis visual. Por otra parte, durante los experimentos sobre la lectura se utilizó un algoritmo estático para el procesamiento de imágenes. Por consiguiente, se xx llevó a cabo una última serie de experimentos para investigar las eventuales ventajas o desventajas relacionadas a estímulos más realistas, variando las características temporales y espaciales del algoritmo de reducción de información. Se evaluó el efecto de dichas simplificaciones en la tarea más “exigente” en términos de información: la lectura de páginas de texto. Primero se comparó el rendimiento de lectura de páginas de texto procesadas utilizando algoritmos de pixelización estática (imágenes pre-procesadas) con aquellas procesadas con algoritmos de pixelización dinámica (procesamiento en tiempo real de la imagen presentada en la ventana de visión). Este comparativo se realizó a diferentes niveles de resolución de imagen. El rendimiento de lectura (tasa y velocidad de lectura) medidas en 5 voluntarios con visión normal mostró que la pixelización dinámica representa una ventaja comparada a su equivalente estático, ya que mediante los movimientos oculares los sujetos pueden integrar imágenes ligeramente distintas de una misma palabra y reconocerla con más facilidad. En segundo lugar se compararon simulaciones en las que se utilizaron píxeles cuadrados con otras utilizando píxeles cuya intensidad variaba de acuerdo a distribuciones gaussianas con diferentes dispersiones (σ). Éste comparativo demostró que con ciertas dispersiones gaussianas óptimas (0.143 < σ < 0.571) el rendimiento de lectura es muy similar o ligeramente superior al obtenido con la pixelización cuadrada equivalente. Este conjunto de experimentos demuestra que simulaciones más realistas (pixelización del estímulo en tiempo real) conducen a una mejora en el rendimiento de lectura de aproximadamente 30%. Sin embargo, dicho efecto no es suficiente para reducir de manera significativa (por ejemplo, a la mitad) la cantidad de píxeles necesarios para un buen rendimiento de lectura. Además, para lograr un buen rendimiento sería conveniente utilizar parámetros de estimulación que produzcan fosfenos15 con dispersiones dentro del rango de valores óptimos determinados en nuestros experimentos. Los resultados de futuros estudios electrofisiológicos mostrarán las posibilidades reales. Conclusión Este conjunto de resultados sugiere que alrededor de 500 fosfenos, distribuídos retinotópicamente sobre una superficie retinal de 10° x 7° (lo que corresponde a un implante de 3 x 2 mm2), es la información mínima requerida para restituir una función visual útil. Si este criterio es respetado, sería posible restablecer ciertas capacidades de lectura a los futuros usuarios de prótesis visuales. La coordinación visuomotriz y la movilidad parecen ser menos exigentes en términos de contenido de información que la lectura. Sin embargo, el campo visual efectivo representado en la superficie activa del implante deberá optimizarse para cada tipo de actividad. Para una lectura eficaz, es necesario un campo visual efectivo con mucho aumento que contenga de 4 a 6 letras y 2 líneas de texto (lo que corresponde a un campo visual de 2° x 1.4° para un periódico normal; aprox. 180 píxeles/deg2). Un campo visual 15 Percepción visual (punto luminoso) generada mediante una estimulación diferente a la luz (por ejemplo con corrientes eléctricas). xxi efectivo de alrededor de 16° x 12° parece permitir un desempeño adecuado (lento pero preciso) en las tareas de coordinación visuomotriz. La movilidad requiere un campo visual efectivo de aproximadamente 33° x 23°. Finalmente, si estos dispositivos deben implantarse lejos de la fovea, se requerirá un periodo de aprendizaje relativamente largo para obtener un rendimiento óptimo. Todas las prótesis visuales deben intentar satisfacer estos criterios para proveer una rehabilitación funcional adecuada a los pacientes ciegos. xxii 1 Introduction The eyes are not responsible when the mind does the seeing. Publilius Syrus (~100 B.C.) Blindness is generally considered as one of the most serious handicaps for the human being. Due to the complexity of the visual system and despite numerous research efforts, rehabilitation developments in this field seem to be slow. However, this pessimistic picture might change soon since technological advances offer a whole new range of possibilities. Several projects aiming towards developing visual prostheses have been launched recently. Such devices would restore lost function by bypassing the damaged structures and electrically stimulating the remaining visual pathway. Obviously, damage to other structures should be avoided and the ‘artificial vision’ provided by the prosthesis has to be useful to the patient. A number of important factors (electrical, surgical, biocompatibility, psychophysical) have thus to be thoroughly investigated and considered. This chapter intends to set the necessary background to understand visual perception in the context of artificial vision and the importance of the determination of minimum requirements for a visual prosthesis to restore useful vision. First, the basic anatomy and physiology of the visual system will be outlined and the basic issues on blindness and low vision will be discussed. Further along, the concept of visual prostheses will be explained in more detail. The different design approaches will be described and compared, summarizing the current status of research. Finally, alternative prosthetic approaches, interfacing with the visual system by other means than electrical stimulation, will be introduced. 1.1 Anatomy and Physiology of Vision Many consider vision as the most important sense for man and it is one of the best-studied senses since its intricacy has fascinated many researchers. Senses are the input channels from which we perceive, understand and figure out the surrounding world. Perception begins in the receptor cells, sensitive to some type of stimuli. The information gathered is then transferred through the different sensory pathways to the cerebral cortex. The visual pathway is schematized in figure 1. In the case of the visual system, the physical stimulus is light (electromagnetic waves in the visible spectrum). Light enters the eye and is transformed into electrical signals by the retina. The resulting neural signals leave the retina through fibers that constitute the optic nerve. Optic nerves coming from both eyes get reorganized at the optic chiasm, forming the optic 1 2 INTRODUCTION tract. Finally, the optic tract projects to a number of neural structures including the visual cortex, where the brain makes sense of it all, completing the retino-cortical pathway. All along the visual pathway, the visual image is processed hierarchically through parallel channels beginning already at the retina (Livingstone & Hubel, 1988). The most important are the magnocellular (M) and parvocellular (P) pathways, which originate in the retinal ganglion cell layer. Briefly, the M pathway is mainly dedicated to the perception of depth and motion, while the P pathway is mostly concerned with the perception of color and fine detail. In the following sections, the main structures of the visual pathway will be exposed in more detail. 1.1.1 The Eye Figure 1. Schematic view of the visual pathway. Reproduced from Bartleby.com©16 (Gray, 1918). The eye can be considered as an advanced optical device designed to focus the visual stimulus on the receptors, avoiding all possible distortion. In humans, each eye constitutes a separate optical system, each forming a single image. The structure of the eye is schematized in figure 2a. It is composed of a set of fluid-filled chambers: the anterior chamber (between the cornea and the iris; filled with aqueous humor), the posterior chamber (between the iris, the zonule fibers and the crystalline lens; filled with aqueous humor), and vitreous chamber (between the crystalline lens and the retina; filled with vitreous humor). Three layers of tissue cover these chambers. The cornea (frontal transparent surface), the sclera (white and opaque surface covering most of the eye), and the limbus (annular tissue dividing the first two; see fig. 2b) form the outer layer. The middle coat, or uveal tract, is made of three distinct but continuous structures: the iris (annular tissue just behind the cornea), the ciliary body (a muscular ring), and the choroid (mainly blood vessels and dense melanin pigment). The pupil is the hole in the center of the iris through which light enters the eye cavity. The inner layer, the retina, constitutes the neural part of the eye. It is located at the image plane of the eye’s optical system and is juxtaposed to the pigment epithelium. Light, focused by the cornea and crystalline lens, traverses the vitreous chamber to reach the retina. The eye being an advanced optical system, it is capable of 16 http://www.bartleby.com/107/illus763.html MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) 3 b) Figure 2. a) Structure and optics of the eye. Adapted from Webvision©17 (Kolb et al., 2003). b) Schematic representation of the limbus. Modified from the website of the Department of Optometry and Visual Science of the City University of London18. adapting to environment conditions and/or task requirements. The iris controls pupil size so that more or less light is allowed to enter the eye. Through a procedure called accommodation, the processes of the ciliary muscle constantly modify the refractive power of the crystalline lens in order to form a sharper image converging on the retinal visual axis or fovea. Any light that is not absorbed by the retina is absorbed by the pigment epithelium, thus preventing image degradation that could result from reflections on the back of the eye. 1.1.1.1 The Retina The retina is, by far, the most complex structure in the eye. It actually forms part of the central nervous system, representing, therefore, an excellent model for studying sensory transduction and for understanding information processing in higher brain circuits. Processing at this stage deserves to be described separately and in more detail. The retina presents a laminar structure (fig. 3a) consisting of three layers of neural cell bodies or nuclear layers, and two layers of synaptic connections or plexiform layers. Additionally, an outer limiting membrane separates it from the choroid and an inner limiting membrane separates it from the vitreous chamber. The retinal pigment epithelium lays adjacent to the neural retina. Even though this melanin pigment has no neural tissue, its role is essential for optimal visual perception. Its main functions are: preventing light reflection, providing metabolic support for photoreceptors, and contributing to adaptation. The outer nuclear layer (ONL) constitutes the photosensitive coat of the retina formed by photoreceptor cells of two types: rods and cones. Cones function in bright light and are responsible for fine discrimination and color vision. Rods function in dim 17 18 http://www.webvision.med.utah.edu/imageswv/draweye.jpeg http://www.city.ac.uk/optometry/Biolabs/Outer%20Coat%20Lab/Outer%20Coat.htm 4 a) INTRODUCTION b) Figure 3. a) Simplified structure of the retina. The retina is composed of three layers of neural cells and two synaptic layers surrounded by limiting membranes and the pigment epithelium. Modified after the original taken from Webvision©20 (Kolb et al., 2003). b) Density of rods and cones across the human retina. Image taken from Webvision©21 (Osterberg, 1935). Cone density peaks in the fovea and falls rapidly outside this region. Maximum rod density is found at around 18° eccentricity. There are no photoreceptors in the optic disc (blind spot). light settings, and are responsible for night vision. These photoreceptors are not equally distributed across the retina (see fig. 3b; Osterberg, 1935; Curcio et al., 1987). The fovea contains exclusively cones, providing the highest image resolution. At 10° eccentricity19, cone density rapidly decreases down to a concentration of 5% of the local photoreceptor count. Inversely, rod density grows rapidly up to 18° of eccentricity. The inner nuclear layer (INL) contains several classes of cells: horizontal, bipolar, amacrine, and interplexiform. The ganglion cell layer (GCL) is formed of ganglion cell bodies and some displaced amacrine cells (Wässle et al., 1989). Ganglion cells are the retinal neurons that ultimately transmit the visual output of the retina to the remaining visual pathway. Similar to the photoreceptors, ganglion cell distribution varies across the retina (Sjöstrand et al., 1999b). The fovea contains no ganglion cells; ganglion cell density increases rapidly to a maximum at around 5° (foveal border) and then decreases again towards the retinal border. The nerve fiber layer (NFL) is formed by the unmyelinated axons of ganglion cells crossing the retina towards the optic disc (optic nerve head). At the outer plexiform layer (OPL) synapses are formed between: (1) different photoreceptors, (2) photoreceptors and bipolar cells, and (3) photoreceptors and horizontal cells. The inner plexiform layer (IPL) contains synapses between: (1) bipolar and ganglion cells, (2) different amacrine cells, and (3) amacrine and ganglion cells. Photoreceptor, horizontal, and bipolar cells work with graded potentials while amacrine and ganglion cells generate neural action potentials. 19 1 mm in the retina corresponds approximately to 3.6° of visual angle (Drasdo & Fowler, 1974). MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 5 Information transfer in the retina follows a columnar model. Light must pass through all retinal layers in order to activate the photoreceptors, lying in the most distal part of the retina. The visual pigment of photoreceptors absorbs light photons, and these cells translate the information to an electrochemical message. Bipolar cells divide the dynamic range by separating the information into ON/OFF pathways and relay the information to ganglion cells. As soon as the stimulation signal reaches threshold, ganglion cells respond with action potentials of a frequency proportional to the graded stimulus. In addition, vertical modules composed by horizontal and amacrine cells integrate information from neighboring regions to maximize information content and highlight important image features. a) b) Figure 4. a) Schematization of subsequent connections of retinal cells, illustrating the complexity of the retinal circuitry. A single ganglion cell might code the information of several photoreceptors, and, at the same time, a single photoreceptor might interact with various neurons. Taken from the website22 of the Virginia-Maryland Regional College of Veterinary Medicine. b) Section of the human fovea illustrating the lateral displacement of photoreceptor-ganglion cell connections. Adapted from Webvision©23 (Kolb et al., 2003). Signals are transformed in many ways as they travel through the retina so that a final message containing several basic image organization features is transmitted towards the brain. The image processing circuitry of the visual system is already launched at the early photoreceptor stage to avoid signal deterioration. Photoreceptor sensitivity is optimized through a huge range of light intensities (from dark night to bright sunlight) by an adaptive process. At a given background illumination level, photoreceptors can only detect intensity differences of about three orders of magnitude. As luminous conditions fluctuate, their operating range is shifted up or down the intensity scale. Contrast detection is thus developed to the 20 21 22 23 http://www.webvision.med.utah.edu/imageswv/schem.jpeg http://www.webvision.med.utah.edu/imageswv/Ostergr.jpeg http://education.vetmed.vt.edu/Curriculum/VM8054/EYE/RETWIRES.JPG http://www.webvision.med.utah.edu/imageswv/hufovea.jpeg 6 INTRODUCTION utmost: perception is possible over a large range of intensities without sacrificing discrimination (Cotter, 1990). Further along, bipolar cells perform some form of data compression by responding only at borders between dark and light areas (center/surround receptive fields). These receptive fields also allow for relative measurements of color and brightness independent of lighting conditions (Stetten, 2000). Another important consideration concerns retinal cell distribution, proportions, and subsequent connections. There is a dramatic decrease from photoreceptor count (about 125 million) to number of ganglion cells (about 1 million), and it has already been mentioned that the different retinal cells are not uniformly distributed. As a result, several photoreceptors contact a bipolar cell, and many bipolar cells contact a single ganglion cell. At the same time, information gets splitted as one photoreceptor may interact with various neurons (see fig. 4a). It has been estimated that around the fovea (2°-3° of eccentricity) a maximum of 3 cones are connected to each retinal ganglion cell (Sjöstrand et al., 1999a). This cone to ganglion cell connection ratio decreases with eccentricity, reaching 1 at about 10° and 0.5 at eccentricities of 19° and beyond. Due to retinal topography, these connections are laterally displaced: ganglion cells connected to central photoreceptors are distributed over a larger area and are located at greater eccentricities. This lateral displacement becomes less important as eccentricity increases (see fig. 4b). Temporal coding of multiple inputs and nonlinear properties of synaptic cells are used to prevent any information loss (Slaughter, 1990). 1.1.2 The Optic Nerve and Optic Tract The optic nerve and the optic tract are formed by the ensemble of axons of retinal ganglion cells and constitute the wiring of the visual system. Ganglion cell axons become myelinated at the optic disc, forming the optic nerve. The central artery and vein of the retina pass through its center. It has been suggested that there is a rough topographic representation within the optic disc and that visuotopic organization varies across the nerve’s length (Fitzgibbon & Taylor, 1996). Optic nerves from both eyes join at the optic chiasm, forming the optic tract. Fibers get reorganized so that each optic tract contains axons from the opposite visual hemifield (see fig. 1). Optic tracts project to several structures. Some fibers reach the suprachiasmatic nucleus (SCN) in the hypothalamus, whose main function is the regulation of circadian rhythms24. Input reaching the pretectum is used for pupil control and accommodation reflexes. The superior colliculus uses the information for saccadic eye movement control as well as for orienting and attention movements to novel stimuli. Only the input reaching the lateral geniculate body is transmitted to the cerebral cortex and ultimately generates visual perception. The actual function of the geniculate nucleus is not clear yet, but it is believed to control retinal information flow to the cortex through its feedback connections from other neural regions. 24 Approximate 24-hour cycle modulating physiological processes. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 7 1.1.3 The Visual Cortex The visual cortex is the brain region devoted to the integration and discrimination of the image. This interpretation results in the conscious perception of images as a representation of the real world. As outlined in figure 5a, it is divided in several hierarchic areas across which the stimulus is continuously segmented to ultimately generate perception. The visual first processing center in the brain is the primary visual cortex (striate cortex, visual area 1, or V1). Each cerebral hemisphere receives topographically organized information from the opposite half of the visual field (fig. 5b). Approximately half of its surface receives input from high-resolution regions (fovea and its surroundings) and the remainder represents larger peripheral areas. Visual information is greatly segmented in V1. It is organized into vertical processing columns of different types. Each column type is concerned with a particular image feature like orientation, color perception, and spatial frequency. Another type of columns, ocular dominance columns, receive input from either the right or the left eye and are thought to be the foundation for stereoscopic vision (ability to perceive depth and relief). a) b) Figure 5. The visual areas in the brain. a) Unfolded and flattened map of the right hemisphere displaying the location of different visual areas in the cerebral cortex of the macaque monkey. Reprinted with permission from Van Essen et al., SCIENCE 255:419-423 (1992) and Felleman et al., CEREBRAL CORTEX 1, 1 (1991). Copyright 2006 AAAS and Oxford University Press. b) Retinotopic map of V1. Image adapted from Mason & Kandel (1991). Copyright 2006 McGraw-Hill Companies, Inc. From V1 a number of connections are sequentially made with other visual areas (see fig. 5a). From V2 and beyond, visual information aspects are further segregated to specialized areas and organization complexity increases. For example, V4 is thought to participate in color perception while V5 may play a role in movement detection and depth estimation. 8 INTRODUCTION 1.2 Blindness and Low Vision Simply speaking, blindness is the absence of perception of visual stimuli. The international ICD-1025 standard defines it as a visual acuity of less than 3/60 (0.05) in the better eye with the best possible correction. In parallel, low vision corresponds to a best-corrected visual acuity of less than 6/18 (0.3) but better or equal to 3/60. In 1990, the worldwide estimate of visually impaired people was of 148 million (Thylefors et al., 1995). Of these, approximately 38 million people were blind, and 110 million were low vision cases at risk of becoming blind. Alarmingly, these numbers could double by the year 2020. To this date, however, the exact numbers remain unknown due to an important lack of epidemiological information. What we certainly know is that blindness represents a lot more than a mere health problem. On one hand, blind people usually face serious social constraints leading to poorer social lives, lower education levels, lower employment opportunities, and lower life expectancies than sighted people (WHO, 1997). A 14-country study on disability ranked blindness as the fifth most disabling condition behind quadriplegia, dementia, active psychosis, and paraplegia (Ustun et al., 1999). On the other hand, the financial burden of blindness is considerable. Based on 1993 figures, it has been calculated as US$168 billion (Smith & Smith, 1996). The global economic productivity loss is estimated to grow from 19 billion in the year 2000 to US$50 billion by the year 2020 if no preventive measures are taken (Frick & Foster, 2003). Now that the complexity of the visual system has been discussed, it is easy to realize that blindness or low vision can result from lesion or malfunction at any level of the visual pathway. The seriousness of the affection depends directly on the structure affected. The World Health Organization (WHO) has dedicated a set of fact sheets to blindness and its impact (WHO, 1997). More recently, some authors (Margalit & Sadda, 2003; Congdon et al., 2003) have published comprehensive reviews on visual impairment causes. The major causes of blindness are exposed in figure 6. These are cataract, trachoma, glaucoma, and onchocerciasis (river blindness). Other diseases’ impact is also acknowledged to be important, but specific numbers are unavailable to this date. Diabetic retinopathy is publicly documented as the primary cause of visual impairment amid working age adults (Congdon et al., 2003). Age-related macular degeneration (AMD), disabling approximately 8 million people worldwide (WHO, 1997), constitutes the most common non-avoidable cause of visual disability. Retinitis pigmentosa (RP) is the principal cause of inherited blindness with a prevalence estimated in 1 out of 3000 (Humphries et al., 1992). Statistics from Prevent Blindness America rank it as the 6th leading cause of blindness in the United States (4.7%) affecting approximately 100,000 americans (Leonard & Gordon, 2002) and approximately 1.5 million people worldwide (Boughman et al., 1980; Haim et al., 1992). In addition, trauma is estimated to be responsible for half a million blindness cases (Thylefors, 1992). 25 International Statistical Classification of Diseases and Related Health Problems – 10th Revision MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 9 Figure 6. Major causes of blindness worldwide. Data taken from Thylefors et al. (1995). Causes of blindness vary significantly across economic regions (fig. 6). In developing countries most disabling conditions could be treated or prevented. Cataract can be successfully corrected with surgery; trachoma can be treated through hygiene, antibiotic administration, and corrective surgery; childhood blindness could be reduced by means of immunization, better nutrition, prophylaxis, and avoidance of harmful medicines (WHO, 2002). An ambitious initiative aiming to eradicate avoidable blindness through prevention and eye care programs, VISION 2020, has been launched by the WHO (2000). In developed countries, like Switzerland, non-avoidable diseases are most common. The impact of these conditions, mainly age related, is expected to increase due to current trends of population ageing. Medical intervention is not expected to significantly reduce their impact in a near future since clinical treatments for the major diseases in this category are unavailable nowadays. Laser photocoagulation is roughly the only therapy available for AMD and benefits only a limited number of patients. Other experimental treatments for this disease like photodynamic therapy, pharmacologic inhibition, surgical intervention, and radiation therapy are being explored (Ciulla et al., 1998). Periodic screening and early laser treatment have proven to be helpful tools for preventing blindness in patients suffering from diabetic retinopathy, and alternative therapies are currently being studied (Harding, 2003). Genetic therapy is expected to be the best alternative for retinitis pigmentosa (Hims et al., 2003). 10 INTRODUCTION In this context, the role of rehabilitation becomes crucial. Low vision and blindness aids for daily living have greatly evolved from guide dogs and canes to complex technological devices, although traditional methods are still greatly appreciated and frequently used. A number of studies have demonstrated the efficacy of these systems in improving quality of life and reducing perceived disability (Margrain, 1999; Margrain, 2000). New systems compensate the visual deficit either with augmentation devices (strong eyeglasses, telescopes, and video/computer magnifiers) or by sensory substitution (replacing vision with another sense such as hearing or touch). The variety of the available aids is enormous; a simple internet search will return plenty of references and good overviews of such systems can be easily found in the literature (Peli et al., 1991; Kaczmarek, 2000; Peli, 2001). 1.3 Visual prostheses as a means to rehabilitate blindness Research and technology are also trying to make use of existing knowledge to restore visual function when blindness is irreversible. The principle is quite simple: the broken visual information path would by ‘repaired’ by substituting the defective structure with some kind of artificial system. Recently, a new alternative has come into focus: visual prosthetic devices. The foundations of the visual prosthetic field were established as early as 1755, when LeRoy discovered that electricity applied to a blind eye resulted in light perception (Clausen, 1955). Through the years, the effects of electricity on the human body continued to be explored. In particular, the revolutionary work of Einthoven gave new insights into the therapeutic use of electricity (see e.g. Einthoven & Jolly, 1908). The relationship between electricity and vision were, however, not discussed again until the 20th century when a group of researchers described phosphenes26 elicited by direct electrical stimulation of the cortex while performing surgery (Löwenstein & Borchardt, 1918; Krause, 1924; Foerster, 1929; Urban, 1937; Penfield & Jasper, 1954). These findings led Giles Brindley and his colleagues to the first attempt of a “visual prosthetic implant” (Brindley & Lewin, 1968a; Brindley & Lewin, 1968b; Brindley, 1973). Two volunteers were implanted with arrays of platinum electrodes over the occipital cortex and stimuli were delivered by radio transmission. Some years later, Dobelle followed Brindley’s footsteps. Several experiments with acute electrode configurations were performed before proceeding to the implantation of permanent devices (Dobelle & Mladejowsky, 1974; Dobelle et al., 1974; Klomp et al., 1977). Several volunteers participated in these experiences, and two have kept the implant for more than 20 years (Dobelle, 2000). Results from both groups 26 The Concise Oxford English Dictionary (Oxford Reference Online, 2004) defines the word phosphene as: “a sensation of a ring or spot of light produced by pressure on the eyeball or direct stimulation of the visual system other than by light”. This term will appear frequently throughout this dissertation but the reader must take it with caution since its definition is quite ambiguous. On one hand, it makes no allusion to the exact site on the visual pathway where the perception originated (e.g. visual cortex or retina). On the other hand, this designation does not take into account the intensity of the perception nor its temporal profile. We use it despite its ambiguity because there is not a more accurate one and because it is broadly used in the artificial vision community. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 11 demonstrated that phosphenes could be successfully evoked, and Dobelle was even able to obtain patterned perceptions (Dobelle et al., 1976). Yet, these first attempts encountered a number of significant difficulties related to the use of surface electrodes, like merging phosphenes, multiple phosphenes elicited by a single electrode, fading perceptions, and high currents needed to reach stimulation threshold. None of these implants proved to be useful. Nevertheless, these pioneering efforts demonstrated the feasibility of the approach. Since then, technological advances and success in other rehabilitation fields, like cochlear implants (Rauschecker & Shannon, 2002) have boosted interest on the idea of developing visual neuroprostheses. Such a device will be composed of two modules, one external and one implanted (see fig. 7). In general, the external module will contain an image capture unit (mini-camera), an image-processing unit, and a wireless transmission unit communicating with the implanted module. The internal module will contain all stimulator electronics and the neural interface unit (electrode array). Some detailed descriptions of a system of this nature can be found in the scientific literature (Warren & Normann, 2000; Liu et al., 2003). Figure 7. Basic elements of a visual neuroprosthesis. The external module captures the visual stimulus, processes and transmits the information to the implanted module. The implanted module communicates directly with the target neural tissue. In a few words, the labor of the external module is to capture the visual scene, transform it into an ‘electrical image’ that can be correctly interpreted by the brain, and transmit the signals to the implanted module. The image capture unit consists of a photodiode array, a CCD, or a miniaturized camera. Due to the limited number of electrodes in the implant, spatial resolution will not impose any particular constraints on this material. Temporal resolution is not expected to be a problem either since the response of the human visual system is relatively slow (around 30Hz). The role of image processing is to modify the input image so that the stimulus that will ultimately reach the brain contains enough topographic information to be effectively identified and used. The complexity of this stage will therefore depend directly on the implantation site (especially on its visuotopic organization) and on the degree of plasticity of the remaining visual pathway. An encoder for spatial remapping of video signals on retinal prostheses is currently being developed by Eckmiller (1997). The description of several image processing techniques for information content enhancement in artificial vision systems can be found in Boyle et al. (2002). Wireless transmission will be used to pass on the information to the implanted module and to deliver power to its components at the same time. This transfer can be achieved by radio frequency or electromagnetic waves. The number of electrodes in the implant and the data compression/encoding algorithms used by the image-processing unit 12 INTRODUCTION will determine the bandwidth needed for transmission. Since the distance between the transmitter and the receiver will be rather short (approximately 1 to 3 cm), power coupling can be achieved quite efficiently. The implanted module will be in charge of communicating with the nervous system, obviously imposing important physical and biological biocompatibility considerations. The role of the stimulator is to ‘transduce’ the electrical signals into neural signals that can correctly stimulate the neurons at the particular implant location. The main design considerations for this element have been outlined in detail by Jones & Normann (1997) and in more recent reviews (Maynard, 2001; Margalit et al., 2002). The electrode array constitutes the actual interface with the neural tissue. Oxidized iridium is the material most frequently used for stimulation electrodes in implantable neuroprostheses as it has proven to be highly biocompatible and effective (Blau et al., 1997; Weiland & Anderson, 2000). In order to avoid tissue heating, electrolysis and electrode cross-talk, the size and density of this element will be mainly limited by the intensity of the stimulating currents used. Stimulation currents will in turn depend directly on electrode geometry, the type of cells being stimulated, as well as the distance between target cells and the stimulating electrodes (Palanker et al., 2004). Currently several groups are working towards the development of a visual prosthesis, each of them attempting to restore visual function at different levels of the visual pathway. Several reviews on the subject have been published recently (Greenberg, 2000; Warren & Normann, 2000; Maynard, 2001; Margalit et al., 2002; Zrenner, 2002b; Lakhanpal et al., 2003; Weiland et al., 2005). The main biocompatibility, electrical, and psychophysical design considerations common to all design approaches have been outlined in a number of research papers (Warren & Normann, 2000; Humayun, 2001; Maynard, 2001; Margalit et al., 2002). In the following sections, the different approaches will be presented. Prosthesis designs using alternatives to electrical stimulation will also be mentioned. Afterwards, the advantages and disadvantages of each design will be discussed. 1.3.1 Cortical Stimulation Cortical prostheses attempt to restore vision by direct electrical stimulation of the primary visual cortex (fig. 8). This approach was the first to be seriously considered. The pioneering efforts outlined earlier in this chapter (Brindley & Lewin, 1968a; Brindley & Lewin, 1968b; Dobelle & Mladejowsky, 1974; Dobelle et al., 1974), correspond to this category. These experiments encountered a number of problems, related to the use of surface electrodes. Because of the large surface area of the electrodes (1 mm2), high currents (from 1 mA to 3 mA) were needed to generate phosphenes. Inter-electrode spacing had to be of 3 mm in order to minimize interactions between electrodes and even then, subjects reported seeing ‘halos’ surrounding and joining individual phosphenes. The perception a spatially organized set of multiple phosphenes could never be achieved. Therefore, these devices never proved to be useful to implanted patients. However, some interesting results have been published lately by Dobelle (2000). The vision of one of the volunteers implanted in 1978 with an array of surface electrodes (Klomp et al., 1977), has MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 13 improved significantly due to more adequate processing of the visual information by a 5th generation stimulation system. New advances in fabrication and microtechnology have led to the design and development of more selective neural interfaces (Rutten, 2002). In the 1990’s, Schmidt and his group conducted a series of experiments using a penetrating electrode array implanted on the primary visual cortex of a human Figure 8. Illustration of the concept of a cortical volunteer (Bak et al., 1990; Schmidt et visual prosthesis. Image taken from the John A. al., 1996). Stimulation thresholds were Moran Eye Institute website27 at the University as low as 1.9 µA, and separate of Utah. phosphenes were detected with closely spaced stimulating electrodes (only 250 µm or 500 µm apart). This study clearly demonstrated the advantage of using penetrating electrode arrays instead of surface electrodes, setting the physiological foundation of most cortically based artificial vision systems being developed nowadays. Recent efforts in this field have concentrated in the development of high electrode count arrays (Jones et al., 1992; Hoogerwerf & Wise, 1994; Kewley D.T. et al., 1997; Bai et al., 2000; Bai & Wise, 2001). A group at the University of Utah has developed a silicone based, 10x10 penetrating electrode matrix: the Utah Electrode Array (Campbell et al., 1991; Jones et al., 1992), specifically conceived as an interface for the cerebral cortex. This electrode array projects out of a 0.2 mm substrate designed to rest on the cortical surface (fig. 9a). Electrodes are 1.5 mm long ending in platinum coated conical tips with a radius of curvature of about 3 µm (fig. 9b). A pneumatic tool for adequately inserting the Utah Electrode Array into the cortex and the surgical procedure for implantation have also been developed (Rousche & Normann, 1992; Maynard et al., 2000). A series of behavioral experiments conducted in the auditory cortex of the cat demonstrated that a response could be obtained over periods of about 100 days with stable thresholds, indicating no damage to neurons in the vicinity (Rousche & Normann, 1999). Chronic single and multi-unit responses in the cat and monkey have been recorded over several years, providing preliminary evidence of the functionality and biocompatibility of the implant (Maynard et al., 1999). However, these studies have also highlighted a significant problem concerning the mechanical stability of the implant on the brain. Formation of adhesions between the dura matter28 and the electrode array have been observed as a consequence of the immunological response of the implanted tissue (Rousche & 27 28 http://www.moraneyecenter.org/research/normann/normann.htm Outermost and thickest of the three membranes (meninges) covering the brain and the spinal cord. 14 a) INTRODUCTION b) Figure 9. The Utah Electrode Array. a) Penetrating electrode array developed at the University of Utah. b) Platinum coated tips of the Utah Electrode Array. Reprinted from VISION RES, 39(15), Normann et al., A neural interface for a cortical vision prosthesis, 2577-2587, Copyright 1999, with permission from Elsevier. Normann, 1998b). This provoked constant relative movement between the brain and the electrode array29. Histological analyses revealed that this mechanical coupling resulted in constant displacement of the electrodes within the surrounding cortical structures, causing local trauma and modifying electrode impedance (Rousche & Normann, 1998a). A new technique to prevent these dural adhesions, has been proposed (Maynard et al., 2000). It consists in placing a Teflon® sheet between the electrode array and the dura matter. This procedure appears to be effective as long as the Teflon® cover remains in its initial position. The biocompatibility of the Utah Electrode Array is still being assessed and validated. Once it is completed the research group plans on proceeding with psychophysical studies of phosphene perception on human volunteers (Normann et al., 1999). These encouraging results, altogether with the development of new and more selective interfaces with the nervous system, have given birth to other visual prosthesis designs, stimulating the visual system at more peripheral sites, such as the retina or the optic nerve. 1.3.2 Optic Nerve Stimulation A research group at the Université Catholique de Louvain in Brussels, Belgium, has launched a particular visual prosthesis development initiative, interfacing with 29 Brain tissues are not attached together; instead, the brain “floats” on the cerebrospinal fluid, inside the cranial cavity (Rowland et al., 1991). This configuration provides the necessary support to maintain the brain’s 3D structure and constitutes a mechanical cushion protecting the nervous tissue from harmful forces resulting from head movement and impact. Therefore, there is permanent relative movement between the brain and surrounding tissue. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 15 the visual system at the optic nerve: the Microsystems Based Visual Prosthesis (MiViP; Veraart et al., 1998). At this level, the entire visual field is represented in a relatively small area; phosphenes could be, therefore, evoked over a large portion of the visual field using only a few contacts. In February 1998, a female volunteer, totally blind from RP, was implanted with a 4-contact self-sizing spiral cuff electrode placed around the optic nerve (Veraart et al., 1998). This particular electrode design had proven effective selective activation in previous studies (Veraart et al., 1993). The four electrode contacts were labeled 0°, 90°, 180°, and 270° according to their angular position around the optic nerve. Stimulation Figure 10. Retinotopic distribution of 64 currents were brought to the electrode phosphenes according to the active contact in the self-sizing spiral cuff electrode. Near through a percutaneaous connector. The threshold a certain relationship between the first results showed that the electrode did stimulation quadrant and the perception not induce any sensations other than quadrant was preserved. Reprinted from BRAIN visual. Phosphenes of different forms, RESEARCH, 813(1), Veraart et al., Visual colors, and sizes could be successfully sensations produced by optic nerve stimulation using an implanted self-sizing spiral cuff elicited. These phosphenes were electrode, pp. 181-186, Copyright 1998, with disorderly distributed around a visual field permission from Elsevier. of approximately 60° vertically and 85° horizontally (Veraart et al., 1998). Nevertheless, a certain relationship between the stimulation quadrant30 and the perception quadrant31 was respected near threshold (fig. 10). In August 2000, the percutaneous connector was replaced by an implanted neurostimulator and an antenna used for telemetry (Delbeke et al., 2002). The concept of the system as it is implemented nowadays is schematized in figure 11a. The implanted components are visible in the x-ray of the volunteer presented in figure 11b. For prostheses to provide any form of useful vision, a precise correlation between stimulation parameters and the character of the perceived phosphenes must therefore be established. A set of equations intended to define this relationship have been derived (Delbeke et al., 2003a; Delbeke et al., 2003b). In this case, a correlation seems to exist between perception threshold and pulse duration, number, and frequency. Conversely, phosphene characteristics such as luminosity, size, and 30 31 Electrode position around the optic nerve. Phosphene position in the visual field. 16 a) INTRODUCTION b) Figure 11. Elements of the optic nerve visual prosthesis a) Schema illustrating the concept of the system. b) X-ray of the blind volunteer showing the implanted components. Reprinted from Veraart et al., ARTIF ORGANS 27(11):996-1004 (2003). With permission of Blackwell Publishing. position seem to be best predicted by stimulus intensity. A screening test for identifying potential optic nerve prosthesis candidates has also been developed (Delbeke et al., 2001). Sets of psychophysical studies have been carried out to assess the potential benefits of the optic nerve prosthesis. For these experiments, interleaved stimulation was used to evoke patterns of 4 to 24 phosphenes and the volunteer was able to scan the environment using a head-mounted camera. After several months of training, the volunteer was able to accurately identify, localize, and grasp different daily life objects located among others (Lambert et al., 2003). However, the time needed to complete the task was considerable: about 60 s to grasp a particular object surrounded by others. Performance also increased significantly with practice in pattern recognition and orientation discrimination tasks (Delbeke et al., 2002; Veraart et al., 2003). These tasks were evaluated using images constituted of bars with different orientations, subtending a visual angle of 32° x 2.2°. For pattern recognition, the volunteer reached a score of 63% correct in a processing time of 60 s. Concerning orientation discrimination, the volunteer reached a score of 100% correct in 8 s. Altogether, these results undoubtedly demonstrate the functionality and safety of the system. The issue of usefulness of this prosthesis remains however unclear. Veraart’s group claims that certain basic tasks do not require much resolution, and that with enough training the volunteer has benefit from the limited visual input provided by the prosthesis. This is not obvious from the results of psychophysical tests. For example, it took 60s for the volunteer to correctly identify and grasp a required object, under high contrast conditions and after training. This processing time cannot be judged as acceptable under any point of view; one can easily demonstrate that it takes considerably less time to achieve the same task using touch. Warren & Normann (2000) suggest that a number of issues be investigated to MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 17 determine the feasibility of the approach: (1) the significance and viability of functional optic nerve fiber populations; (2) the role of electrical stimulation in preserving the optic nerve from continued degeneration; (3) the number of phosphenes required to achieve given levels of task performance; and (4) if penetrating electrode array designs would produce more focalized stimulation and better control of phosphene parameters. 1.3.3 Retinal Stimulation The retina bears a strong interest in the context of artificial vision. Due to its relatively simple structural organization and surgical accessibility, it has been particularly targeted as a feasible implantation site for visual prostheses. A number of studies have revealed that when blindness is due to progressive destruction of rods and cones, inner retinal Figure 12. Retinal implant design approaches: the epiretinal cells are preserved (Santos implant and the subretinal implant. Reprinted with permission from Zrenner, SCIENCE 295:1022-25 (2002). Copyright 2006 et al., 1997; Medeiros & AAAS. Curcio, 2001; Cursiefen et al., 2001; Kim et al., 2002a; Kim et al., 2002b). This occurs in AMD and RP, which, as already discussed, are diseases that have a significant impact in developed countries like Switzerland. This last approach consists, thus, in electrically stimulating the visual system through retinal cell layers that are still functional. A research group at the Johns Hopkins Hospital completed a series of acute experiments with temporary electrode arrays placed over the surface of the retina of blind volunteers. Their results demonstrated that electric stimulation at this level results in visual perception, and that simple forms can be perceived in response to patterned electrical stimulation (Humayun et al., 1996; Weiland et al., 1999; Humayun et al., 1999). On this basis, two different retinal prosthesis designs have been envisioned (fig. 12). In the first approach, the epiretinal implant, the stimulating electrode array is placed over the retinal surface, between the vitreous humor and the inner limiting membrane. In the second approach, the subretinal implant, the electrode array is to be positioned in the subretinal space, substituting the degenerate photoreceptors. 1.3.3.1 Epiretinal Implant The configuration of an epiretinal implant is similar to the prosthesis designs mentioned beforehand. It consists of an implanted module including the electrode array and the stimulator, and an external module comprising a camera that captures the visual scene and an image processor that transforms the input into a pattern of 18 INTRODUCTION currents that can be correctly interpreted by the brain (fig. 13). This approach has been adopted by several research groups all around the world (Wyatt & Rizzo, 1996; Humayun et al., 1996; Rizzo & Wyatt, 1997; Humayun et al., 1999; Grumet et al., 2000; Suaning & Lovell, 2001; Humayun, 2001; Liu et al., 2003). Implantable electrode arrays have been developed and tested in animals. A research group in Australia has developed a specific circuit containing 100 stimulation channels intended Figure 13. Concept of an epiretinal implant. An external for retinal neurostimulation camera captures the image (A). The signals are wirelessly (Suaning & Lovell, 2001), and transmitted (B) to the implanted module (C). The the corresponding surgical stimulating electrode array (D) is implanted over the retinal implantation technique has been surface. Reprinted from VISION RES, 43(24), Humayun et developed and tested in the al., Visual perception in a blind subject with a chronic microelectronic retinal prosthesis, pp. 2573-2581, Copyright ovine eye (Kerdraon et al., 2003, with permission from Elsevier. 2002). Preliminary results confirmed that there was no evidence of macroscopic trauma. However, further experimentation is required to extensively evaluate both the biocompatibility of the implant and the surgical procedure. Another research group at the Doheny Retina Institute (Los Angeles, California, U.S.A.) implanted 4 mixed-breed sighted dogs with 5x5 platinum discshaped electrode arrays. The implants remained in place during a follow-up period of several months (Majji et al., 1999). Electrophysiological and histological tests revealed that the retinal tissue under the electrode array was preserved and remained functional. The feasibility of the surgical procedure and the biocompatibility of the implanted material were thus demonstrated. Meantime, a 1st generation retinal implant designed to be used on humans has been developed by the research group at the Doheny Retina Institute (Fujii et al., 2003). Two blind volunteers were implanted with 4x4 platinum electrode arrays attached to an external microelectronic circuit (Yanai et al., 2003). Phosphenes evoked by a single electrode were described either as a round spot of light or as a lighted center surrounded by a black ring, darker than the background (Humayun et al., 2003). Statistical analysis of perception thresholds measured, on one subject, over the first 10 weeks of testing showed no significant change for 10 electrodes, a significant decrease for 3 electrodes, and a significant increase for the remaining 3 electrodes. When stimulation was computer-controlled, the subjects were able to describe the direction of two sequentially activated electrodes as up, down, left, or right in 70% of the cases. When scanning the environment using a head-mounted MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 19 camera, the subjects were able to detect lighting conditions in 100% of the cases and to recognize simple forms (the orientation of an L) with 75% of accuracy (Yanai et al., 2003). Other tests conducted with the head-mounted camera on only one subject showed that he was able to detect the movement of a flash of light in a dark room in 100% of the cases, to detect the movement of an object in 80% of the cases, and to discriminate movement direction in 70% of the cases (Humayun et al., 2003). Another research group at the Harvard Medical School performed in-vivo experiments on acute epiretinal stimulation during surgical trials on humans (Rizzo et al., 2003a; Rizzo et al., 2003b). The main purpose of these studies, in which five subjects totally blind from RP and one with normal vision32 participated, was to determine perceptual thresholds and to explore the relationship between the pattern of electrical stimulation and the perception induced. Electrical stimulation was delivered with external current sources and through either needle electrodes (250µm of diameter), or an iridium oxide microelectrode array (electrode diameters of 400µm, 100µm, or 50µm). The results showed that perception thresholds were significantly higher in blind patients, exceeding safe charge density estimates. Furthermore, thresholds increased with the severity of blindness. The lowest thresholds detected in blind volunteers, with the 400 µm electrodes, were above 0.32 mC/cm2, compared to that of the normal volunteer of 0.08 mC/cm2. These findings question the feasibility of long-term epiretinal stimulation as the means to restore vision. Single electrodes induced percepts that were considerably smaller than the size of the active electrode. Blind subjects perceived forms that matched the electrical stimulation patterns only in 48% and 32% of the cases for single-electrode and multiple-electrode trials, respectively. Stimulation patterns and percepts matched in 57% of the cases in the normal subject. The low matching score observed in the normally sighted patient suggests that the results observed in blind patients were not due to retinal pathology alone, but also to the lack of effective stimulation methods. 1.3.3.2 Subretinal Implant In the case of subretinal implants, the optics of the eye and an array of microphotodiodes replace the external image capture module of the general visual prosthesis model (fig. 14). In other words, the photodiodes incorporated into the electrode array capture and transform the 32 Figure 14. Concept of a subretinal implant. A microphotodiode array is used to transform the light entering the eye into a pattern of electrical stimulation currents. Source: Alfred Stett, NMI Reutlingen. The volunteer with normal vision underwent enucleation of the eye because of orbital cancer. 20 INTRODUCTION incident light into electric stimulation currents in situ. This way, the microphotodiodes replace the function of the lost photoreceptors and the optics of the eye is used to project the light on these detectors. Neither an external capture module, nor an image-processing unit are therefore needed in this configuration. Two research groups have adopted this approach (Chow & Chow, 1997; Zrenner et al., 1997; Peyman et al., 1998; Zrenner et al., 1999; Zrenner, 2002b). It is also worth mentioning that quite recently the research group from Harvard Medical School decided to change the design of their prosthesis from the epiretinal approach (Wyatt & Rizzo, 1996; Rizzo & Wyatt, 1997) to a subretinal design because its inherent biocompatibility and engineering advantages (Yamauchi et al., 2004; Rizzo et al., 2004). To this date, two prototypes of subretinal implants have been developed. These are silicon-based chips of about 3 mm to 2.5 mm of diameter containing several hundreds or even thousands of micro-photodiodes. Each of the photodiodes is connected to a microelectrode that can be fabricated in gold, platinum, oxide iridium or TiN (Zrenner et al., 1997; Peachey & Chow, 1999). The surgical techniques for implanting such prototypes have been developed. The classic procedure, ab-interno, is displayed in figure 15a. It consists in entering the back of the eye by the vitreous chamber and placing the implant under the retina through a small incision using a special implantation tool (Peyman et al., 1998; Zrenner, 2002a). The German consortium, led by Zrenner, has adopted another approach, ab-externo (fig. 15b). A small scleral flap is prepared and the implant is pushed between the pigment epithelium and the retina with a custom-made plastic foil. Both techniques have been tested and validated in animals. a) b) Figure 15. Surgical procedures for implantation of subretinal visual prosthesis. a) Ab-interno approach. b) Ab-externo approach. Images courtesy of Jan Monzer. Biocompatibility tests performed in vitro and in vivo in different animal models have returned very encouraging results. Rabbits and pigs were implanted during 14 months (Schwahn et al., 2001; Kohler et al., 2001). The implants remained in place and the histology of the retina was not pathologically transformed. Similar tests have been completed in cats (Pardue et al., 2001; Chow et al., 2001). Follow-ups up to 27 MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 21 months after surgery revealed the stability of the implant in the subretinal space. The comparison of the ERG response of normal and implanted eyes showed that the latter presented normal waveforms, only slightly smaller in amplitude. Nonetheless, the outer nuclear layer covering the implant disappeared almost completely, suggesting that there was some kind of obstruction of the flow of nutrients to these layers. Future implants will probably have to be perforated in order to allow for the exchange of nutrients between the pigment epithelium and the surviving retinal layers. Concerning the long-term stability of the implants it has been reported that TiN electrodes do not show any signs of corrosion after 18 months of implantation and can be considered bio-stable. This was also the case for oxide iridium electrodes (Chow et al., 2002), but not for electrodes fabricated in gold (Chow et al., 2001). Spatial resolution and operational range for multisite electric stimulation have been evaluated on isolated chicken retina (Stett et al., 2000). Ganglion cell sensitivity, related to locally applied electric charges, seems to be well delimited in space. An array with an inter-electrode spacing of about 100 µm should allow for retinotopic stimulation. It has also been demonstrated that light arriving to the retina in natural conditions does not contain enough energy for the photodiodes to produce adequate neuronal stimulation (Zrenner et al., 1997). It appears therefore imperative to provide additional energy (induction or IR) to the implant to cope with this deficit. Recently, a new idea for a self-powered prosthesis has been proposed by Palanker et al. (2003). In this design, ambient light falling in regions of the retina not covered by the implant is gathered with additional photodiodes (placed, for example, in the anterior chamber). The extra power supplied by these secondary photovoltaic cells could provide enough energy for adequate stimulation. The first attempts of implantation on human volunteers have been performed recently (Chow et al., 2002; Chow et al., 2003). Six subjects received a circular implant measuring 2 mm of diameter and containing approximately 5000 electrodes. These researchers report that the patients did not have any problems with the implant; there was no sign of important infection, rejection, inflammation, migration, erosion, or retinal detachment. Apparently, all of them presented an improvement of visual perception (subjective and objective). These surprising results have originated an intense debate, especially because improvements have been observed outside of the retinal area being stimulated by the implant and since there is no additional supply of energy in this model. In this case, it is most probable that the improvement of visual function experienced by subjects was related to some kind of neurotrophic effect (Chow et al., 2003). 1.3.3.3 The “CMOS-retina”: a Swiss project The work for the present dissertation was elaborated within the framework of the CMOS-retina Swiss project. The ultimate goal of this effort is to develop a prosthesis, which will effectively restore useful vision to blind patients using subretinal stimulation. To this purpose, the microtechnical, neurophysiological, psychophysical and surgical aspects involved in prosthetic vision are being simultaneously 22 INTRODUCTION investigated. This way, all the necessary fundamental medical and technical knowledge will be established. This project involves the collaboration of interdisciplinary teams, each of which is renowned in its field: the Ophthalmology Clinic of the Geneva University Hospitals (HUG)33 experienced in clinical ophthalmology, visual psychophysics, and eye surgery; the Institute for Microsystems (IMS) and the Microelectronics Laboratory (LEG) at the Lausanne Federal Polytechnic School (EPFL), experienced in microfabrication techniques; and the Department of Physiology at the medical center of the University of Geneva (CMU), experienced in retinal physiology. A diagram illustrating the general organization of the project is presented in figure 16. Figure 16. Institutional diagram of the CMOS-retina Swiss project. This project unifies synergistic efforts of a highly interdisciplinary consortium composed by specialists in clinical ophthalmology and human psychophysics (Geneva University Hospitals, HUG), in microelectronics (Lausanne Federal Polytechnic School, EPFL) and in electrophysiology (Medical Center of the University of Geneva, CMU). During the last years, two layouts for a subretinal implant have been developed, integrated and tested (Ziegler, 2002; Ziegler et al., 2004). The mechanical procedures for the elaboration of these microchips and for its packaging into a polyimide protection film have been studied. Passive implants have been manufactured for in vitro and in vivo testing and a mathematical model of the electrode-retinal tissue contact has been established. A setup for electrophysiological recordings in isolated retina has been prepared and the characteristics for electrical pulses necessary for the stimulation of retinal neurons have been determined (Lecchi et al., 2004; Lecchi et al., 2006). Psychophysical experiments that simulate artificial vision in normal subjects have been performed to determine the fundamental design guidelines of the new device (Sommerhalder et al., 2003; Pérez Fornos et al., 2004; Sommerhalder et al., 2004; Pérez Fornos et al., 2005a). Several algorithms for the pixelization of the stimuli have been tested and compared (Pérez Fornos et al., 2005b). Recently, first inactive implant dummies have been implanted on rat eyes to test biocompatibility and to evaluate surgical techniques. 33 The abbreviations stand for the French names of the institutions. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 23 1.3.4 Alternative approaches A Japanese research group is currently working on an hybrid retinal implant (Yagi et al., 1999; Ito et al., 1999). In this model, neural cells are cultured over a microelectrode array that is attached to a photoelectric device. This approach rests on the supposition that axons can grow from cultured cells and establish functional connections with the central nervous system. It seems, however, very difficult to give a precise direction to axon growth. The latest results presented by a group at Stanford University seem to offer an alternative solution to this problem. A photovoltaic electrode array is superposed to a membrane consisting of a set of low cups with thin microtubes. In this case nerve cell processes can be effectively directed to grow in these precise patterns (Leng et al., 2002; Huie et al., 2002), and even individual electrode-neuron connections might be achieved (Wu et al., 2003), thus minimizing stimulation thresholds and providing more specific stimulation. This would result in higher resolution stimulation with lower power consumption in future devices (Mehenti et al., 2003; Huie et al., 2003; Huie et al., 2004). Another very recent approach using neurotransmitters to stimulate the surviving retinal cells has been presented (Fishman et al., 2002; Iezzi et al., 2003; Safadi et al., 2003; Fishman et al., 2004). In such a retinal prosthesis the electrode array is replaced by a set of microfluidic pumps that deliver caged neurotransmitters (Glutamate or GABA), with a resolution down to 5µm. Flexible polymer devices, measuring 1.5x1.5 mm, have been successfully implanted into the subretinal space of the rabbit (Fishman et al., 2003) and a technique for evaluating the efficacy of this type of stimulation, compared to natural visual stimulation, has been presented lately (Elfar et al., 2004). At a first glance, neurochemical stimulation of retinal cells appears to be more ‘physiologically natural’, yet, there are important issues to solve in this domain. The liberation of great amounts of glutamate, for example, is toxic for neural cells (Walraven et al., 2002; Iezzi et al., 2002). Research has been undertaken to determine the toxicological profiles of different neurotransmitter molecules (Kapi et al., 2004; Iezzi et al., 2004) and to cope with this excitotoxic effect (Walraven et al., 2003; Gasperini et al., 2003; Walraven et al., 2004). 1.3.5 Comparison of the different approaches Certain design issues to be considered are more or less challenging depending on the particular implantation site for the prosthesis. The particular problems and advantages of each approach are condensed in table 1. Cortical stimulation presents two main advantages. The first is that this approach would rehabilitate the maximum of blind patients, including those in which retinal and/or optic nerve stimulation is not possible. Second, the visual cortex is a particularly robust implantation site. Protected by the skull, it constitutes a very anatomically stable location compared to the eye34. On the other hand, several 34 As long as there is no mechanical coupling between the electrode array and the cranium (originated from the immunologic reaction of the implanted tissue), as already discussed in the section describing cortical prostheses. 24 INTRODUCTION significant disadvantages must be mentioned. The surgical complications at this level would be the most serious. In addition, such a system would bypass all peripheral visual processing. Since the visuotopic organization of the visual cortex is nonconformal (Normann et al., 2001), the electronic treatment of the stimulus will probably have to be extremely complex in order to evoke meaningful patterns at this level. The only advantage of optic nerve stimulation, compared to cortical stimulation is that the consequences of surgical complications would be less important. However, weighed against retinal stimulation, it does not present any fundamental advantage. If blindness results from diseases where retinal ganglion cells are affected, the optic nerve is also condemned to degeneration. Therefore, the patients that could be treated with this approach, essentially those suffering from retinal degenerations, would also be able to benefit from retinal implants. Furthermore, meaningful and reproducible percepts appear to be very difficult to obtain due to the particular visuotopy of the optic nerve. Retinal stimulation presents the advantage that, compared to the others, the consequences of surgical complications would be the least serious. Moreover, this particular location would benefit from most of the natural peripheral processing of the visual system. This is particularly significant in the case of subretinal stimulation, where adequate retinotopic organization could be obtained without further processing of stimulation patterns and where patients would be able to scan the environment using normal eye movements. Furthermore, electrical stimulation at this level could help restore ‘non-visual’ functions relying on luminous stimulation such as the regulation of circadian rhythms35. Alternatively, both approaches have the inconvenient that at least the retinal ganglion cell layer and the optic nerve must remain functional. Hence, only patients suffering from diseases such as RP or AMD would benefit from these devices. In addition, epiretinal stimulation will face two important issues related to the location of the implant (in front of the retina). First, the implant will be subject to fast rotation eye movements (up to 700°/s), due to which its attachment and stable positioning relative to the eye will be difficult. Second, it is not clear yet if not only nearby ganglion cell bodies will be stimulated, but also traveling axons of distant ganglion cells. This would greatly complicate the issue of visuotopic stimulation. A computational model aiming to determine precisely the neural target according to electrical stimulation parameters has been presented (Greenberg et al., 1999). Subretinal stimulation faces a different constraint, already mentioned in the previous section. Since light entering the eye does not provide enough energy to achieve adequate retinal stimulation (Zrenner et al., 1997), an external power source might be needed. Recently, a research group (Palanker et al., 35 Recently, a new photopigment, melanopsin, has been identified as the main biological transducer for the regulation of circadian rythms (Provencio et al., 2000; Reppert & Weaver, 2002; Provencio et al., 2002). This opsin is expressed in the dendrites of a special population of retinal ganglion cells, most of which project directly to the SCN (Gooley et al., 2001). Therefore, direct electrical stimulation of the inner retinal layers could have an effect on circadian regulation, provided that these particular ganglion cells are preserved from degeneration and depending on their particular respose to electric stimulation. 25 MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION Table 1. Advantages and disadvantages of the different approaches towards visual prosthesis development according to implantation site. Cortical Optic Nerve Epiretinal Subretinal Population of blind patients concerned largest retinal degenerations (RP, AMD) retinal degenerations (RP, AMD) retinal degenerations (RP, AMD) Surgical complications serious less serious least serious least serious easy easy difficult easy difficult difficult easy easy Preserves peripheral visual processing NO NO YES YES Follows eye movements NO NO NO YES Fully implantable NO NO NO YES Processing flexibility YES YES YES possible difficult difficult difficult easy Attachment (mechanical stability) Visuotopic stimulation Large scale integration 2003) has focused in solving this specific issue with novel designs of self-powered subretinal chips. In conclusion, retinal implants seem to be the most elegant and promising way to approach artificial vision. They could profit from natural processing in the still intact peripheral structures of the visual system. Surgery is less invasive than for other stimulation sites, which is an important clinical advantage. It is important to point that visual prostheses are not the only alternatives proposed to rehabilitate blindness nowadays. Scientific progress has also lead to the exploration of novel genetic and cellular therapies (see e.g. McFarland et al., 2004; Leal et al., 2005). We acknowledge such approaches, but they will not be considered since they are clearly out of the scope of this thesis. Within the current dissertation, subretinal implants are considered as the most probable model of visual prostheses, but most of the results presented will be beneficial to all artificial vision projects. 1.4 Minimum requirements for useful artificial vision Despite the enormous progress that has been made in the field, there are several fundamental questions that should still be systematically addressed. The status of research described in the previous section clearly shows that most efforts have concentrated on developing technological solutions for visual prostheses. In particular, psychophysical aspects related to artificial vision seem to have received little attention. Yet, the ultimate goal of these devices, rehabilitating blind patients, should not be forgotten. The minimum information that should be transmitted to the brain in order to restore ‘useful’ visual function should be, therefore, thoroughly investigated. 26 INTRODUCTION Figure 17. Information path of a visual prosthesis, from the stimulus to the brain. Senses function in the same way any information system does: they capture physical data, convert it into biochemical and electrical signals, process and transmit the information to higher integration centers, to finally use the input data. For replacement within the system, one must determine where it has failed and whether a stage of the system can be artificially bypassed. As described in previous sections, most of the visual prostheses being developed nowadays use electrical stimulation as the means of interaction with the visual system. All designs work in the same way. First, a sensor captures the stimulus, transforming the visual input into electrical signals. Afterwards, a processor transforms this ‘electrical image’ into patterns that should be correctly interpreted by the nervous system. A stimulator then transmits the information to the target neural tissue through a microelectrode array. Finally, the brain attempts to make sense of it all. How can we determine the minimum requirements for such a system to work? The brain will be capable to achieve useful function only if it is provided with sufficient information (see fig. 17). The first major site where information might be lost is the processor/stimulator interface. At this level visual information is split into a finite number of processing channels corresponding to the number of electrodes available in the implant. Therefore, enough information should be transmitted via this first processing stage in order to achieve useful visual function. The second major site of possible information loss is the electrode-nerve interface. The detailed characteristics of neural activation at this boundary are largely unknown at present, and will depend on the exact nature and site of activation. The handicap of low vision patients in everyday life is extremely severe (Weih et al., 2000). It can result in problems with small object recognition, specifically reading, and with spatial orientation, including whole-body mobility and visuomotor coordination. Difficulties with reading are mainly associated to disorders of the central visual field, whereas difficulties with mobility and visuomotor coordination may also result from defects in the peripheral visual field. Research in all these areas, both in normal subjects and in low vision patients, is extensive. These particular studies will be detailed in the introduction of the corresponding chapters. The present section will focus on research specifically addressing issues related to prosthetic vision. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 27 There are very few studies related to reading using a visual prosthesis. Cha and coworkers used a pixelized vision system to simulate artificial vision in normal subjects (Cha et al., 1992b). Their head-mounted experimental setup consisted of a video camera sending images to a monochrome monitor that projected to the subject’s right eye (maximum viewing angle of 1.7°). Pixelization was achieved by overlaying the monitor with opaque masks containing a variable number of square perforations (pixels). Their results show that a 25 x 25 array (625 pixels), representing four letters of text and projected on a foveal visual field of 1.7°, is sufficient to provide reading rates near 170 words/min (WPM) using scrolled text36, and near 100 WPM using fixed text37. Another research group measured reading speeds and facial recognition rates with simulated prosthetic vision in the central visual field using a head mounted video display (Dagnelie et al., 2000; Thompson et al., 2000; Humayun, 2001). Subjects used eye movements to scan the stimuli through a pixelizing grid. Several grid parameters were explored. Subjects achieved reading speeds up to 100 WPM and close to perfect face recognition. In reading, performance decreased significantly when the grid size covered less than 4 letters, when a grid density of less than 4 pixels per letter width was used, when contrast was less than 10%, or when more than 50% of the pixels were randomly turned off. The limits for facial recognition were when the face was 3 times wider than the grid, when grid density was less than 8 pixels per face width, when contrast was less than 20%, when less than 4 gray levels were used, and with more than 50% random pixel drop-out. More recently, another study on facial recognition has been presented by the same group (Thompson et al., 2003). Simulation methods were similar to their first studies, and again, the effect on performance of different grid parameters were evaluated at high (99%) and low (12.5%) contrast conditions. In both conditions, the threshold parameters allowing good performance were: a minimum grid size of 25 x 25, a maximum random pixel dropout of 30%, a minimum of 6 gray levels, and a maximum pixel spacing of 4.5 minutes of arc. The optimum range for dot (pixel) size ranged from 0.5° to 1°. Face recognition accuracy was higher in high contrast conditions. A learning effect, particularly evident in low-contrast conditions, was also revealed. Cha et al. (1992a) were the only ones to directly address whole-body mobility under conditions simulating artificial vision. Normal human volunteers had to walk through a maze including a series of obstacles, while their visual input was restricted by a pixelized vision simulator similar to the one used for their reading experiments (Cha et al., 1992b). Walking speed and number of obstacle contacts were measured as a function of pixelization, object reduction and field of view. Performance improved with large head movements, which however led to balance problems associated with an abnormal vestibulo-ocular reflex. Their results suggested that, similar to reading performance, an array of 25 x 25 pixels, projected on a foveal visual field of 1.7° but encompassing a field of view of about 30°, could provide useful mobility performance in environments not requiring a high degree of pattern recognition. 36 The line of text scrolled automatically across a 10 characters wide horizontal window, therefore no eye movements were needed for reading. 37 The text was static and subjects used their eye movements for navigation. 28 INTRODUCTION Only some qualitative experiments were carried out to explore visuomotor coordination tasks in conditions mimicking artificial vision (Humayun, 2001; Hayes et al., 2003). A head mounted video display and pixelizing software were used for their simulations. Almost all subjects were able to pour candies from one cup to another using a grid of 16 x 16 pixels and about 50% of the subjects were able to cut a sheet of paper under the same conditions. Similar to the psychophysical experiments on reading and mobility mentioned previously (Cha et al., 1992a; Cha et al., 1992b; Dagnelie et al., 2000; Thompson et al., 2000; Thompson et al., 2003), all experiments were carried out using central vision. In summary, the information contained in 625 pixels appears to be sufficient to reach close to normal reading performance and useful mobility. However, these experiments were conducted using oversimplified experimental conditions. Neither visuomotor coordination, nor mobility in large-scale environments simulating natural settings, were really studied in conditions relevant for artificial vision. None of the presented studies did really mimic artificial vision, such as provided by retinal implants, placed at well-defined and fixed retinal positions38. Furthermore, possible eccentric locations for the implant were not explored in any of the previously mentioned studies. This is particularly relevant in the context of retinal prostheses, since the anatomo-physiology of the retina does not favor a foveal implant location. Retinal prostheses are meant to treat cases involving photoreceptor loss (e.g. RP). In these cases, the target neurons for electrical stimulation are surviving cells at the inner retinal layers: bipolar and ganglion cells. These neurons are not present in the central retina. In the parafovea, these inner retinal cells are arranged in several superimposed layers that make it difficult to activate them in predictable patterns. The best sites for retinotopic activation without major distortion would therefore be located at an eccentricity of 10° and more. This mapping issue is especially important when considering retinal implants transforming incident light into stimulation currents in situ (Zrenner, 2002a; Chow et al., 2003). When an external camera is used to capture the stimuli, as done in other retinal prosthesis prototypes (Rizzo & Wyatt, 1997; Humayun et al., 2003), an image processing module including remapping routines adapted to the position of the retinal stimulator can be incorporated. In this case, a more central location of the implant could be envisioned, but only on the account of very sophisticated hardware and/or software. 1.5 Scope of this thesis It is clear that more realistic simulations of artificial vision had to be done in order to determine adequately the minimum requirements for useful artificial vision. The work presented here intends to be a methodical assessment of the minimum requirements to obtain useful artificial vision, concentrating essentially on the first site of information loss: the processing stage. Performance on a set of tasks was measured while systematically varying the amount and type of information transmitted through the processing stage. Then, we made the ‘ideal’ assumption that 38 The impact of this issue on performance and, more in particular, on the rehabilitation expectations of visual prosthesis wearers has been lately acknowledged by one of the research groups mentioned above (Dagnelie et al., 2004; Kelley et al., 2004) MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 29 no information was lost at the electrode-nerve interface. The minimum visual information critical to perform a specific function was identified through the analysis of the experimental results. The supposition that the brain can use all the information transmitted via the processing stage while evaluating the needs for basic vision allowed us, therefore, to determine the minimum requirements for useful artificial vision. This approach has already been used to study speech perception cochlear implant users (Shannon et al., 1995; Dorman & Loizou, 1997; de Balthasar et al., 1999; Loizou et al., 1999). First, the general methods, common to all experiments, will be detailed. In the following chapters, the specific issues related to each basic function will be outlined and the corresponding results will be presented. In order to complete the global assessment of minimum visual requirements for useful artificial vision, the last chapter will present an evaluation of the effects on performance of more realistic simulations considering some characteristics of the electrode-nerve interface. At this point, it is important to detail my specific contribution to this investigation. I joined the visual psychophysics research group at the Ophthalmology clinic of the HUG in April 2001. At that date, the studies aiming to determine the minimum requirements for useful reading were already on their way. More in particular, some pilot experiments on the reading task had already been completed (reading isolated letters and 4-letter words; Bagnoud et al., 2001; Sommerhalder et al., 2003). Therefore, my actual participation started with the experiments exploring full-page reading (section 3.5). The pilot experiments with 4-letter words (section 3.4) are, however, also included in this dissertation for the sake of completeness. 1.5.1 Significance The goal of this project is to determine minimum requirements to achieve useful artificial vision. What can we consider ‘useful’ vision? The research effort presented in this dissertation obviously relies on this definition. We believe that, for a retinal prosthesis to be useful to future implant wearers, it has to satisfy their major rehabilitation expectations. Based in our own clinical experience, and after extensive discussions with several associations for the blind in Switzerland, we observed that what blind patients mainly expect from these devices is to recover some kind of reading abilities. Conversely, they generally believe that they manage pretty well already in other every-day tasks. The knowledge of the minimum information that has to be transmitted to the brain to restore useful function is essential, theoretically and practically, to design visual prostheses. Some authors may argue that psychophysical studies will have only limited value until actual devices are implanted and tested (Margalit et al., 2002). The history of cochlear implant development demonstrates that this is not true, and clearly illustrates the importance of modeling studies. The first cochlear implants developed in the 60s were single-channel devices that provided modest rehabilitation to the deaf (Doyle et al., 1963). Some years later, on the basis of modeling studies, Kiang and coworkers demonstrated that multi-channel stimulation was required for high-level speech recognition (Kiang et al., 1979). Multi-channel 30 INTRODUCTION cochlear implants became commercially available at about the same time. However, single-channel cochlear implants remained in common use for more than 15 years, until it became clear that their clinical results could not match those obtained with multi-channel implants. Simulations of artificial hearing on normal subjects (Shannon et al., 1995; Dorman & Loizou, 1997; Loizou et al., 1999; Hamzavi et al., 2000) clearly demonstrated the fundamental reasons underlying these differences in performance, but came too late to prevent the unnecessary extended use of singlechannel implants. The research effort presented in this dissertation is an attempt to learn from past history and to provide this type of information to the artificial vision research community at an adequate time, with the hope of preventing large-scale use of prototype retinal implants with insufficient numbers of stimulation contacts. In the particular case of visual prostheses, suppose for example, that one can demonstrate that the perception of about N spatially distinct phosphenes, distributed in a certain way throughout the visual field, is necessary to code the information needed to perform a given visual function. The value of systems that do not provide this capability will be limited. It appears therefore imperative to have such knowledge before proceeding to human implantation trials. The experimental approach that will be presented here is designed to mimic visual perceptions provided by retinal implants. While these prostheses represent one of the most elegant and promising designs to approach artificial vision, the results from the proposed studies will be of general interest to all research groups working on artificial vision since they focus on the minimum visual information necessary to achieve a particular task (which is fundamentally limited by the task itself, not by the means of stimulation). Furthermore, this investigation focuses on conditions mimicking problems encountered in every-day life. Using simulations of artificial vision on normal subjects is meaningful for addressing pertinent questions. On one hand, blind patients using visual prostheses are not really available at this time. On the other hand, by using normal observers with a simulated impairment one can look at the effect of a single parameter without biasing its effect with that of others. The use of simulations makes it easy to repeat experiments within a single subject and a given parameter can be varied over a full range. These advantages of simulations have been recognized by others and used to address specific questions (Pelli, 1987; Cornelissen & Van den Dobbelsteen, 1999). The results presented in this dissertation will provide essential indications for the design of future visual prostheses and will help judge the level of visual rehabilitation that could be provided with such devices. Hopefully, this work will benefit academic institutions, hospitals and industry in Switzerland, and particularly blind patients all over the world. 2 General Methods Too much sanity may be madness. And maddest of all, to see life as it is and not as it should be! Miguel de Cervantes Saavedra (1547 - 1616) 2.1 Basic principles of the simulation methodologies Our simulations attempt to mimic percepts elicited by a subretinal implant transforming incident light into stimulation currents in situ: • Retinal prostheses will be implanted at a fixed and most probably eccentric location of the retina. They will not cover the whole surface of the retina. Visual perception will therefore be restricted to this part of the visual field. • The information conveyed in the ‘images’ perceived by implant wearers will be of reduced (low) resolution, due to the limited number of stimulation contacts. Figure 18. Illustration of the simulation procedure. Due to the limitations imposed by a subretinal implant, the environment will only be visible through a small restricted viewing window (equivalent to implant size), stabilized at a particular region of the visual field (implant location), and of reduced resolution (due to the limited contacts in the implant). For simulation purposes, this means that the environment should only be visible through a low resolution, small, and fixed-size viewing window that will always appear at the same position relative to the subject’s center of fixation, thus following his/her eye movements. This process is illustrated in figure 18. 31 32 GENERAL METHODS This chapter will describe in detail how these simulations were achieved. First, the image processing techniques and algorithms used will be explained. Later on, the experimental setup will be described. The particular issues related to the different tasks will be presented in the specific methods section of the corresponding chapter. 2.2 Image processing a) b) All the images used as stimuli were 8-bit bitmap (BMP) grayscale images. Information content reduction was performed through basic image processing techniques that decomposed the original image into a given number of pixels (pixelization). The pixelization methods will be described hereafter. The particular algorithm used in each experiment will be Figure 19. Pixelization algorithms used: a) square specified in the corresponding pixelization using a block-averaging algorithm; b) gaussian chapter. The stimulus pixel pixelization using a 2D gaussian function. geometry depended on the algorithm used: square or gaussian pixelization. Either of these pixelization methods could be presented to the subject in their off-line or real-time versions. 2.2.1 Square pixelization Square pixelization was performed using a simple block-averaging algorithm. This technique consists in merging N x N pixel arrays of the original image into single pixels with uniform luminance values corresponding to the mean grayscale levels of the original N x N matrices (see fig. 19a), as defined in equation 1: (µ y + N ) 2 (1) A(µ x , µ y ) = ∑ (µ x + N ) 2 ∑ i(x , y ) i j j = ( µ x − N )i = ( µ x − N ) 2 2 2 N where A(µx,µy) denotes the luminance value (grayscale level) of the stimulus pixel with center coordinates µx and µy. i(xi,yj) represents the luminance value of the corresponding pixels in the original image. N stands for the number of vertical and horizontal pixels in the original image that are merged together in the pixelized image. Figure 20 displays sample stimuli processed at different pixelization levels (N values). 33 MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) b) c) Figure 20. Text windows processed using square pixelization containing: a) 28000 pixels (N = 1); b) 572 pixels (N = 7); and c) 231 pixels (N= 11). 2.2.2 Gaussian pixelization Figure 21. Gaussian pixelization. A 2D gaussian function is applied to each pixel. Block averaging was used to determine the peak of the gaussian function. σ represents the standard deviation used in the gaussian function; µx and µy are the center coordinates of the stimulus pixel to which the function is applied. Gaussian pixelization consisted in applying a 2D gaussian function to each pixel of the pixelized image (see fig. 19b), as determined in equation 2: (2) I (x, y ) = A(µ x , µ y )⋅ G( x, y ) where I(x,y) denotes the luminance value (grayscale level) at coordinate (x,y) in the pixelized image. A(µx,µy) stands for the mean grayscale level of the original N x N matrix constituting the stimulus image pixel with center coordinates µx and µy (see square pixelization). G(x,y) symbolizes the 2D gaussian function defined in equation 3: (3) G ( x, y ) = − 1 2πσ 2 e ( x − µ x )2 + ( y − µ y )2 2σ 2 where σ represents the standard deviation of the particular gaussian function around its horizontal and vertical center coordinates µx and µy. In our case, σ (the gaussian 34 GENERAL METHODS width) determines the amount of overlap of each pixel onto its neighbors and the center coordinates for each pixel correspond to its horizontal and vertical means (see fig. 21). Figure 22 shows gaussian pixelized stimuli for several gaussian widths σ. a) b) c) Figure 22. Pixelization with various gaussian widths σ (pixel overlapping). Gaussian pixelizations with: (a) σ = 0.071 pixels (no overlap), (b) σ = 0.286 pixels (medium overlap), and (c) σ = 1.143 pixels (large overlap). 2.2.3 Off-line/Real-time pixelization Image stimuli could be processed either off-line or online (real-time pixelization). In the first case, the original image was pixelized in the experiment preparation phase. Then, during the experiments, this pre-pixelized image was presented on the screen and masked by a gray overlay. The image could be explored through a transparent window that moved according to the subject’s gaze position. Hence, the luminosity of all pixels in the stimulus image was fixed, and the subject scanned portions of this ‘frozen’ image. For real-time pixelization, only a small part of the original image was pixelized online, during the experiment. The part of the image that was pixelized corresponded to the content of the viewing window, which changed as the viewing window moved across the stimulation screen. Therefore, the luminosity level of each pixel in the stimulus image changed according to instantaneous gaze position. 2.3 Experimental setup The experimental setup was based on a commercial high-speed video based gaze tracking system, the SMI EyeLink I (SensoMotoric Instruments GmbH, Teltow/Berlin, Germany). The specifications of this system, as provided by the manufacturer, are presented in appendix A. Briefly, this system consists in a lightweight headband and 2 personal computers: the operator PC and the subject PC. A schematic view of the EyeLink headband is presented in figure 23a. It is fixed by adjusting two clamps (top and rear). Two miniature infrared (IR) cameras track both eyes simultaneously at a 250Hz frame rate. Binocular or monocular eye tracking is possible since each eye is monitored independently. A third camera that tracks 4 IR markers attached to the stimulation screen is used for head movement compensation. A picture of a subject wearing the headband is shown in figure 23b. a) b) MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 35 Figure 23. The EyeLink headband. a) Schematic view of the helmet highlighting its main components. Image downloaded from the EyeLink product website39 (SR Research©). b) Photograph of one of the subjects wearing the headband. A dedicated image-processing card (full-length ISA card) is installed in the operator PC. This card uses the information transmitted by the three headband cameras for online gaze position computation. The pupil is detected as the darkest surface in the eye. Its center is tracked and calculated using a centroid calculation algorithm (Van der Geest & Frens, 2002; Cornelissen et al., 2002) with a theoretical noise-limited resolution of 0.01° and less than 3°/s velocity noise (manufacturer’s specifications). Heuristic filtering is available for single-sample artifact removal (Stampe, 1993). Gaze position coordinates on the stimulation screen are obtained by combining eye and head position measurements (gaze-dependent display). The system’s 9-point calibration procedure has been described by Stampe (1993). Mapping of eye coordinates into a head-referenced coordinate system is performed with a quadratic (monocular eye-tracking mode) or biquadratic (binocular tracking mode) function (Stampe, 1993; Cornelissen et al., 2002). A MS-DOS program (EyeLink Operator PC Software version 2.01) running on the operator PC communicates with the ISA card. Eye position data may be recorded to a file and/or transmitted in real-time to the subject PC via an Ethernet link. If required, data may also be output as analog voltage signals. The subject PC is used for experiment flow and control and is directly connected to the stimulation screen. This computer runs the main experiment program, executing all stimuli capture, processing, and display algorithms. Hence, the computing power needed for this piece of equipment varies according to the complexity of the experiment. According to specifications, gaze position data transferred via Ethernet from the operator PC arrives with a delay (after the actual physical movement) of 6 ms when heuristic filtering is disabled and of 10 ms when heuristic filtering is enabled. Interfacing with the eye tracking system is achieved through the EyeLink Windows API library (version 24.06.98), provided by the manufacturer. Figure 24 displays a schematic view of the typical EyeLink I system configuration. This system was chosen because its high frame rate (250Hz) allowed for the detection of very rapid eye movements (i.e. reflexive saccades). In a recent study by 39 http://www.eyelinkinfo.com/mount_system_config.php 36 GENERAL METHODS Figure 24. Typical configuration of the SMI EyeLink I system. Van der Geest & Frens (2002), the EyeLink system (video-based) was compared to another eye movement measurement technique: scleral search coils. Results demonstrated that the outputs of both systems were highly correlated, and that the only disadvantage of video-oculography was that its relatively low sample rate led to noisy estimates of small eye movements. Other research groups have already reported using the EyeLink I system in different experimental paradigms (Tant et al., 2002; Huk et al., 2002; Li et al., 2002). In our simulations, the subjects used their own eye movements to scan the stimulation screen, which was visible only through a restricted viewing window of a determined size (fig. 25). Gaze position (calculated by the eye tracking system) was used to move the target stimuli (viewing window containing the processed images) on the stimulation screen. As a result, images could be steadily projected onto a defined (central or eccentric) area of the retina. A pilot study conducted in our laboratory demonstrated that this experimental setup was Figure 25. The stimulation screen as viewed by the subject. adequate for accurately The environment was only visible through a defined viewing stabilizing targets in the visual window moving on the screen according to the direction of field by online compensation gaze. of the gaze position (Bagnoud MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 37 et al., 2001). The remaining area of the screen was filled with a gray value corresponding to approximately the mean illumination of the original image. Depending on the experiment, the viewing window could be stabilized either in central vision or at determined eccentricities40. Eccentric stimuli were always presented in the lower visual field since it has been demonstrated that human subjects generally perform tasks better when stimuli are presented in this area (Previc, 1990; Chen et al., 2004). Furthermore, low vision patients with central visual field defects usually tend to place the field defect above the new area used for fixation (Fletcher & Schuchard, 1997). In addition, for the reading task this choice offered an additional practical advantage: the retinal eccentricity of the target varies less when it is projected to the lower or upper visual field, than when projected to the left or the right visual field. Off-line square pixelization was carried out with the mosaic-pixelizing filter included in Adobe Photoshop® 5.5 (Adobe Systems Incorporated, San Jose, CA, USA). All the remaining algorithms and experiment programming was done under Microsoft Visual C++ 6.0 SP5 (Microsoft, Redmond, WA, USA) and the latest Platform SDK library (Windows API, GDI, Direct X) available at the time the experiment began. The eye cameras were positioned so that the pupil was clearly visible and well defined at any gaze position. At the beginning of each experimental session a standard 9-point calibration of the eyetracker was performed. The calibration was checked regularly for possible drifts or artefactual movements, and if necessary, slightly corrected to insure an exact control of the viewing Figure 26. The stationary system (typical configuration of the window position during SMI Eyelink I system. In the picture shown, a subject is wearing the eye tracking system during one of the Reading each experimental session. experiments (Chapter 3). For the experiments, subjects wore the head mounted SMI eye tracking system in one of two configurations: a stationary or a mobile system. 40 The point of reference for the stimulus eccentricity was the center of the viewing window. 38 GENERAL METHODS 2.3.1 Stationary system The stationary system was used to explore the reading task. In this setup, the SMI EyeLink I eye tracker was used in its standard configuration (see fig. 25). The operator PC was a Compaq Deskpro EP (Celeron-400). The subjects were comfortably seated facing the stimulation screen, a 22” high refresh rate monitor (Elsa ECOMO 22H99; see fig. 26) connected to the subject PC (P3-450 equipped with a Matrox G200 graphics card). Subjects were requested not to move during the experimental sessions. The stimulation screen was set to a resolution of 800 x 600 pixels and a refresh rate of 120 Hz. Eye-to-screen distance was of 57 cm41; at this distance, the 40 cm x 30 cm surface of the screen subtends a visual field of 40° x 30°, 1° corresponding to 20 screen pixels (at the screen resolution chosen). 2.3.2 Mobile system Since it is impossible to simulate mobility and visuomotor coordination tasks with our stationary setup (while sitting in front of a computer screen), a similar, but mobile setup based on the same EyeLink system was developed (fig. 27). a) b) Figure 27. The mobile system. The stationary setup was modified in order to allow for mobility. A rapid LCD display was fixed in front of the subject’s eyes and a webcam mounted: a) on the side (for visuomotor coordination tasks) or b) on the top of the system (for mobility tasks) was used to capture images from the environment. A small and rapid LCD display (NEC NL6448BC26-01), measuring 170.09 mm x 128.2 mm, was fixed in front of the subject’s eyes, at an eye-to-screen distance of 23 cm. The LCD display subtended, thus, the same visual field of 40° x 30°. All the electronics needed for the LCD display were attached as counterweight in the back of the headband. A cover of black cloth prevented the subject from seeing anything else than the screen, and a bite-bar guaranteed the necessary rigidity for reliable eye tracking and stimulus stabilization. A small webcam (Philips ToUCam Pro) was used to capture environment images at a 30 Hz frame rate and was connected directly to the subject PC. The stimulation screen was set to a resolution of 640 x 480 pixels (largest image frame size provided by the webcam) and a refresh rate of 75 Hz 41 The eye position being aligned to the table border it was easy for the examiner to control whether the eye to screen distance was maintained stable. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 39 (maximum allowed by the LCD display). In this configuration, 1° of visual angle corresponded, thus, to 16 screen pixels. The standard image capture angle of the webcam was of 33° horizontally and 24.75° vertically. For visuomotor coordination experiments, the webcam was mounted on the side of the system, at eye-height (fig. 27a). For mobility experiments, a custom objective allowing a larger image capture angle (66° x 49.5°) was adapted to the webcam, which was mounted on the top of the system (fig. 27b). Most of the material used for these modifications was aluminum so that the system was kept as light as possible. A Dell Latitude C840 (P4-M, 2.2 GHz) notebook equipped with a nVidia GeForce4 440 Go 64-bit graphics card, running Windows XP SP1, was used as the subject PC in order to increase mobility and computing power. Both, the operator and the subject PC’s were installed on a mobile rack and connected with an approximately 10 m long cable to the headband-mounted items. 2.4 Data analysis and statistics The majority of the data analysis methods used will be the same throughout this document, irrespective of the task being explored. Eventual learning effects were explored by fitting the data to a non-linear exponential function (whenever the data allowed it), in order to average session-to-session variability. For example, learning curves were established on the basis of performance evolution versus time. Curve stabilization was determined on the basis of the time constant42 of the corresponding exponential function used (3τ). Statistical effects on performance were determined using linear correlation (Pearson’s correlation) or standard (paired) t tests with a significance level of 0.05. 2.4.1 Percentage scores When analyzing performance data from the different tasks, results will be often expressed as percentage (%) correct scores. Nonetheless, such proportional scales are not adequate for statistical analysis since they fit a binomial probability distribution, where variance is not correlated with the mean. In other words, data is not normally distributed around the mean and scale values are not linear in relation to test variability. An adequate scale transformation must be, thus, applied to the data in order to obtain statistically valid results. The arcsine or angular transformation (AT), defined in equation 6 (Thornton & Raffin, 1978), is generally known to be the most appropriate for proportional values as it spreads data along both ends of the scale (0% and 100%) while it compresses the middle. In this equation, X stands for the number of samples being positive or negative (proportion or percentage score) and N designates the total number of samples (number of samples equivalent to 100% in the case of percentage scores). 42 The time constant (τ) of an exponential function corresponds to the time required for the function to decrease by a factor of 1/e (approximately 0.368). The stabilization time of an exponential function is generally estimated as 3τ. 40 GENERAL METHODS (6) AT = arcsin X / ( N + 1) ) + arcsin ( X + 1) / (N + 1)) However, such a transformation has the significant drawback of generating values that are very different to the original scale and are, hence, difficult to interpret intuitively. For example, the arscine-transformed equivalent of a 0% score is approximately 0.10, of 50% it is about 1.57, and of 100% it is around 3.04. This shortcoming can be surpassed with the rationalized arcsine transform (RAT) defined in equation 7 (Studebaker, 1985). The values generated by this transform, the socalled “rationalized arcsine units” (RAU), have the advantage of being numerically close to the original percentage range, while they retain all of the desirable properties of the angular transform. For example, for a sample size of 50, a score of 0% corresponds to -16.5 RAU, 50% to 50 RAU and 100% to 116.5 RAU. (7) RAU = 46.47324337 AT − 23 All percentage results will be therefore transformed to RAU units prior to any statistical analysis. For better clarity, however, an approximate %-correct scale will always be shown on the right ordinates of the graphs and will also be used in the text. 2.5 Ethical considerations All experiments were conducted according to the ethical recommendations of the Declaration of Helsinki, and were approved by local ethical authorities43. 43 The «Comité d’Etique de la Recherche sur l’Etre Humain» (CEREH) of the HUG. 3 Experiments on Reading I took a speed-reading course and read ‘War and Peace’ in twenty minutes. It involves Russia. Woody Allen (1935- ) 3.1 Foreword Reading is an extremely important activity in our modern societies. It is strongly associated with vision-related estimates of quality of life, and represents one of the main goals of low vision patients seeking rehabilitation (Elliott et al., 1997; Wolffsohn & Cochrane, 1998; McClure et al., 2000; Hazel et al., 2000; Margrain, 2000). The thorough analysis of this task is, thus, fundamental for the evaluation of the rehabilitation prospects of visual prostheses to blind patients. 3.2 Introduction Reading is a complex task that requires the conjunction of several oculomotor, cognitive, and visual processes (Reichle et al., 2003). Understanding its fundamentals has received plenty of attention. The low vision research group at the University of Minnesota has systematically studied various aspects of reading in normal subjects and low vision patients. For normal subjects (Legge et al., 1985a), they reported that maximum reading rates are achieved for characters subtending 0.3° to 2° of visual angle; that reading rate increases with field size, but only up to 4 characters, independently of character size; and that, when the text is pixelized, reading rates increase with pixel density, but only up to a critical density that depends on character size. Reading was also found to be very tolerant to either luminance or color contrast reductions (Legge & Rubin, 1986; Legge et al., 1987; Legge et al., 1990). At very low (< 10%) luminance contrast however, reading speed drops due to prolonged fixation times and to an increased number of saccades, presumably related to a reduced visual span (Legge et al., 1997). When testing the effect of print size on reading speed in eccentric vision, they found that the use of larger characters improved peripheral reading to some extent, up to a critical print size (Chung et al., 1998). However, maximum reading speed decreased from about 808 WPM (words/min) for foveal vision to about 135 WPM for eccentric vision at 20° eccentricity44. Thus, print size was not the only factor limiting maximum reading speed in normal eccentric vision. These findings contradict the scaling hypothesis (Toet & Levi, 1992; Latham & Whitaker, 1996), which states that eccentric reading can match foveal reading only by increasing print size. 44 Such high reading rates were achieved by using rapid serial visual presentation (RSVP). 41 42 EXPERIMENTS ON READING In low-vision patients, reading is similar to normal reading in several aspects (Legge et al., 1985b; Rubin & Legge, 1989; Legge et al., 1990; Legge et al., 1997), but difficult to predict on the basis of routine clinical evaluation (Legge et al., 1992). As a rule however, it can be stated that low-vision patients with central field defects achieve lower reading rates than those with preserved central fields (Legge et al., 1985b; Rubin & Legge, 1989). Reading in every-day life often requires certain page navigation abilities. Page navigation not only implies the stabilization of gaze on a particular point of interest, but also rather accurate oculomotor control. Small successive saccades should be performed towards each word in the lines of text, and larger saccades are required to jump from the end of one line to the beginning of the next. In previous literature, page navigation has essentially been studied in connection with the use of special field of view magnifiers, intended as reading aids for low vision patients. Beckmann & Legge (1996) measured reading rates of normal and low vision subjects in two conditions: with horizontally drifting text requiring no page navigation and with a closed-circuit television magnifier (CCTV) requiring manual page navigation. Manual page navigation resulted in significantly lower reading rates. This effect was more pronounced on normal subjects than on low vision patients, suggesting that overall reading performance was reduced in these patients essentially because of other visual factors, and not because of navigational factors. A second comparative study of the same research group, including RSVP text presentation and manual (mousecontrolled) page navigation, confirmed their previous findings (Harland et al., 1998). The use of RSVP and drifting text presentation resulted in better reading performance than the use of CCTV or manual navigation. Interestingly, they did not observe significant differences in reading rates across the four methods of text presentation in a group of patients with central field loss (for subjects who were forced to use eccentric fixation for reading). On one hand, full-page reading might be expected to be easier than deciphering isolated words, because subjects can make use of context information to facilitate reading. We are better at reading meaningful sentences than random words (Latham & Whitaker, 1996; Fine & Peli, 1996). The benefits of context are however controversial when it comes to peripheral vision. It has been suggested that readers with central field loss would be less efficient in using context to facilitate reading (Baldasare & Watson, 1986), but this hypothesis is contradicted by other studies. For example, Fine & Peli (1996) compared reading rates for meaningful sentences to reading rates for random words for normally sighted subjects and for subjects with central field loss, and found that speed gains due to context were present and equivalent for both groups of subjects when using RSVP and scrolled text presentation. On the other hand, full-page reading can also be expected to be more difficult than deciphering isolated words, because successful reading of several lines of text requires page navigation abilities (accurate oculomotor control). This can be difficult to achieve with a restricted and stabilized viewing window, especially with eccentric retinal locations. In humans, selective attention is mainly focused around the fovea, the retinal area providing the highest spatial resolution. The oculomotor system is MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 43 constructed to essentially subserve foveal function by directing and stabilizing images of interest to that retinal location. When the fovea is lost as a result of disease, affected subjects strive to use optimally spared retinal areas as a replacement. Adaptation to this viewing condition might involve several processes. Spared retinal areas with best visual acuity and/or appropriate visual field (‘visual span’) should be identified. Such eccentric retinal locations are commonly known as “preferred retinal loci” or PRL (Von Noorden & Mackensen, 1962; Cummings et al., 1985). Selective attention must be transferred to these eccentrically located PRL (Altpeter et al., 2000). In addition, oculomotor control mechanisms should be reorganized to allow shifting images of interest directly to the PRL (Heinen & Skavenski, 1992). The development of eccentric fixation seems to appear prior to the ability to perform saccades shifting the image of interest onto that new fixation area. An experimental study where bilateral foveal lesions were performed in three adult monkeys showed that while both fixation and saccadic mechanisms may adapt to foveal loss, saccadic adaptation requires a much lengthier process (Heinen & Skavenski, 1992). In that experiment, eccentric fixation occurred already one day following the lesion, and new PRL stabilized within two days. In contrast, numerous reflexive saccades inappropriately projecting visual stimuli onto the damaged fovea were still observed the first days after lesion. Saccades gradually adapted to reference the newly developed PRL over a period that lasted several weeks. Two months following lesions, two of the three animals were able to generate saccades bringing the PRL directly or close to the target image. This distinction between the development of eccentric fixation and the adaptation of eccentric (non-foveating) saccades suggests that oculomotor adaptation to peripheral viewing relies on multiple mechanisms. 3.2.1 Reading in the context of artificial vision The studies cited above (as well as many others) have led to the identification of a series of important parameters that are critical for reading in normal and low vision subjects. To our knowledge, however, there are only a limited number of studies, which specifically address visual prosthesis development issues. These have already been introduced. Briefly, Cha et al. (1992b) used a pixelized vision system to simulate artificial vision in normal subjects. Their results showed that a 25 x 25 array of pixels representing four letters of text projected on a foveal visual field of 1.7° is sufficient to provide reading rates near 170 WPM using scrolled text, and near 100 WPM using fixed text. Another group at the John Hopkins University of Baltimore conducted experiments on the properties of pixelized vision (Dagnelie et al., 2000; Thompson et al., 2000; Thompson et al., 2003). Several parameters were explored. Tested individuals achieved reading speeds up to 100 WPM, which dropped off when the pixelizing grid was smaller than 4 letters, with grid densities lower than 4 pixels/letter width, or when more than 50% of the pixels were randomly shut off. An 44 EXPERIMENTS ON READING eccentric implantation site and the fact that a retinal implant would stimulate a fixed area of the retina have not been fully taken into consideration yet45. It is important to investigate the effect of stimulus eccentricity on performance, because, as already exposed in Chapter 1, the anatomo-physiology of the retina does not favor a foveal location for retinal prostheses (see e.g. Sjöstrand et al., 1999a). The best sites, potentially preserving retinotopic activation without major distortion, are located beyond 10° eccentricity. Consequently, the vision of future users of retinal prosthesis will probably be restricted to small peripheral areas of their visual field. However, due to the decreasing gradient of visual acuity throughout the retina and to the cortical magnification factor, our ability to identify objects in the periphery is poor. Especially reading words of several letters is very difficult due to contour interaction. This phenomenon is generally known as the “crowding effect” (Toet & Levi, 1992). The first aim of the work presented in this chapter was to assess reading performance with a system projecting stimuli onto defined, stabilized areas of the visual field. Four letters of text visible at glance is about the minimum lettersequence allowing normal or close to normal reading speeds46 (Legge et al., 1985a). Therefore, in a set of pilot experiments, we explored the basic information requirements for the reading task using isolated 4-letter words. First, we studied the influence of stimulus information content (pixelization level), stimulus eccentricity and stimulus size on reading performance for isolated 4-letter words. Second, we explored whether low eccentric reading performances can be significantly improved by training. Obviously, these first experiments did not require page navigation during reading. It is difficult to predict how future retinal prosthesis wearers would cope with the page navigation problem. Neither horizontally drifting text nor RSVP do realistically mimic text reading using retinal implants, since both methods are expressively intended to minimize eye movements. Mouse-controlled navigation and CCTV reading are both quite unnatural conditions, because they rely on manual page navigation. The main objective of this investigation was, therefore, to address the issue of fullpage reading in conditions mimicking artificial vision as provided by a retinal implant, taking the page navigation problem into account. We conducted two successive experiments. In experiment 1, subjects were asked to read pixelized fullpage texts using a viewing window stabilized on the fovea. In experiment 2, subjects were asked to perform the same task, but using a viewing window stabilized at 15° eccentricity. 45 The research group at the John Hopkins University has recently begun using image stabilization on the retina and acknowledged that it has a significant effect on reading performance (Kelley et al., 2004). 46 Maximal reading speeds would be favored with viewing windows containing a higher number of characters. However, working in the field of low vision, we considered the number of 4 letters as an adequate minimum value to obtain reading speeds, which may not be maximal, but are close to normal. This issue will be revisited in the discussion section of this chapter. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 45 The results presented in this chapter also offer a unique opportunity to study the overall process through which subjects adapt to eccentric viewing. Eye movements recorded during the experiments were also analyzed with the purpose of better defining the processes of oculomotor adaptation to eccentric reading. 3.3 Specific methods for the reading experiments 3.3.1 Subjects Subjects were recruited from the staff of the Ophthalmology Clinic of the Geneva University Hospitals. Their age ranged from 25 to 47 years. All had normal or best corrected visual acuity of 20/20 on the tested eye and a normal ophthalmologic status. All of them were fluent French speakers and were familiar with the purpose of this study. 3.3.2 Experimental setup To simulate visual percepts produced by a retinal implant, images were projected on a defined and stabilized retinal area. The details of the simulation procedures have already been described in the General Methods Chapter. For all reading experiments, the apparatus used corresponded to the stationary setup. The imageprocessing algorithm used was off-line square pixelization. Subjects were comfortably seated at 57 cm of the screen (see fig. 26). At the beginning of each run, eye-to screen-distance was checked and a standard 9-point calibration was performed. Subjects were requested not to move during the session. The actual experimental sequence started afterwards. Gaze position was used to move the viewing window containing the target stimuli (BMP images) on the stimulation screen (see fig. 28). Images could thus be steadily projected onto a defined (central or eccentric) area of the retina, the reference point for eccentricity being the center of the viewing window. Eccentric stimuli were always Figure 28. The stimulation screen as viewed by the subject. The viewing window, containing fragments of pixelized text, moves on the screen according to the direction of gaze and with a certain offset (in this case, 15° of eccentricity). The background of the remaining screen area was kept in a gray color corresponding to the mean luminosity of the target stimuli (4-letter words of full-page texts). 46 EXPERIMENTS ON READING presented in the lower visual field (please refer to Chapter 2 for more details). 3.4 Pilot experiment: Reading of isolated 4-letter words As already mentioned in section 1.5, these pilot experiments had already been completed when I joined the project. Nevertheless, these experiments have been included in this dissertation to show a complete picture of the minimum requirements for useful reading. In addition, these results are required to fully understand some of the chief main theoretical foundations for the main experiments presented in this chapter: those exploring full-page reading. 3.4.1 Stimuli Stimuli were presented in rectangular white areas (viewing windows) filled with black 4-letter words of common French language (including accented characters and capital letters for proper names). The largest possible Arial font (Helvetica) style was chosen because it is commonly used and has proved enabling good reading in low vision subjects (Buultjens et al., 1999). The stimuli used for the experiments were pre-processed BMP images. Figure 29 shows an example of one of the stimuli words processed at different pixelizations. maximum screen resolution 140 pixels 875 pixels 286 pixels 83 pixels Figure 29. The 4-letter word “rang” illustrating the five degrees of pixelization used in the experiment. For each run, a block of 50 words, randomly chosen among a library of 500 common French 4-letter words, was presented. The subject had to say the word he/she recognized for each item of the run. The response (right or wrong47) was entered by the examiner into the operator PC and stored for further analysis. After each word presentation, the calibration was checked for possible drifts, and eventually slightly corrected, to insure an exact control of the position of the target image during the entire experiment. 47 We were strict when attributing these scores. Words had to be perfectly recognized (gender and number mistakes were considered as complete errors) to be considered as correctly read. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 47 3.4.2 Acute experiments with 4-letter words Reading performance was assessed versus a number of variables, each being an important parameter of prosthetic vision: 1) Stimulus size. Two viewing windows were investigated. First, a viewing window that subtended a visual field of 20° x 7°, which allowed the use of a print size greater than the critical print size needed for optimal reading performance at an eccentricity of 20° (Chung et al., 1998). The height of a small letter ‘x’ of the Arial font size used for this large viewing window corresponded to a visual angle of 3.6°. Second, a viewing window subtending 10° x 3.5°, which corresponded to a surgically manageable, realistic retinal prosthesis (3 x 1 mm2 on the retina). The height of a small letter ‘x’ of the Arial font size used for this small viewing window corresponded to a visual angle of 1.8°. 2) Stimulus pixelization (i.e. number of pixels in the viewing window). Five degrees of pixelization were used (see fig. 29): maximum screen resolution48, 875, 286, 140, and 83 pixels. At maximum screen resolution, the large viewing window enclosed 4 times more pixels than the small viewing window. Otherwise, tests were performed at equal pixel resolution for both viewing window sizes. Note that using the same number of pixels on both viewing windows implied that pixels were 4 times larger on the larger (20° x 7°) viewing window. 3) Stimulus eccentricity. Five different eccentricities were tested: 0°, 5°, 10°, 15°, and 20° in the lower visual field. 3.4.2.1 Experimental protocol Five subjects participated in this experiment, and all tests were conducted monocularly. Each subject performed one run in each condition. Testing always started at the lowest eccentricity using maximum screen resolution first, then 875 pixels, 286 pixels, 140 pixels, and finally 83 pixels. The same procedure was repeated using the next eccentricity. Possible global learning effects would therefore favor performance at low pixelization levels and at high eccentricities. Word presentation duration was of 3 s. When stimuli were presented in eccentric vision, a fixation aid (a red filament crossing the screen) was installed to make it easier for the inexperienced subject to keep the target on screen. 3.4.2.2 Performance with the 20° x 7° viewing window Figure 30 presents mean reading performance versus pixelization level for the large viewing window, at various eccentricities. In central vision, reading 48 Expressed in x by y terms these pixelizations result in: maximum screen resolution = 400 x 140 pixels for the larger viewing window and 200 x 70 pixels for the smaller viewing window. 48 EXPERIMENTS ON READING performance of 4-letter words was close to perfect (over 90% correct) for pixelizations down to 286 pixels. For pixelizations below that value, reading performance dropped abruptly. This result indicates that approximately 300 pixels are necessary to transmit the relevant information for reading 4-letter words. In peripheral vision, maximum reading performance decreased with growing eccentricity. At an eccentricity of 10°, almost perfect reading Figure 30. 4-letter word reading performance versus number of pixels in a 20° x 7° stabilized viewing window. (> 90% correct) was still Mean reading scores in RAU ± SEM (left scale) and in % possible at high pixel (right scale) for 5 normal subjects at 5 eccentricities in the resolutions. At 15° and 20° lower visual field. eccentricities, perfect reading was never achieved (not even with high pixel resolutions). Maximum reading performance was limited to values of 88% and 63% correctly read words, respectively, in these cases. 3.4.2.3 Performance with the 10° x 3.5° viewing window Figure 31 presents mean reading performance versus pixelization level for the small viewing window, at various eccentricities. In central vision, results observed for the small viewing window were very similar to those obtained with the large window. Reading performance of 4-letter words was also perfect (> 90% correct) for pixelizations down to 286 pixels and dropped dramatically afterwards. The same limiting criterion of about 300 pixels was, thus, found to transmit the relevant information. In eccentric Figure 31. 4-letter word reading performance versus vision, the decrease in number of pixels in a 10° x 3.5° stabilized viewing window. maximum reading Mean reading scores in RAU ± SEM (left scale) and in % (right scale) for 5 normal subjects at 5 eccentricities in the performance with growing lower visual field. eccentricity was more MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 49 pronounced than that observed with the 20° x 7° viewing window: at eccentricities of 10°, 15° and 20°, maximum reading performance was limited to values of 89%, 57%, and 30% correct, respectively. 3.4.2.4 Normalized data in both viewing windows The raw observations presented in the two preceding figures demonstrate that both pixel resolution and eccentricity of the stimuli affected reading performance of 4-letter words. The data were normalized to the values obtained at maximum screen resolution in order to better compare the effect of pixelization at different eccentricities (fig. 32). These normalized data demonstrate that pixelization affected reading performance quite similarly at all eccentricities and on both viewing windows. This result is consistent with the fact that pixelization directly influences the information content of the source image. Conversely, stimulus eccentricity seemed to affect the way this source information was processed by the visual system, limiting maximum reading performance. a) b) Figure 32. Normalized reading performances for 4-letter words versus number of pixels in a stabilized viewing window of a) 20°x 7° and b) 10° x 3.5°. Mean normalized reading scores ± SEM for 5 normal subjects at 5 eccentricities in the lower visual field. Data was normalized to mean reading performance values at maximum screen resolution. 3.4.2.5 Single letter recognition versus 4-letter word reading At eccentricities beyond 10°, most subjects reported having problems recognizing letters in the middle of the words. One of the underlying reasons for poor reading performances might thus be the “crowding effect” (Tychsen, 1992). An additional experiment, using isolated letter stimuli instead of 4-letter words, was designed to verify this hypothesis. Briefly, isolated single letters of the same font type and size as used for 4-letter words were created for the small viewing window. The letter was 50 EXPERIMENTS ON READING presented in the center of the viewing window, which contained the same number of pixels than in the word experiments. Blocks of 50 letters were chosen among the French alphabet according to their frequency of use in our pool of 500 words. These letters were randomly presented to five new subjects. The results of this additional experiment are summarized in figure 33. Up to an eccentricity of 15°, Figure 33. Isolated letter recognition performance versus isolated letter recognition was number of pixels in the 10° x 3.5° stabilized viewing window. Mean letter recognition scores in RAU ± SEM (left scale) and almost independent of in % (right scale) for 5 normal subjects at 5 eccentricities in eccentricity. At an eccentricity the lower visual field. of 20°, maximum letter recognition was still about 90% correct for high pixelizations. Figure 34. Reading performance versus eccentricity for 286pixel resolution stimuli in a 10° x 3.5° stabilized viewing window. Isolated letter recognition (red plot) is compared to 4-letter word reading (blue plot). Mean reading scores in RAU ± SEM (left scale) and in % (right scale) for 5 normal subjects. A probabilistic estimate to recognize 4-letters in sequence is also plotted for comparison (green plot). 49 Figure 34 compares reading performance of isolated letters to that of 4letter words at 286-pixel resolution for the small viewing window. It is clear that isolated letter recognition was much less affected by eccentricity than 4-letter word reading. To compare both results, we computed the intrinsic probability to correctly identify 4 isolated letters in successive sequence, on the basis of the probability to recognize single letters49 (p4 = p14). This rough estimation still fell short to account for the very low scores observed in the wordreading task. Therefore, even if both tasks are difficult to Obviously, this estimate is a very simplified lowest limit since many words can be correctly identified when less than all 4 letters are recognized. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 51 compare quantitatively, this observation suggests that 4-letter word reading was significantly impaired at high eccentricities by the fact that the letters to be recognized were flanked by others. The crowding effect may be the underlying mechanism. Finally, it is also interesting to note that at high eccentricities, isolated letter recognition performance was significantly better at a target resolution of 875 pixels than at maximum screen resolution (fig. 34; p = 0.016 at 15° eccentricity, p = 0.018 at 20° eccentricity). The data for 4-letter word reading on the small viewing window (fig. 32) showed the same trend. This finding might indicate that at high eccentricities a certain blur of the target (due to pixelization) leads to better reading performance, when letter size is below the critical print size. A study by Li, Nugent, & Peli (2001) compared letter recognition of pixelized and smoothed anti-aliased letters on a CRT display. They found no significant difference between both conditions in peripheral vision up to 12.5° eccentricity. The tendency we observed appeared only at higher eccentricities (beyond 15°). However, the stimuli used in the mentioned research work are difficult to compare with ours. 3.4.3 Habituation to reading 4-letter words in eccentric vision This experiment was dedicated to investigate if eccentric reading performance, in conditions mimicking vision with a retinal implant, could improve with training. We investigated the effects of training on eccentric reading by presenting isolated words in a 10° x 3.5° viewing window (corresponding to a surgically manageable retinal implant surface of 3 x 1 mm2), located at 15° of eccentricity in the lower visual field (corresponding to a physiologically favorable location on the retina) and containing 286 pixels (corresponding to a pixelization level that allowed close to perfect word recognition in central vision). In this same condition, subjects could identify correctly only between 20% and 48% of the words in the previous experiment. Two additional control conditions with the same viewing window (10° x 3.5°) were used for comparison: stimuli containing 286 pixels, presented at 0° eccentricity (central reading); and stimuli containing 14’000 pixels (maximum screen resolution), but presented at 15° eccentricity. 3.4.3.1 Experimental protocol Two subjects, AR and EO, participated in this experiment. They were naïve to the task (i.e. they did not participate in any of the previous studies). Subject AR made all tests in monocular condition since retinal implants will certainly be used monocularly (at least for first generation implants). However, it was interesting to compare monocular to binocular learning. Therefore, subject EO therefore performed all tests in binocular condition. Three experimental sessions were conducted each working day of the week (5 days per week). Each session included one run consisting of a 50-word block, in each of the 3 different conditions, in the following order: 52 EXPERIMENTS ON READING 1) Control condition 1: 286 pixels at 0° eccentricity. 2) Control condition 2: 14’000 pixels at 15° eccentricity. 3) Main condition: 286 pixels at 15° eccentricity. The easiest condition was thus tested first and the most difficult last, so that within-session learning would favor results in the most difficult condition. Stimulus presentation time was limited to a maximum of 10 s, and subjects were instructed to press a key as soon as they recognized the projected word. Response time was recorded with the word recognition score. At the end of each run, reading score (number of correctly recognized words) and mean response time (s) were automatically computed by the program. Each experimental session lasted about 20 minutes. Consequently, the three daily sessions represented about 1 hour of training. A total of sixty-nine sessions were conducted on each subject. The regular daily flow of sessions was interrupted only for weekends and exceptionally once (AR) or twice (EO), for 3-day vacations. Learning curves were computed for reading scores and mean response times using the exponential functions presented in Chapter 2. Significant learning effects were determined using simple linear correlation (Pearson’s correlation). 3.4.3.2 Learning effects on eccentric reading of pixelized words Figure 35a presents reading score results versus session number for each subject tested in the main condition (viewing window containing 286 pixels, 15° eccentricity). Impressive learning effects can be observed. Both subjects started the experiment with low reading scores. With training, their scores improved by about 60%. These improvements were highly significant for both subjects (Pearson’s correlation: r = 0.80, p < 0.0001 for EO and r = 0.86, p < 0.0001 for AR). The exponential fit to the data revealed some noticeable individual differences. At the beginning of the learning period, subject EO was able to identify correctly about 23% of the words, whereas subject AR identified correctly only 6% of them. Both progressed over time. During final sessions, subject EO achieved scores of about 85% correct, and subject AR of about 64% correct. EO’s scores asymptoted for the last 15 sessions, while AR’s scores never stabilized. Note that EO was tested in binocular condition and AR in monocular condition. Although overall improvements were similar for both of them, these performance differences might reflect a binocular advantage. A second experimental observation consistent with a learning process appears in the analysis of the mean response time (fig. 35b). During the first sessions, typical response times ranged between 2-5.5 s. For both subjects mean response time decreased significantly as session number increased (Pearson’s correlation: r = -0.79, p < 0.0001 for EO and r = -0.38, p = 0.001 for AR). The reduction in response time is more pronounced for subject EO tested in binocular mode (2.4 s), than for subject AR tested in monocular mode (0.6 s). Interestingly, the longer initial response times of subject EO are also associated with better initial reading scores (compare with fig. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) 53 b) Figure 35. Eccentric reading performance of pixelized 4-letter words versus training session number for 2 normal subjects, expressed as: a) reading scores in RAU (left scale) and in % (right scale), and b) mean response time [s]. The viewing window contained 286 pixels and was stabilized at 15° in the lower visual field. The solid lines indicate the best fit to the data. 35a), suggesting differences between subjects in individual strategies to accomplish this difficult task. Taken together, these data demonstrate that important improvements in eccentric reading of pixelized isolated words can be obtained with training. They demonstrate that subjects can improve reading accuracy and response rate over time as they familiarize with the task. It is interesting to explore in more detail some of the parameters influencing this learning effect. 3.4.3.3 Influence of eccentricity and of pixelization on the learning process Figure 36 presents reading scores for both subjects in the 2 control conditions. The influence of eccentricity can be observed by comparing data obtained with a 10° x 3.5° viewing window, containing 286 pixels, but presented at 0° eccentricity (central reading; red plots in fig. 36) to that obtained in the main condition (same viewing window size, same number of pixels; black plots in fig. 36). As expected on the basis of the acute experiments presented in section 3.4.2, central reading performance was already close to perfect during the first sessions for both subjects. Both subjects improved their eccentric reading performance with training; however, they never reached the same performance than in central vision. Results for subject EO (binocular mode) asymptoted after about 15 sessions, while subject AR (monocular mode) showed a slower improvement. The influence of pixel number is demonstrated by comparing data collected with a 10° x 3.5° viewing window, presented at 15° of eccentricity, but at maximum screen resolution (14000 pixels; blue plots in fig. 36) to that obtained in the main condition (same viewing window size, same eccentricity). The learning process for eccentric 54 EXPERIMENTS ON READING Figure 36. Reading scores for 4-letter word deciphering versus training session number in central vision using a viewing window at 286-pixel resolution (red plot) and at 15° eccentricity in the lower visual field using a viewing window at maximum screen resolution (blue plot). The solid lines indicate the best fit to the data in these two conditions. The best fit to the data in the main condition (black solid line) is also shown for comparison. reading of words presented at high resolution and for eccentric reading of words presented at 286-pixel resolution was strikingly similar for both subjects. All through the duration of the experiments, data gathered at the high-resolution condition was about 10% to 20% higher than that collected at 286-pixel resolution. Altogether, these results reveal that the improvements measured in the main condition can be mainly attributed to the adaptation process of eccentric word reading. Conversely, the habituation to decipher pixelized words plays only a minor role. It can be therefore concluded that habituation to eccentricity is a dominant component in the learning process. Besides this, the visual system does not seem to be able to use all the information presented at a 15° eccentricity. Scores collected at 15° eccentricity asymptote remarkably below those collected with central reading. Providing more resolution can improve performance to some extent, but does not totally compensate for the loss due to eccentricity. 3.4.3.4 Effect of familiarization with the word-set For each run, 50 words randomly chosen out of a 500-word pool were presented to the subjects. Performance might have improved because, since subjects were always confronted to the same finite set of words, they were remembering better and better the set of possible correct answers. We therefore decided to investigate how this artefactual bias influenced our results. A new pool of 200 words was generated. Blocks of 50 words were randomly extracted amongst this new set and presented to the subjects in a new set of experimental sessions, occurring once the main experiment ended. The remaining experimental conditions were identical. Figure 37a compares mean reading scores MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) 55 b) Figure 37. Comparison of mean reading performance between the original word set used during the main learning experiment and a new pool of unpracticed 4-letter words. Bars indicate mean values ± SD calculated on the basis of three runs: the first and the last 3 runs of the main experiment (red and blue bars, respectively), and 3 additional runs with unpracticed words (green bars). Experimental conditions: 15° eccentricity using a viewing window of 10° x 3.5° containing 286 pixels. Results expressed as: a) mean reading scores in RAU ±SD (left scale) and in % (right scale), and b) mean response time ±SD [s]. obtained with the new word set to those obtained using the original 500-word pool. For both subjects, reading scores using the new word set were significantly higher (p = 0.002 for EO; p < 0.001 for AR) than those achieved at the beginning of the main experiment. Conversely, reading scores for unpracticed words were only a little lower than those obtained at the end of the main experiment with the original 500-word pool. This difference was significant only for subject AR (p = 0.03) but not for subject EO (p = 0.2). These findings demonstrate that subjects could identify unpracticed words with a similar accuracy to that they achieved with the old set of words after learning. The analysis of mean response times completes this evaluation (fig. 37b). Both subjects required more time to identify the new words than when using the old word set at the end of the main study (non-significant for EO at p = 0.07; significant for AR at p = 0.006). This suggests that the increased difficulty in reading unpracticed words might be better reflected by response time measurements than by reading accuracy. One can conclude from this additional test that the repeated use of the same pool of words did not significantly bias our results. Therefore, the impressive improvements observed were real improvements in accomplishing the task. Interestingly, familiarization with the word pool seems to be important for reading 56 EXPERIMENTS ON READING speed. Pixelized words that are familiar to the reader are recognized more rapidly than unpracticed words presented in the same conditions. 3.4.3.5 Binocular versus monocular performance Subject EO performed all tests using binocular vision while subject AR did all tests in monocular vision. The final scores reached by subject EO were about 20% higher than those of subject AR (see fig. 35a). Two important issues can be raised: Is this difference reflecting an advantage of binocular vision? How would subjects perform if they used the condition they did not use previously? At the end of the main experiment, we measured reading scores in inverted viewing conditions for each subject (i.e. in monocular mode for EO, and in binocular mode for AR). The remaining experimental conditions were identical to our main experiment (viewing window containing 286 pixels, presented at 15° eccentricity). No significant reading performance difference was found for any subject in such inverted viewing conditions (fig. 38). Individual differences in reading scores between subjects were preserved. This finding indicates learning is independent of the condition in which training was conducted. Binocular learning benefits monocular eccentric reading and monocular learning benefits binocular eccentric reading. There was however a slight, though non-significant, within subject trend for better scores with binocular vision. This small advantage is possibly due to binocular summation or to inter-ocular suppression effects. Figure 38. Effect of using reversed viewing conditions (untrained versus trained) on reading scores. The bars indicate mean values ± SD calculated on the basis of three runs. Subject EO: three additional runs in monocular condition (untrained – red bar) versus the last three runs of the main experiment in binocular condition (trained – blue bar). Subject AR: three additional runs in binocular condition (untrained – red bar) versus the last three runs of the main experiment in monocular condition (trained – blue bar). Experimental conditions: 15° eccentricity using a viewing window of 10° x 3.5° containing 286 pixels. We also investigated if learning gathered monocularly transferred to the nontrained eye. Subject AR, who did all the tests monocularly with her dominant right MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 57 eye, was also tested using her non-dominant left eye. Figure 39 clearly shows that there is no significant difference in monocular reading performance across both eyes, in all three different experimental conditions. Figure 39. Comparison of reading scores between the trained and the untrained eye at the end of the training process for subject AR. The bars indicate mean values ± SD calculated on the basis of three runs: last three runs of the main experiment and three additional runs conducted on the untrained eye. All three experimental conditions are compared. 3.4.3.6 Persistence of learning We finally decided to investigate if the benefits of learning could persist after a prolonged period of non-practice. Subject EO did not participate in any testing for a 2 months after the end of the experiments. Her reading performance was then remeasured using the main experimental condition. Figure 40 compares her performance: (1) at the beginning of the main experiment (day 1); (2) at the end of the training period (day 36); and (3) after 2 months of non-practice (day 99). Performance was significantly better, both in terms of reading scores (p = 0.0004) and in terms of mean response time (p = 0.02), when comparing the 1st training session to the results obtained after the 2-month break. Conversely, no significant change in performance (reading scores or mean response time) can be observed between the last training session and the measures taken 2 months later. These findings indicate that learning of eccentric reading persists after extended periods of non-practice. 58 a) EXPERIMENTS ON READING b) Figure 40. Reading performance 2 months after training compared to the reading performance at the beginning and at the end of training for subject EO. Mean values (±SD) calculated on the basis of 3 runs: first 3 runs of the main experiment (day 1), last 3 runs of the main experiment (day 36), and 3 additional runs conducted tow months after completion of the experiment (day 99). Experimental conditions: 15° eccentricity using a viewing window of 10° x 3.5° containing 286 pixels in binocular vision. Results expressed as: a) reading scores in RAU (left scale) and in % (right scale); b) mean response time [s]. 3.5 Full-page reading The second objective pursued in this chapter was to address the issue of full-page reading in conditions mimicking artificial vision as provided by a retinal implant. We conducted 2 successive experiments. First, subjects read pixelized full-page texts using a viewing window stabilized on the fovea. Second, subjects performed the same task, but using a viewing window stabilized at 15° eccentricity. Experimental sessions were repeated daily, until reading scores stabilized. Using central vision, reading scores asymptoted within a few sessions. A more important and progressive learning process was observed when using eccentric vision: almost two months were necessary for reading scores to asymptote. From the previous experiments using 4-letter words, we knew that a sampling density of 286 pixels, distributed over a viewing window subtending 10° x 3.5° of visual field, would allow for close to perfect word recognition. We noticed, however, that the 3.5° vertical visual span limited page navigation, because it did not allow visualization of the adjacent lines of text. Pilot experiments in central vision were therefore conducted to determine a more adequate viewing window height. The visualization of two lines of text at once was found to be very helpful to orient page MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 59 navigation. In our experiments, this was achieved by doubling the height of the viewing window (7°). Larger vertical visual spans (≥ 10°) did not result in further improvement. A viewing window subtending 10° x 7° of visual field was thus chosen for the full-page reading experiments. We used the same pixel density as determined in the isolated 4-letter word reading experiments presented previously: 572 pixels50. Such a viewing window corresponds to a still surgically manageable implant size of 3 x 2 mm2. 3.5.1 Stimuli A pool of 100 articles of diverse contents (culture, politics, economics, sports, etc…) were downloaded from the website51 of a popular information (neither too elementary, nor too sophisticated) Swiss newspaper and converted to BMP text images. We used Figure 41. A segment of pixelized full-page text as the same font than in the presented on the computer screen. The three dots, at the previous experiments (the beginning and at the end, indicate a text segment situated height of the small letter ‘x’ somewhere in the body of an article. Texts were not justified. corresponded to a visual angle of 1.8° at a 57 cm viewing distance). In these conditions, a segment of 7 successive lines of text could be displayed on the screen, and about 6 successive characters could be visualized in the viewing window at once. Hyphenation was used to maximize word presentation, resulting in an average of 25 words per text segment. Each article was divided into 10 successive segments. Figure 41 shows an example of such a stimulus. 3.5.2 Analysis methodology 3.5.2.1 Reading performance Reading performance was measured in terms of reading scores (expressed as % of correctly read words per session) and in terms of reading rates (expressed as average number of correctly read words per minute during each session). Reading scores were statistically analyzed using scores expressed in RAU units (please refer 50 51 Double the window height = double the number of pixels. http://www.letemps.ch 60 EXPERIMENTS ON READING to Chapter 2 for more details on this issue), but an approximate %-correct scale52 is indicated on the right ordinates of the graphs for better clarity. 3.5.2.2 Text comprehension Qualitative comprehension of the text was judged by two examiners using an arbitrary 4-grade scale: ‘None’ meaning that the text was not understood at all; ‘insufficient’ meaning very partial comprehension, insufficient to understand the issue reported in the text; ‘good’ meaning that the main issue was grasped but not all details; ‘excellent’ meaning a perfect and detailed comprehension of the text53. After each reading session, subjects had to describe what they had read and were then questioned by the two examiners, who had no difficulties attributing one of the four comprehension levels. Subjects spontaneously reported being satisfied when they reached ‘excellent’ or ‘good’ levels of comprehension, associated with reading rates of about 20 words per minute. From a clinical point of view, these two later levels might be considered as gratifying and useful full-page reading performance. 3.5.2.3 Eye movements Eye movements were recorded throughout the experiment. Saccades detected on-line by the automatic parser of the eye tracking system were analyzed in order to define the various stages of the oculomotor adaptation process for eccentric reading. For a saccade to be detected by the system, several criteria had to be fulfilled: a minimum eye displacement of 0.1°, a velocity threshold of at least 30°/s, and a minimum acceleration threshold of 8000°/s2. Detected saccades were categorized into 3 main groups according to their orientation (fig. 42a): horizontal saccades (those with an angle of ±20° around the horizontal axis, and directed either rightwards or leftwards), vertical saccades (those with angles between 70° and 110° around the vertical axis, and directed either upwards or downwards), and oblique saccades (those not fitting into any of the preceding categories). Horizontal saccades were further subcategorized (fig. 42b) into: progressions (horizontal saccades directed rightwards and less than 10° in amplitude), regressions (horizontal saccades directed leftwards and less than 10° in amplitude), and line-jumps (horizontal saccades directed leftwards and larger than 20° in amplitude). Saccade frequency was calculated as the total number of saccades performed during an experimental session (i.e. 4 full-pages of text). Saccade amplitude was computed as the total absolute eye displacement (length) between the eye position at the beginning of the saccade and its end position. Average saccade amplitude for 52 Note that the %-correct to RAU transformation is dependent of sample size (in our case the total number of words used in one session). Approximate %-correct scales are therefore based on the average number of words computed across all sessions presented on the graphs. 53 Such an uncommon 4 level scale was used because it is much easier to judge first if a subject understood the main issue of a text and then to ask some questions to determine whether the subjects grasped some parts of the text or if the subject really had a detailed understanding. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) 61 b) Figure 42. Saccade categorization. (a) Saccadic eye movements were categorized as horizontal (oriented between –20° and +20° around the horizontal axis, and directed either rightwards or leftwards), vertical (oriented between 70° and 110° around the vertical axis, and directed either upwards or downwards), and oblique. (b) According to their direction and amplitude, horizontal saccades were further subcategorized into progressions, regressions, and line-jumps. a given experimental session was calculated on the basis of the absolute amplitude of all saccades performed during the session. 3.5.2.4 Learning process Whenever the results allowed it, learning curves were computed using the exponential functions presented in Chapter 2. Significant learning effects were determined using simple linear correlation (Pearson’s correlation). 3.5.3 Experimental protocol Three subjects (AD, female, 24 years old; DV, female, 23 years old; DS, male, 30 years old) participated in these experiments. All of them were tested monocularly using their dominant eye. During each session, they had to read aloud the first 4 text segments (about 100 words) of an article and their voice was recorded for further analysis. After each text segment presentation, calibration was checked for possible drifts and if necessary, slightly corrected to insure an exact control of the viewing window position during the entire experimental session. In very rare cases, these controls revealed a significant drift, meaning that the position of the viewing window was not stable during the presentation of the text segment. The results from the corresponding segment were discarded and an additional text segment was read. A qualitative comprehension test was performed at the end of each session (i.e., after reading 4 successive text segments), by questioning the subject on the content of the article. A different article was used in each session (none of the subjects read the same article twice). In experiment 1, several sessions were conducted using a viewing window stabilized in central vision. This experiment lasted until subjects became familiar with 62 EXPERIMENTS ON READING the task (reading pixelized text using a small viewing window for page navigation). Experiment 2, testing eccentric reading, began once the subjects had adapted to central reading. Possible learning effects were investigated by repeatedly performing experimental sessions for a period of almost 2 months. Two sessions were conducted each working day of the week (5 days/week). The duration of each experimental session was variable throughout the experiment, but never exceeded 30 minutes. Two sessions represented therefore less than 1 hour of daily training. This experiment was stopped once reading scores asymptoted. 3.5.4 Experiment 1: Full-page reading in central vision This experiment was dedicated to familiarize normal subjects with the unusual task of reading pixelized, full-page texts using a small viewing window for page navigation. For this experiment, subjects read 6 text segments per session instead of the 4 segments per session used in the more difficult experiment 2. Figure 43 presents reading performance in central vision versus session number for each subject. All three subjects achieved perfect or close to perfect reading scores (> 95% correct) already in the first sessions. No significant learning effect was observed in the analysis of reading scores versus time. Reading rates improved with time for all three subjects. Analysis of the experimental data revealed that the average reading rate almost doubled from 71 to 122 WPM for AD. It improved from 65 to 89 WPM for DV, and from 60 to 72 WPM for DS. This improvement was, however, statistically significant only for subject AD (Pearson’s correlation: r = 0.78, p = 0.003). Interestingly, subject AD also achieved reading rates that were quite a) b) Figure 43. Reading performance during experiment 1 for three normal subjects. Full-page texts were read using central vision (10° x 7° viewing window containing 572 pixels). Results expressed as: a) reading scores expressed in RAU units (left scale) and in approximate % (right scale) versus experimental session number; and b) reading rates expressed in WPM (words/min) versus experimental session number. The solid lines indicate the best fits to the data. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 63 superior to those obtained by the remaining 2 subjects at the end of this experiment. Reading rates measured for the same 3 subjects, in normal viewing conditions (for articles read directly from the same journal), were significantly higher, ranging between 160 and 180 WPM. These data clearly demonstrate that full-page reading can be achieved under conditions mimicking artificial vision in the central visual field. This means that relevant information for reading could be transmitted and captured by the visual system. Almost all words could be correctly deciphered. However, reading rates were significantly lower than normal due to the increased difficulty of page navigation using a restricted viewing window and to the fact that this viewing window contained pixelized stimuli. 3.5.5 Experiment 2: Full-page reading in eccentric vision Experiment 2 started when subjects had adapted to performing the task in central vision. Based on the previous results on eccentric reading of isolated 4-letter words, we expected eccentric full-page reading to require significant adaptation to reach best performance. Between 55 and 68 sessions per subject were necessary to fulfill this criterion. Figure 44a presents individual reading scores versus session number for full-page reading at 15° eccentricity. Experimental data were fitted with exponential regression functions. Reading performance for 2 subjects improved enormously throughout the a) b) Figure 44. Reading performance during experiment 2 for 3 normal subjects. Full-page texts were read using eccentric vision (with a 10° x 7° viewing window stabilized at 15° eccentricity in the lower visual field, and containing 572 pixels). Results expressed as: a) reading scores expressed in RAU units (left scale) and in approximate % (right scale) versus experimental session number; and b) reading rates expressed in WPM versus experimental session number. The solid lines indicate the best fits to the data. 64 EXPERIMENTS ON READING experiment. During the first sessions, subjects DV and DS were able to identify only about 13% of the words in the text, while at the end they achieved scores of 86% and 98% correct, respectively. In contrast, subject AD already performed well in the initial sessions (~ 85% correct), and ended up with almost perfect scores (~ 98% correct). Her learning curve was therefore less spectacular. Reading score improvements were highly statistically significant for all 3 subjects (Pearson’s correlation: r = 0.57, p < 0.0001 for AD; r = 0.81, p < 0.0001 for DV; and r = 0.77, p < 0.0001 for DS). Figure 44b presents individual reading rates achieved during experiment 2. Large inter-session variability can be observed for all 3 subjects (particularly in the case of AD). Nevertheless, improvements were significant for all 3 subjects: AD from 5 WPM to 26 WPM (Pearson’s correlation: r = 0.74, p < 0.0001), DV from 3 WPM to 14 WPM (Pearson’s correlation: r = 0.81, p < 0.0001), and DS from 1 WPM to 28 WPM (Pearson’s correlation: r = 0.90, p < 0.0001). At the end of experiment 2, reading rates for eccentric reading were still significantly below values obtained in similar conditions for central reading, and of course below normal reading rates. Yet, they were remarkable when compared to what subjects achieved during the first sessions. It is also important to note that reading rates continued to improve after almost two months of training, suggesting that higher reading rates could still have been achieved with more practice. Even if word recognition scores and reading rates constitute helpful experimental values to demonstrate changes in performance, they do not reflect the degree to which text content was understood. Text comprehension is not easy to quantify, but we tried to assess this parameter using the qualitative four-level scale described in section 3.5.2.2. Figure 45 presents the evolution of text comprehension throughout experiment 2, for the 3 subjects. In the beginning, subjects DV and DS experienced major problems understanding the texts they read. ‘Good’ understanding could only be achieved after 16 sessions or more. In contrast, subject AD achieved ‘good’ to ‘excellent’ text comprehension since the beginning. At the end of experiment 2, subjects AD and DS systematically achieved ‘excellent’ text comprehension, but not subject DV. These results fit well with the performance curves in figure 44 where subject AD achieved high reading scores from the beginning and subject DV finished with the lowest performances. Figure 45. Text comprehension estimates during experiment 2 versus session number for the 3 subjects. 65 MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION Figure 46. Text comprehension estimates versus reading scores and reading rates. Data collected on the 3 subjects were merged. Box plots indicate median values, 25th and 75th percentile values (colored box) as well as 10th and 90th percentile values (vertical bars). Circles indicate outliners. reading rates. It is interesting to plot the results of text comprehension versus reading scores and reading rates (fig. 46). Reading scores over 85% correct were required to reach ‘good’ to ‘excellent’ text comprehension levels. Text understanding seemed to be impossible for scores below 60% correct. The distribution of comprehension levels against reading rates was more variable. ‘Excellent’ or ‘good’ comprehension levels, for example, were reached over a large range of reading rates, and even occasionally at reading rates below 10 WPM. Text comprehension appeared thus to be more closely associated to high reading scores than to high Taken together, results from experiment 2 demonstrate that an important learning process occurred for eccentric full-page reading. Subjects achieved functionally useful eccentric full-page reading after almost two months of daily training. The evolution was however expressed quite differently across subjects. Subject DS, for example, improved impressively in each of the 3 measured parameters, all through the experiment. In contrast, subject AD begun the experiment with relatively high reading scores and good text comprehension. In her case, the learning process was best expressed by major reading rate improvements. AD DV DS Figure 47. Gaze position recorded for each subject while performing the reading task in central vision (last session of experiment 1). The solid line represents the trajectory of the center of the viewing window relative to the text (see fig. 28). The panels on the right represent frequency histograms of the vertical coordinates of gaze recorded every 4 ms. Gray bars indicate the position of the lines of text. 66 EXPERIMENTS ON READING Subject DV, while showing significant improvements in all aspects, did not attain the same level of performance than the other 2 subjects in the same period of time. 3.5.5.1 Analysis of eye movements Illustrative samples of gaze position recordings are shown in figures 47 (central reading) and figure 48 (eccentric reading). During the first training sessions for eccentric reading, oculomotor behavior appeared quite inappropriate for the reading task: large vertical saccades predominated. Subjects seemed unable to fixate words or to roughly follow a line of text. Oculomotor behavior evolved gradually. Eye movements intended to decipher single words were already visible as early as in the 5th session, especially for subject DV. At the end of the training period, all subjects AD DV DS 1st 5th 15th Last Figure 48. Gaze position recorded for each subject during various sessions (1st, 5th, 15th, and last) in experiment 2. The solid line represents the trajectory of the center of the viewing window relative to the text (see fig. 28). The panels on the right represent frequency histograms of the vertical coordinates of gaze recorded every 4 ms. Gray bars indicate the position of the lines of text. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 67 developed a structured page navigation strategy. It is interesting to compare final central and eccentric reading strategies. After training, both eye movement patterns share several similarities. The viewing window focused on consecutive words and across successive lines of text. Forward-directed saccades shifting fixation from one word to the next (progressions) and saccades shifting fixation from the end of one line to the beginning of the next (line-jumps) could be clearly distinguished. Occasionally, subjects traced back on the same line (regressions), to visualize again specific words. However, differences could also be noted between central and eccentric reading. In eccentric vision, regressions occurred more frequently. Moreover, horizontal saccades seemed less precise; therefore more small corrective saccades were required. Gaze stability was quantified by computing histograms of the vertical position of the viewing window during each experimental session (plotted on the right side of figs. 47 and 48). During the first sessions of eccentric reading, the histograms were broad and roughly centered on the screen. There is no evidence for successful focusing on single lines of the text. The histogram is completely different for the last session. A series of small peaks at regular vertical intervals (corresponding to that of the lines of text) can be observed in the histogram. This analysis also revealed that subjects had the tendency to place the center of the viewing window slightly below the lines, probably minimizing the eccentricity of the relevant part of the target image. From the figures above, it is clear that the overall control of eye movements improved impressively during the experiment. Gaze position recordings were used to a) b) Figure 49. Mean cumulative length of the total trajectory described by each subject’s eye movements versus session number. Distances along each one of the 2D axes were calculated separately for: a) the vertical coordinate, and b) the horizontal coordinate of gaze position data. The solid lines indicate the best fits to the data. 68 EXPERIMENTS ON READING compute the mean cumulative length of the vertical (fig. 49a) and horizontal (fig. 49b) components of eye movements on the screen, for each experimental session. Best fits to these data are also presented for each subject. The mean cumulative length of vertical eye movements decreased dramatically for all subjects. Initial values ranged between 35-48 m per text segment, while final values significantly dropped to 5-9 m per text segment (Pearson’s correlation: r = 0.69, p < 0.0001 for AD; r = 0.39, p = 0.04 for DV; and r = 0.84, p < 0.0001 for DS); a five-fold decrease. Total vertical trajectories asymptoted within 3 to 10 sessions for subjects DV and AD. Values for subject DS stabilized after about 36 sessions. Horizontal trajectories decreased significantly only in subjects AD and DS (Pearson’s correlation: r = 0.77, p < 0.0001; and r = 0.87, p < 0.0001, respectively). Compared to their vertical counterparts, this decline was less impressive (from initial values ~ 21-27 m per text segment, to ~ 7-14 m at the end of training) and more progressive (values in AD stabilized after ~ 43 sessions, while in DS these were still decreasing at the end of the experiment). Total horizontal trajectories for subject DV remained stable allthrough the experiment. The distribution of saccades performed during the 1st, 5th, 15th and last eccentric reading sessions is plotted in figure 50. During the first training session, bundles of large vertical saccades were observed. Many of these eye movements were between 10° and 20° in amplitude, probably reflecting recurring (reflexive) attempts to bring the stimulus image onto the fovea (foveating saccades), followed by an equivalent saccade of opposite direction attempting to bring the viewing window back on the stimulation screen. In the 5th session, these movements were no longer visible in subjects AD and DV, and only a few of them were still observed in subject DS. The amplitude of the remaining vertical saccades decreased gradually, to become hardly visible at the end of training. In contrast, structured patterns of horizontal eye movements developed in the 5th session in 2 subjects (AD and DV). From the 15th session on, horizontal saccades predominated over the initially prevailing vertical pattern. In the last training session, eye movements essentially consisted of progressions, regressions, line-jumps, and other small corrective saccades. Changes in saccade counts (frequencies) by category, are plotted in figure 51. The total number of vertical saccades decreased significantly over time in all subjects (Pearson’s correlation: r = 0.58, p < 0.0001 for AD; r = 0.39, p < 0.01 for DV; and r = 0.72, p < 0.0001 for DS). An approximately 15-fold drop was observed after 3, 20, and 25 sessions in subjects DV, AD, and DS, respectively. Slighter (about 5-fold) but significant (Pearson’s correlation: r = 0.72, p < 0.0001 for AD; r = 0.73, p < 0.0001 for DV; and r = 0.82, p < 0.0001 for DS) frequency decays were observed for oblique saccades. In subjects AD and DS, the process was slower (33 and 38 sessions, respectively) than for vertical saccades. In subject DV, values were still decreasing when the experiment ended. Evolution of horizontal saccade counts was more complex and data could not be fitted with an exponential curve. In AD and DV, these increased significantly during the first 15 sessions (respectively, Pearson’s correlation: r = 0.60, p < 0.05 and r = 0.72, p < 0.01) and then significantly decreased (respectively, Pearson’s correlation: r = 0.48, p < 0.001 and r = 0.31, p < 0.05). In subject DS, horizontal saccade counts increased significantly during the first 69 MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 7 sessions (Pearson’s correlation: r = 0.91, p < 0.01) and then decreased significantly (Pearson’s correlation: r = 0.82, p < 0.0001). AD DV DS 1st 5th 15th Last Figure 50. Angular distribution of the saccades performed each subject during training for eccentric reading at different times of the learning process (1st, 5th, 15th, and last training sessions). Additional results were obtained following horizontal saccade subcategorization (see fig. 52). The proportion of progressions increased significantly in all 3 subjects, from values ranging between 45% and 65% in the first sessions up to about 65% by the end of training (Pearson’s correlation: r = 0.74, p < 0.0001 for AD; r = 0.43, p < 0.001 for DV; and r = 0.74, p < 0.0001 for DS). Only subject AD reached an 70 a) EXPERIMENTS ON READING b) c) Figure 51. Changes in saccade frequency versus session number for each subject during training of eccentric reading, by saccade category: a) vertical saccades, b) horizontal saccades, and c) oblique saccades. Average values in central vision (black dashed lines) are also shown for comparison. asymptote (after 50 sessions). Regressions behaved inversely. In the beginning of training, they represented about 41%, 34%, and 43% of the total number of horizontal saccades in AD, DV, and DS, respectively. These proportions significantly decreased to 17%, 26%, and 27%, respectively (Pearson’s correlation: r = 0.70, p < 0.0001 for AD; r = 0.65, p < 0.0001 for DV; and r = 0.81, p < 0.001 for DS). At the end of the experiment, the proportion of regressions were still decreasing in subjects DV and DS, while in subject AD values stabilized after about 30 sessions. The total number of line-jumps increased significantly with training in DV and DS (Pearson’s correlation: r = 0.64, p < 0.0001 and r = 0.61, p < 0.0001, respectively). Line-jump counts in AD were more variable, but also tended to increase over time (Pearson’s correlation: r = 0.20, p = 0.1). Values in subjects AD and DV stabilized after around 16 and 27 sessions. In the case of subject DS, line-jump counts had not asymptoted when the experiment ended. a) b) c) Figure 52. Evolution of the different horizontal saccade subcategories versus session number for each subject during training of eccentric reading: a) proportion (%) of regressions; b) proportion (%) of regressions; and c) total number of line jumps. The proportions of progressions and regressions were calculated on the basis of the total number of horizontal saccades. Average values for central vision (black dashed lines) are also shown for comparison. 71 MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION Average amplitude of the different saccade categories was also modulated throughout the training period (fig. 53). For vertical saccades, amplitudes dropped significantly from initial values of 5°-8° down to final values of around 3° (Pearson’s correlation: r = 0.56, p <0.0001 for AD; r = 0.69, p < 0.0001 for DV; and r = 0.72, p < 0.0001 for DS). Asymptotes were reached after 13, 20, and 27 sessions in subjects DV, AD, and DS, respectively. Average amplitude of oblique saccades remained stable in subject DS, and decreased very slightly but significantly in subjects AD and DV (respectively, Pearson’s correlation: r = 0.34, p < 0.01 and r = 0.47, p < 0.0001). In contrast, average amplitude of horizontal saccades significantly increased from values ranging between 5°, 4°, and 2.5°, up to 7°, 6°, and 4° in subjects AD, DV, and DS (correspondingly, Pearson’s correlation: r = 0.42, p < 0.001; r = 0.51, p < 0.001; and r = 0.80, p < 0.0001). In subject DS, amplitudes never stabilized, while in subjects AD and DV curves asymptoted after 20 and 23 sessions. a) b) c) Figure 53. Changes in saccade amplitude (°) versus session number for each subject during training of eccentric reading, by saccade category: (a) vertical saccades, (b) horizontal saccades, and (c) oblique saccades. Average values for central vision (black dashed lines) are also shown for comparison. 3.6 Discussion 3.6.1 Main outcome of these experiments In central vision, the first set of reading experiments clearly demonstrate that about 300 distinctly perceived points (pixels), distributed around a 10° x 3.5° visual field, are necessary to read 4-letter words. For the second set of experiments, subjects had to move a small viewing window on a computer screen to navigate across full pages of pixelized text using their own eye movements. We kept the same pixel density and used a viewing window with double vertical visual span (10° x 7°). About 600 pixels were sufficient for useful full-page reading. These data extend the work of Cha et al. (1992b), but end on a similar conclusion: 300-600 pixels are needed to read small strings of characters. This pixel density appears therefore to be an intrinsic criterion: more related to the type of stimuli to be deciphered than to the presentation protocol. 72 EXPERIMENTS ON READING In eccentric vision (≥ 10°) initial reading performance was poor, even at high pixelization levels (see figs. 30 and 31). Therefore, the main factor limiting reading performance at high eccentricities is not pixel resolution but rather the fact that only part of the information is grasped by the visual system. The “crowding effect” seems to play an important role, because isolated letters were perfectly recognized at eccentricities where 4-letter words were impossible to read (see fig. 34). The use of large fonts (and accordingly of large viewing windows) can attenuate the negative effect of eccentricity on reading performance, but cannot totally compensate for it. Strictly speaking, these results suggest that eccentric implant locations (≥ 10°) would strongly impair reading performance. It might, however, be required to place retinal prostheses at such high eccentricities to keep image distortion minimal. These considerations raise the question of whether subjects can adapt to eccentric reading and, as a consequence, achieve higher levels of performance with training. This is particularly important since our experiments were conducted with untrained observers, who were not used to such viewing conditions. Complementary experiments were designed to investigate if eccentric reading, under conditions simulating retinal implants, could be improved by learning or if it was limited by fundamental properties of the visual system. The studies presented in this chapter demonstrate that subjects are able to adapt to the unnatural task of eccentric reading. Remarkable improvements could be observed during the course of both studies, for all the subjects that participated in the investigations. Therefore, these results demonstrate that useful reading can be achieved in conditions mimicking a retinal implant. This outcome is very promising for the future of retinal prostheses. However, it is not surprising, as several experimental observations suggest that eccentric reading can be improved with training. Westheimer (2001) demonstrated that learning in peripheral vision is taskspecific. Improvements were observed for stereoscopic, orientation, vernier acuity, bisection, and time discrimination tasks, but not for resolution or Landolt C acuities. Westheimer’s results confirmed those by other authors (Beard et al., 1995; Schoups et al., 1995; Crist et al., 1997), indicating that spatial visual functions, which rely on important processing in higher cortical areas, can be improved by training in the visual periphery. There is also extensive evidence in the low vision literature that educational training is an important factor for successful eccentric reading by patients with macular scotoma (see e.g. Peli, 1986). Nilsson (1990), for example, trained patients with advanced age-related macular degeneration to use optical aids and demonstrated that they greatly improved their reading capacities with only about 5 hours training. Half of the evaluated subjects had to use eccentric viewing due to an absolute central scotoma. The situation encountered when educating low vision patients to use optical aids for reading is however not identical to simulating an eccentric retinal implant on normal subjects. Low vision patients are generally able to use large parts of their retina situated relatively close to the fovea. The stimuli used in this study were restricted to small viewing windows stabilized at high eccentricities in the lower visual field. Moreover, the information content of the stimuli was MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 73 reduced (pixelized), which is not the case for the stimuli presented to low vision patients through optical aids. Some improvement of eccentric reading capacities could be therefore expected on the basis of clinical experience with low vision patients, but it was still crucial to demonstrate that practical effects are significant for the specific conditions of retinal implants. Since our experimental setting was particularly designed to simulate vision as will be produced by a retinal implant, it obviously did not illustrate the functional constraints and remaining retinal capacities found in conditions associated with central scotomas and eccentric reading. Despite these methodological limitations, the present results also offer remarkable indications of how mechanisms for eccentric reading are constructed, at least in certain circumstances. 3.6.2 Analysis of the learning process Subjects had to cope with several difficulties during their adaptation to reading using an eccentric area of the visual field. For example, they had to suppress unwanted reflexive eye-movements, focus attention to this peripheral region of the visual field, and extract a maximum of information out of low resolution (pixelized) stimuli. In addition, for full-page reading, subjects had to get accustomed to scanning several lines of text using an eccentric and restricted viewing window and reconstructing meaningful sentences out of words and phrase fragments. This list of difficulties is surely not exhaustive, and all had to be surmounted to achieve the task. Although it is impossible to analyze these factors in an isolated way, it is interesting to discuss in more detail how some potentially contribute to the learning process, while others limit reading performance. 3.6.2.1 The “crowding effect” In the first eccentric reading study presented in the chapter, using pixelized isolated 4-letter words, significant learning effects could be observed. These improvements took about 70 experimental learning sessions. In these experiments, page navigation was not required, suggesting that one important factor of the overall learning process is independent of the accurate control of eye movements. Such component is likely to be associated with performance improvements in deciphering eccentric low-resolution stimuli. One can wonder to which extent the lower reading rates observed in eccentric vision could be attributed to the decreased spatial resolution in peripheral regions of the retina. Visual acuity at an eccentricity of 15° is expected to be about 20/125 (Daniel & Whitterridge, 1961; Cowey & Rolls, 1974). Whittaker & Lovie-Kitchin (1993) suggest the use of font sizes several times bigger than the acuity threshold, to reach optimal reading rates. Bowers & Reid (1997) recommended print sizes of at least four times the acuity threshold. The character size used in our experiments corresponds to a visual acuity of about 20/400. This size was thus just adequate, and did not significantly limit reading rates for eccentric reading in this study. Hence, the 74 EXPERIMENTS ON READING low reading performance observed cannot uniquely be attributed to decreased resolution in the periphery. Our measurements confirmed that eccentric recognition of single letters is much easier than eccentric reading of entire words. These results fit well with findings showing that the fovea and periphery have different center-surround interactions that cannot be completely explained by the cortical magnification factor (Xing & Heeger, 2000). The phenomenon of reduced discrimination in presence of surrounding stimuli, known as the “crowding effect”, seems to be of cortical and not of retinal origin (see e.g. Levi et al., 1985). Electrophysiological experiments in the monkey, testing the modifications of the functional properties of the primary visual cortex V1 accompanying perceptual learning suggest that it is possibly due to a concomitant decrease in the “crowding effect” (Crist et al., 2001). Moreover, the decrease of crowding has been found to be related to attention (Leat et al., 1999), a component that could potentially be improved by training, as already indicated by experiments on visual search (Sireteanu & Rettenbach, 1995; 2000). A significant decrease of the “crowding effect” is thus very likely to be an important part of the overall learning process. 3.6.2.2 Text comprehension and the influence of context information Interestingly, subjects had to achieve relatively high reading scores (> 85% correct) in order to achieve useful text comprehension (i.e. ‘good’ or ‘excellent’ text comprehension levels – see fig. 46). Lower reading scores were almost always paired with insufficient text comprehension. It appears, thus, that reading scores must be rather high to allow for useful reading. This finding, however, must be considered with care, since it is based on a very simple qualitative comprehension test. The influence of context information on reading performance remains a difficult issue to assess. The comparison of the data on full-page reading to that on isolated words is interesting in this respect. After training, we observed mean reading scores of about 75% correct for isolated words whereas mean reading scores of about 94% correct were obtained for full-page reading. While this difference is not statistically significant for such a small number of subjects, it is in agreement with the hypothesis that the use of context information helps reading performance, even in eccentric vision (Fine & Peli, 1996; Fine et al., 1999). 3.6.2.3 Influence of the restricted viewing window It is also interesting to examine the impact the restricted viewing window has on reading performance. The width of the viewing window used in this study limited the maximum visual span to about 6 letters, consequently reducing maximum reading rates for central vision. Legge et al. (2001) suggested that the average visual span shrinks from at least 10 letters in central vision to about 1.7 letters at 15° eccentricity. This low value could be however increased upon prolonged observation times. Therefore, at 15° eccentricity, the viewing window restriction was even more pronounced, not because of our experimental limitation, but because of the ‘natural’ MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 75 visual span reduction at high eccentricities. Subjects had therefore either to increase the number of saccades to decipher a given word, or to increase fixation time to extend the visual span; both strategies leading to lower reading rates, which is consistent with our experimental observations. 3.6.2.4 Central versus eccentric reading Even if subjects adapted well to the eccentric reading tasks, reading rates appeared to be significantly limited by target eccentricity. Average reading rates using eccentric vision were considerably lower (by a factor 2.5 to 5.8) than those achieved with central vision. Other authors have already reported low reading rates for eccentric vision. Wensveen et al. (1995), for example, found that simulated central scotomas resulted in dramatic decrements of reading rates. In their younger subjects, a 3-fold reduction of reading rates was found for 8° central scotomas. It is, however, difficult to compare quantitatively these results to ours, because of marked differences in the experimental conditions. In this context it should also be noted that, when the experiments were terminated, reading rates had not really asymptoted. This means that subjects could still have improved reading rates with prolonged training (see figs. 35b and 44b). 3.6.2.5 Oculomotor adaptation to eccentric viewing Eccentric vision requires adaptation of oculomotor control to such specific viewing conditions. Reflexive foveating mechanisms must be suppressed and saccadic eye movements must be redirected to the new fixation locus. Our data demonstrate that the pattern of eye movements changed impressively throughout the learning process. Certain oculomotor adaptation stages appeared consistently in all tested subjects. Two essential adaptation processes could be distinguished: a faster ‘vertical’ phase aimed at suppressing reflexive foveation, and a slower ‘horizontal’ phase dedicated to the restructuring of the horizontal eye movement pattern. During the first sessions, numerous vertical foveating saccades could be observed. Interestingly, the first rapid ‘vertical’ adaptation process appears to include two relatively distinct, parallel phases: one consisting in the reduction of vertical saccade count, the second in the reduction of both oblique saccade count and vertical saccade amplitude. According to our results, the former occurred promptly, and the latter, although rapid, was more progressive. It is reasonable to presume that both aim at reducing reflexive foveation, but each relies on distinct mechanisms, as suggested by their different time-course. The second, slower adaptation phase concerned the restructuration of the horizontal eye movement pattern. In the initial sessions, no structured reading sequence could be distinguished. The frequency of horizontal saccades increased during the first 7 to 15 sessions, and then slowly decreased, while their average amplitude increased all through the learning process. The proportion of progressions increased gradually. It has been demonstrated that, in eccentric vision, the visual 76 EXPERIMENTS ON READING span can increase with training (Chung et al., 2004). This should result in fewer but longer saccades, as observed in our data. A significant reduction in the proportion of regressive saccades was also observed in all subjects. As a rule, when reading difficulty decreases, saccade length increases and the frequency of regressions diminishes (Pirozzolo, 1983; Rayner, 1998). Subjects spontaneously reported that the task became easier with training, resulting in better word recognition during eccentric fixation. Thus, fewer regressions were necessary for deciphering. Linejumps developed gradually and better calibration of progressive saccades could be achieved with training. Hence, as better eccentric oculomotor control was developed, fewer corrective saccades were needed. Two parallel, presumably related phenomena might therefore be distinguished during the development of horizontal saccade control. The first one corresponded to the adaptation of the amplitude of horizontal saccades (mainly progressions) to the text presented. The second one consisted in the reduction in number of regressions. Our results showed that even when optimal eccentric reading performance has been attained, oculomotor behavior was not optimal compared to that observed in central vision (compare results for central and eccentric reading in figs. 51-53). Although subjects adapted to the eccentric reading task, vertical saccades did not disappear completely. More horizontal and oblique saccades where required in eccentric vision than in central vision. In 2 out of the 3 subjects, more line jumps were performed and horizontal saccades were smaller during eccentric reading. In general, oblique saccades were smaller for eccentric than central viewing conditions. These results clearly demonstrate that, even after extensive training, the characteristics of saccades performed during eccentric and central reading differed. A previous investigation in patients with central scotoma described a similar behavior (Whittaker et al., 1991). Even when these patients had adapted to consistently direct images onto the PRL, characteristics of eccentric saccades still differed from those of foveating saccades. Typically, foveating saccades have shorter latencies and are more accurate than eccentric, non-foveating saccades (Hallett, 1978; Zeevi & Peli, 1979; Whittaker & Cummings, 1990). Taken together, these findings confirm that subjects suppress foveating saccades and then adapt non-foveating saccades to reference the new fixation locus, in accordance with previous reports (Whittaker et al., 1991). 3.6.3 Additional considerations These investigations were designed to explore reading performance in conditions mimicking artificial vision. Several questions concerning the choice of some of the stimulation parameters are worthwhile to be discussed. Why using a font size such that only approximately 4 to 6 characters could be viewed inside the restricted viewing window? Legge et al. (1985a) determined that efficient reading requires grasping sequences of at least 4 to 8 characters at a glance. Several other authors demonstrated that a viewing window containing more letters could favor optimal reading performances, especially for low vision observers. Fine & Peli (1996b) report that, on a scrolling display, while normal observers needed 4 to 5 characters to reach maximal reading rates, visually impaired observers MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 77 required 6 to 7 characters. The same authors (Fine et al., 1996) found that reading rates increased with character sequences as large as 13 when using a fiber optic stand magnifier. Beckmann & Legge (1996) studied reading speeds for normal and low vision subjects on magnified text. They compared a condition requiring page navigation with another one that did not. When page navigation was required, critical viewing window sizes of 14 and 10 characters were required for normal and low vision observers, respectively, to reach 85% of their maximum reading speed. These values were much lower when only 50% of maximum reading speed was required: 4.7 characters for normal subjects and 3.5 characters for low vision subjects. Without page navigation they obtained values in the order of 4.7 (normal) and 5.2 (low vision) to reach 85% of the maximum reading speed while 1.2 (normal) and 2.0 (low vision) characters were needed for 50% of the maximum reading speed. A high number of visible characters seems thus to be favorable essentially for page navigation. Nevertheless, there is another argument that favors using a small number of characters in the viewing window, especially when eccentric vision is concerned. Using fewer letters permits the use of larger fonts, letter size being an important limiting factor for eccentric reading. The font size was thus chosen because it represented a reasonable compromise between a low limit value concerning the reading speed and the advantage of a small number of big letters for eccentric reading. Why use a proportionally spaced font and not an equally spaced font (e.g. Courier) with enlarged letter spacing to minimize the “crowding effect” in eccentric reading? Enlarged letter spacing has been found to be significantly beneficial for eccentric reading (Latham & Whitaker, 1996; Chung, 2004), especially for attenuating the “crowding effect” (Arditi et al., 1990; Toet & Levi, 1992). Proportionally spaced letters are closer together than equally spaced ones, thus favoring the adverse “crowding effect”. However, printed matters (books, journals, etc…) are almost exclusively printed in such proportional fonts. Therefore, although the use of a proportionally spaced font increased the difficulty of the eccentric reading task, it was essential to adapt our experiments to the reality of common printed materials. Finally, why not use RSVP or scrolled text presentation? Because they do not represent realistic simulation conditions for retinal implants. Nevertheless, we certainly admit that these would have been interesting examination conditions to study eccentric reading in a general way. 3.7 Conclusions With the first set of experiments of this study we demonstrated that the amount of information conveyed by about 300 separate points (pixels), distributed around a visual area of 10° x 3.5°, is sufficient to allow reading of isolated words in the central visual field. We also demonstrated that reading of isolated words at high eccentricities could be significantly improved with practice at the same, relatively low, pixel resolution. With practice, one can learn to use a highly eccentric part of the retina for reading, an abnormal task for normal subjects. 78 EXPERIMENTS ON READING With the second set of experiments we confirmed that about 600 stimulation points, distributed around a 10° x 7° visual field (the same image resolution than above), allowed useful full-page reading abilities. A significant learning process was however required to reach optimal performance with eccentric vision. One of the main issues involved in the learning process was the adjustment of oculomotor control in order to reference, as accurately as possible, the eccentric viewing window used to navigate across text pages. Adaptation of eye movements seems to include at least two parallel processes, a ‘fast’ vertical adaptation phase essentially involved in suppressing reflexive foveation and a more progressive restructuration of the horizontal eye movement pattern. Even after systematic training, eccentric reading remains a difficult task resulting in low reading rates. The evaluation of the reading task is particularly important if one is to assess the rehabilitation prospects of a visual prosthesis since it is strongly associated with vision-related estimates of quality of life and represents one of the main goals of low vision patients seeking rehabilitation (Elliott et al., 1997; Wolffsohn & Cochrane, 1998; Margrain, 2000; McClure et al., 2000; Hazel et al., 2000). 3.8 Publications resulting from this research Sommerhalder, J., Oueghlani, E., Bagnoud, M., Leonards, U., Safran, A.B., & Pelizzone, M. (2003). Simulation of artificial vision: I. Eccentric reading of isolated words, and perceptual learning. Vision Research, 43(3), 269-283. Sommerhalder, J., Rappaz, B., de Haller, R., Pérez Fornos, A., Safran, A.B., & Pelizzone, M. (2004). Simulation of artificial vision: II. Eccentric reading of full-page text and the learning of this task. Vision Research, 44(14), 1693-1706. Pérez Fornos, A., Sommerhalder, J., Rappaz, B., Pelizzone, M., & Safran, A.B. (2006). Processes involved in oculomotor adaptation to eccentric reading. Invest Ophthalmol Vis Sci, 47(4), 14391447. 4 Experiments on Visuomotor Coordination When it is obvious that the goals cannot be reached, don't adjust the goals, adjust the action steps. Confucius (551 – 479 BC) 4.1 Foreword From everyday experience, we intuitively know that most of our motor actions are visually guided. A variety of daily life and leisure activities involve gathering information from the environment and using it to visually guide hand movements towards a certain target (e.g. operating a telephone, locating and taking items from a crowded shelf, locating and using items on a dinner table, etc…). Although these actions seem simple enough, the processes involved are complex. Visuomotor tasks require the combination of various abilities, like object identification/recognition but also certain motor skills such as reaching, grasping, or pointing. Encoding spatial information and using it to direct a particular motor response might impose various constraints to a visual prosthesis. 4.2 Introduction For reaching towards objects, the nervous system should solve various issues. The target towards which the motor action is to be directed should be identified and localized in space. In addition, the initial status of the actuator (limb) has to be determined. The appropriate motor command can then be planned and generated. Finally, throughout the movement, the motor command has to be closely monitored and corrected if necessary. A considerable amount of work has been carried out to understand the processes involved in each of these stages (for a comprehensive review, see Desmurget et al., 1998). The first step in reach-to-grasp tasks consists in identifying the target and in determining its position in space as accurately as possible. Several systems interact during this process. Simply speaking, an initial ‘eye-centered’ representation of the target is constructed by combining visual input encoding the topographic features of the stimulus within the retina with extra-retinal signals monitoring eye position. Among these extra-retinal signals, it has been demonstrated that non-proprioceptive signals monitoring gaze displacement play the most important role in target localization (Sparks & Mays, 1983; Guthrie et al., 1983). A slighter, but significant contribution of ocular proprioception has also been demonstrated (Gauthier et al., 1990; Blouin et al., 1996), especially in the absence of a structured visual background (Blouin et al., 1993). Then, all this information is translated to a ‘bodycentered’ reference frame, which is compatible with the action to be performed. This is achieved by integrating the initial ‘eye-centered’ representation of the target with 79 80 EXPERIMENTS ON VISUOMOTOR COORDINATION proprioceptive signals encoding the position of the body in extrapersonal space. This proprioceptive information is gathered mainly from the vestibular system as well as from the muscles of the neck and the body (Dichgans et al., 1974; Jeannerod, 1981; Jeannerod, 1984; Roll et al., 1986). Vision and proprioception are the main sources of information used by the sensorimotor system for planning and executing motor commands (Prablanc et al., 1986; Pelisson et al., 1986). The influence of each of these information sources on visuomotor performance has been thoroughly investigated. Movement accuracy is obviously maximized when both sensory inputs are available (Rossetti et al., 1994; Rossetti et al., 1995). Early deafferentation studies revealed that without proprioception and vision of the actuating limb, monoarticular pointing tasks can still be performed with relative accuracy (Kelso & Holt, 1980; Rothwell et al., 1982; Bizzi et al., 1984), but multi-joint movements are severely impaired (Bossom, 1974; Taub et al., 1975; Rothwell et al., 1982). If vision of the arm is prevented during movement execution, pointing accuracy decreases (Merton, 1961; Held & Freedman, 1963; Foley & Held, 1972). Allowing vision of the hand only before movement initiation already resulted in a significant improvement of movement accuracy both in normal subjects (Prablanc et al., 1979; Rossetti et al., 1994; Desmurget et al., 1997) and in deafferented patients (Ghez et al., 1995). Rossetti et al. (1995) explored the effect of introducing a sensory conflict between visual and proprioceptive information sources in a pointing task. The initial position of the hand was optically displaced with prisms while the vision of targets was kept undistorted. Vision of the limb was not available during the movement. Results indicated a systematic pointing error directed opposite to the optical visual displacement of the hand. The perturbation remained, however, undetected to most subjects. A more recent study used virtual reality to isolate both information sources (Lateiner & Sainburg, 2003). Results revealed that visual (virtual) input predominated over proprioceptive (real) input when adjusting the direction of movement. Altogether, these studies demonstrate that both visual and non-visual information are used in conjunction during visuomotor tasks. Continuous monitoring of the motor apparatus significantly contributes to the accuracy of goal-directed movements. In addition, when visual and non-visual sensory signals diverge, visual input appears to be privileged. 4.2.1 Vision and visuomotor coordination The findings summarized previously substantiate the fact that visual information is continuously used by the nervous system to solve the different issues it faces when performing visuomotor tasks. Yet, an important question remains open: What kind of visual information is used and in which context? Based on the different visuomotor deficits observed in animals and patients as a consequence of localized brain damage, Schneider (1969) postulated that two distinct neural mechanisms are involved when reaching towards objects: one responsible for target identification and another responsible for target localization. Ungerleider & Mishkin (1982) further specified that visual information was selectively MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 81 Figure 54. Illustration of visuomotor behavior during a reach-to-grasp task. Reaching behavior is functionally separated in two parallel visual channels, one dedicated to target identification and the other with encoding target location. Modified from Paillard (1982). With permission of MIT Press. processed to encode intrinsic (size, shape, weight, etc…) and extrinsic (distance, location, etc…) target cues in the inferior temporal and posterior parietal cortex, respectively (see also Jeannerod & Biguer, 1982). Following this line of thought, Paillard (1982) subdivided reach-to-grasp tasks into the distinct behavioral elements illustrated in figure 54. Goodale & Milner (1992) reformulated this idea of separate processing pathways focusing more on output task requirements than on target characteristics. They suggested that both the ventral (V1 Æ inferior temporal cortex) and dorsal (V1 Æ posterior parietal cortex) streams process all visual information (structure and location), but each selectively transforms it with different purposes: perception (object recognition/identification) or action (intervening in visuomotor actions directed at such objects). Figure 55 illustrates this functional segregation along the entire visual pathway. According to the previous view, if all visual information is processed through the parallel streams, central and peripheral vision should contribute in a particular manner to each visuomotor mechanism. There is substantial evidence from psychophysical experiments outlining the differential roles of foveal and peripheral vision during visual search for potential targets. On one hand, a number of studies suggest that detailed object information is primarily coded in the fovea and its surroundings. Parker (1978) explored eye movement behavior during a picture recognition task. In his experiments, subjects had to detect changes in a visual scene consisting in a matrix of 6 objects separated from each other by 10°. Results showed that almost all objects had to be fixated in order to detect a change in the scene. Later, Nelson & Loftus (1980) demonstrated that a particular feature of a scene is more likely to be detected when it has been directly or closely (within 2.6°) fixated. Other studies have confirmed these findings, indicating that foveal processing is required for encoding detailed object features (see e.g. Nodine et al., 1979; De Graef et al., 1990; Hollingworth et al., 2001; Henderson & Hollingworth, 2003). On the other hand, it has been suggested that the perceptual span in scene perception is larger than it is for reading (Rayner & Pollatsek, 1992; Henderson et al., 1997). In 82 EXPERIMENTS ON VISUOMOTOR COORDINATION other words, during visual search, meaningful information can apparently be extracted from relatively broad visual areas within a single fixation. This assumption arises from a number of experimental observations. In the previously mentioned study by Parker (1978), subjects were able to detect scene changes without directly fixating the object concerned Figure 55. Simplified diagram of the information flow along in 85% of the trials. In the visual pathway. Visual input stimulating the retina addition, changed objects reaches V1 through the lateral geniculate nucleus (LGN). were fixated sooner than From V1, visual information projects through the ventral unchanged objects. This stream to the posterotemporal (occipito-temporal) cortex, reveals that useful and through the dorsal stream to the posteroparietal cortex. The dorsal stream also receives retinal information projected information about changes of by the superior colliculus through the pulvinar. Reprinted the visual environment can be from CURR OPIN NEUROBIOL, 14(2), Goodale & Westwood, gathered in the peripheral An evolving view of duplex vision: separate but interacting visual field (as far as 10° cortical pathways for perception and action, pp. 203-211, eccentricity), and that such Copyright 2004, with permission from Elsevier. information can be used either to elicit a perceptual response (such as reaching towards an object) or to redirect successive fixations. Other studies confirm that subjects tend to fixate areas of the visual scene containing meaningful information based on information gathered on the periphery of the visual field (Antes, 1974; Loftus & Mackworth, 1978). A later experiment using artificial scotomas in normal subjects, demonstrated that good object identification accuracy could be achieved with eccentric vision (Henderson et al., 1997). However, eye movement behavior was disrupted, probably due to the additional processing required for identifying objects in the periphery. All these evidence indicates that, while visual information extracted from the fovea and its surroundings is beneficial for object identification/recognition, peripheral areas of the visual field play an important role in identifying ‘informative’ regions of the visual field and subsequently redirecting eye movements towards these areas. All these findings fit well with the anatomical and physiological characteristics of the central and peripheral areas of the visual field (refer to Chapter 1 for details). It is thus not surprising that central vision is functionally specialized in high-resolution sampling of spatial information, while peripheral vision mainly contributes to encoding dynamic (movement) and relative distance cues. It can be therefore concluded that central vision plays an important role in target identification and in fine limb trajectory adjustments, while peripheral vision is mainly responsible of determining and controlling eye and hand movements towards the target’s location MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 83 (Paillard, 1982; Sivak & Mackenzie, 1992; Hooge & Erkelens, 1999; Cornelissen et al., 2005). 4.2.2 Visuomotor coordination in the context of artificial vision Our previous experiments exploring the reading task do not allow us to directly extrapolate to tasks involving visuomotor coordination. Clinical and epidemiological findings have revealed that several visual factors have different effects on visionrelated daily activities (see e.g. Owsley et al., 2001; West et al., 2002; Nelson et al., 2003). Visual acuity deficits (i. e. disorders of the central part of the visual field) affect visuomotor tasks requiring detailed vision, such as those involving object identification. In addition, defects of the peripheral visual field affect localization and orientation abilities, critical for visuomotor coordination. Only some qualitative experiments have been carried out to explore visuomotor coordination tasks in conditions mimicking artificial vision (Humayun, 2001; Hayes et al., 2003; refer to Chapter 1 for details). However, fundamental aspects of prosthetic vision (stabilized retinal projection and probable eccentric implant location) have been neglected. More recently, the same group presented results of psychophysical testing involving simple tasks on a blind subject wearing an epiretinal prosthesis containing 4 x 4 stimulating electrodes (Humayun et al., 2003). The subject was able to perform the tasks54 with 75% - 100% accuracy. An important learning effect was also observed. This study was designed to describe quantitatively the outcome of one of the first chronic implantation trials on humans. It also contributed to the validation of the epiretinal prosthesis concept and gave important information on the nature and type of percepts that could be evoked with electrical stimulation. Nevertheless, this study did not give much information regarding rehabilitation prospects of such devices. The tasks evaluated were very simple, and did not mimick realistic, every-day situations. Furthermore, the different aspects of visual function were not entirely considered. The main objective of the investigation presented in this chapter was to systematically assess visuomotor coordination performance in conditions mimicking artificial vision. With this purpose, we developed a portable system capturing images representing different portions of environment, and projecting pixelized stimuli onto defined, stabilized areas of the visual field. In a first set of experiments we determined the minimum requirements for useful visuomotor coordination, by studying the influence of stimulus information content (pixelization level and available field of view) on visuomotor performance with a viewing window stabilized in central vision. A second set of experiments was dedicated to explore whether 54 Performance was evaluated on tasks using either computer controlled electrical stimulation or camera controlled electrical stimulation. In the first case, the subject had to identify the order and location of phosphenes evoked with different electrodes activated sequentially. In the second case, the subject used a head-mounted camera to control the electrical stimulation pattern. The tasks evaluated were the detection of the presence or absence of ambient light, motion detection, target localization, and simple shape recognition. 84 EXPERIMENTS ON VISUOMOTOR COORDINATION naïve subjects could learn to perform visuomotor coordination tasks in eccentric vision, under similar experimental conditions. 4.3 Specific methods for the experiments on visuomotor coordination 4.3.1 Subjects Subjects were recruited either from the staff of the Ophthalmology Clinic of the Geneva University Hospitals or from the staff of the University of Geneva. They were familiar with the purpose of the study. All had visual acuity better than 16/20 on the tested eye, normal ophthalmologic status, and normal haptic55 perception. 4.3.2 Visuomotor tasks Two tests were especially developed for our studies based on common clinical tests and on previous studies of visuomotor coordination in natural tasks and settings (Pelz, 1995; Purdy et al., 1999; Land et al., 1999; Pelz & Canosa, 2001; Pelz et al., 2001; Humayun, 2001). a) b) Figure 56. Tasks used to assess visuomotor coordination performance: a) The chips task consisted in placing wooden chips following a randomized model; b) The LEDs task consisted on pointing on random targets as accurately as possible. 4.3.2.1 The chips task First, we explored a simple manipulation task (fig. 56a). Subjects had to recognize simple figures and place them in the adequate position and orientation on 55 Haptic perception involves both tactile perception through the skin and proprioceptive perception of the position and movement of joints and muscles. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 85 randomized templates. The template was a 5 x 4 array of square wooden chips, each representing one of 20 different black figures drawn on a white background. The chips measured 8 x 8 cm2 and were covered with a smooth and transparent plastic sheet to remove tactile cues. The total working surface of the model was, therefore, 40 x 32 cm2. The figures appearing on the chips measured 3 - 6 cm along each axis. For each experimental run, a custom program randomly determined the position of each chip on the template (none of the subjects was presented with the same chips configuration twice). At the beginning of each run, the randomized template was placed in front of the subject, and he received a box containing a copy of each chip. The score (1 = correct position and orientation; 0.5 = correct position but wrong orientation; 0 = wrong position) for each chip was noted once the subject released it at a certain position on the template. Then, the examiner removed the placed chip to avoid the use of structural and tactile cues for identifying and positioning the remaining chips. The experiment ended once subjects placed all chips and the total time needed to complete the task was recorded. Performance was determined on the basis of the %-score of correctly placed chips and of the mean chip placement time (calculated as the total time required for placing all chips divided by the number of correctly placed chips, in s). Similar to the reading experiments, %-correct scores were transformed to RAU units for all statistical analyses, but equivalent %-scales are shown on the right axes of the graphs for clarity. 4.3.2.2 The LEDs task Second, we examined a simple pointing task (fig. 56b). Subjects had to point with the finger, as precisely as possible, on bright targets lighting up randomly on a rectangular panel in front of them. The panel was a 6 x 4 array of red light emitting diodes (LEDs) surrounded by aluminum reflectors. The array of LEDs was covered with a smooth red plastic filter to avoid that the potential targets were seen when not lit. A transparent 19.7” touch screen (3M Touch Systems, Massachusetts, USA; refer to Appendix B for detailed specifications) was placed over the filtered LEDs panel. The viewable area of the touch screen subtended 39 x 31.5 cm2. Distance between LEDs (center to center) was of 6 cm and the distance between the touch screen borders and most exterior LEDs was of 4 cm. When lit, the diameter of the circular bright spot of the LEDs subtended approximately 1 cm. Subjects were presented with a different random target order for each experimental run (all 24 targets were lit and the same target was never lit twice). Random target order per subject and per run was pre-established by a custom program. The touch screen registered the position where the subjects pointed on screen coordinates (pixels), and these values were transformed to cm56. Pointing position and time for each target were recorded. 56 A screen resolution of 640 x 480 pixels (as used in these experiments) resulted in horizontal and vertical touch screen resolutions of 16.46 and 15.21 pixels/cm, respectively. 86 EXPERIMENTS ON VISUOMOTOR COORDINATION Performance was measured as mean pointing error (calculated as the cumulative pointing error57 for all targets divided by the number of targets, in cm) and mean pointing time per target (calculated as the total time required for pointing on all targets divided by the number of targets, in s). 4.3.3 Effective field of view For the reading experiments, 5 to 7 characters were visible at glance, and this visual information was projected on a retinal surface of 3 x 2 mm2. This corresponds to a quite narrow tunnel vision with high resolution. Small EFFECTIVE FIELD OF VIEW Medium Large 17920 pixels 498 pixels 124 pixels Figure 57. Effect of varying simultaneously the size of the effective field of view and the resolution of the image projected in the viewing window for the chips task. Columns: visual fields of 8.25°x5.8°, 16.5°x11.6°, and 33°x23.1°. Lines: resolutions of 17920, 498, and 124 pixels. Previous research has demonstrated that the size of the effective field of view has a significant influence in performance for tasks involving visual search and orientation, such as visuomotor and mobility tasks (see e.g. Kerkhoff, 1999; Zihl, 2000; Szlyk et al., 2001; Rubin et al., 2001; Nelson et al., 2003). Compared to reading, these tasks require much larger portions of the visual scene to be visible at a glance. Figure 57 shows several examples of the visual scene for the chips task 57 Pointing error for each target was calculated as the absolute distance between the actual target location and the position where the subject pointed. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 87 subtending different effective fields of view. In this case, the pertinent visual information is typically ‘what is at hand reach while sitting at a table’. Seeing the whole scene at once (large field of view) requires an image resolution close to normal vision, which is clearly out of reach of envisioned prostheses. The smallest field of view provides useful information at lower resolutions, but implies timeconsuming ‘tunnel’ scanning of the scene. The various compromises between the effective field of view available and resolution (pixelization level) must, therefore, be thoroughly investigated when considering visuomotor tasks. In our experiments, we examined this issue by projecting different portions of the environment (subtending different effective fields of view) onto a stabilized viewing window. This was achieved by modifying the frame size of the image captured by the webcam. In our mobile setup the stimulation screen subtended 40° x 30° of visual field, and was set to a resolution of 640 x 480 pixels. Using its standard optics, the webcam captured images of the environment corresponding to 33° x 24.75°. Therefore, when the webcam’s image frame size was set to the same resolution than the screen (640 x 480), 1° on the screen corresponded to 0.83° of the environment. Consequently, the 10° x 7° viewing window represented a portion of the environment subtending 8.25° x 5.8°. Similarly, setting the image frame size of the webcam to 320 x 240 pixels58 or to 160 x 120 pixels59 resulted in portions of the environment of 16.5° x 11.6° or 33° x 23.1° being projected onto the 10° x 7° viewing window. 4.3.4 Experimental setup The details of the simulation procedures have already been described in the General Methods Chapter. The apparatus used corresponded to the mobile setup. The image-processing algorithm used was real-time square pixelization. The experimental procedure was very similar to that used for the reading Figure 58. One of the subjects wearing the mobile setup experiments. Briefly, subjects during the chips task. were seated wearing the mobile setup (see fig. 58). At the beginning of each run, a standard 9-point calibration was performed and the experimental sequence started afterwards. The viewing window (10° x 7°), contained pixelized images extracted from the frames captured by the webcam. Gaze 58 59 1° on the screen = 1.65° of the environment. 1° on the screen = 3.3° of the environment. 88 EXPERIMENTS ON VISUOMOTOR COORDINATION position compensation was used to project this viewing window onto defined (central or eccentric) areas of the retina. The background of the remaining screen surface was gray (corresponding to the mean luminosity of the visual scene). Tests were performed monocularly (using the dominant eye). Test sessions frequently included several runs, but they never lasted longer than 30 minutes to avoid subjects’ fatigue. Eye movement data for each experimental session were recorded and stored for further analysis. 4.4 Acute experiments on visuomotor coordination Visuomotor performance in central vision was assessed versus 2 variables of prosthetic vision: the pixelization level and the effective field of view. With the mobile setup, subjects could explore the environment (modify the stimulus image displayed in the viewing window) in two ways: with eye movements and/or by moving their head and trunk. It is interesting to examine how subjects used these movements to cope with the different viewing conditions. Head movement data for each experimental session were also recorded. This analysis, however, does not directly concern the main purpose of this dissertation. Therefore, the detailed analysis of eye and head movements is presented in Appendix D. 4.4.1 Experimental protocol Three subjects (CR, male, 24 years old; AP, female, 27 years old; JS, male, 42 years old) participated in the experiments. Before starting the actual experimental sequence, all subjects performed 3 control sessions for each task. These control sessions were conducted in normal viewing conditions (subjects were not wearing the mobile setup). These performance results were used as baseline measures for ‘normal’ visuomotor performance. Table 2. Testing sequences (latin square permutation) for the effective fields of view during experiments 5 and 6. Chips LEDs AP CR JS AP CR JS 1 33° x 23.1° 16.5° x 11.6° 8.25° x 5.8° 16.5° x 11.6° 8.25° x 5.8° 33° x 23.1° 2 8.25° x 5.8° 33° x 23.1° 16.5° x 11.6° 8.25° x 5.8° 33° x 23.1° 16.5° x 11.6° 3 16.5° x 11.6° 8.25° x 5.8° 33° x 23.1° 33° x 23.1° 16.5° x 11.6° 8.25° x 5.8° Subjects first performed all tests for the chips task, and then for the LEDs task. Performance was measured with viewing windows presented at 5 pixelization levels60 (17920, 1991, 498, 221, and 124 pixels) and 3 effective fields of view (8.25° x 5.8°, 16.5° x 11.6°, and 33° x 23.1°; see fig. 57). Three successive runs were performed per experimental condition (a given effective field of view and pixelization level). The 60 Equivalent to those used in our previous study on reading of isolated 4-letter words. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 89 order in which each effective field of view was presented to each subject was permuted using a latin square61 (see table 2). With each field of view, subjects started with the easiest (highest) pixelization level and progressed towards the most difficult (lowest) one. Once all pixelization levels for a given field of view where completed, subjects progressed to the next one. Possible global learning effects favoring a particular effective field of view would be therefore minimized, but would still favor performance at low pixelization levels. Results were calculated as the mean of the cumulative data of each subject ± standard error of the mean (SEM). Statistically significant differences were determined using standard (paired) t tests with a significance level of 0.05. 4.4.2 Experiment 3: Manipulation – The chips task a) b) Figure 59. Visuomotor performance versus number of pixels in the 10°x7° viewing window for 3 normal subjects performing the chips task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Mean correct scores expressed in RAU ±SEM (left scale) and in % (right scale). (b) Mean chip placement time (mean time required to identify and correctly place a chip) expressed in s ±SEM. The solid black lines indicate mean performance results (±SEM) during control sessions (normal viewing conditions). Figure 59 compares mean visuomotor performance for the chips task, with each effective field of view, versus number of pixels in the viewing window. Individual performances in each experimental condition were established on the basis of 3 sessions. Chip placement scores were close to perfect (> 95%) in most viewing conditions. Accuracy dropped below 95% only at 124 pixels with the 16.5° x 11.6° field of view (blue plots in fig. 59), and at 221 and 124 pixels with the 33° x 23.1° field of view (green plots in fig. 59). 61 A latin square is an array of N x N elements arranged so that no orthogonal (column or line) contains the same element twice. These permutations are used to avoid learning effects favoring performance in a certain experimental condition. 90 EXPERIMENTS ON VISUOMOTOR COORDINATION Mean chip placement time appeared to be more sensitive to pixelization level. With the 8.25° x 5.8° field of view (red plots in fig. 59), values were statistically equivalent across all pixelization levels. However, time tended to increase at 221 and 124 pixels. In addition, a non-significant learning effect was observed at 1991 and 498 pixels. With the 16.5° x 11.6° field of view, a significant slow-down was observed at 498 (p = 0.04) and 221 pixels (p = 0.02), but did not persist at 124 pixels (p = 0.09) due to the high variability of the results. With the 33° x 23.1° field of view, time increased significantly at 498 pixels (p = 0.02). This effect was also visible at 221 pixels, but it was not significant (p = 0.1). The significant slow-down manifested again at 124 pixels (p = 0.004). Even at the highest pixelization levels, chip placement time was approximately 2 - 6 times slower with the 3 effective fields of view than in normal viewing conditions (~ 2 s; p < 0.05; black solid lines in fig. 59). a) b) Figure 60. Normalized visuomotor performance versus effective resolution of the environmental space in the 10°x7° viewing window for 3 normal subjects performing the chips task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Normalized scores ±SEM. (b) Normalized chip placement time ±SEM. The solid black lines indicate the best fit to the data. Performance data for the chips task were normalized to values achieved at the highest pixelization (17920 pixels), for each of the effective fields of view. Figure 60 displays mean results ± SEM plotted versus the effective resolution of the environmental space62. Data obtained with the different fields of view were fitted together to single exponential functions63 (solid black lines in fig. 60). Best fit for normalized scores reveals that maximum scores can be achieved with effective environmental resolutions down to approximately 1.10 pixels/deg2. Mean scores 62 Calculated as the number of pixels needed to represent a field of view of 1° x 1° in each condition, expressed in pixels/deg2. 63 y = yo + ae-bx MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 91 decrease markedly below this effective resolution level. A similar trend can be observed for normalized time results. Best fit to the data shows that the mean time needed to correctly identify and place a chip increases notably at effective environmental resolutions below 1.40 pixels/deg2. 4.4.3 Experiment 4: Pointing – The LEDs task a) b) Figure 61. Visuomotor performance versus number of pixels in the 10°x7° viewing window for 3 normal subjects performing the LEDs task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Mean pointing error expressed in cm ±SEM. (b) Mean pointing time (average time required for finding and pointing on a target), expressed in s ±SEM. The solid black lines indicate mean performance results (±SEM) during control sessions (normal viewing conditions). Figure 61 compares mean visuomotor performance for the LEDs task, with each effective field of view, versus number of pixels in the viewing window. Individual performances in each experimental condition were established on the basis of 3 sessions. At 17920 and 1991 pixels, the 3 effective visual fields yielded pointing errors of approximately 1 cm. With the 8.25° x 5.8° field of view (red plots in fig. 61), errors remained at the same level even at the lowest pixelization. Nonetheless, a slight tendency towards larger errors was observed at 124 pixels. With the 16.5° x 11.6° field of view (blue plots in fig. 61), errors tended to increase (non-significantly) at 498 pixels and below. With the 33° x 23.1° field of view (green plots in fig 61), pointing errors increased at 498 pixels and below. This loss of pointing precision was significant only at 221 (p = 0.03) and 124 (p = 0.003) pixels. Mean pointing time was influenced by the size of the effective field of view projected in the viewing window. However, no significant effect of the pixelization level was observed. The slowest pointing times were obtained with the 8.25° x 5.8° field of view (~ 10 s). With the 16.5° 11.6° field of view, mean pointing times were of approximately 6 s. The fastest pointing times were obtained with the 33° x 23.1° 92 EXPERIMENTS ON VISUOMOTOR COORDINATION field of view, which yielded values of about 5 s at the highest pixelizations. Mean pointing times with this largest field of view slightly increased to approximately 6 s at 221 and 124 pixels. Comparison of these results with performance obtained in normal viewing (black solid lines in fig. 61) reveals that pointing errors were 2 - 3 times larger in our particular experimental conditions. Pointing times were 3 – 7 times slower with the 3 effective fields of view than in normal viewing conditions. Performance data for the LEDs task were also normalized to values achieved with the highest pixelization (17920 pixels), for each effective field of view. These results (mean ± SEM) are plotted versus the effective resolution of the environmental space in figure 62. Data obtained with the different fields of view were fitted together to single exponential functions (solid black lines in fig. 62). Best fit for normalized pointing errors reveals that accuracy decreases at effective environmental resolutions below 2.2 pixels/deg2. Normalized pointing time appears to be less sensitive to the effective resolution of the environmental space. In this case, best fit for the data indicates that temporal performance is stable down to effective resolutions of about 0.8 pixels/deg2. Time needed to localize and point on a target increases below this value. a) b) Figure 62. Normalized visuomotor performance versus effective resolution of the environmental space in the 10°x7° viewing window for 3 normal subjects performing the LEDs task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Normalized pointing errors ±SEM. (b) Normalized pointing time ±SEM. The solid black lines indicate the best fit to the data. 4.4.4 Summary of the results of these experiments Altogether, results from experiments 5 and 6 demonstrate that both the number of pixels contained in the viewing window as well as the effective visual field MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 93 projected inside it selectively affect visuomotor performance. Various combinations of resolution and field of view allowed good performance on these tasks. Nevertheless, these data reveal a fundamental limit for visuomotor performance: a minimum effective resolution of about 2 pixels/deg2 was necessary to achieve both tasks with reasonable accuracy and speed. In addition, a 16.5° x 11.6° effective field of view seems to be the best compromise for visuomotor performance, providing a reasonably large visual span while still maintaining reasonable image resolution. 4.5 Habituation experiments on visuomotor coordination We conducted 2 successive experiments. First, subjects were asked to perform the visuomotor tasks using a viewing window stabilized on the fovea. In a second experiment, subjects were asked to perform the same tasks, but using a viewing window stabilized at 15° of eccentricity. To be consistent with our previous experiments on reading, a resolution of 498 pixels in the viewing window was judged to be the most adequate for the habituation experiments on visuomotor coordination. An effective field of view of 16.5° x 11.6° was chosen on the basis of experiments 5 and 6. This combination results in an effective resolution of the environmental space of approximately 3 pixels/deg2. 4.5.1 Experimental protocol Three subjects (AP, female, 27 years old; AW, male, 34 years old; MV, male, 28 years old) participated in the experiments. All of them were naïve to eccentric viewing and were tested monocularly using their dominant eye. One of the subjects (AP) was already familiar with the tasks since she also participated in the first set of experiments exploring the minimum requirements for visuomotor coordination. For each experimental session, the visuomotor tasks were intercalated: subjects first performed one run of the chips task, then one run of the LEDs task. The remaining aspects of the experimental procedure were identical to those described for the acute experiments on visuomotor coordination. Eye movements were recorded all through the experiment and stored for further analysis. The detailed analysis of eye movements is presented in Appendix D. Each run started with a calibration of the eye tracker, and at the end the calibration was checked for possible drifts. Whenever the average error obtained in the calibration check was ≥1°, the results for the corresponding session were removed from the analysis. This was never the case in the preparatory experiment (central vision). In experiment 5 (eccentric vision), 4 sessions of the chips task (12.5%) were discarded for subject AP. In the case of subject AW, 8 sessions for the chips task (25%) and 7 sessions for the LEDs task (21%) were discarded. Finally, for subject MV, 14 sessions for the chips task (41%) and 4 sessions for the LEDs task (12.5%) had to be discarded. Possible learning effects were investigated by repeatedly performing experimental sessions for more than 1 month. The criterion used to stop the experiments was the 94 EXPERIMENTS ON VISUOMOTOR COORDINATION stabilization of temporal performance (chip placement time and pointing time). In general, 2 - 3 experimental sessions were conducted each working day of the week (5 days per week). The duration of each experimental session was variable throughout the experiment, but never exceeded of 30 minutes of testing. Two periods of testing represented therefore less than 1 hour of daily training. In a preparatory experiment, several sessions were conducted using a viewing window stabilized in central vision. This experiment lasted until subjects became familiar with the tasks (performing both visuomotor tasks while exploring the environment using a small viewing window). Experiment 5, testing eccentric visuomotor performance, began once the subjects had adapted to the central viewing condition. Learning curves were computed using exponential functions as described in Chapter 2. Significant learning effects were determined using simple linear correlation (Pearson’s correlation). 4.5.2 Preparatory experiment: Learning in central vision This experiment was dedicated to familiarize subjects with the unusual activity of performing visuomotor tasks using a small viewing window containing pixelized segments of the environment. Approximately 18 to 27 sessions were necessary for time to asymptote. Figure 63 presents performance in central vision versus session number for the chips task. All three subjects achieved good chip placement scores (> 85% correct) already in the first sessions. Significant learning effects were observed in the analysis of chips scores versus time for 2 subjects (Pearson’s correlation: r = 0.48, p < 0.05 a) b) Figure 63. Performance versus session number obtained for 3 normal subjects performing the chips task in central vision (10°x7° viewing window containing 498 pixels and subtending a 16.5°x11.6° field of view). Results expressed as: (a) Chip placement scores expressed in RAU (left scale) and in % (right scale). (b) Chip placement time expressed in s. The solid lines indicate the best fits to the data. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 95 for AW; and r = 0.69, p < 0.001 for MV). In the case of subject AP, no significant learning effect was observed since she achieved perfect scores (100% correct) already in the first sessions. Chip placement time improved significantly with training for all three subjects (Pearson’s correlation: r = 0.73, p < 0.001 for AP; r = 0.63, p < 0.001 for AW; and r = 0.77, p < 0.0001 for MV). Analysis of the experimental data revealed that the average time required for correctly identifying and placing a chip diminished from 7 to 4.5 s for AP, from 20 to 7 s for AW, and from 16 to 7 s for MV. Figure 64 shows performance in central vision versus session number for the LEDs task. Subjects achieved average pointing errors between 2 and 1 cm in the first sessions. A significant learning effect was observed in the analysis of pointing errors versus time only for AW (Pearson’s correlation: r = 0.65, p < 0.001), who improved his results from about 1.5 cm down to approximately 1 cm. Mean pointing errors for subject AP remained stable around 1.1 cm. Pointing errors for subject MV slightly declined with training from approximately 2 cm down to about 1.4 cm. Mean pointing time significantly improved with training for all three subjects (Pearson’s correlation: r = 0.54, p < 0.05 for AP; r = 0.71, p < 0.0001 for AW; and r = 0.54, p < 0.05 for MV). Results improved from 4.7 to 4 s for AP, from 5.5 to 3 s for AW, and from 7 to 4.8 s for MV. a) b) Figure 64. Performance versus session number obtained for 3 normal subjects performing the LEDs task in central vision (10°x7° viewing window containing 498 pixels and subtending a 16.5°x11.6° field of view). Results expressed as: (a) Mean pointing error expressed in cm. (b) Mean pointing time expressed in s. The solid lines indicate the best fits to the data. These data clearly demonstrate that accurate but relatively slow visuomotor performance can be obtained under conditions mimicking artificial vision in the central visual field. This means that all necessary information could be transmitted and captured by the visual system. Almost all chips could be correctly identified and placed. Leds were localized with reasonable accuracy. However, time variables for both tasks were noticeably lower than results reported for normal viewing conditions 96 EXPERIMENTS ON VISUOMOTOR COORDINATION in experiments 5 and 6 (compare figs. 63b and 64b with figs. 59b and 61b). This outcome is not surprising due to the increased difficulty of exploring the environment using a restricted viewing window. 4.5.3 Experiment 5: Learning in eccentric vision This experiment was dedicated to explore whether subjects could adapt to the unusual activity of performing visuomotor tasks using a small viewing window containing pixelized segments of the environment, and stabilized at 15° eccentricity in the lower visual field. In this case, temporal performance for both tasks asymptoted within 30 sessions. Figure 65 shows performance in eccentric vision (15° in the lower visual field) versus session number for the chips task. Significant learning effects were observed in the analysis of chip placement scores versus time for the 3 subjects (Pearson’s correlation: r = 0.47, p < 0.05 for AP; r = 0.47, p < 0.05 for AW; and r = 0.73, p < 0.001 for MV). Scores for subject AP improved impressively: from initial scores below 10% correct, up to final scores above 97%. Surprisingly, subject AW achieved scores above 90% correct already in the initial sessions, and achieved perfect (100% correct) scores at the end of the experiment. Subject MV also started the experiment with relatively high scores, around 90% correct. He consistently achieved perfect scores after about 20 sessions. Improvements in chip placement time were more gradual and impressive. Significant learning effects were observed for all subjects (Pearson’s correlation: r = 0.80, p < 0.0001 for AP; r = 0.97, p < 0.0001 for AW; and r = 0.81, p < 0.0001 for a) b) Figure 65. Performance versus session number obtained for 3 normal subjects performing the chips task in eccentric vision (15° in the lower visual field). Experimental conditions: 10°x7° viewing window containing 498 pixels and subtending a 16.5°x11.6° field of view. Results expressed as: (a) Correct scores expressed in rationalized arcsine units [RAU] (left scale) and in % (right scale). (b) Chip placement time expressed in s. The solid lines indicate the best fits to the data. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 97 MV). Subject AP showed an approximately 4-fold improvement: from above 30 s in the first sessions, to reaching an asymptote around 7 s in approximately 13 sessions. In subject AW, chip placement time decreased from around 26 s in the initial sessions, down to 9 s after about 7 sessions. Subject MV started the experiment with values around 25 s, and reached an asymptote around 9 s after approximately 30 sessions. Figure 66 shows performance in eccentric vision versus session number for the LEDs task. Pointing error results were showed a high variability. Pointing errors for subject AP remained roughly stable throughout the experiment, around a value of 1.2 cm. Subject AW initially achieved pointing errors around 1 cm, and with time values significantly increased to approximately 1.4 cm (Pearson’s correlation: r = 0.61, p < 0.01). A significant learning effect was observed in the analysis of pointing errors versus time for MV (Pearson’s correlation: r = 0.58, p < 0.01), who improved his results from around 1.6 cm to 1.2 cm. Results for this subject were still decreasing when the experiment ended. Pointing time improved significantly with training for subjects AP and MV (Pearson’s correlation: r = 0.68, p < 0.0001 for AP; and r = 0.63, p < 0.001 for MV). Values improved from 21 to 6 s for AP (in ~ 7 sessions) and from 22 to 6.5 s for MV (in ~ 9 sessions). Subject AW started the experiment with relatively fast pointing times (~ 7 s). With training, values for this subject slightly (non-significantly) declined to approximately 5 s. a) b) Figure 66. Performance versus session number obtained for 3 normal subjects performing the LEDs task in eccentric vision (15° in the lower visual field). Experimental conditions: 10°x7° viewing window containing 498 pixels and subtending a 16.5°x11.6° field of view. Results expressed as: (a) Mean pointing error expressed in cm. (b) Pointing time expressed in s. The solid lines indicate the best fits to the data. 98 EXPERIMENTS ON VISUOMOTOR COORDINATION Taken together, results from experiment 5 demonstrate that an important learning process occurred for both visuomotor tasks. The evolution was expressed quite differently across subjects. Subject AP, for example, improved impressively, all through the experiment, in 3 out of the 4 measured parameters (chip placement score, chip placement time, and target pointing time). In contrast, subject AW begun the experiment with perfect chip placement scores, while his pointing errors (LEDs task) appeared to worsen with time. In his case, the learning process was best expressed in terms of chip placement time and target pointing time. At the end of experiment 5, all subjects achieved similar levels of visuomotor performance, reaching the same level than after the preparatory experiments in central vision. We can consider, thus, that after the 1-month training period, the 3 subjects that participated in the experiments attained functionally useful visuomotor performance. 4.6 Discussion The first goal of the experiments presented in this chapter was to explore the minimum requirements for useful visuomotor coordination in central vision. We assessed the influence of the particular visual conditions that will most probably result from the use of retinal prosthetic devices. Simple visuomotor tasks could be achieved with reasonable speed and accuracy at effective resolutions of the environmental space above 2 pixels/deg2 (e.g. ~ 400 pixels with the 16.5° x 11.6° field of view). Below this fundamental value, visuomotor performance was significantly impaired. Still, each of the visual constraints imposed in our artificial vision simulations had an impact on visuomotor performance. It is, thus, interesting to discuss the influence of these factors in more detail. Visuomotor performance was poorer in conditions simulating artificial vision than in normal viewing conditions, even at the highest resolution levels. At the highest pixelization level investigated, chip placement time was already 2 - 8 times slower in than in normal viewing. Pointing time for the LEDs task displays a similar picture, showing a 2-fold to 5-fold slow-down. This confirms that the simple fact of having to explore the environment with a small visual area significantly affects visuomotor performance by itself. Restricting the size of the effective field of view further limited visuomotor performance. Both visuomotor tasks were performed faster as larger portions of the environment were available at glance: a 2 to 3-fold time difference was observed between the 33° x 23.1° field of view and its 8.25° x 5.8° counterpart. Substantial increases in visual search times have been obtained in other studies investigating the influence of artificial scotomas on normal subjects (Henderson et al., 1997; Cornelissen et al., 2005). The main explanation for this finding is probably that, since input from the visual periphery is limited, there is no information for redirecting eye/head movements towards ‘informative’ regions of the environment (Antes, 1974; Loftus & Mackworth, 1978) and to plan efficient scanning strategies (Cornelissen et al., 2005). Other studies demonstrated that visual degradations such as visual field restrictions result in slower limb movements (Servos & Goodale, 1994; Servos, 2000; Loftus et al., 2004). Authors hypothesized that such slow-down is probably required by the nervous system to gather enough feedback to correct initial movement errors and avoid unwanted collisions. Therefore, the increase in the time MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 99 required to perform our visuomotor tasks is probably due to both lengthier scanning of the environment and to a reduced speed of arm movements towards the targets. Pointing precision was also fundamentally limited by our artificial ‘tunnel vision’ conditions. Irrespective of the size of the effective field of view projected in the restricted 10° x 7° viewing window and at maximum target resolution, pointing errors were almost double than average pointing precision obtained in normal viewing conditions. Pointing errors were approximately double with the smallest field of view when compared to its larger counterparts. This result fits well with findings showing that visual field restrictions and monocular viewing have an adverse effect in the accuracy of distance estimations. Coello & Grealy (1997) reported that when targets were displayed in narrow fields of view, aiming accuracy was poorer than in normal viewing conditions. A research group of the Indiana University studied the effect of different perturbations of the visual information available to subjects during reaching tasks (Bingham & Pagano, 1998). The task consisted in inserting a stylus into a target hole located at variable distance in front of the subject. Their findings confirmed that visual field restrictions in monocular viewing resulted in underestimations of target distance. In addition, their results demonstrated that the accuracy of distance estimations decreased with increasing target distance. Others explored whether estimates of object distance and size were affected by peripheral field restrictions per-se, or whether these effects varied with visual field size (Watt et al., 2000). Subjects were requested to reach towards white paper rectangles in 5 binocular visual field conditions (4°, 8°, 16°, 32°, and 64°). Experiments were performed in the dark (no visual feedback) and tactile information was removed by covering the table where the targets were positioned with a transparent acetate sheet. Subjects systematically underestimated the distance towards the target to be reached, and this underestimation increased linearly as the size of the field of view decreased. There was no evidence of misjudgment of object size across the different visual conditions tested. A more recent study (Loftus et al., 2004) demonstrated that such distance estimation errors could be reduced or even eliminated in visually rich and structured environments, as previously suggested by others (Coello & Grealy, 1997; Bingham & Pagano, 1998; Magne & Coello, 2002), and when haptic feedback was available. However, results indicated when visual field restrictions were present, the variability of the results increased. It appears, thus, that the fact of having to explore the environment with a restricted viewing window presented monocularly (in the poorly structured visual environment provided for the LEDs task), already limited the subjects’ capacity to estimate the target (LED) location. Furthermore, no tactile feedback about target location was provided. This probably resulted in the larger pointing errors observed even when images were presented at maximum screen resolution. As expected, the number of pixels in the restricted viewing window affected visuomotor performance. With the small and medium fields of view, almost perfect chip placement scores could be achieved even at low pixelization levels. With the largest field of view, chip placement scores seemed to be limited at target resolutions below 498 pixels. Pointing precision for the LEDs task worsened around 498 to 221 pixels, depending on the field of view explored. These results are in accordance with those reported for the reading task in the previous chapter, and agree with 100 EXPERIMENTS ON VISUOMOTOR COORDINATION consistent observations in low vision patients. Target resolution determines the capacity of discriminating detail in a visual image. The effect in reading is obviously more pronounced, since text characters are complex ‘objects’ requiring very fine and detailed spatial discrimination capabilities. Correctly identifying a chip required some image discrimination abilities, which were notably limited when only a few pixels were available to represent large portions of the environment (as was the case for the largest field of view at low pixelization levels). This issue was more visible in chip placement time. As less pixels became available, image discrimination became more difficult and it took subjects longer times to accurately recognize and locate the position of the chip in the template. The number of pixels in the viewing window also affected pointing precision for the LEDs task. This was particularly important in the case of the largest field of view. The rapid loss of image detail resulted in less precise estimates of target location. Head dispersion results for the chips task confirm these observations (refer to the analysis of head movements in Appendix D). Head movements for this task were noticeably influenced by the number of pixels in the viewing window, especially about the transversal axis. As the image projected in the viewing window lost resolution, subjects approached the chips template to compensate for the loss of detail. Results were quite variable for each of the subjects that participated in the experiments. In addition, only a relatively small number of subjects (only 3) participated in the experiments. However, the tendencies mentioned are clear, and we they outline rather well how the probable constraints of artificial vision devices impact visuomotor performance. In addition, our results also illustrate how the impact of these constraints can be minimized (for example, optimizing the effective field of view available for the task) so that some visuomotor coordination abilities can be restored to blind patients wearing such devices. The second goal of this investigation was to investigate whether subjects could adapt to the unnatural conditions of performing visuomotor tasks using a small restricted viewing window containing pixelized fractions of the environment and stabilized at 15° eccentricity. Our results clearly indicate that subjects are able to adapt quite well to the tasks investigated, and that performance can improve significantly with time. About 1 month of daily training was necessary in this case to achieve optimum visuomotor performance. A couple of issues still deserve to be mentioned. On one hand, our experiments do not point out the importance of eye movements for visuomotor coordinated tasks. Since there is evidence that both efferent and afferent eye position signals are used by the saccadic system to locate and encode targets, visual prostheses that allow the user to explore the environment using eye movements (as in subretinal implants transforming light into stimulation currents in-situ) could allow for better performance in these tasks than systems where the environment has to be explored with head movements. This issue should still be examined. On the other hand, our results might underestimate actual visuomotor performance under severely degraded visual conditions since we deliberately took out all possible tactile cues and experiments were performed in poorly structured visual backgrounds. Previous research has demonstrated that, for example, the simple fact of providing a MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 101 structured visual environment significantly reduced the adverse effects of visual field restrictions (see e.g. Magne & Coello, 2002; Loftus et al., 2004). Therefore, we could expect future visual prosthesis wearers to face less dramatic limitations in most real life situations than those depicted in our experiments. Yet, in our methodology we always try to use the worst possible case scenario, in order to provide the most realistic picture of the minimum visual requirements for each task category explored. 4.7 Conclusions The data reported in this chapter clearly demonstrate that useful (accurate but slow) visuomotor performance can be obtained under conditions mimicking artificial vision in the central visual field. This means that all necessary information could be transmitted and captured by the visual system. Almost all chips could be correctly identified and placed. Leds were localized with reasonable accuracy. However, visuomotor performance (specially the time required to complete the tasks) was poorer than in normal viewing conditions. This outcome is not surprising due to the increased difficulty of exploring the environment using a restricted viewing window. The results presented in this chapter also demonstrate that, after a relatively short adaptation process, useful visuomotor performance can be achieved even if retinal implants have to be placed in the periphery of the visual field. Compared to the reading task, visuomotor coordination is less demanding in terms of visual information content. Thus, at this point, we estimate that about 500600 distinctly perceived phosphenes, distributed on a 3 x 2 mm2 implant, remain the minimum criterion to achieve useful reading and visuomotor coordination. 4.8 Publications resulting from this research Pérez Fornos, A., Sommerhalder, J., Pittard, A., Safran, A.B., & Pelizzone, M. (2005). Minimum requirements for visuomotor coordination and learning of this task in eccentric vision. ARVO Meeting Abstracts, 46, 1533 (abstract). Pérez Fornos, A., Sommerhalder, J., Pittard, A., Safran, A.B., & Pelizzone, M. (2006). Minimum requirements for useful visuomotor coordination and learning of such tasks in eccentric vision. In preparation. 5 Experiments on Mobility What is the difference between exploring and being lost? Dan Eldon (1970 - 1993) 5.1 Foreword In the preceding chapters, we studied reading and visuomotor performance in conditions simulating artificial vision. An essential category of tasks should still be investigated: those involving whole-body mobility and orientation. Strelow (1985) characterizes mobility as “the skill of traveling through the spatial environment, avoiding obstacles, and traveling directly or indirectly toward goals”. Foulke (1971) more specifically defines efficient orientation and mobility as the abilities to accurately localize one’s own body in space and to travel “safely, comfortably and independently”. Visually driven motor performance is essential for various daily activities (walking, heading, way-finding, avoiding obstacles, etc…) and has different visual requirements than the previously studied tasks. For example, for stepping over an obstacle, pertinent information includes encoding the obstacle’s width, height, location and eventually speed/direction (if the obstacle is moving). Yet, other information such as color (required, for instance, for identifying targets in reaching/grasping tasks) would not be relevant. Whole-body mobility might therefore impose different constraints to an artificial vision system. The determination of minimum visual requirements for mobility is, however, not straightforward since performance on these tasks is difficult to quantify: experimental variables are not easy to manipulate and responses are difficult to measure; there is no single, most representative task; and, finally, demands of the mobility task vary according to each particular environment (Strelow, 1985). Evaluating whole-body mobility is important since, altogether with reading, it is strongly associated with vision-related estimates of quality of life and represents one of the main goals of low vision patients seeking rehabilitation (Pelli, 1987; Wolffsohn & Cochrane, 1998). 5.2 Introduction Essentially, whole-body mobility requires the capacity to judge egocentric64 and exocentric65 distances for solving issues such as localization of body in space, perception of movement, distance estimation, and speed estimation (Stoffregen, 1985; Warren, 1995; Cutting & Vishton, 1995; Apfelbaum et al., 2006). Among the sources of information used for this purpose, vision is one of the most valuable since 64 65 Distances measured from the observer to particular locations in the environment. Distances measured between two points in the environment. 103 104 EXPERIMENTS ON MOBILITY it simultaneously (and almost instantaneously) supplies static and dynamic information regarding the near and far environment (Patla, 1997). In addition, different aspects of visual information such as visual field, acuity, and contrast sensitivity, selectively influence the way we perceive the environment. For example, the size of the available visual field fundamentally limits the area in which different features of the environment (e.g. obstacles, objects of interest…) can be detected. Conversely, acuity and contrast thresholds determine how much image detail can be perceived. Between all these visual information variables, which are fundamental requirements for mobility and to which point can this input be degraded? Pelli (1987) studied this issue by artificially restricting vision (available field of view, contrast sensitivity, and visual acuity) in normally sighted subjects. Mobility tasks were performed in two environments: a laboratory maze (long corridor cluttered with randomly positioned vertical foam rubber columns) and a shopping mall (L-shaped trajectory, 250 m walking distance). In both settings, performance was nearly unimpaired down to very restricted vision, suggesting that very little information is required to walk through indoor environments with reasonable accuracy and speed. The critical thresholds he found for whole-body mobility in the laboratory maze were 10° of visual field, visual acuity of 20/2000, and 4% of normal contrast. The corresponding critical values for the shopping mall were 4° of visual field, visual acuity of 20/2000, and 2% of normal contrast. The author stated, however, that low vision patients who should, according to these criteria, have enough vision to travel with reasonable accuracy and speed, still complained of mobility problems. 5.2.1 What have we learned from low vision patients? Low vision patients generally complain of severe problems while performing mobility tasks. The nature and impact of the handicap obviously depends on the type of visual deficit, but also appears to be influenced by a number of environmental variables, such as light level, contrast, and type of obstacles involved in the task. These patients represent, thus, an ideal model to highlight the fundamental visual requirements for mobility performance. At the same time, data collected on these patients also provides valuable indications on how will the different visual constraints imposed by visual prostheses affect performance on mobility tasks. Several authors have studied mobility in low vision patients. Marron & Bailey (1982) investigated the influence of visual field, visual acuity, and spatial contrast sensitivity in mobility performance. Nineteen low vision patients participated in the experiments. Mobility and orientation were evaluated using indoor (12.2 x 2.4 m corridor cluttered with cylindrical obstacles of variable diameter and length hanging from the ceiling) and outdoor (rectangular city block including different every-day obstacles) courses. Their results showed that both visual field and contrast sensitivity have a significant effect on mobility performance, but not visual acuity. A later study examined mobility performance in 88 visually impaired veterans, divided in groups according to the type of vision loss (Kuyk et al., 1996). Travel time and total number of object contacts were measured in an indoor course. In general, mobility was influenced by light level, object contrast and object type. Performance also varied MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 105 according to the type of visual deficit: subjects with peripheral field restriction had greater difficulty than those with acuity loss. Later, the same authors (Kuyk et al., 1998; Kuyk & Elliott, 1999) presented similar studies but using real world settings (indoor hallway and outdoor course in a residential area). Their results confirmed that reduced illumination notably impaired mobility. Similar to previously mentioned findings by Marron & Bailey (1982), contrast sensitivity and visual field extent were found to be the most important predictors of performance. Laboratory results correlated well to those obtained on real world situations, but inter-subject variability was considerable, probably due to differences in vision characteristics between diseases and to task complexity. Geruschat et al. (1998) compared mobility performance of patients suffering from retinitis pigmentosa (RP) with those of normal subjects. The task consisted in walking through a predefined course as quickly and safely as possible, avoiding all obstacles in their path. Travel time, number of mobility incidents and self-perceived estimates of mobility performance were measured under normal and reduced illumination conditions. In general, RP patients traveled more slowly than normally sighted subjects. All subjects (normal and RP) were affected by reduced illumination, but mobility incidents were 5 times more frequent in RP patients. Walking speed was significantly correlated with 3 visual variables: visual acuity, contrast sensitivity and visual field extent. Turano & Wang (1992) measured spatial motion thresholds66 in both normal and RP subjects. In general, these motion thresholds were higher in RP patients than in normal subjects. They were also significantly higher when simulating random photoreceptor (pixel) dropout above 25% in normal subjects. These findings confirm the hypothesis that a reduction in spatial photoreceptor density contributes to motion-threshold elevation. The same research group tried to categorize a series of 35 mobility situations for patients at various stages of RP (Turano et al., 1999). They used a questionnaire scaling from 1 (no difficulty) to 5 (extreme difficulty). The mobility situations requiring the least and most visual ability were, respectively, “moving about in the home” and “walking at night”. A research group at the Arlene R. Gordon Research Institute (Lighthouse International) proposed new methodologies to determine the minimal visual requirements for driving a car (Higgins et al., 1996; Higgins & Wood, 1998; Higgins & Wood, 2005). Indicators of driving performance were abilities such as steering, reading road signs, and recognizing road hazards. Acuity degradation produced selective losses in some aspects of driving performance (e.g. decreased ability to recognize high contrast signs and to avoid large, low contrast road hazards; slower driving). Other aspects of driving performance (perception of lateral clearance, maneuvering or ‘slaloming’ through a series of traffic cones) were largely unaffected by low visual acuity. Altogether, these findings reveal that several important aspects of vision are particularly important for whole-body mobility. Two of these factors deserve particular attention due to the probable constraints of future visual prosthetic devices: the number of pixels available in the viewing window (i.e. visual acuity) and the available field of view. 66 Minimum displacement required for correctly detecting the direction of motion. 106 EXPERIMENTS ON MOBILITY 5.2.2 Mobility in the context of artificial vision Cha et al. (1992a) were the only ones to directly address whole-body mobility under conditions simulating artificial vision. Briefly, normal subjects had to walk through an indoor maze while wearing the same pixelized vision simulator used in their previous reading experiments (Cha et al., 1992b). Their results suggested that, similar to reading, an array of 25 x 25 pixels, projected on a foveal visual field of 1.7°, but encompassing a field of view of about 30°, could provide useful mobility performance in environments not requiring a high degree of pattern recognition. This previous study neglected, however, fundamental aspects of vision with a retinal implant (images were not stabilized at a particular retinal location, nor were they subserved to the subjects’ eye movements; eccentric implant locations were not explored). Minimum requirements for whole-body mobility must, therefore, still be systematically studied if one expects visual prostheses to restore these abilities, at least to a certain point. The main objective of the investigation presented in this chapter was, thus, to systematically assess mobility performance in conditions mimicking artificial vision as provided by a retinal implant transforming incident light into stimulation currents ‘insitu’. In a first series of experiments we determined the minimum requirements for useful mobility, by studying the influence of stimulus information content (pixelization level and available field of view) on mobility performance with a visual area stabilized in central vision, in a variety of situations. A second experiment was dedicated to explore whether naïve subjects could learn to perform whole-body mobility tasks in eccentric vision, under similar experimental conditions. 5.3 Specific methods for the experiments on mobility 5.3.1 Subjects Subjects were normal volunteers, familiar with the purpose of the study, and recruited either from the staff of the Ophthalmology Clinic of the Geneva University Hospitals, or from the staff of the University of Geneva. Their age ranged from 22 to 49 years. All had visual acuity better than 16/20 on the tested eye, normal ophthalmologic status, and normal haptic perception. 5.3.2 Effective field of view Similar to the Visuomotor Coordination experiments, we examined this issue by projecting different portions of the environment (subtending different effective fields of views) into the 10° x 7° stabilized viewing window (see fig. 57). This was achieved by modifying the frame size of the image captured by the webcam. Using the custom-made objective, the webcam captured images of the environment corresponding to 66° x 49.5°. Therefore, setting the image frame size of the webcam to 640 x 480, 320 x 240, and 160 x 120 pixels, respectively resulted in 16.5° x 11.6°, MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 107 33° x 23.1°, and 66° x 46.2° portions of the environment represented inside the same 10° x 7° viewing window. Please refer to section 4.3.3 for more details. 5.3.3 Experimental setup The details of the simulation procedures have already been described in the Chapter 2. The apparatus used corresponded to the mobile setup with the webcam (with the custom-made objective) mounted on the top of the system (see fig. 27b). The image-processing algorithm used was real-time square pixelization. The experimental procedure was very similar to that used for our previous experiments. At the beginning of each run, a standard 9-point calibration was performed and the actual experimental sequence started afterwards. The viewing window (10° x 7°), contained fragments of pixelized images, extracted from the frames captured by the webcam. Gaze position compensation was used to project this viewing window onto defined (central or eccentric) areas of the retina (see fig. 25). The background of the remaining screen surface was gray (corresponding to the mean luminosity of the visual scene). Tests were performed monocularly (using the dominant eye). Test sessions frequently included several runs, but they never lasted longer than 30 minutes to avoid subjects’ fatigue. Eye movement data for each run were recorded and stored for further analysis. 5.4 Acute experiments on mobility The amount of visual information required for achieving satisfactory mobility varies according to the type of environment in which the task is to be performed. In order to present an adequate overall picture of the visual information requirements for useful mobility, we developed a series of tasks involving different realistic situations. 5.4.1 Experiment 6: Laboratory maze This task was conceived to assess mobility performance in familiar, randomized indoor environments. The task consisted in walking through an indoor maze consisting of 6 obstacles frequently encountered in daily life and positioned randomly on the course. In the example shown in figure 67a, the subject had to, successively: pass between 2 poles, open and pass through a door, climb over stairs, walk on square marks placed on the floor while avoiding the circular mark, sit in front of a table and put a pencil inside a plastic cup, and finally slalom around 3 poles. Figure 67b shows a picture of one of the subjects wearing the artificial vision simulator while performing the task. 108 EXPERIMENTS ON MOBILITY a) b) Figure 67. The ‘Laboratory maze’ task. (a) Scheme of the indoor course used for the experiments. The task consisted in completing a circular course composed of 6 randomly positioned, familiar obstacles. (b) One of the subjects wearing the mobile setup during the task. 5.4.1.1 Experimental protocol Three subjects (AP, female, 28 years old; CF, male, 32 years old; JS, male, 43 years old) participated in the experiments. Before starting the actual experimental sequence, all subjects performed 3 control runs for each task. These control sessions were conducted in normal viewing conditions, and results were used as baseline measures for ‘normal’ mobility performance. Performance was measured with viewing windows presented at 5 pixelization levels (17920, 1991, 498, 221, and 124 pixels) and subtending 3 effective fields of view (16.5° x 11.6°, 33° x 23.1°, and 66° x 46.2°). Three successive runs were performed per experimental condition (a given effective field of view and pixelization level). The order in which each effective field of view was presented to each subject was permuted using a latin square (see table 3). With each field of view, subjects started with the easiest (highest) pixelization level and progressed towards the most difficult (lowest) one. Once all pixelization levels for a given field of view where completed, subjects progressed to the next one. Possible global learning effects favoring a particular effective field of view would be therefore minimized, but would still favor performance at low pixelization levels. Table 3. Testing sequences (latin square permutation) for the effective fields of view during experiment 6. AP CF JS 1 16.5° x 11.6° 66° x 46.2° 33° x 23.1° 2 66° x 46.2° 33° x 23.1° 16.5° x 11.6° 3 33° x 23.1° 16.5° x 11.6° 66° x 46.2° MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 109 Mobility performance was measured as total time required for completing the course and number of errors per course. We considered as errors: stepping out of the marked path (green lines in fig. 67a), involuntarily touching any object, using the sense of touch to achieve a particular sub-task (e.g. finding the doorknob when trying to open the door), or failing to complete a sub-task at a particular object (e.g. dropping or touching the plastic cup when trying to put the pencil inside it, while sitting at the table). Results were calculated as the mean of the cumulative data of each subject ± SEM. Statistically significant differences were determined using standard (paired) t tests with a significance level of 0.05. 5.4.1.2 Results Figure 68 compares mean mobility performance for the laboratory maze task with each effective field of view, versus number of pixels in the viewing window. Individual performances in each experimental condition were established on the basis of 3 runs. With the 3 effective fields of view, mobility errors were approximately 1 for pixelizations down to 498 pixels. With the 16.5° x 11.6° field of view (red plots in fig. 68) error counts were statistically equivalent across all pixelizations. With the 33° x 23.1° field of view (blue plots in fig. 68), error counts remained around 1 down to 221 pixels. At 124 pixels values significantly increased to 2 (p = 0.04). With the 66° x 46.2° field of view (green plots in fig. 68), mobility errors increased noticeably at 221 and 124 pixels. This increase was significant at a) b) Figure 68. Mobility performance versus number of pixels in the 10°x7° viewing window for 3 normal subjects performing the ‘Laboratory maze’ task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 16.5°x11.6° (red plot), 33°x23.1° (blue plot), and 66°x46.2° (green plot). (a) Mean number of errors per course ±SEM. (b) Mean time per course expressed in s ±SEM. The solid black lines indicate mean performance results (±SEM) during control sessions (normal viewing conditions). 110 EXPERIMENTS ON MOBILITY 221 pixels (p =0.04) but not at 124 pixels (p = 0.07) due to high inter-subject variability. Interestingly, a learning effect could be visible at 1991 pixels with the 3 effective fields of view (significant at p = 0.01 for 33° x 23.1°), and at 498 pixels with the 16.5° x 11.6°. Results for the mean time per course are similar (fig. 68b). With the 16.5° field of view, average time was approximately 120 s and statistically equivalent across all pixelization levels. With the 33° x 23.1° field of view, time per course remained around 110 s down to 221 pixels. At 124 pixels, values slightly increased to 130 s (p = 0.05). With the 66° x 46.2° field of view, mean time per course was approximately 110 s down to 1991 pixels. Values increased noticeably below this pixelization level (p = 0.09 at 498 pixels; p < 0.05 at 221 and 124 pixels). A non-significant learning effect could also be observed at 1991 pixels, for the effective 3 fields of view. This tendency was, however, less pronounced than for mobility errors. In normal viewing conditions (black solid lines in fig. 68), subjects made no mobility errors and completed the course in approximately 30 s. Mobility errors were only slightly higher in most of our experimental conditions (except for 221 and 124 pixels with the 66° x 46.2° field of view). In contrast, it took subjects 4 to 6 times longer to complete the course in all experimental conditions than in normal viewing. Performance data for this mobility task were normalized to values achieved at 17920 pixels, for each of the effective fields of view investigated. Mean results ± SEM are plotted versus the effective resolution of the environmental space in figure 69. Data obtained with the different viewing angles were fitted together to single a) b) Figure 69. Normalized mobility performance versus effective resolution of the environmental space in the 10°x7° viewing window for 3 normal subjects during the ‘Laboratory maze’ task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 16.5°x11.6° (red plot), 33°x23.1° (blue plot), and 66°x46.2° (green plot). (a) Mean normalized error counts ±SEM. (b) Mean normalized time ±SEM. The solid black lines indicate the best fit to the data. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 111 exponential functions (solid black lines in fig. 69). Best fits for normalized errors and for normalized time reveal that, for the ‘Laboratory maze’ task, best mobility performance can be achieved with effective environmental resolutions down to approximately 0.2 pixels/deg2. Error counts and time required for completing the course increased markedly below this level. 5.4.2 Experiment 7: Random forest This task was designed to assess mobility performance in randomized, unpredictible indoor environments including some dynamic elements. The task consisted in walking through an ‘artificial forest’, from a random starting position (A in fig. 70a) to a random end position (B in fig. 70a). The forest measured 16 x 8 m2, and was composed of 52 randomly positioned obstacles or ‘trees’. Fifty of these trees were white and the remaining 2 were black. Subjects had to avoid contacting the white trees, but were requested to localize and touch the black trees as they passed through the forest. In addition, a variable number of persons (2, 1, or none; marked as arrows in fig. 70a) could cross the forest while subjects were performing the task, and subjects had to avoid bumping into them. Figure 70b shows a picture of one of the subjects wearing the experimental setup while performing the task. a) b) Figure 70. The ‘Random forest’ task. (a) Scheme of one of the forest configurations used in the experiments. The task consisted in passing through a random course made of 52 obstacles (trees) from point A to point B. Please note that the gridlines are only schematic and were not visible to subjects during the task. (b) One of the subjects wearing the mobile setup during the task. 5.4.2.1 Experimental protocol Six subjects (LC, female, 22 years old; FM, male, 23 years old; CU, female, 25 years old; XS, male, 25 years old; JS, male, 45 years old; and FS, female, 49 years 112 EXPERIMENTS ON MOBILITY old) participated in this experiment. Before starting the experiment, all subjects performed 3 control runs in normal viewing conditions. These measures constituted baseline measures for ‘normal’ mobility performance. Performance was measured with viewing windows presented at 5 pixelization levels (17920, 1991, 498, 221, and 124 pixels) and 3 effective fields of view (16.5° x 11.6°, 33° x 23.1°, and 66° x 46.2°). Three successive runs were performed per experimental condition (a given effective field of view and pixelization level). The order in which each effective field of view was presented to each subject was permuted using a latin square (see table 4). With each field of view, subjects started with the easiest (highest) pixelization level and progressed towards the most difficult (lowest) one. Once all pixelization levels for a given field of view where completed, subjects progressed to the following one. Possible global learning effects favoring a particular effective field of view would be therefore minimized, but would still favor performance at low pixelization levels. Table 4. Testing sequences (latin square permutation) of the effective fields of view during experiment 7. LC FM CU 1 66° x 46.2° 33° x 23.1° 16.5° x 11.6° 2 16.5° x 11.6° 66° x 46.2° 33° x 23.1° 3 33° x 23.1° 16.5° x 11.6° 66° x 46.2° XS JS FS 1 33° x 23.1° 16.5° x 11.6° 66° x 46.2° 2 16.5° x 11.6° 66° x 46.2° 33° x 23.1° 3 66° x 46.2° 33° x 23.1° 16.5° x 11.6° Mobility performance was measured as total time required for crossing the forest (going from point A to point B, passing by the black trees) and total number of errors per course. We considered as errors: touching a white tree, missing one of the black trees, bumping into a crosser, stepping out of the marked path (black perimeter in fig. 70a), and missing the arrival point (B). Results were calculated as the mean of the cumulative data of each subject ± SEM. Statistically significant differences were determined using standard (paired) t tests with a significance level of 0.05. 5.4.2.2 Results Figure 71 shows mobility performance results for the ‘Random forest’ task, analyzed against the number of pixels available in the viewing window, for each of the 3 effective fields of view investigated. Down to 1991 pixels, approximately 1 error was performed with all fields of view. With the 16.5° x 11.6° and the 33° x 23.1° fields of view (respectively red and blue plots in fig. 71), average errors increased significantly to 2 at 498 pixels and below (p < 0.05). With the 66° x 46.2° MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 113 field of view (green plots in fig. 71) mobility errors increased to about 2 at 221 pixels and to about 5 at 124 pixels. These important increases were, however, not significant (p > 0.05) due to the high variability of the results. A slight learning effect could be observed at 1991 pixels for the 16.5° x 11.6° (p > 0.05) and the 66° x 46.2° (p = 0.01) fields of view. Analysis of the mean time per course (fig. 71b) reveals that all the effective fields of view were similarly affected by the number of pixels in the viewing window. Furthermore, the 33° x 23.1° field of view yielded the fastest times per course at all pixelization levels. With the 16.5° x 11.6° field of view, significant slow-downs were observed at 221 and 124 pixels (respectively, p = 0.02 and p = 0.001). With the 33° x 23.1° field of view, time required to complete the course increased significantly at 498 pixels already (p = 0.006). Significant slow-downs were also observed at 221 and 124 pixels (respectively, p = 0.01 and p = 0.005). Results for the 66° x 46.2° field of view increased significantly at 498, 221, and 124 pixels (respectively: p = 0.0002, p = 0.02, and p = 0.02). Subjects made approximately 1 error with the 3 fields of view at 17920 and 1991 pixels, while no errors were performed in normal viewing conditions (black dashed lines in fig. 71). This difference increased to 2 - 5 errors at 498 pixels and below. At the highest pixelization levels, mean time required to complete the course was already 7 - 9 times slower than that required in normal viewing conditions (~ 20 s). Performance data for this mobility task were normalized to values achieved at the highest resolution tested (17920 pixels), for each of the effective fields of view a) b) Figure 71. Mobility performance versus number of pixels in the 10°x7° viewing window for 6 normal subjects performing the ‘Random forest’ task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 16.5°x11.6° (red plot), 33°x23.1° (blue plot), and 66°x46.2° (green plot). (a) Mean number of errors per course ±SEM. (b) Mean time required to cross the forest, expressed in s ±SEM. The solid black lines indicate mean performance results (±SEM) during control sessions (normal viewing conditions). 114 EXPERIMENTS ON MOBILITY investigated. Mean results ± SEM are plotted versus the effective resolution of the environmental space in figure 72. Surprisingly, this figure reveals that mobility performance for this task was very different from one condition to the other. Therefore, results could not be fitted to an exponential function. a) b) Figure 72. Normalized mobility performance versus effective resolution of the environmental space in the 10°x7° viewing window for 6 normal subjects during the ‘Random forest’ task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 16.5°x11.6° (red plot), 33°x23.1° (blue plot), and 66°x46.2° (green plot). (a) Mean normalized error count ±SEM. (b) Mean normalized time ±SEM. 5.4.3 Experiment 8: Real street crossing This task was intended to assess the visual requirements for mobility in a real-life, dynamic environment. We evaluated the capacity of subjects of estimating speed and distance of approaching objects (cars). The task consisted in judging the possibility of crossing a medium-traffic street (without actually crossing it for obvious safety reasons). Subjects stood on the street-side and, at the signal of the experimenter67, had to observe the traffic and estimate when they would be able to cross safely. An experimental run consisted in one street-crossing estimate. After each run subjects were requested to estimate, in a 0 to 5 scale, the difficulty of the task in the particular experimental condition (0 easy; 5 impossible) and how safe they felt about their estimation (0 completely safe; 5 not safe at all). In addition, we asked 2 subjects (FG and FL) to also estimate the extent to which they used hearing to accomplish the task (0 no use; 5 only used hearing since not enough visual information). Figure 73 shows a picture of one of the subjects during the task. 67 The experimenter gave the “start” signal after a first vehicle passed in front of the subject. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 115 We performed pilot experiments to roughly explore the visual requirements of the task and adapt our experimental protocol accordingly. This evaluation revealed that the lowest pixelization level tested in the previous experiments (124 pixels) was too difficult for this task, even when small fields of view were used. We therefore decided not to include it in this experiment. In addition, our pilot experiments suggested that the minimum information requirements for this task could lay somewhere between 1991 and 498 pixels. Figure 73. One of the subjects wearing the mobile setup Consequently, we decided to during the ‘Real street crossing’ task. intercalate 2 pixelization levels in this range. Finally, the visual span requirements for the task appeared to be very variable. We therefore decided to investigate the effect of the 4 fields of view that we are able of simulating with our mobile setup. 5.4.3.1 Experimental protocol Four subjects (LC, female, 22 years old; XS, male, 25 years old; FG, female, 23 years old; and FL, male, 25 years old) participated in the experiments. Performance was measured with viewing windows presented at 6 pixelization levels (17920, 1991, 1120, 717, 498, and 221) and 4 effective fields of view (8.25° x 5.8°; 16.5° x 11.6°, 33° x 23.1°, and 66° x 46.2°). Three successive runs were performed per experimental condition (a given effective field of view and pixelization level). The order in which each effective field of view was presented to each subject was permuted using a latin square (see table 5). With each field of view, subjects started with the easiest (highest) pixelization level and progressed towards the most difficult (lowest) one. Once all pixelization levels for a given field of view where completed, subjects progressed to the next one. Possible global learning effects favoring a particular effective field of view would be therefore minimized, but would favor performance at low pixelization levels. Mobility performance was measured in terms of the difficulty, safety, and hearing index determined by subjects after each trial. For difficulty and safety results, results were calculated as the mean of the cumulative data of each subject ± SEM. Statistically significant differences were determined using standard (paired) t tests with a significance level of 0.05. No statistics were performed on hearing index 116 EXPERIMENTS ON MOBILITY Table 5. Testing sequences (latin square permutation) of the effective fields of view during experiment 8. LC XS FL FG 1 8.25° x 5.8° 66° x 46.2° 33° x 23.1° 16.5° x 11.6° 2 16.5° x 11.6° 8.25° x 5.8° 66° x 46.2° 33° x 23.1° 3 33° x 23.1° 16.5° x 11.6° 8.25° x 5.8° 66° x 46.2° 4 66° x 46.2° 33° x 23.1° 16.5° x 11.6° 8.25° x 5.8° results because these were only available for 2 subjects, a small sample size not allowing for valid statistical analyses. 5.4.3.2 Results Results of the analysis of mobility performance with each effective visual field, versus the number of pixels available in the viewing window are presented in figure 74. Difficulty estimates at the highest pixelization (17920 pixels) were below 1, and statistically equivalent for the 4 effective fields of view. Perceived task difficulty increased as fewer pixels were available in the viewing window. With the 8.25° x 5.8° field of view (red plots in fig. 74), values were statistically equivalent down to a 498 pixels. At 221 pixels, difficulty estimates increased significantly (p = 0.005). With the 16.5° x 11.6° and 33° x 23.1° fields of view (respectively, blue and green plots in fig. 74), difficulty estimates increased significantly at 1120 pixels (p = 0.002). Values remained roughly stable at 717 pixels, and then significantly increased at 498 and 221 pixels (p < 0.05). With the 66° x 46.2° field of view (yellow plots in fig. 74), difficulty estimates increased significantly at 1991 pixels already (p = 0.01). This significant increase persisted at the remaining lower pixelization levels (p = 0.006 at 1120 pixels, p = 0.03 at 717 pixels, p = 0.003 at 498 pixels, and p = 0.03 at 221 pixels). Safety estimates (fig. 74b) yielded similar results. At maximum target resolution, subjects judged their crossing estimates as safe (values below 1) with the 4 effective fields of view tested. The feeling of safety decreased as fewer pixels were available in the viewing window. With the 8.25° x 5.8° field of view, results were statistically equivalent down to a target resolution of 498 pixels. At 221 pixels, a significant (p < 0.05) increment (a decrease in the feeling of safety) was observed. With the medium fields of view (16.5° x 11.6° and 33° x 23.1°) safety indexes increased significantly at 717, 498, and 221 pixels (p < 0.05). Safety estimates for the 66° x 46.2° field of view increased significantly at 1120 pixels and below (p < 0.05). Estimations of the use of hearing (fig. 74c) were also very sensitive to pixelization level. With the 8.25° x 5.8°field of view, hearing was used to accomplish the task (values ≥ 2) for pixelization levels of 717 and 221 pixels, but surprisingly not for 498 pixels. With the 16.5° x 11.6° and 33° x 23.1° fields of view, hearing seemed to be required for target resolutions of 1120 pixels and below. Finally, with the 66° x 46.2° MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) 117 b) c) Figure 74. Mobility performance versus number of pixels in the 10°x7° viewing window for 4 normal subjects performing the ‘Real street crossing’ task. Four effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25° x 5.8° (red plot); 16.5°x11.6° (blue plot), 33°x23.1° (green plot), and 66°x46.2° (yellow plot). (a) Mean task difficulty estimates ±SEM. (b) Mean safety appraisal of crossing estimates ±SEM; (c) Mean hearing index (results for only 2 subjects). field of view, hearing appeared to be necessary at 1991 pixels already. Values successively increased as fewer pixels were available in the viewing window. Figure 75 presents the same results but plotted versus the effective resolution of the environmental space. Interestingly, 2 clear tendencies can be observed. With the 2 smallest fields of view (8.25° x 5.8° and 16.5° x 11.6°; respectively red and blue plots in fig. 75), difficulty and safety estimates increased significantly (p < 0.05) at effective resolutions below 10 pixels/deg2. With the largest fields of view (33° x 23.1° and 66° x 46.2°; respectively green and yellow plots in fig. 87) significant (p < 118 EXPERIMENTS ON MOBILITY 0.05) increments could be observed for effective resolutions below 2 pixels/deg2. Estimates for the use of hearing appear to follow the same trend. a) b) c) Figure 75. Normalized mobility performance versus effective resolution of the environmental space in the 10°x7° viewing window for 4 normal subjects performing the ‘Real street crossing’ task. Four effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25° x 5.8° (red plot); 16.5°x11.6° (blue plot), 33°x23.1° (green plot), and 66°x46.2° (yellow plot). (a) Mean task difficulty estimates ±SEM. (b) Mean safety appraisal of crossing estimates ±SEM; (c) Mean hearing index (results for only 2 subjects). 5.4.4 Summary of the results of these experiments Altogether, results from experiments 8, 9, and 10 confirm that minimum information requirements appear to be closely linked to the type of environment on which mobility tasks have to be performed. Mobility in well-known, indoor environments required relatively little visual information: approximately 0.2 pixels/deg2 (e.g. ~ 150 pixels with the 33° x 23.1° field of view) emerge as the fundamental limit for mobility performance in such environments. Large fields of view did not seem to be of particular advantage in these settings. Mobility tasks in less predictable environments incorporating some dynamic elements, such as that the ‘Random Forest’ task, appear to be more sensitive to the number of pixels available on the viewing window. In these settings, minimum information requirements lay around 498 pixels. Similar performance could be achieved with all fields of view, however, the 33° x 23.1° field of view tended to yield the best mobility performance. Finally, 498 pixels appear to be insufficient for subjects to feel safe while performing mobility tasks in unknown, dynamic environments, such as that of the ‘Real street crossing’ task. As fewer pixels were available in the viewing window, subjects needed to compensate with additional information sources (i.e. hearing). Approximately 1000 pixels and smaller fields of view providing more detailed visual information seem to be advantageous in these settings. However, it is important to highlight that subjects almost never attempted to cross the street in dangerous situations. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 119 5.5 Habituation experiments on mobility This set of experiments was dedicated to explore whether naïve subjects could learn to perform whole-body mobility tasks in eccentric vision. According to the previous experiments, a field of view of 33° x 23.1° seems to be the best compromise between a large enough field of view while still maintaining reasonable image resolution. Subjects also spontaneously reported preferring this particular field of view to the others. This field of view was thus chosen for the second set of experiments. According to the results obtained in the 1st set of mobility experiments, and to be consistent with our previous experiments on reading, a resolution of 498 pixels in the viewing window was judged to be the most adequate for learning the task in eccentric vision (effective resolution of 0.65 pixels/deg2). We used the ‘Laboratory Maze’ task described in the previous section (see fig. 79). Two successive experiments were conducted. First, in a preparatory experiment, subjects were asked to perform the mobility task using a viewing window stabilized on the fovea. Second, in experiment 9, the subjects’ ability to perform mobility tasks with eccentric vision (using a viewing window stabilized at 15° eccentricity) was investigated. Experimental sessions were repeated daily. Using central vision, performance asymptoted within 10 sessions. A lengthier learning process was observed when using eccentric vision: 35 to 45 sessions were necessary for mobility performance to asymptote. 5.5.1 Experimental protocol Three subjects (MS, female, 27 years old; HB, male, 31 years old; KC, male, 37 years old) participated in the experiments. All of them were naïve to eccentric viewing and were tested monocularly using their dominant eye. Possible learning effects were investigated by repeatedly performing experimental sessions for a period of more than 1 month. In general, 2 to 3 periods of testing were conducted each working day of the week (5 days per week). The duration of each experimental session was variable throughout the experiment. Each experimental session consisted in, first, a run in which mobility performance was measured on a random indoor obstacle course. Then, subjects were allowed to practice by completing as many successive courses (the obstacle order was not changed and performance was not measured) as possible to complete 30 minutes of testing. This had to be done since, after only a few sessions, subjects performed the task very rapidly (less than 2 minutes). Therefore, an experimental session consisting only on the measured run would have represented very short periods of eccentric viewing. The criterion used to stop the experiments was the stabilization of the time required to complete an entire course. Mobility performance results are presented as previously (total time required for completing the course and total number of errors per course). Oculomotor adaptation to eccentric viewing was assessed by calculating the cumulative distance of the subjects’ eye movements, for each experimental session. This analysis of oculomotor behavior is presented in Appendix E. 120 EXPERIMENTS ON MOBILITY Learning curves were computed using the exponential functions presented in Chapter 2. Significant learning effects were determined using simple linear correlation (Pearson’s correlation). 5.5.2 Preparatory experiment: Learning in central vision In this experiment, several sessions were conducted using a viewing window stabilized in central vision. It lasted until subjects became familiar with the task (performing the ‘Laboratory Maze’ task while exploring the environment using a small viewing window). Time required to complete the course stabilized within 10 sessions. Figure 76 presents performance in central vision versus session number. Relatively high error counts were observed in the first sessions. However, values decreased rapidly and stabilized after only 4 - 10 sessions. Significant learning effects were observed in the analysis of error counts versus time only for subject MS (Pearson’s correlation: r = 0.66, p < 0.05). In the case of subjects HB and KC the reduction in the total number of errors per course manifested as a clear tendency (respectively, Pearson’s correlation: r = 0.63, p = 0.05 and r = 0.55, p = 0.08). Time required for completing a course significantly improved with time for all three subjects (Pearson’s correlation: r = 0.67, p < 0.05 for HB; r = 0.91, p < 0.001 for MS; and r = 0.77, p < 0.01 for KC). Analysis of the experimental data revealed that the average time per course stabilized within 10 sessions, diminishing from 360 to 110 s for HB, from 420 to 140 s for MS, and from 470 to 110 s for KC. a) b) Figure 76. Mobility performance versus session number obtained for 3 normal subjects performing the ‘Laboratory maze’ task in central vision. Experimental conditions: 10° x 7° viewing window containing 498 pixels and subtending a 33° x 23.1° field of view. Results expressed as: (a) total number of errors per course; and (b) total time required to complete the course expressed in s. The solid lines indicate the best fits to the data. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 121 These data clearly demonstrate that adaptation to the mobiliy task in central vision is very rapid. However, even after training, time required to complete the course was still about 4 times slower than normal (approximately 30 s; see fig. 68b). This is essentially due to the increased difficulty of scanning the environment using a restricted viewing window. 5.5.3 Experiment 9: Learning in eccentric vision This experiment was dedicated to explore whether normal subjects could adapt to the unusual activity of performing mobility tasks using a small viewing window, containing pixelized fragments of the environment, and stabilized at 15° eccentricity in the lower field of view. In this case, average time per course stabilized after 35 45 sessions. Figure 77 presents mobility performance in eccentric vision versus session number. In the first sessions, 3 - 4 errors were observed for subjects MS and KC. Subject HB performed 10 - 14 errors. For all subjects, values decreased and stabilized within 12 sessions. Significant learning effects were observed in the analysis of error counts versus time for subjects HB and MS (respectively, Pearson’s correlation: r = 0.44, p < 0.005 and r = 0.45, p < 0.005). Results for subject KC were very variable all through the training period, therefore no significant learning effect could be noted. Improvements in the time required to complete the course were highly statistically significant for all 3 subjects (Pearson’s correlation: r = 0.81, p < 0.0001 for HB; r = 0.85, p < 0.0001 for MS; and r = 0.81, p < 0.0001 for KC). a) b) Figure 77. Mobility performance versus session number obtained for 3 normal subjects performing the ‘Laboratory maze’ task in eccentric vision (15° in the lower visual field; 10° x 7° viewing window containing 498 pixels and subtending a 33° x 23.1° field of view). Results expressed as: (a) total number of errors per course; and (b) total time required to complete the course expressed in s. The solid lines indicate the best fits to the data. 122 EXPERIMENTS ON MOBILITY Analysis of the experimental data revealed that the average time per course stabilized within 33 sessions, diminishing from approximately 400 to 75 s for HB, from 300 to 70 s for MS, and from 180 to 60 s for KC. Interestingly, for all 3 subjects temporal performance achieved at the end of this experiment was faster than that reached at the end of the previous experiment in central vision. However, it was still about 2 times slower than that obtained in normal viewing conditions (compare figs. 68b and 77b). Taken together, results from experiment 9 demonstrate that an important learning process occurred for mobility with eccentric vision. The evolution was similar in all subjects. Error counts decreased and stabilized rather rapidly. Time improvements were more gradual and impressive. After training, subjects could achieve the task even more rapidly than in central vision. 5.6 Discussion The first goal of the experiments presented in this chapter was to explore the minimum requirements for useful mobility. We assessed the influence of the particular visual conditions that will most probably result from the use of subretinal prosthetic devices transforming light into electric currents ‘in-situ’. Essentially, retinal implants might affect whole-body mobility abilities since such tasks are known to require wide fields of view. Relatively little visual information is needed for mobility in well-known environments: an effective resolution above 0.2 pixels/deg2 (i.e. 150 pixels with the 33° x 23.1° field of view) seems to be necessary for useful (accurate but slow) performance in such environments. Subjects can cope with severely fragmented information as soon as they recognize a familiar obstacle. Our results also demonstrate that mobility in unpredictable environments including dynamic elements is more demanding in terms of visual information requirements than mobility in highly predictable static environments. At least 498 pixels seemed to be necessary in this case, irrespective of the field of view used. Medium fields of view (around 33° x 23.1°) tended to yield the best performance. In unpredictable environments including moving, eventually hazardous objects, higher image resolutions (~ 1000 pixels) are needed for subjects to feel safe. Furthermore, other sources of information (such as hearing) seem to be useful for compensating the lack of visual information. Blind subjects and low vision patients commonly use such compensation strategies to enhance their mobility performance (Rieser et al., 1992; Hill et al., 1993). These results are in agreement with every-day clinical observations in low vision patients. These patients (including those with reduced visual fields) behave surprisingly well in known environments. At home they can do almost everything, except for tasks demanding an important amount of visual information (like reading or watching TV). In contrast, these same patients are greatly handicapped when moving in unknown environments or if something unexpected happens. Indeed, both RP and glaucoma patients report having much more problems moving in unfamiliar than in familiar environments (Nelson et al., 1999; Turano et al., 1999). MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 123 Why do visual requirements for whole-body mobility differ in diverse settings? When moving in well-known environments, subjects can compensate for the lack of visual information with a series of visual and motor strategies to deal with difficulties in egocentric and exocentric distance estimations (Turano et al., 2001; Apfelbaum et al., 2006). In addition, tacit and explicit levels of knowledge, acquired progressively by subjects with practice, conduct to performances based less on visual information (Berthoz, 1997). For example, after a certain period of practice, subjects only have to apply the motor sequences they constructed for a certain obstacle, and associate this strategy to their mental map of the environment. Furthermore, an unknown environment might be scattered not only with static, but also dynamic elements (people or vehicles moving). Anticipation of forthcoming events implies observation and extraction of a great amount of central and peripheral visual information (Warren & Kurtz, 1992; Chanderli, 2002), which can take a considerable amount of time if the visual field is of 20° or less (Turano et al., 2001). Moreover, depending on the situation, more or less visual anticipation and shorter or longer reaction times are necessary. These observations also contribute to explaining the learning effects (i.e. tendency towards fewer errors, faster times per course) observed for the ‘Laboratory maze’ task at high pixelization levels (see fig. 68). A similar but slighter effect was visible for the ‘Random forest’ task (see fig. 70). This could reflect habituation to the experimental conditions and increased familiarization with the obstacle courses. However, learning effects were not observed for the ‘Real street crossing task’. This suggests that learning mainly consisted in the familizarization with the indoor tasks, as suggested by Berthoz (1997). This was more difficult for the less predictable ‘Random forest’ task than for the highly predictable ‘Laboratory maze’ task. Familiarization with the task seemed to be impossible in the unpredictable and dynamic environment of the ‘Real street crossing’ task. Another interesting issue arises from the observation that mobility performance for the ‘Random forest’ task was very different from one visual condition to the other (see fig. 72). The strategy used by subjects to explore the environment was almost the same despite of the size of the effective field of view available. In this case, their strategy seemed to be mainly influenced by the number of pixels available in the viewing window (see also fig. 71). This striking difference with the other tasks is probably due to the spatial configuration of the environment. The ‘Random forest’ was cluttered with obstacles that were quite close to each other (1 m of separation between neighboring trees). This probably forced subjects to deal primarily with their near-environment, not allowing them to fully exploit the advantage of larger fields of view. It is also worth mentioning that although subjects seem to require relatively high amounts of information to feel safe in dynamic and unknown environments (such as that of our ‘Real street crossing’ task), they rarely put themselves in dangerous situations (e.g. attempt to cross the street when a car was too close or when a car was approaching too fast). This was true even when very little visual information was available in the viewing window. In general, subjects compensated for the lack of visual information with audition: they waited until they could not hear any car 124 EXPERIMENTS ON MOBILITY approaching to attempt the crossing. It seems thus that, at least in this particular setting, auditory information was enough to complete the task safely most of the time. Furthermore, as already pointed out by Pelli (1987), subjects seem to be quite inaccurate when judging the danger of a particular situation. However, this issue must be taken with caution, because, on one hand, our results only allow for a very qualitative evaluation of the role of audition for achieving the task. Besides, the experiments were carried out in young subjects (22 to 24 years old), that presumably had very good auditory function. Obviously, auditory cues might be less useful to older patients, which might present hearing deficits. On the other hand, even one single misjudgement in a task like this one could have terrible consecuences. Therefore, it is very important that subjects feel safe and sure of their estimations. The second goal of the experiments presented in this chapter was to explore whether mobility tasks could be efficiently performed with a restricted viewing window stabilized at 15° eccentricity in the lower visual field. Error counts for an indoor course (familiar environment) asymptoted rapidly, within 10 sessions. Improvements in the time required to complete the course were more gradual and better depicted the learning process: around 33 sessions were required in this case. Surprisingly, after training, the mobility task was performed more rapidly in eccentric vision than in central vision in similar experimental conditions (p < 0.05; compare figs. 76b and 77b). The fact that subjects could learn to perform the mobility task in such unnatural viewing conditions is not surprising in light of the similar findings reported in the previous chapters. In addition, several studies have systematically studied the effect of mobility/orientation training on low vision patients, demonstrating significant improvements with time (Geruschat & Del'Aune, 1989; Straw & Harley, 1991; Kuyk et al., 2004). During training in central vision, mobility performance improved because subjects adapted to performing the task in our particular experimental conditions, but also because subjects familiarized with the obstacles and the course. However, such a ‘familiarization’ effect did not influence the results of our eccentric viewing experiments. These began only after mobility performance in central vision asymptoted. We can consider, thus, that once subjects started the experiments in eccentric vision, familiarization with the obstacle course was complete. Hence, we can consider that in experiment 9 the learning process mainly consisted in the adaptation to eccentric viewing. 5.7 Conclusion These data clearly demonstrate that useful mobility performance can be obtained under conditions mimicking artificial vision in the central visual field. This means that all necessary information could be transmitted and captured by the visual system. Similar to visuomotor tasks, mobility performance in our particular experimental conditions (stabilized 10° x 7° viewing window subtending an effective field of view of 33° x 23.1° and containing 498 pixels) is noticeably slower than in normal viewing conditions. This outcome is mainly due to the increased difficulty of exploring the environment using a restricted viewing window. Our results also indicate that useful MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 125 mobility performance can be achieved even if retinal implants have to be placed in the periphery of the visual field. At this point, we estimate that about 500-600 distinctly perceived phosphenes, distributed on a 3 x 2 mm2 implant, remain the minimum criterion to achieve useful reading, visuomotor coordination, and whole-body mobility. An image resolution of 1000-2000 pixels would, however, greatly improve the feeling of security for mobility in unknown, dynamic environments. 5.8 Publications resulting from this research Pérez Fornos, A., Sommerhalder, J., Chanderli, K., Pittard, A., Baumberger, B., Fluckiger, M., Safran, A.B., & Pelizzone, M. (2004). Minimum requirements for mobility in known environments and perceptual learning of this task in eccentric vision. ARVO Meeting Abstracts, 45, 5445 (abstract). Sommerhalder, J., Pérez Fornos, A., Chanderli, K., Colin, L., Schaer, X., Mauler, F., Safran, A.B., & Pelizzone, M. (2006). Minimum requirements for mobility in unpredictable environments. ARVO Meeting Abstracts, 47, 3204 (abstract). Sommerhalder, J., Pérez Fornos, A., Chanderli, K., Pittard, A., Safran, A.B., & Pelizzone, M. (2006). Minimum requirements for useful mobility and learning of such tasks in eccentric vision. In preparation. 6 Towards Better Simulations of Artificial Vision Imagination and fiction make up more than three quarters of our real life. Simone Weil (1909 - 1943) 6.1 Foreword The psychophysical studies presented in the previous chapters used different simplified techniques to simulate the limited number of discrete stimulation contacts available in a prosthesis. Essentially, stimulation images were decomposed into a finite number of pixels with a simple block-averaging algorithm (refer to Chapter 2 for a detailed description of this algorithm). This resulted in an image composed of a mosaic of square pixels of various gray levels, the gray level within each pixel being constant (square pixelization). However, according to electrophysiological research in the field (Weiland et al., 1999; Stett et al., 2000; Rizzo et al., 2003b; Lecchi et al., 2006): • The patterns of neural activity elicited by electric stimulation of the retina depend on the strength of the stimulation current. • Neural activation diminishes progressively as the distance between the electrode contact and the neural target increases. • Spatially selective activity could be obtained for contact spacings of around 100 µm, when using adequate stimulation parameters68. These facts imply that phosphenes elicited by electrical stimulation of the retina should not be of constant luminosity, but brighter in the center, and of course, not of ‘square’ shape. Furthermore, depending on the strength of the stimulation current, the percepts might develop from a collection of isolated phosphenes towards more continuous patterns with different degrees of overlap across neighboring phosphenes. More realistic simulations of artificial vision are, therefore, required to explore the impact that image processing simplifications had in the results reported previously. In order to validate our previous studies as well as to improve our simulation methods for future studies, we decided to specifically investigate the influence of the spatial and temporal characteristics of stimulus pixelization on reading performance. 68 The fact that spatially selective activation can be achieved with inter-electrode spacings of about 100 µm is very encouraging. It is consistent with the image resolutions required for useful function, according to our previous experiments. However, it should still be confirmed if such resolutions could actually be realized in chronic implants for human use, while respecting safe charge density limits (Brummer et al., 1983). 127 128 IMPROVED SIMULATIONS OF ARTIFICIAL VISION 6.2 Introduction Square pixelization could be considered an adequate method to simulate the reduced information content of the stimuli transmitted by a retinal implant. In a given condition, the detailed shape of each pixel does not alter the overall information content of the image. However, a number of studies on face recognition have demonstrated that detection is considerably hampered when images are decomposed into uniform, square pixels. Harmon & Julesz (1973) suggested that the oriented high frequency noise introduced at block borders masked image features essential for recognition. Yet, this explanation does not completely account for the significant performance decrease observed in a number of studies where this image processing technique was used (Costen et al., 1994; Uttal et al., 1995a; Uttal et al., 1995b; Bachmann & Kahusk, 1997). Gestalt psychologists (Bachmann, 1991; Uttal et al., 1997) further proposed that square pixelization distorts the image to the point of modifying its intrinsic gestalt properties69. Bachmann & Kahusk (1997) also suggest a complementary hypothesis: the ‘block’ constituents or pixels of the processed image compete for attention with the particular features of the image, thus affecting recognition. If one wants more accurate simulations of artificial vision, square pixelization should be replaced by other types of image processing featuring softer borders and allowing for variable amounts of overlap. In addition, in our studies exploring the reading task (Chapter 3) another potential flaw can be identified: the pixelization algorithm was applied off-line over the entire original image (e.g. seven lines of full-page text), and this pre-processed image was used for the experiments. Subjects were allowed to scan this image through a viewing window containing a subset of pixels, the gray level of these ‘frozen’ pixels being independent of the point of gaze on the image. This will not be the case in artificial vision systems, since stimulation intensity at each electrode contact will depend on the exact point of gaze relative to the image observed. For retinal implants transforming light falling on the retina into stimulation currents ‘in situ’ (Zrenner, 2002b; Chow et al., 2003; Ziegler et al., 2004), this will happen due to eye movements. Head movements will act similarly in systems using an external head-mounted camera for stimulus generation (Rizzo & Wyatt, 1997; Normann et al., 1999; Dobelle, 2000; Humayun et al., 2003; Veraart et al., 2003). In the case of reading, when focusing on a string of a few characters, its appearance will change upon small eye (or camera) movements. Temporal cues seem to play a significant role in visual perception: the human visual system is optimized for detecting structural changes in dynamic images. A dynamic sequence of slightly different pixelized images might contain more information than one frozen pixelized image. Therefore, dynamic (real-time) pixelization is likely to enhance information transmission to the visual system. Major object identification features (such as shape or location) are extracted from different spatial patterns (such as local contrast changes or relative position changes) resulting from image motion. Improved sensitivity for moving contrast changes, compared to their static equivalents, has 69 Gestalt psychologists suggest that the visual system uses certain image features (proximity, similarity, symmetry, contour closure, smoothness) as cues to extract and identify objects. Refer to Leeuwenberg (2003) for more details on Gestalt features. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 129 previously been demonstrated (Lappin et al., 2002). Moreover, it has already been established that dynamic presentations lead to better performance in tasks like facial recognition (Christie & Bruce, 1998; Lander et al., 1999; Thornton & Kourtzi, 2002). Hence, if one wants more accurate simulations of artificial vision, pixelization should be performed in real-time and the gray level of each pixel should vary dynamically, according to gaze position. In the present chapter, a series of three paired comparisons of the effects of different pixelization methods on full-page reading will be presented. Reading performance was compared: 1) between off-line square pixelization and real-time square pixelization of the image, 2) between off-line square pixelization and off-line gaussian pixelization of the image, and 3) between real-time square pixelization and real-time gaussian pixelization of the image. 6.3 Specific methods for these simulations 6.3.1 Subjects Ten subjects aged between 23 and 41 years were recruited from the staff of the Geneva University Ophthalmology Clinic. All of them had perfect knowledge of French, corrected visual acuity of 20/20 or better, and normal ophthalmologic status. They were familiar with the purpose of the study. 6.3.2 Experimental Setup The experimental setup was the same as that used for the studies on full-page reading described in Chapter 3. The apparatus corresponded to the stationary setup. Please refer to Chapters 2 and 3 for a more detailed description of the experimental setup. Stimuli consisted of full-page texts generated following the same procedure as in our previous study on full-page reading. The stimulus generation procedure has already been described in Chapter 3. Briefly, articles were extracted from the Internet website of the Swiss newspaper Le Temps and cut into 7-line text segments of about 25 words. Arial font (Helvetica) was used. At a viewing distance of 57 cm, the height of the small letter ‘x’ corresponded to a visual angle of 1.8°. The information content of the stimuli was reduced using one of two pixelization algorithms, square or gaussian, which differed in the resulting shape of the pixels. These algorithms were applied either off-line, yielding images with ‘frozen’ pixels, or 130 IMPROVED SIMULATIONS OF ARTIFICIAL VISION in real-time, yielding ‘dynamic’ pixels that changed with gaze position. Please refer to Chapter 2 for a detailed description of the image processing techniques used. The remaining aspects of the experimental procedure were exactly the same as described in the preceding full-page reading study. Tests were performed monocularly (using the dominant eye) and in central vision. For each run, subjects had to read aloud several text segments of an article, randomly chosen out of a pool of 50 (none of the subjects read an article twice). Test sessions frequently included several runs, but they never lasted longer than 30 minutes to avoid subjects’ fatigue. Similar to the previous experiments of full-page reading, performance was determined on the basis of reading scores (in RAU units and in approximate %), and reading rates (in WPM). More details can be found in Chapters 2 and 3. 6.4 Experiment 10: Real-time Square vs. Off-line Square Pixelization This experiment was designed to explore the effects of using real-time versus offline square pixelization on full-page reading at various image resolutions. 6.4.1 Experimental protocol Five volunteers (VR, female, 22 years old; MF, male, 23 years old; LP, male, 24 years old; AP, female, 26 years old; and RS, male, 28 years old) read full-page texts using off-line and real-time square pixelization. Five piexelization levels were tested: 28000, 1750, 572, 280, and 166 pixels in the viewing window70. All subjects started with the easiest condition (highest pixelization) and progressed towards the most difficult one (lowest pixelization). The first four text segments of an article (approximately 100 words) had to be read in each run, and three runs were performed per each pixelization condition. Off-line and real-time pixelization conditions alternated71. 6.4.2 Results Figure 78 compares mean reading performance versus number of pixels in the viewing window for off-line and real-time pixelizations. Individual performances in each experimental condition were established on the basis of 12 text segments and data were fitted with exponential functions. Down to a target resolution of 572 pixels, average reading scores were close to perfect (> 95% correct) and statistically equivalent for both conditions. At 280 pixels, 70 These pixelization levels were identical to those used in our previous study on reading of isolated 4letter words. 71 Note that the first pixelization level (28000 pixels) corresponded to maximum screen resolution, so no pixelization had to be actually performed. Off-line and real-time pixelization conditions were, thus, identical in this particular case. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) 131 b) Figure 78. Reading performance versus number of pixels in the 10°x7° viewing window for 5 normal subjects. Two stimuli generation procedures are compared in central vision: real-time pixelization (dynamic stimuli – red plots) and off-line pixelization (static stimuli – blue plots). (a) Mean reading scores expressed in RAU ±SEM (left scale) and in % (right scale). The dashed black line indicates reading scores corresponding to good to excellent text comprehension. (b) Mean reading rates expressed in WPM ±SEM. subjects achieved reading scores of 94.3% with real-time pixelization, but of only 76.4% with off-line pixelization. This difference was statistically significant (p = 0.0017), and persisted at the lowest pixelization (166 pixels; 56.1% versus 29.3%; p = 0.013). It is interesting to estimate the critical pixelization for subjects to reach useful reading performances. In the previous study on full-page reading, we found that adequate (good to excellent) text comprehension was closely correlated to high reading scores (see fig. 46). This criterion was fulfilled when median scores of at least 96.8% of correctly read words were reached. In the present case, the fits to the data indicate that this score is reached at 498 pixels in the case of off-line pixelization and at 322 pixels for real-time pixelization (see fig. 78a). Reading rates appeared to be even more sensitive to the number of pixels in the viewing window. At the highest resolutions, subjects reached an average reading rate of 93 WPM. At 572 pixels, mean reading rates already dropped significantly (p < 0.0001) to 80 WPM for real-time pixelization and to 64 WPM for off-line pixelization (see fig. 78b). The difference between both pixelization conditions was also statistically significant (p < 0.0001), and persisted at 280 pixels (34 WPM for realtime pixelization versus 18 WPM for off-line pixelization; p = 0.002). The lowest pixelization condition (166 pixels), was so difficult that reading rates were very low (4 to 6 WPM) in both cases. Taken together these results indicate that the same functional rehabilitation could be reached at a significantly lower resolution when real-time pixelization is used. 132 IMPROVED SIMULATIONS OF ARTIFICIAL VISION 6.5 Experiment 11: Off-line Gaussian vs. Off-line Square Pixelization This experiment was designed to investigate the influence of pixel shape on reading performance by comparing the use of gaussian pixels to the use of square pixels. The effect of varying the gaussian width (i.e. different levels of overlap across neighboring pixels) on full-page reading was also assessed. 6.5.1 Experimental protocol Tests were performed on six subjects (AP, female, 26 years old; CB, female, 29 years old; EO, female, 29 years old; AC, male, 33 years old; MB, male, 34 years old; and JS, male, 41 years old). Pixelizations with six different gaussian widths (σ values of 0.036, 0.071, 0.143, 0.286, 0.571, and 1.143 pixels) were tested and compared to square pixelization. In all conditions, the 10° x 7° viewing window contained 572 pixels (minimum information for useful text reading; see results from experiments 3 and 12). Each subject had to read an article of about 250 words (i.e. 10 consecutive text segments), per condition. Three subjects started the experiment with gaussian pixelization at the smallest σ value, progressed towards the larger gaussian widths, to finish with square pixelization. The remaining three subjects conducted the experiment in the inverse order. 6.5.2 Results Mean reading performances versus gaussian function width (σ) are shown in figure 79. Mean performances using square pixelization are also indicated for comparison. Individual performance values in each experimental condition were computed on the basis of all 10 consecutive text segments. Four gaussian width values (σ = 0.071, 0.143, 0.286 and 0.571 pixels) resulted in reading scores above 94% correctly read words. These scores were very close to those obtained with square pixelization (see fig. 79a). Mean reading scores with σ = 0.143 and σ = 0.286 pixels were found to be significantly better than those obtained with square pixelization (p = 0.04 and p = 0.009, respectively). Scores with σ = 0.071 and σ = 0.571 pixel were not statistically different from those obtained with square pixelization. Reading scores dropped markedly for the two extreme gaussian widths tested (σ = 0.036 and σ = 1.143 pixels). In these conditions, less than 80% of the texts were read because either overlapping was too pronounced or pixels were reduced to small isolated points of light. Mean reading rates display a similar picture (see fig. 79b). A maximum reading rate of 70 WPM was achieved at σ = 0.286 pixels. This value is significantly higher (p < 0.001) than the reading rate of 57 WPM achieved with square pixelization. Reading rates with σ = 0.143 and σ = 0.571 pixels were not statistically different from those obtained with square pixelization. For σ = 0.036, 0.071 and 1.143 pixels, reading rates dropped markedly below 40 WPM. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) 133 b) Figure 79. Reading performance versus gaussian function width (σ) used for stimulus pixelization, for 6 normal subjects. Results are compared to reading performances obtained with square pixelized stimuli (dashed line ±SEM). The resolution of the 10°x7° viewing window in central vision was kept constant at 572 pixels. (a) Mean reading scores expressed in RAU ±SEM (left scale) and in % (right scale). (b) Mean reading rates expressed in WPM ±SEM (left scale). Taken together, these results reveal that gaussian pixelization can lead to slightly, but significantly better reading performance compared to its square counterpart. 6.6 Experiment 12: Real-time Gaussian vs. Real-time Square Pixelization Results of experiment 11 demonstrated that off-line gaussian pixelization could lead to significantly better reading performance than off-line square pixelization. Another experiment was thus dedicated to extend this comparison to real-time mode. 6.6.1 Experimental protocol For this comparison we would have rather used the ‘optimal’ gaussian width determined in the second experiment (σ = 0.286 pixels). However, the total processing time needed to simulate this condition turned out to be too important to insure adequate image stabilization on the retina. Using the second best condition (σ = 0.143 pixels) allowed us to keep processing time below 10 ms (refer to Chapter 2 for more details on this issue). The same 6 volunteers who had participated in experiment 11 were requested to read 10 text segments in each of two conditions: real-time square pixelization and real-time gaussian pixelization at σ = 0.143 pixels. In both conditions the 10° x 7° viewing window contained 572 pixels. Three subjects started with real-time square pixelization, and then switched to real-time gaussian pixelization. The remaining three subjects performed the experiment inversely. 134 IMPROVED SIMULATIONS OF ARTIFICIAL VISION 6.6.2 Results The results of this experiment are summarized in table 6. No significant difference in performance could be found between both types of pixelization. However, reading scores and reading rates tended to be slightly higher with square pixelization. Comparing those ‘real-time’ scores with their ‘off-line’ counterparts gathered in the second experiment reveals that both real-time conditions yield better performance. This performance gain was significant for square pixelization (reading scores: p = 0.003; reading rates: p = 0.008), but not for gaussian pixelization (reading scores: p = 0.12; reading rates: p = 0.25). Table 6. Mean reading performances for real-time pixelization, for 6 normal subjects. Gaussian pixelization is compared to square pixelization using a 10°x7° viewing window containing 572 pixels. Mean reading scores Gaussian pixelization Square pixelization RAU ± SEM % RAU ± SEM % p 115.8 ± 3.6 99.6 117.2 ± 3.4 99.8 0.22 (ns) Mean reading rates Gaussian pixelization Square pixelization WPM ± SEM WPM ± SEM p 69 ± 12 74 ± 15 0.35 (ns) ns: non significant 6.7 Discussion Experiment 10 clearly shows that for stimulus resolutions below a critical value (about 1000 pixels in a 10°x7° viewing window) real-time square pixelization yields better reading performances than its off-line equivalent. The major reason for this advantage lays probably in the capability of the visual system to integrate various low-resolution images, enhancing stimulus contrast and resolution in order to improve perception (Lappin et al., 2002). This effect is also used in standard video: when several low-resolution images are presented in a rapid sequence, the resulting perception is that of a continuous, higher-resolution motion picture. In our experiments, at constant pixel resolution, the readability of pixelized text images depends on the exact position of the pixelization grid relative to the original stimulus image. Therefore, the image can be modified with minor eye movements to optimize viewing conditions. Figure 80 illustrates this effect for a series of minor changes in grid position. We observed that subjects quickly adopted this strategy: when resolution decreased, they increased the number of small saccades around the word they were trying to decipher. 135 MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION a) b) c) Figure 80. Illustration of the effect of the initial position (reference point) of the pixelization grid on the readability of the pixelized word. A single position does not provide enough information to identify the word unambiguously, but by integrating all three of them, the French word ‘niveau’ can be easily recognized. Other effects are also likely to influence reading performance. Previous research on face recognition revealed that ‘blocked’ images lead to poorer performance than images filtered using other techniques (Harmon & Julesz, 1973; Bachmann, 1991; Costen et al., 1994; Bachmann & Kahusk, 1997). Square pixelization adds some artefactual high frequency components to the target image that may mask essential features for identification (Uttal et al., 1997). Real-time pixelization does not suffer from the same artefactual bias because pixel movement acts as a low-pass filter subtracting some of these parasitic frequencies. This is, most probably, one of the reasons why in experiment 11 off-line gaussian pixelization yielded better reading performance than off-line square pixelization (for a restricted range of gaussian widths around σ = 0.286 pixels). Another reason for this finding could be the structural difference between both pixelizations. Blocks are important distracters competing for attention with the overall image features hidden within the structure of the pixelized image (Bachmann & Kahusk, 1997). An important factor could also be the configurational distortion introduced by blocks, modifying the underlying gestalt properties of the image (Bachmann, 1991; Uttal et al., 1995a; Uttal et al., 1995b; Bachmann & Kahusk, 1997). While in this work measured performance differences were not very important, additional research would be necessary to thoroughly investigate these effects, especially at lower resolutions. It should also be stressed that extreme gaussian widths noticeably impaired performance. When very small gaussian widths were used, pixels appeared as isolated small points of light, making it almost impossible to extract a cohesive picture. With large gaussian widths, overlap was too pronounced leading to very low contrast stimuli. Several authors have already demonstrated that such low contrast images lead to poor reading performance (Legge & Rubin, 1986; Legge et al., 1987; Thompson et al., 2003). Results of experiment 12 might appear surprising in light of the findings of experiment 11: when using real-time processing, the significant benefits of gaussian pixelization vanished. In fact, this outcome is not astonishing. Real-time processing already eliminates the major ‘handicap’ of square pixelization: the distracting highfrequency noise introduced at pixel borders is low pass filtered by pixel movement. We believe that the use of the ‘optimal’ gaussian width σ = 0.286 pixels (instead of 0.143) would not change this result fundamentally. 136 IMPROVED SIMULATIONS OF ARTIFICIAL VISION 6.7.1 Implications of these results for simulations of artificial vision The exact characteristics of the electrophysiological response of the retina to patterned electrical stimulation remain undetermined to this date. However, the use of 2D gaussian functions for stimulus pixelization is certainly a more physiologically pertinent approach than the use of square pixels, for at least two reasons: pixel borders are smoother and it allows for overlapping between neighboring pixels in a simple way. Subjects consistently described such stimuli as being more comfortable than their square-pixelized counterparts. As soon as the results of electrophysiological experiments on retinal tissue become available, the parameters of such 2D gaussian (or more adequate) functions should be adapted. Our experiments also demonstrated that gaussian width was an important factor for readability. Electrophysiology has already revealed that electrical stimulation can activate patches of retinal tissue, the size of which depends on stimulation current (Weiland et al., 1999; Stett et al., 2000). Consequently, these results suggest that stimulating current strength and electrode spacing might have to be further ‘tuned’ (within safe and comfortable limits) to achieve the most efficient image transmission possible. Real-time processing also yields more realistic simulations of the visual information provided by retinal prostheses. This is essentially the case for devices transforming visual stimuli into electric currents ‘in situ’, but it is also pertinent for prostheses with externally controlled (i.e. head-mounted) cameras. In this series of central reading experiments, real-time pixelization yielded significantly better performance than off-line pixelization, but this benefit was relatively moderate. In order to briefly assess the impact of this same effect on eccentric reading, we performed control measurements on a subject trained to read pages of text through a viewing window stabilized at 15° eccentricity in the lower visual field (subject AD, see Chapter 3). Figure 81 compares her reading performance for offline pixelization at resolutions of 286 and 572 pixels with those obtained with real-time pixelization at 286 pixels. Figure 81. Reading performance at 15° eccentricity in the Consistent with the results lower visual field, for one trained subject (AD). Mean reading presented in this study, at scores [RAU] ±SEM and mean reading rates [WPM] ±SEM. 286 pixels real-time square Four runs of 4 text segments were performed for each pixelization improved reading experimental condition: off-line pixelization at 572 pixels, offscores significantly (p = line pixelization at 280 pixels, and real-time pixelization at 280 pixels in a 10°x7° viewing window. Only the 3 runs 0.01). However, performance yielding the best reading scores were used for data analysis. remained significantly lower One was suppressed because the subject was in bad shape, than off-line pixelization at which resulted in considerably lower reading performances. 572 pixels (mean reading MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 137 scores: p = 0.032; mean reading rates: p = 0.005). Everything considered, real-time pixelization better mimics the visual information provided by a retinal prosthesis and enhances performance, but it does not allow for a significant reduction (e.g. a factor of two) of the number of stimulation points. Most probably, this advantage will be even less important in visual prostheses with external head-mounted cameras, since head movements are, in general, larger and less frequent than eye movements. Moreover, recurring head movements could result in an abnormal vestibulo-ocular reflex (Cha et al., 1992a). 6.8 Conclusion These results demonstrate that the spatial and temporal characteristics of image pixelization play a role in artificial vision simulations. Equivalent performance could be reached with a resolution reduction of about 30%, if stimulation parameters were adequate. Small eye movements will help to improve performance with retinal prostheses transforming light ‘in situ’. This effect is, however, not strong enough to fundamentally change the minimum requirements determined in our previous studies on the basis of simplified processing: 400-500 contacts covering a 3 x 2 mm2 retinal area are necessary to transmit sufficient visual information for reading, visuomotor coordination, and whole-body mobility. 6.9 Publications resulting from this research Pérez Fornos, A., Sommerhalder, J., Rappaz, B., Safran, A.B., & Pelizzone, M. (2005). Simulation of artificial vision: III. Do the spatial or temporal characteristics of stimulus pixelization really matter? IOVS, 46: 3906-3912. 7 General Conclusions Questions are never indiscreet, answers sometimes are. Oscar Wilde (1854 - 1900) 7.1 Summary of the results The studies presented here intend to be a systematic assessment of the minimum requirements to obtain useful artificial vision. We assumed that all visual information provided by the prosthesis can be transmitted to the nervous system (i.e. that there is no loss of information at the electrode-nerve interface). Focus was given to the amount and type of visual information critical to perform a set of basic, every-day tasks: reading, visuomotor coordination, and mobility. This type of approach has already been used to study speech perception cochlear implant users (Shannon et al., 1995; Dorman & Loizou, 1997; de Balthasar et al., 1999; Loizou et al., 1999). The results can be summarized as follows: • For images projected onto a 10° x 7° viewing window stabilized in the central visual field, our results indicate that: 1) Between 400-500 pixels are necessary for full-page reading. Strings of 4-6 characters and about two lines of text have to be visualized simultaneously for efficient reading. This corresponds to a (highly magnified) effective visual field of about 2° x 1.4° for a typical newspaper (~ 200 pixels/deg2). 2) About 400 pixels encoding an effective visual field of 16° x 12° allow for efficient visuomotor coordination (~ 2 pixels/deg2). 3) As few as about 200 pixels encoding an effective visual field of 33° x 23° allow for mobility in familiar environments (~ 0.2 pixels/deg2). However, much higher image resolutions (>1000 pixels, ~ 2 pixels/deg2) are needed for subjects to feel safe in unpredictable environments including moving, eventually hazardous objects. • In eccentric vision (15° in the lower visual field), initial performance for all tasks was relatively poor. Remarkable improvements were already observed after a few training sessions. After a period of systematic adaptation of variable length (~ 60 sessions for reading; ~ 30 sessions for visuomotor coordination; and ~ 30 sessions for whole-body mobility), all tasks could be performed with reasonable accuracy and speed in eccentric vision. Our results are in accordance with current clinical observations in low vision patients. Depending on their clinical condition, their handicap can result in problems with small object recognition, specifically reading, and with spatial orientation, including whole-body mobility and visuomotor coordination (Weih et al., 2000). Our results clearly depict the particular visual requirements of each category of tasks: on 139 140 GENERAL CONCLUSIONS one hand, the highly resolution-demanding reading task and, on the other hand, the more important visual field requirements of visuomotor coordination and mobility tasks. We also observed that a period of systematic adaptation was required in order to achieve efficient performance when tasks had to be achieved in eccentric vision. Interestingly, however, adaptation processes for each task appear to be quite different. The lengthier and most complex oculomotor adaptation process was observed for the reading task. For this task, we observed a rapid suppression of the vertical (presumably foveating) movements and then a more progressive restructuration of the horizontal pattern. On the contrary, for visuomotor and mobility tasks, the adaptation of both horizontal and vertical components of the eye movement trajectory were less pronounced and appeared to be simultaneous (see Appendix D and Appendix E). This difference is most certainly due to the fact that during the reading experiments, subjects were forced to explore (navigate) through the pages of text with their eye movements. As a consequence, an important part of the learning process for eccentric reading consisted in the development of relatively precise eccentric oculomotor control. Conversely, in the visuomotor and mobility tasks subjects were not forced to use eccentric eye movements to explore the environment. Instead, they could use head/body movements. In this case, subjects made less use of eccentric saccades, which are difficult to develop and control (Hallett, 1978; Zeevi & Peli, 1979; Whittaker & Cummings, 1990; Whittaker et al., 1991; Heinen & Skavenski, 1992). The learning effects reported for all tasks might appear surprising due to the fact that experiments were performed in normal subjects interleaving short eccentric viewing sessions with much longer periods of normal foveal viewing. One possibility is that learning effects acquired within a single experimental session are somehow carried out to the next one. Another explanation could be that learning results from some kind of perceptual assimilation occurring between sessions. Our experience suggests us that it could be a combination of both. 7.2 Implication of these results for the development of visual prostheses The results summarized above delimit two fundamental parameters of future visual prostheses. On one hand, 400-500 stimulation contacts72, equally distributed on an implant surface of 3 x 2 mm2 (equivalent to a pixel density of ~ 80 pixels/mm2) seem to be the minimum to restore useful function. On the other hand, the optimal effective field of view represented by the active area of the implant seems to depend on the task at hand. This does not imply that each task will require implants of different sizes. It could be easily realized by varying the optics of the system used to capture the visual stimuli. In subretinal implants that transform light into electric currents ‘in-situ’, this could be achieved with different lenses adapted for each task. Such adapted ‘viewing glasses’ would modify the optics of the eye in order 72 Assuming that each stimulation electrode evokes a distinct phosphene. MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 141 to focus larger or smaller portions of the visual environment on the photodiodes. Similarly, in visual prostheses that use an external head-mounted camera to capture the visual stimulus, the different effective fields of view could be achieved by directly modifying the objective of the camera. In addition, subjects will be able of performing head/body movements to move toward or move away of objects/targets in order to dynamically modify the actual field of view according to the instantaneous visual requirements of a particular situation. This is the strategy that we observed during the visuomotor coordination experiments (see Appendix D). As less visual information was available in the viewing window (less pixels and larger effective fields of view), subjects had to approach the working area to recognize a given chip. In contrast to the subjects that participated in our experiments, future users of retinal implants will wear their prosthesis permanently in daily life. Pelli (1987) points out that visual impairment might be less disabling in low vision patients than in normal subjects under conditions simulating restricted vision as a result of long-term learning. This suggests that, since future visual prosthesis wearers will have much more time to adapt to their new vision than the normal subjects who participated in our simulation experiments, they might benefit even more from learning, as well as from other possible brain plasticity mechanisms. In this respect, our results are very encouraging for the future. Since our ultimate goal is the rehabilitation of blind patients, our results should help clinicians in advising their patients on the level of rehabilitation that could be provided with a given device. Suppose, for example, that the first commercially available prostheses have 256 contacts distributed in an active surface of 3 x 3 mm2 (equivalent to a pixel density of ~30 pixels/mm2). Clinicians would be able to tell their patients that with such a device, they could expect to recover certain mobility abilities (in indoor, familiar environments). However, restoration of reading abilities would probably be out of reach with such a prosthesis. In particular, the reading task is known to be one of the most demanding in terms of visual information. We are convinced that future devices should aim to restore reading abilities since these are strongly associated with vision-related estimates of quality of life, and represent one of the main goals of low vision patients seeking rehabilitation (see. e.g. Wolffsohn & Cochrane, 1998; McClure et al., 2000; Hazel et al., 2000). Several alternatives already provide blind patients with access to some written material (e.g. Braille, textto-speech conversion devices). Still, patients are not satisfied with these substitutes since, for example, the offer of texts available in Braille is very limited. Other solutions such as text-to-speech conversion devices require bulky equipment that might be difficult to transport and, consequently, might not be available when needed. Another important behavioral task, judging by the complaints of people with low vision is whole-body mobility (Pelli, 1987; Wolffsohn & Cochrane, 1998). It is thus important to be aware of such minimum conditions when developing visual prostheses even if less sophisticated devices might already bring some clinical benefits to patients. 142 GENERAL CONCLUSIONS 7.3 Future work Visual prostheses that allow users to explore the environment ‘naturally’, with eye movements (as in subretinal implants transforming incident light into electric currents ‘in-situ’) could allow for better performance than systems where the environment has to be explored with head movements (as in epiretinal implants that use external head-mounted cameras). Furthermore, the use of large head movements to explore the environment might lead to balance problems associated with an abnormal vestibulo-ocular reflex (Cha et al., 1992a). The experiments presented on this dissertation do not allow us to determine any eventual advantage of using eye movements during vision-related tasks. This would be a very interesting line of investigation for future psycophysical experiments. For example, performance could on a given task (e.g. full-page reading) could be compared in two conditions: one where the subjects are able to scan pages of text using their own eye movements, and another one where subjects are allowed to scan the text using head movements. Such information is crucial to determine the extent to which it would be desirable for prostheses with head-mounted cameras to incorporate a sub-system that allows for the coupling of eye movements. Future research efforts could also explore the degree to which learning in eccentric vision transfers from one task to another. Since the learning process for each task was different, different factors might have influenced the adaptation to performing each task in eccentric vision. This issue could be easily explored by evaluating performance of subjects trained for one task on another one. For example, one of the subjects trained for eccentric reading could perform a series of sessions of mobility tasks, and the other way around. This investigation would allow for a better outlook of the different processes involved in the adaptation to each task. Another interesting consideration relates to the type of cells that will probably be stimulated. We have pointed out that the best implantation sites for retinal prostheses will be situated at eccentricities beyond 10°. At such high eccentricities, the photoreceptor population is mainly constituted of rods. This family of photoreceptors function in dim lighting (scotopic and mesopic) conditions. However, all the experiments described in this dissertation were carried out in photopic conditions (> 10 cd/m2) and the stimuli used were grayscale images. In these conditions, rods were saturated and the 3 families of cones were stimulated. It would be, thus, interesting to explore in future experiments how would stimulating exclusively one family of photoreceptors (i.e. rods or one type of cones) impact performance on vision-related tasks. This could be carried out by examining performance on a given task in various illumination conditions (e.g. scotopic, photopic but limiting luminous stimuli to a given wavelength/color). Such an investigation will not change the fundamental limits determined in our study (which depend on the task at hand, but on the characteristics of stimulation), but might give valuable indications for efficient electrical stimulation strategies. Additional simulations on normal subjects could still provide important information on image features and additional processing that could help improve performance (i.e. contrast enhancement, edge detection). Furthermore, particular isolated sub- MINIMUM REQUIREMENTS FOR A RETINAL PROSTHESIS TO RESTORE USEFUL VISION 143 tasks (i.e. motion detection thresholds) could still be studied in more detail. However, this knowledge is not essential to understanding visual function with an artificial vision device, and would not fundamentally change the minimum requirements determined in our studies. Finally, at this point it is imperative that a substantial research effort is made to better define the characteristics of transmission around the electrode-nerve interface (spatial selectivity, stimulation thresholds, retinotopy of the perceived stimulus). More in particular, fundamental knowledge will depend on the results of psychophysical experiments on blind subjects both in acute and chronic trials. 7.4 Closing remarks Implantable microelectrode arrays consisting of about 500 active contacts seem feasible using present technology. Some research groups have already manufactured first retinal implant prototypes consisting of several hundreds of electrodes (Zrenner et al., 1999; Palanker et al., 2003; Chow et al., 2003). Our own consortium has already produced a retinal prosthesis containing 200 ‘smart’ pixels/mm2 (photodiode + electronics + electrode; see Mazza et al., 2005). Five hundred contacts covering a surface of 3 x 2 mm2 correspond to an inter-electrode spacing of approximately 100 µm (equivalent to a visual acuity of 20/400; see Palanker et al., 2005). Multisite stimulation measurements on chicken retinae have demonstrated that spatial resolution in this order of magnitude should be possible (Stett et al., 2000; Lecchi et al., 2006). The first visual prosthesis prototypes have been recently implanted in humans with encouraging results (Humayun et al., 2003; Veraart et al., 2003; Chow et al., 2004). Yet, several important challenges still need to be overcome before these devices provide similar benefits to those of cochlear implants in cases of deafness (NIH consensus 1995). The basic notion of patterned vision resulting from the continuous stimulation of several electrodes has not been fully confirmed. Furthermore, an appropriate method of selective stimulation eliciting the adequate psychophysical response has not been developed yet. Multidisciplinary research is, therefore, still needed to determine, if prototype chips can actually reach the required spatial selectivity in neural excitation, as well as if they can preserve retinotopic mapping. One major problem is to achieve efficient electrical stimulation within safe charge density limits (Brummer et al., 1983). The critical parameter is the threshold current needed to achieve stimulation. To remain within safe limits, electrode area has to be enlarged as threshold current increases, which fundamentally limits inter-electrode spacing at the same time. While there is some data on epiretinal stimulation in humans, the exact characteristics of the electrophysiological response of the human retina to subretinal stimulation are still largely unknown. Therefore, depending on the results of future human studies, the use of relatively large stimulation electrodes might turn out to be mandatory, preventing the 100 µm inter-electrode spacing used in our simulations. In this case, we would rather suggest increasing the total area of the retinal array (within feasible limits) than limiting the number of stimulation contacts. A substantial research effort 144 GENERAL CONCLUSIONS is therefore still required to solve these and other open issues before realizing the level of electrode integration suggested by our studies. We consider that our methodical investigation of the minimum requirements for useful artificial vision is now quite complete. On the basis of the results reported here, we can conclude that retinal implants might be able to restore some reading, visuomotor, and whole-body mobility abilities to blind patients. Between 400-500 phosphenes, retinotopically arranged over a 10° x 7° retinal area (corresponding to an implant surface of 3 x 2 mm2), appear to be the minimum visual information required to restore useful function. However, the effective field of view represented by the active area of the implant will have to be optimized for each task. A highly magnified effective visual field simultaneously containing strings of 4-6 characters and about two lines of text (about 2° x 1.4° for a typical newspaper) is required for efficient reading, an effective visual field of 16.4° x 11.6° seems to allow for efficient visuomotor coordination, and an effective field of view of 33° x 23° appears to be necessary for tasks involving whole-body mobility. Adequate lenses/optics could be used to adapt the available field of view to the task at hand. A significant learning process will be required to reach optimal performance with such devices, especially if the implant has to be placed outside the fovea. Visual prostheses should aim to meet these criteria in order to provide efficient functional rehabilitation to blind patients. 8 References Altpeter, E., Mackeben, M., & Trauzettel-Klosinski, S. (2000). The importance of sustained attention for patients with maculopathies. Vision Res, 40(10-12), 1539-1547. Antes, J.R. (1974). The time course of picture viewing. J Exp Psychol, 103(1), 62-70. Apfelbaum, H., Pelah, A., & Peli, E. (2006). Collision detection by "tunnel vision" patients walking in a virtual reality environment . http://www.eri.harvard.edu/faculty/peli/papers/TAP_Collision_detection_051118.05.pdf Arditi, A., Knoblauch, K., & Grunwald, I. (1990). Reading with fixed and variable character pitch. J Opt Soc Am A, 7(10), 2011-2015. Bachmann, T. (1991). Identification of spatially quantised tachistoscopic images of faces: How many pixels does it take to carry identity? Eur J Cogn Psychol, 3, 87-107. Bachmann, T. & Kahusk, N. (1997). The effects of coarseness of quantisation, exposure duration, and selective spatial attention on the perception of spatially quantised ('blocked') visual images. Perception, 26(9), 1181-1196. Bagnoud, M., Sommerhalder, J., Pelizzone, M., & Safran, A.B. (2001). Information visuelle necessaire a la restauration d'une lecture au moyen d'un implant retinien chez un aveugle par degenerescence massive des photorecepteurs. Klin Monatsbl Augenheilkd, 218(5), 360362. Bai, Q. & Wise, K.D. (2001). Single-unit neural recording with active microelectrode arrays. IEEE Trans Biomed Eng, 48(8), 911-920. Bai, Q., Wise, K.D., & Anderson, D.J. (2000). A high-yield microassembly structure for threedimensional microelectrode arrays. IEEE Trans Biomed Eng, 47(3), 281-289. Bak, M., Girvin, J.P., Hambrecht, F.T., Kufta, C.V., Loeb, G.E., & Schmidt, E.M. (1990). Visual sensations produced by intracortical microstimulation of the human occipital cortex. Med Biol Eng Comput, 28(3), 257-259. Baldasare, J. & Watson, G. (1986). Observations from the psychology of reading relevant to low vision research. In: G.C. Woo (Eds.), Low vision principles and applications (pp. 272-286). New York: Springer Verlag. Beard, B.L., Levi, D.M., & Reich, L.N. (1995). Perceptual learning in parafoveal vision. Vision Res, 35(12), 1679-1690. Beckmann, P.J. & Legge, G.E. (1996). Psychophysics of reading XIV. The page navigation problem in using magnifiers. Vision Res, 36(22), 3723-3733. Berthoz, A. (1997). Le sens du mouvement. Paris: Odile Jacob. Bingham, G.P. & Pagano, C.C. (1998). The necessity of a perception-action approach to definite distance perception: monocular distance perception to guide reaching. J Exp Psychol Hum Percept Perform, 24(1), 145-168. Bizzi, E., Accornero, N., Chapple, W., & Hogan, N. (1984). Posture control and trajectory formation during arm movement. J Neurosci, 4(11), 2738-2744. Blau, A., Ziegler, C., Heyer, M., Endres, F., Schwitzgebel, G., Matthies, T., Stieglitz, T., Meyer, J.U., & Gopel, W. (1997). Characterization and optimization of microelectrode arrays for in vivo nerve signal recording and stimulation. Biosens Bioelectron, 12(9-10), 883-892. 145 Blouin, J., Bard, C., Teasdale, N., Paillard, J., Fleury, M., Forget, R., & Lamarre, Y. (1993). Reference systems for coding spatial information in normal subjects and a deafferented patient. Exp Brain Res, 93(2), 324-331. Blouin, J., Gauthier, G.M., Vercher, J.L., & Cole, J. (1996). The relative contribution of retinal and extraretinal signals in determining the accuracy of reaching movements in normal subjects and a deafferented patient. Exp Brain Res, 109(1), 148-153. Bossom, J. (1974). Movement without proprioception. Brain Res, 71(2-3), 285-296. Boughman, J.A., Conneally, P.M., & Nance, W.E. (1980). Population genetic studies of retinitis pigmentosa. Am J Hum Genet, 32(2), 223-235. Bowers, A.R. & Reid, V.M. (1997). Eye movements and reading with simulated visual impairment. Ophthalmic Physiol Opt, 17(5), 392-402. Boyle, J.R., Maeder, A.J., & Boles, W.W. (2002). Image enhancement for electronic visual prostheses. Australas Phys Eng Sci Med, 25(2), 81-86. Brindley, G.S. (1973). Sensory effects of electrical stimulation of the visual and paravisual cortex in man. In: R. Jung (Eds.), Handbook of Sensory Physiology (pp. 583-594). New York: Springer-Verlag. Brindley, G.S. & Lewin, W.S. (1968a). The sensations produced by electrical stimulation of the visual cortex. J Physiol, 196(2), 479-493. Brindley, G.S. & Lewin, W.S. (1968b). The visual sensations produced by electrical stimulation of the medial occipital cortex. J Physiol, 194(2), 54-55P. Brummer, S.B., Robblee, L.S., & Hambrecht, F.T. (1983). Criteria for selecting electrodes for electrical stimulation: theoretical and practical considerations. Ann N Y Acad Sci, 405, 159171. Buultjens, M., Aitken, S., Ravenscroft, J., & Carey, K. (1999). Size counts: The significance of size, font and style of print for readers with low vision sitting examinations. Br J Vis Impair, 17, 5-10. Campbell, P.K., Jones, K.E., Huber, R.J., Horch, K.W., & Normann, R.A. (1991). A silicon-based, three-dimensional neural interface: manufacturing processes for an intracortical electrode array. IEEE Trans Biomed Eng, 38(8), 758-768. Cha, K., Horch, K.W., & Normann, R.A. (1992a). Mobility performance with a pixelized vision system. Vision Res, 32(7), 1367-1372. Cha, K., Horch, K.W., Normann, R.A., & Boman, D.K. (1992b). Reading speed with a pixelized vision system. J Opt Soc Am A, 9(5), 673-677. Chanderli, K. (2002) Stratégies de couplage action perception lors du pointage locomoteur à l'approche d'une cible. PhD thesis No. 300, Université de Genève, Geneva, Switzerland. Chen, H., Yao, D., & Liu, Z. (2004). A study on asymmetry of spatial visual field by analysis of the fMRI BOLD response. Brain Topogr, 17(1), 39-46. Chow, A.Y. & Chow, V.Y. (1997). Subretinal electrical stimulation of the rabbit retina. Neurosci Lett, 225(1), 13-16. Chow, A.Y., Chow, V.Y., Packo, K.H., Pollack, J.S., Peyman, G.A., & Schuchard, R. (2004). The artificial silicon retina microchip for the treatment of vision loss from retinitis pigmentosa. Arch Ophthalmol, 122(4), 460-469. Chow, A.Y., Packo, K.H., Pollack, J.S., & Schuchard, R.A. (2003). Subretinal Artificial Silicon Retina Microchip Implantation in Retinitis Pigmentosa Patients: Long Term Follow-Up. Invest Ophthalmol Vis Sci, 44(5), 4205 (abstract). Chow, A.Y., Pardue, M.T., Chow, V.Y., Peyman, G.A., Liang, C., Perlman, J.I., & Peachey, N.S. (2001). Implantation of silicon chip microphotodiode arrays into the cat subretinal space. IEEE Trans Neural Syst Rehabil Eng, 9(1), 86-95. 146 Chow, A.Y., Peyman, G.A., Packo, K.H., & Pollack, J.S. (2002). The artificial silicon retina (ASR) prosthesis for the treatment of retinitis pigmentosa. Exp Eye Res, 27(2 (suppl.)), 95 (abstract). Christie, F. & Bruce, V. (1998). The role of dynamic information in the recognition of unfamiliar faces. Mem Cognit, 26(4), 780-790. Chung, S.T. (2004). Reading speed benefits from increased vertical word spacing in normal peripheral vision. Optom Vis Sci, 81(7), 525-535. Chung, S.T., Legge, G.E., & Cheung, S.H. (2004). Letter-recognition and reading speed in peripheral vision benefit from perceptual learning. Vision Res, 44(7), 695-709. Chung, S.T., Mansfield, J.S., & Legge, G.E. (1998). Psychophysics of reading. XVIII. The effect of print size on reading speed in normal peripheral vision. Vision Res, 38(19), 2949-2962. Ciulla, T.A., Danis, R.P., & Harris, A. (1998). Age-related macular degeneration: a review of experimental treatments. Surv Ophthalmol, 43(2), 134-146. Clausen, J. (1955). Visual sensations (phosphenes) produced by AC sine wave stimulation. Acta Psychiatr Neurol Scand, 94, 1-101. Coello, Y. & Grealy, M.A. (1997). Effect of size and frame of visual field on the accuracy of an aiming movement. Perception, 26(3), 287-300. Congdon, N.G., Friedman, D.S., & Lietman, T. (2003). Important causes of visual impairment in the world today. JAMA, 290(15), 2057-2060. Cornelissen, F.W., Bruin, K.J., & Kooijman, A.C. (2005). The influence of artificial scotomas on eye movements during visual search. Optom Vis Sci, 82(1), 27-35. Cornelissen, F.W., Peters, E.M., & Palmer, J. (2002). The Eyelink Toolbox: eye tracking with MATLAB and the Psychophysics Toolbox. Behav Res Methods Instrum Comput, 34(4), 613617. Cornelissen, F.W. & Van den Dobbelsteen, J.J. (1999). Heading detection with simulated visual field defects. Vis Impairment Res, 1(3), 71-84. Costen, N.P., Parker, D.M., & Craw, I. (1994). Spatial content and spatial quantisation effects in face recognition. Perception, 23(2), 129-146. Cotter, J.R. (1990). The Visual Pathway: An Introduction to Structure and Organization. In: K.N. Leibovic (Eds.), Science of Vision (pp. 3-15). New York: Springer-Verlag. Cowey, A. & Rolls, E.T. (1974). Human cortical magnification factor and its relation to visual acuity. Exp Brain Res, 21(5), 447-454. Crist, R.E., Kapadia, M.K., Westheimer, G., & Gilbert, C.D. (1997). Perceptual learning of spatial localization: specificity for orientation, position, and context. J Neurophysiol, 78(6), 28892894. Crist, R.E., Li, W., & Gilbert, C.D. (2001). Learning to see: experience and attention in primary visual cortex. Nat Neurosci, 4(5), 519-525. Cummings, R.W., Whittaker, S.G., Watson, G.R., & Budd, J.M. (1985). Scanning characters and reading with a central scotoma. Am J Optom Physiol Opt, 62(12), 833-843. Curcio, C.A., Sloan, K.R.J., Packer, O., Hendrickson, A.E., & Kalina, R.E. (1987). Distribution of cones in human and monkey retina: individual variability and radial asymmetry. Science, 236(4801), 579-582. Cursiefen, C., Holbach, L.M., Schlotzer-Schrehardt, U., & Naumann, G.O. (2001). Persisting retinal ganglion cell axons in blind atrophic human eyes. Graefes Arch Clin Exp Ophthalmol, 239(2), 158-164. Cutting, J.E. & Vishton, P.M. (1995). Perceiving layout and knowing distances: the integration, relative potency, and contextual use of different information about depth. In: W. Epstein & S.J. Rogers (Eds.), Perception of space and motion (pp. 69-117). London: Academic Press. 147 Dagnelie, G., Kelley, A.J., & Yang, L. (2004). Effects of image stabilization on face recognition and virtual mobility using simulated prosthetic vision. Invest Ophthalmol Vis Sci, 45(5), 4223 (abstract). Dagnelie, G., Thompson, R.W., Barnett, D., & Zhang, W.Q. (2000). Visual perception and performance under conditions simulating artificial vision. Perception, 29(suppl.), 84 (abstract). Daniel, P. & Whitterridge, D. (1961). The representation of the visual field on the cerebral cortex in monkeys. J Physiol (Paris), 159, 203-221. de Balthasar, C., Cosendai, G., & Pelizzone, M. (1999). Simulations of the effects of electrical stimulation selectivity on speech reception with cochlear implants. Med Hyg, 2273, 19841988. De Graef, P., Christiaens, D., & d'Ydewalle, G. (1990). Perceptual effects of scene context on object identification. Psychol Res, 52(4), 317-329. Delbeke, J., Gerard, B., Lambert, V., Laloyaux, C., Schmitt, C., & Veraart, C. (2003a). A First Attempt to Translate Images in Optic Nerve Stimuli for a Visual Prosthesis. Invest Ophthalmol Vis Sci, 44(5), 5074 (abstract). Delbeke, J., Oozeer, M., & Veraart, C. (2003b). Position, size and luminosity of phosphenes generated by direct optic nerve stimulation. Vision Res, 43(9), 1091-1102. Delbeke, J., Pins, D., Michaux, G., Wanet-Defalque, M.C., Parrini, S., & Veraart, C. (2001). Electrical stimulation of anterior visual pathways in retinitis pigmentosa. Invest Ophthalmol Vis Sci, 42(1), 291-297. Delbeke, J., Wanet-Defalque, M.C., Gerard, B., Troosters, M., Michaux, G., & Veraart, C. (2002). The microsystems based visual prosthesis for optic nerve stimulation. Artif Organs, 26(3), 232-234. Desmurget, M., Pelisson, D., Rossetti, Y., & Prablanc, C. (1998). From eye to hand: planning goal-directed movements. Neurosci Biobehav Rev, 22(6), 761-788. Desmurget, M., Rossetti, Y., Jordan, M., Meckler, C., & Prablanc, C. (1997). Viewing the hand prior to movement improves accuracy of pointing performed toward the unseen contralateral hand. Exp Brain Res, 115(1), 180-186. Dichgans, J., Bizzi, E., Morasso, P., & Tagliasco, V. (1974). The role of vestibular and neck afferents during eye-head coordination in the monkey. Brain Res, 71(2-3), 225-232. Dobelle, W.H. (2000). Artificial vision for the blind by connecting a television camera to the visual cortex. ASAIO J, 46(1), 3-9. Dobelle, W.H. & Mladejowsky, M.G. (1974). Phosphenes produced by electrical stimulation of human occipital cortex, and their application to the development of a prosthesis for the blind. J Physiol, 243(2), 553-576. Dobelle, W.H., Mladejowsky, M.G., Evans, J.R., Roberts, T.S., & Girvin, J.P. (1976). "Braille" reading by a blind volunteer by visual cortex stimulation. Nature, 259(5539), 111-112. Dobelle, W.H., Mladejowsky, M.G., & Girvin, J.P. (1974). Artifical vision for the blind: electrical stimulation of visual cortex offers hope for a functional prosthesis. Science, 183(123), 440444. Dorman, M.F. & Loizou, P.C. (1997). Speech intelligibility as a function of the number of channels of stimulation for normal-hearing listeners and patients with cochlear implants. Am J Otol, 18(6 (suppl.)), S113-S114. Doyle, J.B., Doyle, J.H., Turnbull, F.M., Abbey, J., & House, L. (1963). Electrical stimulation in eighth nerve deafness. A preliminary report. Bull Los Angel Neuro Soc, 28, 148-150. Drasdo, N. & Fowler, C.W. (1974). Non-linear projection of the retinal image in a wide-angle schematic eye. Br J Ophthalmol, 58(8), 709-714. 148 Eckmiller, R. (1997). Learning retina implants with epiretinal contacts. Ophthalmic Res, 29(5), 281-289. Eddington, D.K., Dobelle, W.H., Brackmann, D.E., Mladejowsky, M.G., & Parkin, J.L. (1998a). Auditory prosthesis research with multiple channel intracochlear stimulation in man. Ann Otol Rhinol Laryngol, 87(S53), 5-39. Eddington, D.K., Dobelle, W.H., Brackmann, D.E., Mladejowsky, M.G., & Parkin, J.L. (1998b). Place and periodicity pitch by stimulation of multiple scalal tympani electrodes in deaf volunteers. Trans Am Soc Artif Intern Organs, XXIV, 1. Einthoven, W. & Jolly, W.A. (1908). The form and magnitude of the electric response of the eye to stimulation by light at various intensities. Q J Exp Physiol, 1(4), 373-416. Elfar, S.D., Cottaris, N.P., Iezzi, R., & Abrams, G.W. (2004). Rapid mapping of cortical multielectrode arrays and its application for the evaluation of retinal prostheses. Invest Ophthalmol Vis Sci, 45(5), 3403 (abstract). Elliott, D.B., Trukolo-Ilic, M., Strong, J.G., Pace, R., Plotkin, A., & Bevers, P. (1997). Demographic characteristics of the vision-disabled elderly. Invest Ophthalmol Vis Sci, 38(12), 2566-2575. Fine, E.M., Hazel, C.A., Petre, K.L., & Rubin, G.S. (1999). Are the benefits of sentence context different in central and peripheral vision? Optom Vis Sci, 76(11), 764-769. Fine, E.M., Kirschen, M.P., & Peli, E. (1996). The necessary field of view to read with an optimal stand magnifier. J Am Optom Assoc, 67(7), 382-389. Fine, E.M. & Peli, E. (1996a). The role of context in reading with central field loss. Optom Vis Sci, 73(8), 533-539. Fine, E.M. & Peli, E. (1996b). Visually impaired observers require a larger window than normally sighted observers to read from a scroll display. J Am Optom Assoc, 67(7), 390-396. Fishman, H.A., Palanker, D.V., Mehenti, N.Z., Marmor, M.F., Bent, S.F., & Blumenkranz, M.S. (2004). Design of a Neurotransmitter-Based Retinal Prosthetic Chip Powered by the Ambient Light. Invest Ophthalmol Vis Sci, 45(5), 3402 (abstract). Fishman, H.A., Peterman, M.C., Leng, T., Huie, P., Lee, C.J., Bloom, D.M., Sanislo, S.R., Marmor, M.F., Bent, S.F., & Blumenkranz, M.S. (2002). The Artificial Synapse Chip: A Novel Interface for a Retinal Prosthesis based on Neurotransmitter Stimulation and Nerve Regeneration. Invest Ophthalmol Vis Sci, 43(12), 2846 (abstract). Fishman, H.A., Peterman, M.C., Marmor, M.F., & Blumenkranz, M.S. (2003). The Artificial Synapse Chip: Multi-Cellular Neurotransmitter-Based Retinal Stimulation. Invest Ophthalmol Vis Sci, 44(5), 5080 (abstract). Fitzgibbon, T. & Taylor, S.F. (1996). Retinotopy of the human retinal nerve fibre layer and optic nerve head. J Comp Neurol, 375(2), 238-251. Fletcher, D.C. & Schuchard, R.A. (1997). Preferred retinal loci relationship to macular scotomas in a low-vision population. Ophthalmology, 104(4), 632-638. Foerster, O. (1929). Beiträge zur pathophysiologie der sehspäre. J Psychol Neurol, 39, 463485. Foley, J.M. & Held, R. (1972). Visually directed pointing as a function of target distance, direction, and available cues. Percept Psychophys, 12, 263-268. Foulke, E. (1971). The perceptual basis for mobility. In: Research Bulletin No. 23 (pp. 1-8). New York: American Foundation for the Blind. Frick, K.D. & Foster, A. (2003). The magnitude and cost of global blindness: an increasing problem that can be alleviated. Am J Ophthalmol, 135(4), 471-476. 149 Fujii, G.Y., Humayun, M.S., Weiland, J., Greenberg, R., Mech, B., Little, J., Rossi, J.V., Yanai, D., Tameesh, M.K., & Panzan, C.Q. (2003). Intraocular Retinal Prosthesis: First Generation Implant and its Surgical Technique. Invest Ophthalmol Vis Sci, 44(5), 5079 (abstract). Gasperini, J.L., Walraven, T.L., McAllister, J.P., Auner, G., Abrams, G., Givens, R., & Iezzi, R. (2003). The Neuroprotective Effects of Aspirin and MK-801 Against Un-Caged CagedGlutamate for Use in a Visual Prosthetic Device. Invest Ophthalmol Vis Sci, 44(5), 5078 (abstract). Gauthier, G.M., Nommay, D., & Vercher, J.L. (1990). The role of ocular muscle proprioception in visual localization of targets. Science, 249(4964), 58-61. Geruschat, D.R. & Del'Aune, W. (1989). Reliability and validity of O&M instructor observations. J Vis Impair Blind, 83, 457-460. Geruschat, D.R., Turano, K.A., & Stahl, J.W. (1998). Traditional measures of mobility performance and retinitis pigmentosa. Optom Vis Sci, 75(7), 525-537. Ghez, C., Gordon, J., & Ghilardi, M.F. (1995). Impairments of reaching movements in patients without proprioception. II. Effects of visual information on accuracy. J Neurophysiol, 73(1), 361-372. Goodale, M.A. & Milner, A.D. (1992). Separate visual pathways for perception and action. Trends Neurosci, 15(1), 20-25. Goodale, M.A. & Westwood, D.A. (2004). An evolving view of duplex vision: separate but interacting cortical pathways for perception and action. Curr Opin Neurobiol, 14(2), 203211. Gooley, J.J., Lu, J., Chou, T.C., Scammell, T.E., & Saper, C.B. (2001). Melanopsin in cells of origin of the retinohypothalamic tract. Nat Neurosci, 4(12), 1165. Gray, H. (1918). Anatomy of the Human Body. Philadelphia: Lea & Febiger; Bartleby.com, accessed 19/03/2004. www.bartleby.com. Greenberg, R.J. (2000). Visual Prostheses: A Review. Neuromodulation, 3(3), 161-165. Greenberg, R.J., Velte, T.J., Humayun, M.S., Scarlatis, G.N., & de Juan Jr., E. (1999). A computational model of electrical stimulation of the retinal ganglion cell. IEEE Trans Biomed Eng, 46(5), 505-514. Grumet, A.E., Wyatt, J.L., & Rizzo, J.F. (2000). Multi-electrode stimulation and recording in the isolated retina. J Neurosci Methods, 101(1), 31-42. Guthrie, B.L., Porter, J.D., & Sparks, D.L. (1983). Corollary discharge provides accurate eye position information to the oculomotor system. Science, 221(4616), 1193-1195. Haim, M., Holm, N.V., & Rosenberg, T. (1992). A population survey of retinitis pigmentosa and allied disorders in Denmark. Completeness of registration and quality of data. Acta Ophthalmologica (Copenh), 70(2), 165-177. Hallett, P.E. (1978). Primary and secondary saccades to goals defined by instructions. Vision Res, 18(10), 1279-1296. Hamzavi, J.S., Baumgartner, W.D., Adunka, O., Franz, P., & Gstoettner, W. (2000). Audiological performance with cochlear reimplantation from analogue single-channel implants to digital multi-channel devices. Audiology, 39(6), 305-310. Harding, S. (2003). Extracts from "concise clinical evidence". Diabetic retinopathy. BMJ, 326(7397), 1023-1025. Harland, S., Legge, G.E., & Luebker, A. (1998). Psychophysics of reading. XVII. Low-vision performance with four types of electronically magnified text. Optom Vis Sci, 75(3), 183190. Harmon, L.D. & Julesz, B. (1973). Masking in visual recognition: effects of two-dimensional filtered noise. Science, 180(91), 1194-1197. 150 Hayes, J.S., Yin, V.T., Piyathaisere, D., Weiland, J.D., Humayun, M.S., & Dagnelie, G. (2003). Visually guided performance of simple tasks using simulated prosthetic vision. Artif Organs, 27(11), 1016-1028. Hazel, C.A., Petre, K.L., Armstrong, R.A., Benson, M.T., & Frost, N.A. (2000). Visual function and subjective quality of life compared in subjects with acquired macular disease. Invest Ophthalmol Vis Sci, 41(6), 1309-1315. Heinen, S.J. & Skavenski, A.A. (1992). Adaptation of saccades and fixation to bilateral foveal lesions in adult monkey. Vision Res, 32(2), 365-373. Held, R. & Freedman, S.J. (1963). Plasticity in Human Sensorimotor Control. Science, 142(3591), 455-462. Henderson, J.M. & Hollingworth, A. (2003). Eye movements and visual memory: detecting changes to saccade targets in scenes. Percept Psychophys, 65(1), 58-71. Henderson, J.M., McClure, K.K., Pierce, S., & Schrock, G. (1997). Object identification without foveal vision: evidence from an artificial scotoma paradigm. Percept Psychophys, 59(3), 323-346. Higgins, K.E. & Wood, J.M. (1998). Predicting closed road sign recognition performance from vision tests. In: Vision science and its applications (pp. 42-45). Washington DC: Optical Society of America. Higgins, K.E. & Wood, J.M. (2005). Predicting components of closed road driving performance from vision tests. Optom Vis Sci, 82(8), 647-656. Higgins, K.E., Wood, J.M., & Tait, A. (1996). Closed road driving performance: effect of degradation of visual acuity. In: Vision science and its applications (pp. 78-81). Washington DC: Optical Society of America. Hill, E., Rieser, J., Hill, M., Halpin, J., & Halpin, R. (1993). How persons with visual impairments explore novel spaces: Strategies of good and poor performers. J Vis Impair Blind, 87, 295301. Hims, M.M., Diager, S.P., & Inglehearn, C.F. (2003). Retinitis pigmentosa: genes, proteins and prospects. Dev Ophthalmol, 37, 109-125. Hollingworth, A., Schrock, G., & Henderson, J.M. (2001). Change detection in the flicker paradigm: the role of fixation position within the scene. Mem Cognit, 29(2), 296-304. Hooge, I.T. & Erkelens, C.J. (1999). Peripheral vision and oculomotor control during visual search. Vision Res, 39(8), 1567-1575. Hoogerwerf, A.C. & Wise, K.D. (1994). A three-dimensional microelectrode array for chronic neural recording. IEEE Trans Biomed Eng, 41(12), 1136-1146. Huie, P., Palanker, D.V., Vankov, A., Aramant, R.B., Seiler, M.J., Fishman, H.A., Marmor, M.F., & Blumenkranz, M.S. (2004). Migration of neural retina through a perforated membrane implanted in the subretinal space of RCS rats: implications for prosthetics. Invest Ophthalmol Vis Sci, 45(5), 4202 (abstract). Huie, P., Palanker, D.V., Vankov, A., Fishman, H.A., Marmor, M.F., & Blumenkranz, M.S. (2003). Perforated Membrane as an Interface for Focal Electrical Stimulation of Retina. Invest Ophthalmol Vis Sci, 44(5), 5055 (abstract). Huie, P., Peterman, M.C., Leng, T., Lee, C.J., Marmor, M.F., Bloom, D.M., Blumenkranz, M.S., & Fishman, H.A. (2002). Tissue-engineered Neurite Conduits to Connect Retinal Ganglion Cells to an Electronic Retinal Prosthesis. Invest Ophthalmol Vis Sci, 43(12), 4475 (abstract). Huk, A.C., Palmer, J., & Shadlen, M.N. (2002). Temporal integration of visual motion information: Evidence from response times. J Vis, 2(7), 228a (abstract). Humayun, M.S. (2001). Intraocular retinal prosthesis. Trans Am Ophthalmol Soc, 99, 271-300. 151 Humayun, M.S., de Juan Jr., E., Dagnelie, G., Greenberg, R.J., Propst, R.H., & Phillips, D.H. (1996). Visual perception elicited by electrical stimulation of retina in blind humans. Arch Ophthalmol, 114(1), 40-46. Humayun, M.S., de Juan Jr., E., Weiland, J.D., Dagnelie, G., Katona, S., Greenberg, R., & Suzuki, S. (1999). Pattern electrical stimulation of the human retina. Vision Res, 39(15), 2569-2576. Humayun, M.S., Weiland, J.D., Fujii, G.Y., Greenberg, R., Williamson, R., Little, J., Mech, B., Cimmarusti, V., Van Boemel, G., Dagnelie, G., & de Juan, E. (2003). Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res, 43(24), 25732581. Humphries, P., Kenna, P., & Farrar, G.J. (1992). On the molecular genetics of retinitis pigmentosa. Science, 256(5058), 804-808. Iezzi, R., Cottaris, N.P., Elfar, S.D., Walraven, T.L., Raza, T.M., Moncrieff, R., McAllister, J.P., Auner, G.W., Johnson, R.R., & Abrams, G.W. (2003). Neurotransmitter-based retinal prosthesis modulation of retinal ganglion cell responses in vivo. Invest Ophthalmol Vis Sci, 44(5), 5083 (abstract). Iezzi, R., Walraven, T., & Abrams, G. (2004). Toxicological profiles of the phototriggerable molecules MNI and MCNI glutamate for use in visual prostheses. Invest Ophthalmol Vis Sci, 45(5), 4221 (abstract). Iezzi, R., Walraven, T.L., McAllister, J.P., Givens, R., Auner, G., & Abrams, G. (2002). Biocompatibility of Caging Chromophores for Use in Retinal and Cortical Visual Prostheses. Invest Ophthalmol Vis Sci, 43(12), 4478 (abstract). Ito, Y., Yagi, T., Kanda, H., Tanaka, S., Watanabe, M., & Uchikawa, Y. (1999). Cultures of neurons on micro-electrode array in hybrid retinal implant. Proc '99 Conf Syst Man Cybern, 4, 414-417. Jeannerod, M. (1981). Intersegmental coordination during reaching at natural visual objects. In: J. Long & A. Baddeley (Eds.), Attention and Performance IX (pp. 153-168). Hillsdale NJ: Lawrence Erlbaum Associates. Jeannerod, M. (1984). The timing of natural prehension movements. J Mot Behav, 16(3), 235254. Jeannerod, M. & Biguer, B. (1982). Visuomotor mechanisms in reaching within extrapersonal space. In: D.J. Ingle, M.A. Goodale, & J.W. Mansfield (Eds.), Analysis of Visual Behavior (pp. 387-409). Cambridge, MA: The MIT Press. Jones, K.E., Campbell, P.K., & Normann, R.A. (1992). A glass/silicon composite intracortical electrode array. Ann Biomed Eng, 20(4), 423-437. Jones, K.E. & Normann, R.A. (1997). An advanced demultiplexing system for physiological stimulation. IEEE Trans Biomed Eng, 44(12), 1210-1220. Kaczmarek, K.A. (2000). Sensory augmentation and substitution. In: J.D. Bronzino (Eds.), The Biomedical Engineering Handbook (pp. 143.1-143.10). Boca Raton: CRC Press. Kapi, S.S., Walraven, T.L., Abrams, G.W., & Iezzi, R. (2004). Caged neurotransmitters for visual prosthesis: Toxicological profiles for the phototriggerable cage NPEC. Invest Ophthalmol Vis Sci, 45(5), 4205 (abstract). Kelley, A.J., Yang, L., & Dagnelie, G. (2004). The effects of stabilization, font scaling and practice on reading in simulated prosthetic vision. Invest Ophthalmol Vis Sci, 45(5), 5436 (abstract). Kelso, J.A. & Holt, K.G. (1980). Exploring a vibratory systems analysis of human movement production. J Neurophysiol, 43(5), 1183-1196. 152 Kerdraon, Y.A., Downie, J.A., Suaning, G.J., Capon, M.R., Coroneo, M.T., & Lovell, N.H. (2002). Development and surgical implantation of a vision prosthesis model into the ovine eye. Clin Experiment Ophthalmol, 30(1), 36-40. Kerkhoff, G. (1999). Restorative and compensatory therapy approaches in cerebral blindness - a review. Restor Neurol Neurosci, 15(2-3), 255-271. Kewley D.T., Hills M.D., Borkholder D.A., Opris I.E., Maluf N.I., Storment C.W., Bower J.M., & Kovacs G.T.A. (1997). Plasma-etched neural probes. Sens Actuators A Phys, 58(1), 27-35. Kiang, N.Y., Eddington, D.K., & Delgutte, B. (1979). Fundamental considerations in designing auditory implants. Acta Otolaryngol, 87(3-4), 204-218. Kim, S.Y., Sadda, S., Humayun, M.S., de Juan Jr., E., Melia, B.M., & Green, W.R. (2002a). Morphometric analysis of the macula in eyes with geographic atrophy due to age-related macular degeneration. Retina, 22(4), 464-470. Kim, S.Y., Sadda, S., Pearlman, J., Humayun, M.S., de Juan Jr., E., Melia, B.M., & Green, W.R. (2002b). Morphometric analysis of the macula in eyes with disciform age-related macular degeneration. Retina, 22(4), 471-477. Klomp, G.F., Womack, M.V., & Dobelle, W.H. (1977). Fabrication of large arrays of cortical electrodes for use in man. J Biomed Mater Res, 11(3), 347-364. Kohler, K., Hartmann, J.A., Werts, D., & Zrenner, E. (2001). Histologische Untersuchungen zur netzhautdegeneration und Gewebeverträglichkeit subretinaler Implantate. Ophthalmologe, 98(4), 364-368. Kolb, H., Fernandez, E., and Nelson, R. (2003). Webvision. John Moran Eye Center, University of Utah, accessed 27/11/2003. http://www.webvision.med.utah.edu. Krause, F. (1924). Die sehbahnen in chirurgischer beziehung und die faradische reizung des sehzentrums. Klin Wochenschr, 3, 1260-1265. Kuyk, T. & Elliott, J.L. (1999). Visual factors and mobility in persons with age-related macular degeneration. J Rehabil Res Dev, 36(4), 303-312. Kuyk, T., Elliott, J.L., Biehl, J., & Fuhr, P.S. (1996). Environmental variables and mobility performance in adults with low vision. J Am Optom Assoc, 67(7), 403-409. Kuyk, T., Elliott, J.L., & Fuhr, P.S. (1998). Visual correlates of mobility in real world settings in older adults with low vision. Optom Vis Sci, 75(7), 538-547. Kuyk, T., Elliott, J.L., Wesley, J., Scilley, K., McIntosh, E., Mitchell, S., & Owsley, C. (2004). Mobility function in older veterans improves after blind rehabilitation. J Rehabil Res Dev, 41(3A), 337-346. Lakhanpal, R.R., Yanai, D., Weiland, J.D., Fujii, G.Y., Caffey, S., Greenberg, R.J., de Juan Jr., E., & Humayun, M.S. (2003). Advances in the development of visual prostheses. Curr Opin Ophthalmol, 14(3), 122-127. Lambert, V., Laloyaux, C., Schmitt, C., Gerard, B., Delbeke, J., & Veraart, C. (2003). Localisation, Discrimination, and Grasping of Daily Life Objects with an Implanted Optic Nerve Prosthesis. Invest Ophthalmol Vis Sci, 44(5), 4208 (abstract). Land, M., Mennie, N., & Rusted, J. (1999). The roles of vision and eye movements in the control of activities of daily living. Perception, 28(11), 1311-1328. Lander, K., Christie, F., & Bruce, V. (1999). The role of movement in the recognition of famous faces. Mem Cognit, 27(6), 974-985. Lappin, J.S., Tadin, D., & Whittier, E.J. (2002). Visual coherence of moving and stationary image changes. Vision Res, 42(12), 1523-1534. Lateiner, J.E. & Sainburg, R.L. (2003). Differential contributions of vision and proprioception to movement accuracy. Exp Brain Res, 151(4), 446-454. 153 Latham, K. & Whitaker, D. (1996). A comparison of word recognition and reading performance in foveal and peripheral vision. Vision Res, 36(17), 2665-2674. Leal, E.C., Santiago, A.R., & Ambrosio, A.F. (2005). Old and new drug targets in diabetic retinopathy: from biochemical changes to inflammation and neurodegeneration. Curr Drug Targets CNS Neurol Disord, 4(4), 421-434. Leat, S.J., Li, W., & Epp, K. (1999). Crowding in central and eccentric vision: the effects of contour interaction and attention. Invest Ophthalmol Vis Sci, 40(2), 504-512. Lecchi, M., Linderholm, P., Pelizzone, M., Picaud, S., Renaud, P., Salzmann, J., Sommerhalder, J., Safran, A.B., & Bertrand, D. (2006). What physiology tells us about electrical stimulation in retinal implants. Invest Ophthalmol Vis Sci, 47(3195 (abstract). Lecchi, M., Marguerat, A., Ionescu, A., Pelizzone, M., Renaud, P., Sommerhalder, J., Safran, A.B., Tribollet, E., & Bertrand, D. (2004). Ganglion cells from chick retina display multiple functional nAChR subtypes. Neuroreport, 15(2), 307-311. Leeuwenberg, E. (2003). Miracles of perception. Acta Psychol (Amst), 114(3), 379-396. Legge, G.E., Ahn, S.J., Klitz, T.S., & Luebker, A. (1997). Psychophysics of reading--XVI. The visual span in normal and low vision. Vision Res, 37(14), 1999-2010. Legge, G.E., Mansfield, J.S., & Chung, S.T. (2001). Psychophysics of reading. XX. Linking letter recognition to reading speed in central and peripheral vision. Vision Res, 41(6), 725-743. Legge, G.E., Parish, D.H., Luebker, A., & Wurm, L.H. (1990). Psychophysics of reading. XI. Comparing color contrast and luminance contrast. J Opt Soc Am A, 7(10), 2002-2010. Legge, G.E., Pelli, D.G., Rubin, G.S., & Schleske, M.M. (1985a). Psychophysics of reading I. Normal vision. Vision Res, 25(2), 239-252. Legge, G.E., Ross, J.A., Isenberg, L.M., & LaMay, J.M. (1992). Psychophysics of reading. Clinical predictors of low-vision reading speed. Invest Ophthalmol Vis Sci, 33(3), 677-687. Legge, G.E. & Rubin, G.S. (1986). Psychophysics of reading. IV. Wavelength effects in normal and low vision. J Opt Soc Am A, 3(1), 40-51. Legge, G.E., Rubin, G.S., & Luebker, A. (1987). Psychophysics of reading V. The role of contrast in normal vision. Vision Res, 27(7), 1165-1177. Legge, G.E., Rubin, G.S., Pelli, D.G., & Schleske, M.M. (1985b). Psychophysics of reading II. Low vision. Vision Res, 25(2), 253-265. Leng, T., Huie, P., Mehenti, N.Z., Peterman, M.C., Lee, C.J., Marmor, M.F., Sanislo, S.R., Bent, S.F., Blumenkranz, M.S., & Fishman, H.A. (2002). Directed Ganglion Cell Growth and Stimulation with Microcontact Printing as a Prototype Visual Prosthesis Interface. Invest Ophthalmol Vis Sci, 43(12), 4454 (abstract). Leonard, R. and Gordon, A. R. (2002). Statistics on Vision Impairment: A Resource Manual. Lighthouse International, accessed 03/12/2003. http://www.lighthouse.org/research_statistics.htm. Levi, D.M., Klein, S.A., & Aitsebaomo, A.P. (1985). Vernier acuity, crowding and cortical magnification. Vision Res, 25(7), 963-977. Li, H.C., Brenner, E., Cornelissen, F.W., & Kim, E.S. (2002). Systematic distortion of perceived 2D shape during smooth pursuit eye movements. Vision Res, 42(23), 2569-2575. Li, L., Nugent, A.K., & Peli, E. (2001). Recognition of jagged (pixelated) letters in the periphery. Vis Impairment Res, 2, 143-154. Liu, W., Sivaprakasam, M., Singh, P.R., Bashirullah, R., & Wang, G. (2003). Electronic visual prosthesis. Artif Organs, 27(11), 986-995. Livingstone, M. & Hubel, D. (1988). Segregation of form, color, movement, and depth: anatomy, physiology, and perception. Science, 240(4853), 740-749. 154 Loftus, A., Murphy, S., McKenna, I., & Mon-Williams, M. (2004). Reduced fields of view are neither necessary nor sufficient for distance underestimation but reduce precision and may cause calibration problems. Exp Brain Res, 158(3), 328-335. Loftus, G.R. & Mackworth, N.H. (1978). Cognitive determinants of fixation location during picture viewing. J Exp Psychol Hum Percept Perform, 4(4), 565-572. Loizou, P.C., Dorman, M., & Tu, Z. (1999). On the number of channels needed to understand speech. J Acoust Soc Am, 106(4 Pt 1), 2097-2103. Löwenstein, K. & Borchardt, M. (1918). Dtsch. Dtsch Z Nervenheilkd, 58, 264-292. Magne, P. & Coello, Y. (2002). Retinal and extra-retinal contribution to position coding. Behav Brain Res, 136(1), 277-287. Majji, A.B., Humayun, M.S., Weiland, J.D., Suzuki, S., D'Anna, S.A., & de Juan Jr., E. (1999). Long-term histological and electrophysiological results of an inactive epiretinal electrode array implantation in dogs. Invest Ophthalmol Vis Sci, 40(9), 2073-2081. Margalit, E., Maia, M., Weiland, J., Greenberg, R., Fujii, G., Torres, G., Piyathaisere, D., O'Hearn, T., Liu, W., Lazzi, G., Dagnelie, G., Scribner, D., de Juan, E., & Humayun, M. (2002). Retinal prosthesis for the blind. Surv Ophthalmol, 47(4), 335-335. Margalit, E. & Sadda, S.R. (2003). Retinal and optic nerve diseases. Artif Organs, 27(11), 963974. Margrain, T.H. (1999). Minimising the impact of visual impairment. Low vision aids are a simple way of alleviating impairment. BMJ, 318(7197), 1504. Margrain, T.H. (2000). Helping blind and partially sighted people to read: the effectiveness of low vision aids. Br J Ophthalmol, 84(8), 919-921. Marron, J.A. & Bailey, I.L. (1982). Visual factors and orientation-mobility performance. Am J Optom Physiol Opt, 59(5), 413-426. Mason, C. & Kandel, E.R. (1991). Central Visual Pathways. In: E.R. Kandel, J.H. Schwartz, & T.M. Jessel (Eds.), Principles of Neural Science (pp. 420-439). Norwalk: Appleton & Lange. Maynard, E.M. (2001). Visual prostheses. Annu Rev Biomed Eng, 3, 145-168. Maynard, E.M., Fernandez, E., & Normann, R.A. (2000). A technique to prevent dural adhesions to chronically implanted microelectrode arrays. J Neurosci Methods, 97(2), 93-101. Maynard, E.M., Hatsopoulos, N.G., Ojakangas, C.L., Acuna, B.D., Sanes, J.N., Normann, R.A., & Donoghue, J.P. (1999). Neuronal interactions improve cortical population coding of movement direction. J Neurosci, 19(18), 8083-8093. Mazza, M., Renaud, P., Bertrand, D., & Ionescu, A. (2005). CMOS pixels for subretinal implant prosthesis. IEEE Sensors Journal, 5(1), 32-37. McClure, M.E., Hart, P.M., Jackson, A.J., Stevenson, M.R., & Chakravarthy, U. (2000). Macular degeneration: do conventional measurements of impaired visual function equate with visual disability? Br J Ophthalmol, 84(3), 244-250. McFarland, T.J., Zhang, Y., Appukuttan, B., & Stout, J.T. (2004). Gene therapy for proliferative ocular diseases. Expert Opin Biol Ther, 4(7), 1053-1058. Medeiros, N.E. & Curcio, C.A. (2001). Preservation of ganglion cell layer neurons in age-related macular degeneration. Invest Ophthalmol Vis Sci, 42(3), 795-803. Mehenti, N.Z., Peterman, M.C., Leng, T., Marmor, M.F., Blumenkranz, M.S., Bent, S.F., & Fishman, H.A. (2003). A Retinal Interface Based on Neurite Micropatterning for Single Cell Stimulation. Invest Ophthalmol Vis Sci, 44(5), 5069 (abstract). Merton, P.A. (1961). The accuracy of directing the eyes and the hand in the dark. J Physiol (Paris), 156, 557-577. 155 Nelson, P., Aspinall, P., & O'Brien, C. (1999). Patients' perception of visual impairment in glaucoma: a pilot study. Br J Ophthalmol, 83(5), 546-552. Nelson, P., Aspinall, P., Papasouliotis, O., Worton, B., & O'Brien, C. (2003). Quality of life in glaucoma and its relationship with visual function. J Glaucoma, 12(2), 139-150. Nelson, W.W. & Loftus, G.R. (1980). The functional visual field during picture viewing. J Exp Psychol [Hum Learn], 6(4), 391-399. Nilsson, U.L. (1990). Visual rehabilitation with and without educational training in the use of optical aids and residual vision. A prospective study of patients with advanced age-related macular degeneration. Clin Vis Sci, 6, 3-10. Nodine, C.F., Carmody, D.P., & Herman, E. (1979). Eye movements during visual search for artistically embedded targets. Bulletin of the Psychonomic Society, 13, 371-374. Normann, R.A., Maynard, E.M., Rousche, P.J., & Warren, D.J. (1999). A neural interface for a cortical vision prosthesis. Vision Res, 39(15), 2577-2587. Normann, R.A., Warren, D.J., Ammermuller, J., Fernandez, E., & Guillory, S. (2001). Highresolution spatio-temporal mapping of visual pathways using multi-electrode arrays. Vision Res, 41(10-11), 1261-1275. Osterberg, G. (1935). Topography of the layer of rods and cones in the human retina. Acta Ophthalmologica (Copenh), 6(Suppl.), 1-103. Owsley, C., McGwin, G., Jr., Sloane, M.E., Stalvey, B.T., & Wells, J. (2001). Timed instrumental activities of daily living tasks: relationship to visual function in older adults. Optom Vis Sci, 78(5), 350-359. Oxford Reference Online (2004). The Concise Oxford English Dictionary. Oxford University Press; Université de Genève, accessed 07/02/2006. <http://www.oxfordreference.com/views/ENTRY.html?subview=Main&entry=t23.e42365>. Paillard, J. (1982). The contribution of peripheral and central vision to visually guided reaching. In: D.J. Ingle, M.A. Goodale, & J.W. Mansfield (Eds.), Analysis of Visual Behavior (pp. 367385). Cambridge, MA: The MIT Press. Palanker, D., Vankov, A., Huie, P., & Baccus, S. (2005). Design of a high-resolution optoelectronic retinal prosthesis. J Neural Eng, 2(1), S105-S120. Palanker, D.V., Vankov, A., Fishman, H.A., Blumenkranz, M.S., & Marmor, M.F. (2004). Physical constraints on resolution of the electronic retinal prosthesis. Invest Ophthalmol Vis Sci, 45(5), 4209. Palanker, D.V., Vankov, A., Huie, P., Fishman, H.A., Marmor, M.F., & Blumenkranz, M.S. (2003). Can a Self-powered Retinal Prosthesis Support 100,000 Pixels in the Macula? Invest Ophthalmol Vis Sci, 44(5), 5067 (abstract). Pardue, M.T., Ball, S.L., Hetling, J.R., Chow, V.Y., Chow, A.Y., & Peachey, N.S. (2001). Visual evoked potentials to infrared stimulation in normal cats and rats. Doc Ophthalmol, 103(2), 155-162. Parker, R.E. (1978). Picture processing during recognition. J Exp Psychol Hum Percept Perform, 4(2), 284-293. Patla, A.E. (1997). Understanding the roles of vision in the control of human locomotion. Gait & Posture, 5(1), 54-69. Peachey, N.S. & Chow, A.Y. (1999). Subretinal implantation of semiconductor-based photodiodes: progress and challenges. J Rehabil Res Dev, 36(4), 371-376. Peli, E. (1986). Control of eye movement with peripheral vision: implications for training of eccentric viewing. Am J Optom Physiol Opt, 63(2), 113-118. Peli, E. (2001). Vision multiplexing: an engineering approach to vision rehabilitation device development. Optom Vis Sci, 78(5), 304-315. 156 Peli, E., Goldstein, R.B., Young, G.M., Trempe, C.L., & Buzney, S.M. (1991). Image enhancement for the visually impaired. Simulations and experimental results. Invest Ophthalmol Vis Sci, 32(8), 2337-2350. Pelisson, D., Prablanc, C., Goodale, M.A., & Jeannerod, M. (1986). Visual control of reaching movements without vision of the limb. II. Evidence of fast unconscious processes correcting the trajectory of the hand to the final position of a double-step stimulus. Exp Brain Res, 62(2), 303-311. Pelli, D.G. (1987). The visual requirements of mobility. In: G.C. Woo (Eds.), Low vision: Principles and applications (pp. 134-146). New York: Springer Verlag. Pelz, J. B. (1995) Visual Representations in a Natural Visuo-motor Task. PhD thesis , University of Rochester, New York. Pelz, J.B. & Canosa, R. (2001). Oculomotor behavior and perceptual strategies in complex tasks. Vision Res, 41(25-26), 3587-3596. Pelz, J.B., Hayhoe, M., & Loeber, R. (2001). The coordination of eye, head, and hand movements in a natural task. Exp Brain Res, 139(3), 266-277. Penfield, W. and Jasper, H. (1954). Epilepsy and the functional anatomy of the human brain. London: Churchill. Pérez Fornos, A., Sommerhalder, J., Chanderli, K., Pittard, A., Baumberger, B., Fluckiger, M., Safran, A.B., & Pelizzone, M. (2004). Minimum requirements for mobility in known environments and perceptual learning of this task in eccentric vision. Invest Ophthalmol Vis Sci, 45, 5445 (abstract). Pérez Fornos, A., Sommerhalder, J., Pittard, A., Safran, A.B., & Pelizzone, M. (2005a). Minimum requirements for visuomotor coordination and perceptual learning of such tasks in eccentric vision. Invest Ophthalmol Vis Sci, 46, 1533 (abstract). Pérez Fornos, A., Sommerhalder, J., Rappaz, B., Safran, A.B., & Pelizzone, M. (2005b). Simulation of artificial vision, III: do the spatial or temporal characteristics of stimulus pixelization really matter? Invest Ophthalmol Vis Sci, 46(10), 3906-3912. Peyman, G., Chow, A.Y., Liang, C., Chow, V.Y., Perlman, J.I., & Peachey, N.S. (1998). Subretinal semiconductor microphotodiode array. Ophthalmic Surg Lasers, 29(3), 234-241. Pirozzolo, F.J. (1983). Eye movements and reading disability. In: K. Rayner (Eds.), Eye movements in reading. Perceptual and language processes. (pp. 499-509). New York: Academic Press. Prablanc, C., Echallier, J.F., Komilis, E., & Jeannerod, M. (1979). Optimal response of eye and hand motor systems in pointing at a visual target. I. Spatio-temporal characteristics of eye and hand movements and their relationships when varying the amount of visual information. Biol Cybern, 35(2), 113-124. Prablanc, C., Pelisson, D., & Goodale, M.A. (1986). Visual control of reaching movements without vision of the limb. I. Role of retinal feedback of target position in guiding the hand. Exp Brain Res, 62(2), 293-302. Previc, F.H. (1990). Functional specialization in the lower and upper visual fields in humans: its ecological origins and neurophysiological implications. Behav Brain Sci, 13(3), 519-575. Provencio, I., Rodriguez, I.R., Jiang, G., Hayes, W.P., Moreira, E.F., & Rollag, M.D. (2000). A novel human opsin in the inner retina. J Neurosci, 20(2), 600-605. Provencio, I., Rollag, M.D., & Castrucci, A.M. (2002). Photoreceptive net in the mammalian retina. This mesh of cells may explain how some blind mice can still tell day from night. Nature, 415(6871), 493. Purdy, K.A., Lederman, S.J., & Klatzky, R.L. (1999). Manipulation with no or partial vision. J Exp Psychol Hum Percept Perform, 25(3), 755-774. 157 Rauschecker, J.P. & Shannon, R.V. (2002). Sending sound to the brain. Science, 295(5557), 1025-1029. Rayner, K. (1998). Eye movements in reading and information processing: 20 years of research. Psychol Bull, 124(3), 372-422. Rayner, K. & Pollatsek, A. (1992). Eye movements and scene perception. Can J Psychol, 46(3), 342-376. Reichle, E.D., Rayner, K., & Pollatsek, A. (2003). The E-Z reader model of eye-movement control in reading: comparisons to other models. Behav Brain Sci, 26(4), 445-476. Reppert, S.M. & Weaver, D.R. (2002). Coordination of circadian timing in mammals. Nature, 418(6901), 935-941. Rieser, J.J., Hill, E.W., Talor, C.R., Bradfield, A., & Rosen, S. (1992). Visual experience, visual field size, and the development of nonvisual sensitivity to the spatial structure of outdoor neighborhoods explored by walking. J Exp Psychol Gen, 121(2), 210-221. Rizzo, J.F. & Wyatt, J. (1997). Prospects for a visual prosthesis. Neuroscientist, 3(4), 251-262. Rizzo, J.F., Wyatt, J., Loewenstein, J., Kelly, S., & Shire, D. (2003a). Methods and perceptual thresholds for short-term electrical stimulation of human retina with microelectrode arrays. Invest Ophthalmol Vis Sci, 44(12), 5355-5361. Rizzo, J.F., Wyatt, J., Loewenstein, J., Kelly, S., & Shire, D. (2003b). Perceptual efficacy of electrical stimulation of human retina with a microelectrode array during short-term surgical trials. Invest Ophthalmol Vis Sci, 44(12), 5362-5369. Rizzo, J.F., Wyatt, J.L., Loewenstein, J., Montezuma, S., Shire, D.B., Theogarajan, L., & Kelly, S.K. (2004). Development of a wireless, ab-externo retinal prosthesis. Invest Ophthalmol Vis Sci, 45(5), 3399. Roll, R., Bard, C., & Paillard, J. (1986). Head orienting contributes to the directional accuracy of aiming at distant targets. Hum Mov Sci, 5(4), 359 (abstract). Rossetti, Y., Desmurget, M., & Prablanc, C. (1995). Vectorial coding of movement: vision, proprioception, or both? J Neurophysiol, 74(1), 457-463. Rossetti, Y., Stelmach, G., Desmurget, M., Prablanc, C., & Jeannerod, M. (1994). The effect of viewing the static hand prior to movement onset on pointing kinematics and variability. Exp Brain Res, 101(2), 323-330. Rothwell, J.C., Traub, M.M., Day, B.L., Obeso, J.A., Thomas, P.K., & Marsden, C.D. (1982). Manual motor performance in a deafferented man. Brain, 105(3), 515-542. Rousche, P.J. & Normann, R.A. (1992). A method for pneumatically inserting an array of penetrating electrodes into cortical tissue. Ann Biomed Eng, 20(4), 413-422. Rousche, P.J. & Normann, R.A. (1998a). Chronic recording capability of the Utah Intracortical Electrode Array in cat sensory cortex. J Neurosci Methods, 82(1), 1-15. Rousche, P.J. & Normann, R.A. (1998b). Chronic recording capability of the Utah Intracortical Electrode Array in cat sensory cortex. J Neurosci Methods, 82(1), 1-15. Rousche, P.J. & Normann, R.A. (1999). Chronic intracortical microstimulation (ICMS) of cat sensory cortex using the Utah Intracortical Electrode Array. IEEE Trans Rehabil Eng, 7(1), 56-68. Rowland, L.P., Fink, M.E., & Rubin, L. (1991). Cerebrospinal fluid: blood-brain barrier, brain edema, and hydrocephalus. In: E.R. Kandel, J.H. Schwartz, & T.M. Jessel (Eds.), Principles of Neural Science (pp. 1050-1060). Norwalk: Appleton & Lange. Rubin, G.S., Bandeen-Roche, K., Huang, G.H., Munoz, B., Schein, O.D., Fried, L.P., & West, S.K. (2001). The association of multiple visual impairments with self-reported visual disability: SEE project. Invest Ophthalmol Vis Sci, 42(1), 64-72. 158 Rubin, G.S. & Legge, G.E. (1989). Psychophysics of reading. VI--The role of contrast in low vision. Vision Res, 29(1), 79-91. Rutten, W.L. (2002). Selective electrical interfaces with the nervous system. Annu Rev Biomed Eng, 4, 407-452. Safadi, M.R., Washko, F., Lagman, A., Jaboro, C., Auner, G.W., Iezzi, R., McAllister, J.P., & Abrams, G. (2003). Development of a Microfluidic Drug Delivery Neural Stimulating Device for Vision. Invest Ophthalmol Vis Sci, 44(5), 5082 (abstract). Santos, A., Humayun, M.S., de Juan Jr., E., Greenberg, R.J., Marsh, M.J., Klock, I.B., & Milam, A.H. (1997). Preservation of the inner retina in retinitis pigmentosa. A morphometric analysis. Arch Ophthalmol, 115(4), 511-515. Schmidt, E.M., Bak, M.J., Hambrecht, F.T., Kufta, C.V., O'Rourke, D.K., & Vallabhanath, P. (1996). Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex. Brain, 119(Pt 2), 507-522. Schneider, G.E. (1969). Two visual systems. Science, 163(870), 895-902. Schoups, A.A., Vogels, R., & Orban, G.A. (1995). Human perceptual learning in identifying the oblique orientation: retinotopy, orientation specificity and monocularity. J Physiol, 483 ( Pt 3), 797-810. Schwahn, H.N., Gekeler, F., Kohler, K., Kobuch, K., Sachs, H.G., Schulmeyer, F., Jakob, W., Gabel, V.P., & Zrenner, E. (2001). Studies on the feasibility of a subretinal visual prosthesis: data from Yucatan micropig and rabbit. Graefes Arch Clin Exp Ophthalmol, 239(12), 961997. Servos, P. (2000). Distance estimation in the visual and visuomotor systems. Exp Brain Res, 130(1), 35-47. Servos, P. & Goodale, M.A. (1994). Binocular vision and the on-line control of human prehension. Exp Brain Res, 98(1), 119-127. Shannon, R.V., Zeng, F.G., Kamath, V., Wygonski, J., & Ekelid, M. (1995). Speech recognition with primarily temporal cues. Science, 270(5234), 303-304. Sireteanu, R. & Rettenbach, R. (1995). Perceptual learning in visual search: fast, enduring, but non-specific. Vision Res, 35(14), 2037-2043. Sireteanu, R. & Rettenbach, R. (2000). Perceptual learning in visual search generalizes over tasks, locations, and eyes. Vision Res, 40(21), 2925-2949. Sivak, B. & Mackenzie, C.L. (1992). The contributions of peripheral vision and central vision to prehension. In: L. Proteau & D. Elliot (Eds.), Vision and Motor Control (pp. 233-259). Amsterdam: Elsevier Science Publishers. Sjöstrand, J., Olsson, V., Popovic, Z., & Conradi, N. (1999a). Quantitative estimations of foveal and extra-foveal retinal circuitry in humans. Vision Res, 39(18), 2987-2998. Sjöstrand, J., Popovic, Z., Conradi, N., & Marshall, J. (1999b). Morphometric study of the displacement of retinal ganglion cells subserving cones within the human fovea. Graefes Arch Clin Exp Ophthalmol, 237(12), 1014-1023. Slaughter, M. (1990). The Vertebrate Retina. In: K.N. Leibovic (Eds.), Science of Vision (pp. 5383). New York: Springer-Verlag. Smith, A.F. & Smith, J.G. (1996). The economic burden of global blindness: a price too high! Br J Ophthalmol, 80(4), 276-277. Sommerhalder, J., Oueghlani, E., Bagnoud, M., Leonards, U., Safran, A.B., & Pelizzone, M. (2003). Simulation of artificial vision: I. Eccentric reading of isolated words, and perceptual learning. Vision Res, 43(3), 269-283. 159 Sommerhalder, J., Rappaz, B., de Haller, R., Perez Fornos, A., Safran, A.B., & Pelizzone, M. (2004). Simulation of artificial vision: II. Eccentric reading of full-page text and the learning of this task. Vision Res, 44(14), 1693-1706. Sparks, D.L. & Mays, L.E. (1983). Spatial localization of saccade targets. I. Compensation for stimulation-induced perturbations in eye position. J Neurophysiol, 49(1), 45-63. Stampe, D.M. (1993). Heuristic filtering and reliable calibration methods for video-based pupiltracking systems. Behav Res Methods Instrum Comput, 25(2), 137-142. Stett, A., Barth, W., Weiss, S., Haemmerle, H., & Zrenner, E. (2000). Electrical multisite stimulation of the isolated chicken retina. Vision Res, 40(13), 1785-1795. Stetten, G. (2000). Vision system. In: J.D. Bronzino (Eds.), The Biomedical Engineering Handbook (pp. 34-42). Boca Raton: CRC Press. Stoffregen, T.A. (1985). Flow structure versus retinal location in the optical control of stance. J Exp Psychol Hum Percept Perform, 11(5), 554-565. Straw, L.B. & Harley, R.K. (1991). Assessment and training in orientation and mobility for older persons: program development and testing. J Vis Impair Blind, 85(7), 291-296. Strelow, E.R. (1985). What is needed for a theory of mobility: direct perception and cognitive maps -- lessons from the blind. Psychol Rev, 92(2), 226-248. Studebaker, G.A. (1985). A "rationalized" arcsine transform. J Speech Hear Res, 28(3), 455462. Suaning, G.J. & Lovell, N.H. (2001). CMOS neurostimulation ASIC with 100 channels, scaleable output, and bidirectional radio-frequency telemetry. IEEE Trans Biomed Eng, 48(2), 248260. Szlyk, J.P., Seiple, W., Fishman, G.A., Alexander, K.R., Grover, S., & Mahler, C.L. (2001). Perceived and actual performance of daily tasks: relationship to visual function tests in individuals with retinitis pigmentosa. Ophthalmology, 108(1), 65-75. Tant, M.L.M., Cornelissen, F.W., Kooijman, A.C., & Brouwer, W.H. (2002). Hemianopic visual field defects elicit hemianopic scanning. Vision Res, 42(10), 1339-1348. Taub, E., Goldberg, I.A., & Taub, P. (1975). Deafferentation in monkeys: pointing at a target without visual feedback. Exp Neurol, 46(1), 178-186. Thompson, R.W., Barnett, G.D., Humayun, M., & Dagnelie, G. (2000). Reading speed and facial recognition using simulated prosthetic vision. Invest Ophthalmol Vis Sci, 41(suppl.), S860 (abstract). Thompson, R.W., Barnett, G.D., Humayun, M.S., & Dagnelie, G. (2003). Facial recognition using simulated prosthetic pixelized vision. Invest Ophthalmol Vis Sci, 44(11), 5035-5042. Thornton, A.R. & Raffin, M.J. (1978). Speech-discrimination scores modeled as a binomial variable. J Speech Hear Res, 21(3), 507-518. Thornton, I.M. & Kourtzi, Z. (2002). A matching advantage for dynamic human faces. Perception, 31(1), 113-132. Thylefors, B. (1992). Epidemiological patterns of ocular trauma. Aust N Z J Ophthalmol, 20(2), 95-98. Thylefors, B., Négrel, A.D., Pararajasegaram, R., & Dadzie, K.Y. (1995). Global data on blindness. Bull World Health Organ, 73(1), 115-121. Toet, A. & Levi, D.M. (1992). The two-dimensional shape of spatial interaction zones in the parafovea. Vision Res, 32(7), 1349-1357. Tong, Y.C., Blamey, P.J., Dowell, R.C., & Clark, G.M. (1983). Psychophysical studies evaluating the feasibility of a speech processing strategy for a multiple-channel cochlear implant. J Acoust Soc Am, 74(1), 73-80. 160 Turano, K. & Wang, X. (1992). Motion thresholds in retinitis pigmentosa. Invest Ophthalmol Vis Sci, 33(8), 2411-2422. Turano, K.A., Geruschat, D.R., Baker, F.H., Stahl, J.W., & Shapiro, M.D. (2001). Direction of gaze while walking a simple route: persons with normal vision and persons with retinitis pigmentosa. Optom Vis Sci, 78(9), 667-675. Turano, K.A., Geruschat, D.R., Stahl, J.W., & Massof, R.W. (1999). Perceived visual ability for independent mobility in persons with retinitis pigmentosa. Invest Ophthalmol Vis Sci, 40(5), 865-877. Tychsen, L. (1992). Binocular vision. In: W. Hart (Eds.), Adler's physiology of the eye (pp. St Louis: Mosby. Ungerleider, L.G. & Mishkin, M. (1982). Two cortical visual systems. In: D.J. Ingle, M.A. Goodale, & J.S. Mansfield (Eds.), Analysis of Visual Behavior (pp. 549-586). London: The MIT Press. Urban, H. (1937). Zur physiologie der occipitalregion des menschen. Z Ges Neurol Psychiat, 257-261. Ustun, T.B., Rehm, J., Chatterji, S., Saxena, S., Trotter, R., Room, R., & Bickenbach, J. (1999). Multiple-informant ranking of the disabling effects of different health conditions in 14 countries. WHO/NIH Joint Project CAR Study Group. Lancet, 354(9173), 111-115. Uttal, W.R., Baruch, T., & Allen, L. (1995a). Combining image degradations in a recognition task. Percept Psychophys, 57(5), 682-691. Uttal, W.R., Baruch, T., & Allen, L. (1995b). The effect of combinations of image degradations in a discrimination task. Percept Psychophys, 57(5), 668-681. Uttal, W.R., Baruch, T., & Allen, L. (1997). A parametric study of face recognition when image degradations are combined. Spat Vis, 11(2), 179-204. Van der Geest, J.N. & Frens, M.A. (2002). Recording eye movements with video-oculography and scleral search coils: a direct comparison of two methods. J Neurosci Methods, 114(2), 185-195. Van Essen, D.C., Anderson, C.H., & Felleman, D.J. (1992). Information processing in the primate visual system: an integrated systems perspective. Science, 255(5043), 419-423. Veraart, C., Grill, W.M., & Mortimer, J.T. (1993). Selective control of muscle activation with a multipolar nerve cuff electrode. IEEE Trans Biomed Eng, 40(7), 640-653. Veraart, C., Raftopoulos, C., Mortimer, J.T., Delbeke, J., Pins, D., Michaux, G., Vanlierde, A., Parrini, S., & Wanet-Defalque, M.C. (1998). Visual sensations produced by optic nerve stimulation using an implanted self-sizing spiral cuff electrode. Brain Res, 813(1), 181-186. Veraart, C., Wanet-Defalque, M.C., Gerard, B., Vanlierde, A., & Delbeke, J. (2003). Pattern recognition with the optic nerve visual prosthesis. Artif Organs, 27(11), 996-1004. Von Noorden, G.K. & Mackensen, G. (1962). Phenomenology of eccentric fixation. Am J Ophthalmol, 53, 642-660. Walraven, T.L., Buddi, R., Kapi, S., Abrams, G.W., & Iezzi, R. (2004). Chronic intravitreal infusion of phototriggerable neurotransmitters for retinal prosthesis, in vivo. Invest Ophthalmol Vis Sci, 45(5), 4211 (abstract). Walraven, T.L., Iezzi, R., McAllister, J.P., Auner, G., Abrams, G., & Givens, R. (2003). The effects of Dextromethorphan against the toxicity of photoactivated caged glutamate in vitro. Invest Ophthalmol Vis Sci, 44(5), 5066 (abstract). Walraven, T.L., Iezzi, R., McAllister, J.P., Auner, G., Givens, R., & Abrams, G. (2002). Biocompatibility of a Neurotransmitter Based Retinal and Cortical Visual Prosthesis. Invest Ophthalmol Vis Sci, 43(12), 4453 (abstract). 161 Warren, D.J. & Normann, R.A. (2000). Visual neuroprostheses. In: W.E. Finn & P.G. LoPresti (Eds.), Handbook of Neuroprosthetic Methods (pp. 11.1-11.45). Boca Raton: CRC Press. Warren, W.H. (1995). Self-motion: Visual perception and visual control. In: W. Epstein & S.J. Rogers (Eds.), Perception of space and motion (pp. 263-325). London: Academic Press. Warren, W.H. & Kurtz, K.J. (1992). The role of central and peripheral vision in perceiving the direction of self-motion. Percept Psychophys, 51(5), 443-454. Wässle, H., Grünert, U., Röhrenbeck, J., & Boycott, B.B. (1989). Cortical magnification factor and the ganglion cell density of the primate retina. Nature, 341(6243), 643-646. Watt, S.J., Bradshaw, M.F., & Rushton, S.K. (2000). Field of view affects reaching, not grasping. Exp Brain Res, 135(3), 411-416. Weih, L., McCarty, C.A., & Taylor, H.R. (2000). Functional implications of vision impairment. Clin Experiment Ophthalmol, 28(3), 153-155. Weiland, J.D. & Anderson, D.J. (2000). Chronic neural stimulation with thin-film, iridium oxide electrodes. IEEE Trans Biomed Eng, 47(7), 911-918. Weiland, J.D., Humayun, M.S., Dagnelie, G., de Juan Jr., E., Greenberg, R.J., & Iliff, N.T. (1999). Understanding the origin of visual percepts elicited by electrical stimulation of the human retina. Graefes Arch Clin Exp Ophthalmol, 237(12), 1007-1013. Weiland, J.D., Liu, W., & Humayun, M.S. (2005). Retinal prosthesis. Annu Rev Biomed Eng, 7, 361-401. Wensveen, J.M., Bedell, H.E., & Loshin, D.S. (1995). Reading rates with artificial central scotomata with and without spatial remapping of print. Optom Vis Sci, 72(2), 100-114. West, S.K., Rubin, G.S., Broman, A.T., Munoz, B., Bandeen-Roche, K., & Turano, K. (2002). How does visual impairment affect performance on tasks of everyday life? The SEE Project. Salisbury Eye Evaluation. Arch Ophthalmol, 120(6), 774-780. Westheimer, G. (2001). Is peripheral visual acuity susceptible to perceptual learning in the adult? Vision Res, 41(1), 47-52. Whittaker, S.G. & Cummings, R.W. (1990). Foveating saccades. Vision Res, 30(9), 1363-1366. Whittaker, S.G., Cummings, R.W., & Swieson, L.R. (1991). Saccade control without a fovea. Vision Res, 31(12), 2209-2218. Whittaker, S.G. & Lovie-Kitchin, J. (1993). Visual requirements for reading. Optom Vis Sci, 70(1), 54-65. WHO (1997). Blindness. World Health Organization, accessed 03/12/2003. http://www.who.int/health_topics/blindness/en/. WHO (2000). Global Initiative for the Elimination of Avoidable Blindness. World Health Organization, accessed 03/12/2003. http://www.who.int/inf-fs/en/fact213.html. WHO (2002). Childhood blindness prevention project launched. Bull World Health Organ, 80(8), 688-688. Wolffsohn, J.S. & Cochrane, A.L. (1998). Low vision perspectives on glaucoma. Clin Exp Optom, 81(6), 280-289. Wu, P., Mehenti, N.Z., Leng, T., Marmor, M.F., Blumenkranz, M.S., & Fishman, H.A. (2003). Cell Demographics from Full Thickness Retinal Explant Growth on Micropatterned Surfaces. Invest Ophthalmol Vis Sci, 44(5), 5008 (abstract). Wyatt, J. & Rizzo, J. (1996). Ocular implants for the blind. IEEE Spectrum, 33(5), 47-53. Xing, J. & Heeger, D.J. (2000). Center-surround interactions in foveal and peripheral vision. Vision Res, 40(22), 3065-3072. 162 Yagi, T., Kameda, S., Hayashida, Y., & Li, L. (1999). An artificial retina with adaptive mechanisms and its application to retinal prosthesis. Proc '99 Conf Syst Man Cybern, 4, 418-423. Yamauchi, Y., Enzmann, V., Franco, L.M., Jackson, D., Naber, J., Rizzo, J.F., Ziv, O.R., & Kaplan, H.J. (2004). The retinal prosthesis - the stimulation threshold is lower with a subretinal microelectrode array. Invest Ophthalmol Vis Sci, 45(5), 4222. Yanai, D., Weiland, J.D., Mahadevappa, M., Fujii, G.Y., de Juan Jr., E., Greenberg, R.J., Williamson, R., Cimmarusti, V., & Humayun, M.S. (2003). Visual Perception in Blind Subjects with Microelectronic Retinal Prosthesis. Invest Ophthalmol Vis Sci, 44(5), 5056 (abstract). Zeevi, Y.Y. & Peli, E. (1979). Latency of peripheral saccades. J Opt Soc Am, 69(9), 1274-1279. Ziegler, D. (2002) Characterization and improvement of an oscillating-pixel-circuit prototype for an artificial retina implant. EPFL, Lausanne. Ziegler, D., Linderholm, P., Mazza, M., Ferazzutti, S., Bertrand, D., Ionescu, A.M., & Renaud, P. (2004). An active microphotodiode array of oscillating pixels for retinal stimulation. Sens Actuators A Phys, 110(1-3), 11-17. Zihl, J. (2000). Rehabilitation of visual disorders after brain injury. Hove, East Sussex, UK: Psychology Press Ltd. Zrenner, E. (2002a). The subretinal implant: can microphotodiode arrays replace degenerated retinal photoreceptors to restore vision? Ophthalmologica, 216(1 (suppl.)), 8-20. Zrenner, E. (2002b). Will retinal implants restore vision? Science, 295(5557), 1022-1025. Zrenner, E., Miliczek, K.D., Gabel, V.P., Graf, H.G., Guenther, E., Haemmerle, H., Hoefflinger, B., Kohler, K., Nisch, W., Schubert, M., Stett, A., & Weiss, S. (1997). The development of subretinal microphotodiodes for replacement of degenerated photoreceptors. Ophthalmic Res, 29(5), 269-280. Zrenner, E., Stett, A., Weiss, S., Aramant, R.B., Guenther, E., Kohler, K., Miliczek, K.D., Seiler, M.J., & Haemmerle, H. (1999). Can subretinal microphotodiodes successfully replace degenerated photoreceptors? Vision Res, 39(15), 2555-2567. 163 Appendix A EyeLink I® System Specifications Tracking Mode Mode Pupil-only Sample Rate 250 Hz Average Delay (filter off) 6 ms Average Delay (filter on) 10 ms Noise (RMS) < 0.01° Stability Affected by headband slip and vibration Operational/Functional Specifications Image Processing Hybrid analog-digital Pupil tracking Hyperacuity Corneal reflection tracking None Sampling Rate 250 Hz Average Data Transit Delay Filter off = 6 ms Filter on = 10 ms Resolution (gaze) Noise limited to < 0.01° Velocity Noise < 3°/s Gaze Position Accuracy < 0.5° average Pupil Size Resolution 0.1% of diameter Pupil Size Noise < 0.01 mm Heuristic Filtering Nearest-neighbor heuristic filter Eye Tracking Range ±30° horizontal, ±20° vertical (pupil only) Gaze Tracking Range ±20° horizontal, ±18° vertical Head Tracking Range 40-140 cm (standard setup), ~300 cm (special markers) 165 Head Rotation Compensation Range ±15° for best accuracy, ±30° conditional on display location Built-in Calibration, Validation Calibration and validation using Pupil-only Operating Environment Required IR-free environment, physical stability Subject Compatibility Most eyeglasses and contact lenses Data File EDF, direct to disk EDF File and link Data Types Eye position, HREF position, gaze position, pupil size, buttons, messages On-line Eye Movement Analysis Saccades, fixations, blinks, fixation updates Real-Time Gaze cursor during recording and validation, eye position cursor during calibration, camera images Physical Specifications Image Processing Card Full-length ISA (13.5” / 343 mm) Headband Leather-padded, height and size adjustments Headband Weight ~420 g Headband Cable Length 5m Eye Camera Distance 40 to 80 mm Binocular Tracking Standard Eye Illumination 925 nm IR, IEC-825 Class 1, <1.2 mW/cm2 Display Markers 925 nm IR, IEC-825 Class 1 Ethernet Link TCP/IP or raw, 10BASE-2 or 10BASE-T, external card with packet driver Response Box Support Digital Analog Output Optional ISA or PCI card Digital Control Configurable Display Operating System API MS-DOS, Macintosh, Windows 166 Appendix B 3M MicroTouch™ Touch Screen Specifications General Part Number 13-8051-03 Sensor Technology ClearTek Capacitive Profile Touch Screen Controller USB EXII 5000UC (P/N: 14-205) Electrical Specifications Input Method Finger. TouchPen available with qualified sensor, attachments and electronics Accuracy and Precision Area Reported touch coordinates are within 1.0% of true position (based on viewing window dimensions) when linearized and used in conjunction with 3M Touch Systems Electronics Touch Screen Resolution• 16k x 16k Optical Specifications Optical Clarity Up to 88% light transmission at 550 nm; dependant on specific surface finish chosen Equipment used: BYK Gardner Haze Gard Plus Surface finish Industrial etch Coating ClearTek◊ Mechanical Specifications Diagonal length 19.71” / 500.63 mm Glass Thickness 0.125” (±0.01”) / 3.18 mm (±0.25 mm) typical Radius Curve 0 Outline Dimensions X: 15.85” / 402.59 mm Y: 12.90” / 327.66 mm • ◊ The maximum number addressable coordinates generated by the controller. Protective glass overcoat that protects the sensor by resisting scratches and increasing durability. 167 Viewable (Active) Area X: 15.31” / 388.87 mm Y: 12.42” / 315.47 mm Linearization Factory linearization values are stored in the touch screen NOVRAM, attached controller or 2D bar-code Touch Contact Requirement 3 ms for finger input. Surface and Scratch Hardness+ Cannot be scratched using any stylus with Mohs’ rating of less than 6.5. Exceeds severe abrasion test per MIL-C-675C. Withstands 10500 grams of force per Balance Beam Scrape Adhesion Mar Tester. MicroScratch tester with 10-µm radius tungsten carbide indenter takes a force of 1.8 Newtons NEMA Rating NEMA sealable Gasketing Complete water-resistant seal obtainable with polyethylene gasket Cleaning Water, isopropyl, alcohol, and similar non-abrasive cleaners Reliability Endurance Test| Over 225 million mechanical touches without noticeable degradation of the surface Surface Obstructions Operation unaffected by surface obstructions such as dirt, grease, dust, smoke, peanut butter, etc. Chemical Resistance ClearTek is highly resistant to corrosives, in accordance with ASTM-D-1308-87 (1993) and ASTMD-F-1598-95 Liquid Resistance Liquids on screen do not impede touch screen performance Liquid Repellence Extremely water repellent (contact angle of 94° and greater measured using Sessile Drop Contact Angle Method) Operating Temperature Range -15°C to 70°C for touch screen Storage Temperature Between –50°C and 85°C (MIL-STD-810E) + Paul N. Gardner Co. model PA-2197 using a loop stylus (0.128” in O.D. Rockwell Hardness 55-61). Mechanical touch activation in single x,y location using a finger-like stylus of 45 durometer, shore “A” hardness, 0.5 inch diameter with a load of 0.46 pounds, ±0.01 pounds of force. | 168 Appendix C Logitech™ 3D Head Tracker Specifications Functional Specifications Available Modes 2D and 3D Tracking Speed Up to 30 inch/s Tracking Area 1.52 m (5 ft), 100° cone 2D Mode Resolution Position: 400 dpi 3D Mode Resolution Position: 0.01 cm (0.004”) Orientation: 0.1° Latency 30 ms Sampling Rate 50 Hz Accuracy 2% of the distance between the transmitter and the receiver Operational Specifications Operating Temperature 5°C – 35°C Operating Relative Humidity 10% - 90% (non-condensing) Reliability 20000 h (Electrical MTBF) Audio Specifications Ultrasonic Frequency 23 kHz Output Amplitude 1 Vp-p, 600 Ω load Bandwidth 15 Hz – 5 kHz Physical Specifications Control Unit Depth: 24 cm (9.5”) Height: 4.1 cm (1.625”) Width: 18.5 cm (7.25”) 169 Transmitter Receiver 170 Appendix D Analysis of Eye and Head Movements during the Experiments on Visuomotor Coordination Measurement of head movements Head/trunk movements were recorded with a 3D head tracker (Logitech Inc., California, USA) attached to the back of the mobile setup. Simply speaking, the 3D head tracker is made of a stationary ultrasonic transmitter that tracks the position of a mobile receiver (attached to the back of the mobile setup) as it moves within the transmitter’s active area (1.52 m, 100° cone; see fig. D1a). The transmitter then sends these signals to a control unit, which transforms this information into 3D position (cm) and orientation (°) coordinates (see fig. D1b) and sends this data to the subject PC at a 50 Hz sample rate. Refer to Appendix C for detailed specifications of the 3D head tracker. a) b) Figure D1. The head tracking system. (a) The 3D head tracker consists of a fixed ultrasonic transmitter that tracks the position of a moving receiver within a 1.52 m active area (100°). The transmitter sends the data to a control unit (CU), which in turn transforms these signals into 3D coordinates of position and orientation and sends them to the Subject PC. Modified from the 3D Mouse & Head Tracker technical reference manual by Logitech™. (b) Positive, three-dimensional direction of receiver movement (X, Y, and Z axes) and positive rotation about these axes (Pitch, Yaw and Roll). Negative movement is in the direction opposite each arrow. 171 Analysis of eye and head movements during the acute experiments on visuomotor coordination The total area explored with eye movements on the screen and with head movements on the working space was estimated by computing separately the dispersion (standard deviation) of eye and head position (cm), along each axis (2D for eye movements and 3D for head movements), across trials. Eye movement behavior during visual search was characterized as average fixation duration (ms). Results for the chips task a) b) Figure D2. Dispersion of eye position coordinates versus number of pixels contained in the 10°x7° viewing window for 3 normal subjects performing the chips task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Horizontal dispersion of eye position (cm) ±SEM. (b) Vertical dispersion of eye position (cm) ±SEM. Figure D2 displays the mean dispersion of eye movements versus number of pixels in the viewing window, for the chips task. Both horizontal and vertical eye dispersion results were statistically equivalent across all pixelization levels for the 8.25° x 5.8° and the 16.5° x 11.6° fields of view. With the 33° x 23.1° field of view, horizontal eye dispersion also remained unperturbed even at the lowest target resolutions. Vertical eye dispersion, however, significantly (p < 0.05) increased at 498 pixels. This difference did not persist at target resolutions of 221 and 124 pixels. The largest eye dispersion values were obtained with the 8.25° x 5.8° field of view (about 2.7 cm horizontally and 1.7 cm vertically, equivalent to 6.3° x 4° on the screen), and the smallest with the 33° x 23.1° field of view (around 1 cm horizontally and 0.8 cm vertically, equivalent to 2.3° x 1.8° on the screen). The difference between each consecutive field of view was of about 0.9 cm horizontally (~ 2°) and 172 0.45 vertically (~ 1°). This could be expected due to the fact that with the smallest field of view the area of the screen that could be explored with eye movements was the broadest. These data also reveal that the subjects explored relatively narrow areas of the image available on the screen. Figure D3 plots the mean dispersion of the 3D (horizontal, vertical, and transversal) coordinates of head position versus number of pixels in the viewing window, for the chips task. At 17920 and 1991 pixels, head dispersion along the 3 axes remained stable and was statistically equivalent with the 3 fields of view. From 498 pixels and below, head dispersion systematically increased. The most dramatic increases were observed for the 33° x 23.1° field of view, especially around the transversal coordinate. This clearly indicates that, as less information was available in the viewing window, subjects had to approach the working model to compensate for the lack of resolution. This strategy also leads to larger horizontal and vertical head movements to explore the working area, as observed in the results. a) b) c) Figure D3. Dispersion of head position coordinates versus number of pixels contained in the 10°x7° viewing window for 3 normal subjects performing the chips task. Three effective visual fields projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Horizontal dispersion of head position (cm) ±SEM. (b) Vertical dispersion of head position (cm) ±SEM. (c) Transversal dispersion of head position (cm) ±SEM. Results for the LEDs task Figure D4 displays the mean dispersion of eye movements versus number of pixels in the viewing window, for the LEDs task. Results were similar to those observed for the chips task. Both horizontal and vertical dispersion remained roughly stable even at the lowest pixelization. Values were quite different when comparing the different fields of view with each other. Largest dispersion was observed with the 8.25° x 5.8° field of view (around 5.9 cm horizontally and 4.6 vertically; equivalent to 13.8° x 10.7° on the screen) while the smallest eye dispersion was obtained with the 33° x 23.1° (about 2.1 cm horizontally and 1.6 vertically; equivalent to 4.8° x 3.8° on the screen). These differences were more pronounced than for the chips task. 173 a) b) Figure D4. Dispersion of eye position coordinates versus number of pixels contained in the 10°x7° viewing window for 3 normal subjects performing the LEDs task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Horizontal dispersion of eye position (cm) ±SEM. (b) Vertical dispersion of eye position (cm) ±SEM. Eye dispersion values were approximately 2.4 x 2 cm2 (~ 5.5° x 4.5°) larger with the 8.25° x 5.8° field of view than with its 16.5° x 11.6° counterpart. Differences between the 16.5° x 11.6° and the 33° x 23.1° fields of view were approximately 1.5 cm horizontally (~ 3.4°) and 1 cm vertically (~ 2.4°). In addition, when comparing these results with those obtained for the chips task, it appears that eye dispersion was about 2 times broader for the LEDs task, in all the conditions investigated. a) b) c) Figure D5. Dispersion of head position coordinates versus number of pixels contained in the 10°x7° viewing window for 3 normal subjects performing the LEDs task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). (a) Horizontal dispersion of head position (cm) ±SEM. (b) Vertical dispersion of head position (cm) ±SEM. (c) Transversal dispersion of head position (cm) ±SEM. 174 Figure D5 plots the mean dispersion of the 3D coordinates of head position versus number of pixels in the viewing window, for the LEDs task. Interestingly, in this case the lack of visual information (i.e. less pixels, larger fields of view) did not seem to have any effect on the head movement strategy used to accomplish the task: head dispersion values remained at the same level across all pixelizations investigated and similar results were obtained with the 3 fields of view. Analysis of fixations Figure D6 displays average fixation duration versus number of pixels for the chips task. Results for the 8.25° x 5.8° field of view remained stable around 400 ms down to 498 pixels. Fixation duration then increased significantly at 221 (p = 0.04) and 124 pixels (p = 0.02). For the 16.5° x 11.6° and 33° x 23.1° fields of view, average fixation duration remained stable around 400 ms across all pixelization levels investigated. Figure D6b displays average fixation duration versus number of pixels for the LEDs task. Results appeared to be mainly influenced by the effective field of view, but not by pixelization level. Largest fixation durations were observed with the 33° x 23.1° field of view, while the shortest were performed with the 8.25° x 5.8° field of view. For all fields of view, average fixation duration remained stable down to a target resolution of 498 pixels. Below this pixelization level, a slight tendency towards a) b) Figure D6. Average fixation duration (ms) ±SEM versus number of pixels contained in the 10°x7° viewing window for 3 normal subjects performing: a) the chips task, and b) the LEDs task. Three effective fields of view projected in the 10°x7° viewing window are compared in central vision: 8.25°x5.8° (red plot), 16.5°x11.6° (blue plot), and 33°x23.1° (green plot). 175 decreasing fixation durations was observed. Interestingly, mean duration of fixations was longer for the LEDs task than for the chips task. Summary of these results Eye and head dispersion results demonstrate that the strategy for visual search was significantly influenced by the viewing conditions used when performing both visuomotor tasks. When small fields of view were available, subjects essentially explored the environment using eye movements, and their search strategy remained almost the same even when stimulus images were presented at low pixel resolutions. When large fields of view were used, subjects used very few eye and head movements at high pixelizations, since large portions of the environment were available at glance. Potential targets were, thus, identified more easily. However, as fewer pixels became available to perform the tasks, subjects had to approach the working area (i.e. with large transversal head movements) to compensate for the lack of resolution (information). This was particularly visible for the chips task. Interestingly, on average subjects presented larger eye dispersions for the LEDs task than for the chips task. Conversely, dispersion of head movements was broader during the chips task, especially around the transversal axis and at lower pixelizations. In general, the LEDs task required lengthier fixations, probably due to the precision requirements of the task. For this task, fixations appeared to be sensitive to the size of the effective field of view projected inside of the viewing window, but not to pixelization level. Analysis of eye movements during the habituation experiments on visuomotor coordination Since oculomotor adaptation to eccentric viewing has already been described in detail for the more complex reading task, adaptation of eye movements to the eccentric viewing conditions in this case was assessed only by calculating the cumulative distance of the subjects’ gaze on the screen, for each experimental session. In the reading experiments presented in Chapter 3, we observed impressive oculomotor adaptation mechanisms. After almost 2 months of training, subjects were able to suppress reflexive foveating saccades and to recalibrate eccentric nonfoveating saccades to achieve adequate page navigation. Since the visual requirements of visuomotor coordination are quite different to those of the reading task, we decided to roughly explore how subjects adapted their eye movements in this case. Samples of eye movements recordings obtained during the last experimental session in central vision, for the chips task, are presented in figure D7. This figure reveals that the 3 subjects used different strategies for exploring the environment. Subject AP explored a relatively small area of the available image with eye 176 movements, especially in the vertical plane. Subject AW appeared to explore only the right half of the screen, while using the whole vertical axis of the available image. The area explored by subject MV was the broadest, including most of the available screen surface. AP AW MV Figure D7. Eye movements recorded for the 3 normal subjects while performing the chips task in central vision (last session). The solid line represents the trajectory of the center of the viewing window relative to the presented image. The panels on the top and right represent frequency histograms of the horizontal and vertical coordinates of eye position on the screen, recorded every 4 ms. Gray bars indicate the position of the area of the screen that could be explored with eye movements. Note that subjects could also explore the environment with head/trunk movements thus modifying the actual image being explored with gaze; therefore, the image of the chips panel shown is only representative of the initial view of the working area. Figure D8 displays recordings of eye movements during several successive experimental sessions (1st, 5th, 15th, and last) for each subject while performing the chips task in eccentric vision. In the beginning, the pattern of eye movements was quite broadly distributed along the vertical axis due to the presence of numerous vertical (foveating) saccades. Less vertical foveating saccades could be observed as training progressed, and frequency histograms of the vertical coordinates became narrower. In the last experimental session, vertical coordinates of eye movements covered only about half of the available exploration area, with maximum frequency peaks at approximately 330, 250, and 280 pixels in subjects AP, AW, and MV, respectively. This reveals that subjects had the tendency to place the center of the viewing window in the lower part of the stimulation image, probably minimizing this way the eccentricity of the relevant part of the target image. A similar strategy was observed for the reading task. In that case, subjects tended to place the center of the viewing window on the lower part of the lines they were reading (see fig. 48). Interestingly, in all 3 subjects, some vertical foveating saccades could still be observed during the last experimental sessions. When recordings of eye position on the screen during the first central viewing experiment are compared to those obtained during the last experimental sessions in eccentric vision, it can be noted that more eye movements were necessary in the 177 AP AW MV 1st 5th 15th Last Figure D8. Eye movements recorded for the 3 normal subjects while performing the chips task during a choice of experimental sessions (1st, 5th, 15th, and last). The solid line represents the trajectory of the center of the viewing window relative to the presented image. The panels on the top and right represent frequency histograms of the horizontal and vertical coordinates of eye position on the screen recorded every 4 ms. Gray bars indicate the position of the area of the screen that could be explored with eye movements. Note that subjects could also explore the environment with head/trunk movements thus modifying the actual image being explored with gaze; therefore, the image of the chips panel shown is only representative of the initial view of the working area. latter condition. Moreover, less vertical portions of the screen were explored in the eccentric viewing condition. 178 To quantify the changes observed in oculomotor behavior with training, we calculated the length of the path described by each subject’s eye movements along each one of the 2D (horizontal and vertical) axes, for each task. Results for the chips task are presented in figure D9, normalized by the score of correctly placed chips. Significant learning effects were observed in the analysis of vertical eye trajectories versus time (Pearson’s correlation: r = 0.48, p < 0.05 for AP; r = 0.70, p < 0.001 for AW; and r = 0.76, p < 0.001 for MV). In the first sessions, distances along the vertical axis were of about 1.5 m/chip for subjects AP and MV, and approximately 1 m/chip in the case of subject AW. During the final sessions, vertical trajectories decreased to approximately 0.5 m/chip for all 3 subjects. Comparison of these results with values obtained during the last sessions in central vision (0.3 to 0.65 m/chip; dashed lines in fig. D9a) indicates that vertical oculomotor adaptation was different for each subject. For subject AP, vertical trajectories at the end of the experiment in eccentric vision were about 2 times longer than those obtained in central vision. In the case of subject AW, final eccentric vertical trajectories were approximately 50% shorter than those obtained during the last sessions in central vision. Final vertical trajectories in central and eccentric vision for subject MV were equivalent. a) b) Figure D9. Mean cumulative length of the total trajectory described by each subject’s eye movements per correctly placed chip, versus session number. Distances along each one of the 2D axes were calculated separately for: (a) the vertical coordinate, and (b) the horizontal coordinate of eye position on the screen. The solid lines indicate the best fits to the data. The dashed lines indicate average values for the last 3 sessions in central vision. 179 Significant learning effects were also observed in the analysis of horizontal distances per chip for all 3 subjects (Pearson’s correlation: r = 0.44, p < 0.05 for AP; r = 0.52, p < 0.01 for AW; and r = 0.67, p < 0.01 for MV). Initial values for subject AP ranged from about 1.5 to 1 m/chip, and decreased to approximately 0.7 m/chip, with results asymptoting after about 14 sessions. The decrease was less pronounced in subject AW, who presented initial horizontal trajectories of 0.6 m/chip that decreased to nearly 0.5 m/chip, and stabilized after around 30 sessions. For subject MV, mean horizontal trajectories per chip were of approximately 1 m/chip and declined to about 0.5 m/chip in the last sessions. Horizontal trajectories for this subject were still decreasing when the experiment ended. When comparing horizontal trajectories described during the last sessions in eccentric vision to those obtained during the last sessions in central vision (0.3 to 0.42 m/chip; dashed lines in fig. D9b), it appears that, for subjects AW and MV, final horizontal trajectories were of similar lengths in central and eccentric vision. For subject AP, horizontal trajectories obtained during the last training sessions in central vision were approximately 40% shorter than those observed at the end of the experiment in eccentric vision. a) b) Figure D10. Mean cumulative length of the total trajectory described by each subject’s eye movements per pointed target, versus session number, for the LEDs task. Distances along each one of the 2D axes were calculated separately for: (a) the vertical coordinate, and (b) the horizontal coordinate of eye position on the screen. The solid lines indicate the best fits to the data. The dashed lines indicate average values for the last 3 sessions in central vision. Figure D10 presents the length of the path described by each subject’s eye movements during the LEDs task, calculated separately for the horizontal (x) and vertical (y) coordinate, and normalized by the total number of presented targets 180 (24). Results for both components of the eye movement trajectory were very similar. Significant learning effects were observed for subjects AP (Pearson’s correlation: r = 0.53, p < 0.01 for the vertical trajectory and r = 0.5, p < 0.01 for the horizontal trajectory) and MV (Pearson’s correlation: r = 0.53, p < 0.01 for the vertical trajectory and r = 0.43, p < 0.05 for the horizontal trajectory). Results for these 2 subjects asymptoted within 4 to 6 sessions. Subject AP started the experiment with vertical trajectories of about 2.2 m/target and horizontal trajectories around 1.4 m/target. With training, results for both coordinates declined to approximately 0.5 m/target. Initial results for subject MV were above 1 m/target and eventually decreased to approximately 0.3 and 0.5 m/target for the vertical and horizontal trajectories, respectively. Results for subject AW remained stable around 0.3 m/target all through the experiment. For all 3 subjects, trajectories measured during the first central vision experiments (dashed lines in fig. D10) and those obtained during the last sessions in eccentric vision were similar. 181 Appendix E Analysis of Eye Movements during the Experiments on Mobility Analysis of eye movements during the habituation experiments on mobility We quantified the changes in the eye movement trajectory with training, by calculating the length of the path described by each subject’s eye movements along each one of the 2D (horizontal and vertical) axes. These results are presented in figure E1. Highly statistically significant learning effects were observed in the analysis of vertical eye trajectories versus time for subjects MS and KC (respectively, Pearson’s correlation: r = 0.77, p < 0.0001 and r = 0.66, p < 0.0001). Results for subject HB were very variable, and only showed a slight tendency to decrease with time (Pearson’s correlation: r = 0.20, p = 0.21). For all subjects, vertical trajectories a) b) Figure E1. Mean cumulative length of the total trajectory described by each subject’s eye movements during training for mobility, versus session number. Distances along each one of the 2D axes were calculated separately for: a) the vertical coordinate, and b) the horizontal coordinate of eye position on the screen. The solid lines indicate the best fits to the data. The dashed lines indicate average values for the last 3 sessions in central vision. 183 were still decreasing when the experiment ended. The analysis of horizontal trajectories revealed highly significant learning effects with time for all subjects (Pearson’s correlation: r = 0.79, p < 0.0001 for HB; r = 0.81, p < 0.0001 for MS; and r = 0.53, p < 0.001 for KC). Horizontal eye trajectories were still decreasing when the experiment was terminated. Final eccentric trajectories around the vertical axis for subject HB were very variable all through the experiment. However, during the last 10 training sessions his vertical eye trajectories reached similar values to those observed during the last sessions in central vision (dashed lines in fig. E1). For subject MS, final vertical eye trajectories were similar in central and eccentric vision. For subject KC, final eccentric vertical trajectories were shorter than in central vision. Interestingly, at the end of training, horizontal eye trajectories were shorter in eccentric than in central vision for all subjects. 184 Publications 1. Reprinted from VISION RES, 43(3), Sommerhalder, J., Oueghlani, E., Bagnoud, M., Leonards, U., Safran, A.B., & Pelizzone, M., Simulation of artificial vision: I. Eccentric reading of isolated words, and perceptual learning, pp. 269-283, Copyright 2003, with permission from Elsevier. 2. Reprinted from VISION RES, 44(14), Sommerhalder, J., Rappaz, B., de Haller, R., Perez Fornos, A., Safran, A.B., & Pelizzone, M., Simulation of artificial vision: II. Eccentric reading of full-page text and the learning of this task, pp. 1693-1706, Copyright 2004, with permission from Elsevier. 3. Reprinted from INVEST OPHTHALMOL VIS SCI, 47(4), Perez Fornos, A., Sommerhalder, J., Rappaz, B., Pelizzone, M., & Safran, A.B., Processes involved in oculomotor adaptation to eccentric reading, pp. 1439-1447, Copyright 2006, with permission from the Association for Research in Vision and Ophthalmology. 4. Reprinted from INVEST OPHTHALMOL VIS SCI, 46(10), Pérez Fornos, A., Sommerhalder, J., Rappaz, B., Safran, A.B., & Pelizzone, M., Simulation of artificial vision, III: do the spatial or temporal characteristics of stimulus pixelization really matter?, pp. 3906-3912, Copyright 2005, with permission from the Association for Research in Vision and Ophthalmology. 185 Vision Research 43 (2003) 269–283 www.elsevier.com/locate/visres Simulation of artificial vision: I. Eccentric reading of isolated words, and perceptual learning J€ org Sommerhalder b a,* , Evelyne Oueghlani a, Marc Bagnoud a, Ute Leonards b, Avinoam B. Safran a, Marco Pelizzone a a Ophthalmology Clinic, Geneva University Hospitals, 1211 Geneva 14, Switzerland Division of Neuropsychiatry, Geneva University Hospitals, 1211 Geneva 14, Switzerland Received 19 December 2001; received in revised form 4 September 2002 Abstract Simulations of artificial vision were performed to assess ‘‘minimum requirements for useful artificial vision’’. Retinal prostheses will be implanted at a fixed (and probably eccentric) location of the retina. To mimic this condition on normal observers, we projected stimuli of various sizes and content on a defined stabilised area of the visual field. In experiment 1, we asked subjects to read isolated 4-letter words presented at various degrees of pixelisation and at various eccentricities. Reading performance dropped abruptly when the number of pixels was reduced below a certain threshold. For central reading, a viewing area containing about 300 pixels was necessary for close to perfect reading (>90% correctly read words). At eccentricities beyond 10°, close to perfect reading was never achieved even if more than 300 pixels were used. A control experiment using isolated letter recognition in the same conditions suggested that lower reading performance at high eccentricity was in part due to the ‘‘crowding effect’’. In experiment 2, we investigated whether the task of eccentric reading under such specific conditions could be improved by training. Two subjects, naive to this task, were trained to read pixelised 4-letter words presented at 15° eccentricity. Reading performance of both subjects increased impressively throughout the experiment. Low initial reading scores (range 6%–23% correct) improved impressively (range 64%–85% correct) after about one month of training (about 1 h/day). Control tests demonstrated that the learning process consisted essentially in an adaptation to use an eccentric area of the retina for reading. These results indicate that functional retinal implants consisting of more than 300 stimulation contacts will be needed. They might successfully restore some reading abilities in blind patients, even if they have to be placed outside the foveal area. Reaching optimal performance may, however, require a significant adaptation process. Ó 2002 Elsevier Science Ltd. All rights reserved. Keywords: Visual prosthesis; Simulation; Reading performance; Eccentric reading; Learning 1. Introduction Over the last few years, several research groups have initiated important projects aiming at the development of visual prostheses for the blind (Chow & Chow, 1997; Dobelle, 2000; Humayun & de Juan, 1998; Normann, Maynard, Rousche, & Warren, 1999; Rizzo & Wyatt, 1997; Veraart et al., 1998; Zrenner et al., 1999). Increasing interest in this domain is essentially due to recent progress in micro-technology. One issue of major importance, when considering the conception of a visual prosthesis, is the determination of minimum requirements for useful artificial vision. We used simulations of * Corresponding author. Fax: +41-2238-28382. E-mail address: [email protected] (J. Sommerhalder). artificial vision with normal subjects to assess this issue. Our simulations were designed to mimic artificial vision produced by a retinal prosthesis, but some of the results may also be of interest for prostheses located at other levels of the visual pathways (e.g. stimulating the optic nerve or the visual cortex). In everyday life, current visual tasks can be divided into three main classes: recognition of (small) shapes as it is specifically required for reading, localisation of objects in 3D familiar-scale environments and spatial orientation including whole body mobility. All of them have to be thoroughly studied to determine what is the minimal visual information required to restore a useful visual function. In this study, we focussed on reading. Understanding the fundamentals of reading has received a lot of attention. One of the main research 0042-6989/03/$ - see front matter Ó 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 2 - 6 9 8 9 ( 0 2 ) 0 0 4 8 1 - 9 270 J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 centres in this field is the laboratory for low vision research at the University of Minnesota. These authors have systematically studied various aspects of reading psychophysics in normal subjects and low vision patients. For normal subjects, Legge, Pelli, Rubin, and Schleske (1985) reported that maximum reading rates are achieved for characters subtending 0.3°–2° of visual angle; that reading rate increases with field size, but only up to 4 characters, independently of character size; that reading rates increase with sample density, but only up to a critical density which depends on character size, when the text is matrix sampled or pixelised. Reading was also found to be very tolerant to either luminance or colour contrast reductions (Legge & Rubin, 1986; Legge, Rubin, & Luebker, 1987; Legge, Parish, Luebker, & Wurm, 1990). At very low (<10%) luminance contrast however, reading speed drops due to prolonged fixation times and to an increased number of saccades, presumably related to a reduced visual span (Legge, Ahn, Klitz, & Luebker, 1997). When testing the effect of print size on reading speed in normal peripheral vision, it was found that the use of larger characters improves peripheral reading to some extent, up to a critical print size (Chung, Mansfield, & Legge, 1998). But maximum reading speed also decreased from about 808 words/min for foveal vision to about 135 words/min for peripheral vision at 20° eccentricity. 1 Thus print size was not found to be the only factor limiting maximum reading speed in normal peripheral vision, contradicting the scaling hypothesis (Latham & Whitaker, 1996; Toet & Levi, 1992) which implies that peripheral word recognition can be made equal to that at the fovea by increasing print size. In low-vision patients, reading is similar to normal reading in several aspects (Legge, Rubin, Pelli, & Schleske, 1985; Legge et al., 1990; Legge et al., 1997; Rubin & Legge, 1989), but difficult to predict on the basis of routine clinical evaluations (Legge, Ross, Isenberg, & La May, 1992). As a rule however, it can be stated that lowvision patients with central field defects achieve lower reading rates than those with preserved central fields (Legge et al., 1985; Rubin & Legge, 1989). The studies quoted above (as well as many others) have led to the identification of a series of important parameters that are critical for reading in normal and low vision subjects. To our knowledge, there is however only a limited number of studies, which were specifically oriented towards the development of visual prostheses. Cha, Horch, Normann, and Boman (1992) used a pixelised vision system to simulate artificial vision in normal subjects. Their results showed that a 25 25 array of pixels representing 4-letters of text projected on a foveal visual field of 1.7° is sufficient to provide reading rates near 170 words/min using scrolled text, and near 100 words/min using fixed text. This investigation was conducted within the frame of a project, which aimed at developing a cortical visual implant (Normann et al., 1999). Another research group, developing a retinal implant to stimulate remaining retinal neurons in photoreceptor degenerative diseases (Humayun et al., 1999), conducted experiments on the properties of pixelised vision at the Johns Hopkins University of Baltimore (Dagnielie, Thompson, Barnett, & Zhang, 2000; Thompson, Barnett, Humayun, & Dagnelie, 2000). Reading speed and facial recognition were measured by simulating prosthetic vision in the central visual field using a head mounted video display. Subjects used eye movements to scan the stimuli through a pixelising grid. Several grid parameters were explored. Results demonstrated reading speeds up to 100 words/ min, which dropped off (a) when the grid size covered less than 4 letters, (b) when a grid density of less than 4 pixels per letter width was used, or (c) when more than 50% of the pixels were randomly turned off. In all previous experiments attempting to mimic conditions of artificial vision, eye movements could be used to scan a target with the fovea. However, the anatomo-physiology of the retina does not favour a foveal location for such prostheses (see e.g. Sj€ ostrand, Olsson, Popovic, & Conradi, 1999). Retinal implants are primarily designed to stimulate neurones of the inner retinal layers in cases of photoreceptor loss (e.g. retinitis pigmentosa). Surviving bipolar and/or ganglion cells are the targets for electrical stimulation. In the central fovea, these neurons are not present. In the parafovea, they are arranged in several superimposed layers that makes it difficult to activate them in predictable patterns. The best sites for retinotopic activation without major distortion are located beyond the parafoveal region. Such eccentric locations as well as the fact that a retinal implant will stimulate a fixed area of the retina have apparently not yet been fully taken into consideration. The aim of the present research work was to assess reading performance with a system projecting stimuli onto defined, stabilised areas of the visual field placed at various eccentricities. In experiment 1, we studied the influence of stimulus pixelisation, stimulus eccentricity and stimulus size on reading performance. In experiment 2, we investigated whether the task of eccentric reading under such specific conditions could be improved by training. 1 Such high reading rates were achieved by using rapid serial visual presentation (RSVP). All subjects were normal volunteers, recruited from the staff of the Geneva University Eye Clinic. Age ran- 2. General methods 2.1. Subjects J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 271 Fig. 1. The SMI EyeLink system. Three cameras are attached to a headband. Two cameras are recording eye movements. One camera is recording IR light points from each corner of the screen to monitor head position relative to the screen. On this basis, the EyeLink software calculates online the gaze position in screen coordinates. In this example, a 4-letter word is projected on a stabilised retinal area located at 5° eccentricity in the lower visual field. The horizontal line crossing the screen represents a fixation aid for the subject (used in experiment 1). ged from 25 to 47 years. All had normal or corrected to normal visual acuity of 20/20 in the tested eye. All of them were native French speakers or had perfect knowledge of French. All experiments were conducted according to the ethical recommendations of the Declaration of Helsinki and were approved by local ethical authorities. 2.2. Experimental set-up To simulate visual percepts produced by a retinal implant, images were projected on a defined and stabilised area of the retina. Target image stabilisation in the visual field was achieved by online compensation of the gaze position on a fast computer display using a high speed video based eye and head-tracking system, the SMI EyeLink Gaze tracking system (SensoMotoric Instruments GmbH, Teltow/Berlin, Germany; see Fig. 1). The experimental set-up consisted of two computers and a headband mounted measuring unit. The ‘‘subjectÕs PC’’ (PIII-450 equipped with a Matrox G200 graphics card) was used to generate the stimuli on a 22’’ ELSA Ecomo 22H99 screen set to a resolution of 600 800 pixels at a refresh rate of 160 Hz. It was connected via Ethernet to the ‘‘operatorÕs PC’’, a Compaq Deskpro EP (Celeron-400), which contained the hardware and software to collect and compute the data from the three head mounted cameras. Gaze position data in screen coordinates were transmitted to the subject PC every 4 ms (250 Hz), and were available for further computing with a time delay of less than 10 ms. The system worked in the following way: gaze position was used to move the target stimuli (bitmap images) on the stimulation screen according to the eye movements of the subject. Images could thus be steadily projected onto a defined (central or eccentric) area of the retina. A pilot study (Bagnoud, Sommerhalder, Pelizzone, & Safran, 2001) demonstrated that this experimental set-up allowed to accurately stabilise targets in the visual field by online compensation of the gaze position. 2.3. Generation and presentation of the stimuli Stimuli were presented in rectangular white areas (viewing areas), which were filled with black 4-letter words of common French language (including accented characters and capital letters for proper names). We used 4-letter words for our experiments because this was considered to be the minimum letter-sequence allowing close to normal reading speeds (Legge et al., 1985). 2 We used the largest possible font size fitting within the viewing area. We chose the proportionally spaced 2 Although maximum reading speeds would be favored by viewing areas containing a higher number of characters, as quoted by several authors, the presentation of only 4 letters allowed to use a large character size favoring peripheral reading. 272 J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 Position of gaze tape Fig. 2. Presentation of the 4-letter word ‘‘tape’’ illustrating the five degrees of pixelisation used in experiment 1: (A) maximum screen resolution, (B) 875 pixels, (C) 286 pixels, (D) 140 pixels, (E) 83 pixels. The pixel numbers indicate the total number of pixels in the viewing area. Helvetica (i.e. Arial) font style because it is commonly used for text printing, and has been shown to provide good reading conditions to low vision subjects (Buultjens, Aitken, Ravenscroft, & Carey, 1999). The stimuli used for the experiments were pre-processed bitmap images, which had been pixelised 3 (mosaic pixelisation) to simulate the reduced information content due to a limited number of parallel processing channels in retinal prostheses. Fig. 2 shows an example of one of our stimuli at different pixelisations. Images were generated using Adobe Photoshopâ 5.5 software. The subjects were comfortably seated facing the screen at an eye-to-screen distance of 57 cm. At this distance, the 30 cm 40 cm surface of the screen subtends a visual angle of 30° 40°, 1° corresponding to 20 screen pixels at the screen resolution of 600 800. The camera monitoring the eye was positioned so that the pupil was clearly visible and well defined at any gaze position. At the beginning of each run the eye to screen distance was checked, adjusted if needed, and a standard 9-point calibration of the eye-tracker was performed. Then, a block of 50 words, randomly chosen among a library of 500 common French 4-letter words was presented. Subjects were requested not to move during the run. Reference point for the stimulus eccentricity was the centre of the viewing area. Eccentric stimuli were presented in the lower visual field (Fig. 3). This offered at least two practical advantages: (1) the retinal eccentricity of each letter varies less when a word is projected below or above the fixation point than when projected to the left or the right; and (2) the lower visual field is most commonly used for eccentric reading (see e.g. Chung et al., 1998). For each item of the run, the subject had to say the word he/she recognised. The response (right or wrong) was entered by the examiner into the operator PC and stored for further analysis. After each single word presentation, the calibration was checked for 3 Mosaic pixelisation (i.e. square pixels of uniform grey level) was used. Such simple patterns were adequate to simulate the reduced information content (e.g. finite quantisation) of the stimuli, but were not intended to mimic the nature (e.g. profile, shape, colour, etc.) of the perceptual pixels elicited by electrical activation of the retina. Window moving according to the direction of gaze 22” Monitor Fig. 3. The stimulation screen seen by the subject. The viewing area, a white surface with black text, was moving on the screen according to the direction of gaze and with a constant offset (eccentricity). The background of the remaining screen area was in a grey colour corresponding to the mean grey level of the target windows. The viewing area subtended in this case a visual field of 20° 7°. possible drifts or artefactual movements, and slightly corrected if needed, to insure an exact control of the target image position during the entire experiment. 2.4. Data analysis Reading performance was determined as the percentage score of fully recognised words out of each 50item block. Results expressed on such a proportional percentage scale are, however, not suitable for statistical analysis. It is well known that with proportional scales, variance is not correlated with the mean. In other words, the data are not normally distributed around the mean and scale values are not linear in relation to the test variability. One can solve this problem by using an arcsine transformation. Studebaker (1985) proposed to use so-called ‘‘rationalised arcsine units’’ (rau), producing values that are numerically close to the original percentage range, while retaining all of the desirable properties of the arcsine transform. For example, for a sample size of 50 responses, 0% correct corresponds to )16.5 rau, 50% to correct to 50 rau and 100% correct to 116.5 rau. All data were statistically analysed using scores expressed in rau. On the right ordinates of the graphs, however, and also for the description of the results, values on the original percent-correct scale are indicated for better clarity. 3. Experiment 1 3.1. Specific methods In experiment 1, reading performance was assessed as a function of a series of variables, each being potentially J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 an important parameter of prosthetic vision. First, the number of contacts in the prosthesis: five different degrees of pixelisation were tested, viewing areas of maximum screen resolution, 875, 286, 140 and 83 pixels (see also Fig. 2). 4 Second, retinal placement of the prosthesis: five different eccentricities in the lower visual field were tested, 0°, 5°, 10°, 15° and 20°. Third, size of the prosthesis: two viewing areas were investigated. The large area, subtending a visual field of 20° 7°, allowed the use of a print size greater than the critical print size needed for optimal reading performance at 20° eccentricity (Chung et al., 1998). The height of a small letter ÔxÕ used on this large viewing area corresponded to a visual angle of 3.6°. The small area, subtending 10° 3:5°, corresponded to a surface of approximately 3 mm 1 mm on the retina, and was used to represent the surface of a smaller, possibly more realistic retinal prosthesis that would be manageable surgically. The height of a small letter ÔxÕ used on this small viewing area corresponded to a visual angle of 1.8°. Note that using the same number of pixels on both viewing areas implied that pixels were larger (4 times) on the large viewing area. All tests were conducted monocularly on five normal volunteers. Each subject performed one run (consisting of a 50-word block) in each condition. Testing always started at the lowest eccentricity, using maximum screen resolution first, then successively coarser resolutions. Then, the same procedure was repeated using the next eccentricity. Possible global learning effects would therefore favour greater performance at low pixel numbers and high eccentricities. Each word was presented during 3 s. When eccentric stimulus presentation was used, a fixation aid (consisting of a horizontal red filament crossing the screen) was installed to make it easier for the inexperienced subject to keep the target on screen. 3.2. Reading performance on the larger viewing area (20° 7°) Mean reading performance versus pixel number for various eccentricities on the larger viewing area is presented in Fig. 4a. In central vision, reading performance of 4-letter words was almost perfect (i.e. higher than 90% correct) for pixelisations down to 286 pixels. At lower resolution, reading performance dropped abruptly. This result indicates that approximately 300 pixels are necessary to transmit the relevant information under optimal conditions. In peripheral vision, maximum reading performance decreased with increasing eccentricity. At an eccentricity of 10°, almost perfect reading (better 4 â Mosaic pixelisation in Adobe Photoshop reduces screen resolution by an integer factor. Therefore in our experimental conditions 875 pixels can be viewed as an array of 50 17:5 pixels, 286 pixels as 28:6 10 pixels, 140 as 20 7 pixels and 83 pixels as 15:4 5:4 pixels. 273 (a) 120 100 110 100 90 90 80 80 70 70 60 50 40 30 60 50 40 30 20 10 0 -10 20 0° 5° 10° 15° 20° 10 0 10000 1000 100 Number of pixels in the viewing area (b) 10° x 3.5° viewing area 120 100 110 100 90 90 80 80 70 70 60 50 40 30 60 50 40 30 20 10 0 -10 20 0° 5° 10° 15° 20° 10 0 10000 1000 100 Fig. 4. Performance for single 4-letter word reading versus number of pixels in a stabilised viewing area of (a) 20° 7° and (b) 10° 3:5°. Mean reading scores in rationalised arcsine units SEM (left scale) and in percent (right scale) for five normal subjects at five eccentricities in the lower visual field. At maximum screen resolution, the large viewing area contained 4 times more pixels than the small viewing area. Otherwise, tests were performed at equal pixel resolution for both viewing areas. than 90% correct) was still possible at high pixel resolutions. At eccentricities of 15° and 20°, almost perfect reading was never achieved even at high resolutions. Maximum reading performance was limited to values of 88% and 63% correctly read words, respectively. 3.3. Reading performance on the smaller viewing area (10° 3:5°) Mean reading performance versus pixel number for various eccentricities on the smaller viewing area is 274 J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 presented in Fig. 4b. In central vision, results with the smaller viewing area were very similar to those with the larger area. Reading performance of 4-letter words was almost perfect (or higher than 90% correct) for pixelisations down to 286 pixels. Then, it dropped abruptly. The same limiting criterion of about 300 pixels was found to transmit the relevant information. In peripheral vision, the decrease in maximum reading performance with increasing eccentricity was more pronounced than on the larger viewing area: at eccentricities of 10°, 15° and 20°, maximum reading performance was limited to values of 89%, 57% and 30% correct, respectively. (a) 3.4. Normalised data on both viewing areas The raw observations presented in Fig. 4 demonstrate that both number of pixels and eccentricity of the stimuli affected reading performance of 4-letter words in our experiments. In order to compare the effect of the pixel number at different eccentricities, we normalised the data to the values obtained at maximum screen resolution (Fig. 5). These normalised data demonstrate that the pixel number affected reading performance very similarly at all eccentricities and on both viewing areas. This result is consistent with the fact that the number of pixels influences directly the information content of the source image. The eccentricity of the stimulus, however, seems to affect the way information is processed by the visual system, and appears to limit maximum reading performance. (b) 3.5. Single letter recognition versus 4-letter word reading At eccentricities of 10° and more, most subjects spontaneously reported that they had problems recognising letters occurring in the middle of the words. This suggested that letters closely flanked by others were more difficult to identify. To check this point, we designed an additional experiment, using isolated letter stimuli instead of 4-letter words. In brief, isolated single letters of identical font type and size as for the word experiments were presented on the small viewing area. The overall surface of the viewing area did not change and it contained the same total number of pixels as for the word experiments. Blocks of 50 letters, chosen among the French alphabet and according to their frequency of use in our pool of 500 words, were randomly presented to five new subjects. The results of this additional experiment are presented in Fig. 6. Up to an eccentricity of 15°, isolated letter recognition was almost independent of eccentricity. At 20° eccentricity, maximum letter recognition was still about 90% correct for high pixel resolutions. Fig. 7 compares reading performance of isolated letters to that of 4-letter words Fig. 5. Normalised reading performance for single 4-letter words versus number of pixels in a stabilised viewing area of (a) 20° 7° and (b) 10° 3:5°. Mean relative reading scores SEM for five normal subjects at five eccentricities in the lower visual field. The data are normalised to the mean reading performance values at maximum screen resolution. at 286 pixel resolution on the small viewing area. It appeared that isolated letter recognition was much less affected by eccentricity than word reading. In an attempt to compare both results, we computed, as a first approximation, the intrinsic probability to correctly identify 4 isolated letters in a successive sequence. This rough estimation still falls short to account for the very low scores observed in the word-reading task. The two tasks are difficult to compare quantitatively in an accurate manner, but this observation suggests that 4-letter word reading was significantly reduced at high eccentricities by the fact that the letters to be recognised J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 Fig. 6. Performance in isolated letter recognition versus number of pixels in the stabilised viewing area of 10° 3:5° at five eccentricities in the lower visual field. Mean letter recognition scores in rau SEM (left scale) and in percent (right scale) for five normal subjects. 275 Finally, it should also be noted, that at high eccentricities, isolated letter recognition was significantly better at a target resolution of 875 pixels than at maximum screen resolution (Fig. 6; p ¼ 0:016 at 15° eccentricity, p ¼ 0:018 at 20° eccentricity). The data for 4letter word reading on the small viewing area (Fig. 4b) show the same trend. This finding may indicate, that at high eccentricities a certain blur of the target (due to pixelisation) leads to better performance, if the letter size is below the critical print size. A recent study by Li, Nugent, and Peli (2001) compared letter recognition of jagged (pixelised) and smoothed (anti-aliased) letters on a CRT display. They found no significant difference between the two conditions in peripheral vision up to 12.5° eccentricity. While the stimuli used by Li and coworkers are not exactly comparable with the stimuli we used, the present result suggests that observable differences may appear only at higher eccentricities (15° and more). 4. Experiment 2 120 100 110 100 90 90 80 80 70 70 60 50 40 30 60 50 40 30 20 20 isolated single letters probabilistic estimate to recognize 4-letters in sequence 4-letter words 10 0 -10 10 0 0 5 10 15 20 Fig. 7. Reading performance versus eccentricity for stimuli presented on the smaller viewing area (10° 3:5°) containing 286 pixels. Results of isolated letter recognition are compared to results of 4-letter word reading. Mean performance in rau SEM (left scale) and in percent (right scale) for five normal subjects. The dotted line indicates the probabilistic prediction to recognise 4-letters in sequence on the basis 4 of the probability to recognise single isolated letters (pwords ¼ pletters ). Note that this simple estimate indicates a lower limit (e.g. some words may be identified without requiring recognition of all 4-letters). are flanked by others. The ‘‘crowding effect’’ 5 (Tychsen, 1992) may be the underlying fundamental mechanism. 5 Increased difficulty in recognising words made up of closely spaced letters, when presented in the peripheral visual field. Results collected in experiment 1 might underestimate possible performances, especially at high eccentricities, because normal subjects were not used to eccentric reading. Blind patients, potential recipients of retinal implants, will have time to fully adapt to the use of their prosthesis. We therefore investigated in experiment 2 the effect of training on eccentric reading. 4.1. Specific methods We attempted to choose a test condition mimicking as closely as possible a realistic retinal prosthesis. According to Sj€ ostrand et al. (1999) a radial one-to-one connection between photoreceptors, bipolar cells and ganglion cells is not guaranteed for eccentricities smaller than about 10°. Retinotopic activation without major distortion is essential if one wants to avoid complex preprocessing of the light falling on the retina. We therefore decided to investigate the effects of training on a viewing area placed at 15° eccentricity in the lower visual field (corresponding to a surgically as well as physiologically favourable location on the retina). We chose the smaller viewing area of 10° 3:5° (corresponding to a surgically manageable surface of 3 1 mm2 on the retina) containing 286 pixels (corresponding to a number of pixels allowing close to perfect word recognition in central vision and representing a number of contacts which is manageable with present technology). Under such conditions in experiment 1, subjects could correctly identify between 20% and 48% of the words. This level of performance was clearly above chance level, but insufficient to provide useful function. For comparison, two 276 J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 additional experimental conditions on the same viewing area were used: (a) stimuli containing the same number of pixels (286 pixels), but presented at an eccentricity of 0° (central reading); (b) stimuli presented at the same eccentricity (15°), but containing 14,000 pixels (maximum screen resolution). Two young female subjects, both 27 years old, participated in this experiment. 6 Subject EO performed all tests in binocular condition, whereas Subject AR performed all tests in monocular condition. 7 They had not participated in any of the previous studies on eccentric reading. Three experimental sessions were conducted each working day of the week (5 days a week). Each session included one run (consisting of a 50-word block) in each of the following three successive conditions: first, 286 pixels at 0° eccentricity; second, 14,000 pixels at 15° eccentricity; and third, 286 pixels at 15° eccentricity. Thus, the easiest condition was tested first, and the most difficult last, so that possible within-session learning effects would favour results in the most difficult condition. Each experimental session lasted about 20 min, the three sessions representing about 1 h of daily training. A total of 69 sessions were conducted with each subject. Except for weekends, the regular daily flow of sessions was interrupted once (AR), or twice (EO), for 3-day vacations. The presentation time of each stimulus was limited to 10 s, but subjects were instructed to press a key as soon as they had recognised the projected word. The response time was recorded together with the nature of the subjectÕs response (ÔrightÕ or ÔwrongÕ). At the end of each run, reading performance (expressed in number of correctly recognised words) and mean response time (expressed in seconds, on the basis of all 50 trials) were automatically computed. Learning curves were established for each experimental condition on the basis of reading scores and also on the basis of mean response time. Data were fitted using the non-linear regression function y ¼ y0 þ að1 ebx Þ: To determine if time (expressed as session number) had a statistically significant effect on performance we used a simple linear correlation (PearsonÕs correlation). 4.2. Learning effects on eccentric reading of pixelised words Fig. 8 presents reading performance versus session number in the main condition (286-pixel resolution at 15° eccentricity). We observed impressive learning effects on both subjects. Both began the experiment with low reading scores and improved over time by about 60% points. These improvements were highly statistically significant (PearsonÕs correlation: r ¼ 0:80, p < 0:0001 for EO and r ¼ 0:86, p < 0:0001 for AR). Experimental data were fitted with the exponential function presented in the methods section to average session-to-session variability. The fits revealed some noticeable individual differences. At the very beginning of the learning period, subject EO was able to identify 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 Session # AR - monocular viewing 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 100 90 80 70 60 50 40 30 20 10 0 6 Since the main goal of the experiment was to show in a general way, that performance in eccentric reading can be improved by training, 2 subjects were estimated to be sufficient to demonstrate such an effect. 7 Retinal implants will certainly essentially be used monocularly. It was, however, interesting to compare monocular to binocular learning in normal subjects who generally use binocular vision. 0 10 20 30 40 50 60 70 Fig. 8. Performance in reading 4-letter words versus session number at 15° eccentricity and using a viewing area containing 286 pixels. The solid line indicates the best fit to the data. J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 about 23% of the words, whereas subject AR identified only 6% of words. Both progressed over time. During final sessions, subject EO achieved scores of about 85% correctly read words, and subject AR scores of about 64% correctly read words. EOÕs scores asymptoted for the last 15 sessions, while ARÕs scores never reached a clear asymptote. It should however be noted that EO was tested in binocular condition and AR in monocular condition. Although overall improvements were similar for both of them, these differences in absolute scores as well as in the learning curve might thus reflect a binocular advantage. A second experimental observation consistent with a learning process appears in the analysis of the mean response time (Fig. 9). During initial sessions, typical response times ranged between 3 and 5 s. During final 6 5 4 3 2 1 0 0 10 20 30 40 50 6 0 Session # 277 sessions, typical response times decreased to 2–3 s. Experimental data were fitted to average session-to-session variability. The fits revealed that both subjects significantly reduced the mean response time as the session number increased (PearsonÕs correlation: r ¼ 0:79, p < 0:0001 for EO and r ¼ 0:38, p ¼ 0:001 for AR). The reduction in response time was more pronounced for subject EO tested binocularly (2.4 s), than for subject AR tested monocularly (0.6 s). Interestingly, the longer initial response times of subject EO were also associated with better initial reading performances, suggesting inter-individual differences in the strategies used to perform this difficult task. This analysis, based on all, correct and incorrect responses, reflects best the effects of the global learning process, but it does occult the time subjects took to read the words they recognised correctly. An analysis based on correct responses only (dashed lines in Fig. 9) revealed that mean response times for correctly read words were generally shorter. In this case, only subject EO significantly reduced her correct response time (PearsonÕs correlation: r ¼ 0:68, p < 0:0001). AR shows the same trend, but this effect is not significant on her data. Taken together, these data clearly indicate that important improvements in performance can be obtained by training. Both subjects progressed from a poor to a relatively useful visual function during the course of this experiment. This suggests that future users of visual prostheses will need time to extract best performances from these devices, as it is the case for deaf users of cochlear implants (see e.g. Pelizzone, Cosendai, & Tinembart, 1999). It is interesting to explore in more detail some of the parameters influencing this learning process. AR - monocular viewing 4.3. Influence of eccentricity and pixel number on the learning process 6 5 4 3 2 1 0 0 10 20 30 40 50 6 0 Fig. 9. Mean presentation time in reading 4-letter words versus training session number at 15° eccentricity in the lower visual field and using a viewing area containing 286 pixels. The solid lines indicate the best fits to the data. The dashed lines indicate the best fits to the data when only correct responses are taken in consideration. Fig. 10 shows the data collected using the two additional experimental conditions mentioned in the method section. The influence of adaptation to read pixelised stimuli is demonstrated by analysing data collected using the same number of pixels, but presented via central reading (0° eccentricity). As expected from experiment 1, central reading performance of pixelised words was close to perfect for both subjects. Although both subjects slightly improved their central reading performance with time, this improvement was small relative to the overall improvements observed upon eccentric reading. Hence, the adaptation process to decipher pixelised words had only a weak influence on reading performance. The influence of adaptation to eccentricity is demonstrated by analysing data collected at the same eccentricity (15°), but using stimuli containing 14,000 pixels 278 J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 Session # AR - monocular viewing 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 100 90 80 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70 Fig. 10. Performance in reading 4-letter words versus training session number in the two control conditions: (1) in central vision using a viewing area containing 286 pixels (grey triangles), and (2) at 15° eccentricity in the lower visual field using a viewing area at maximum screen resolution (white diamonds). The solid lines indicate the best fit to the data in these two conditions. For comparison, the dashed line of the best fit to the data in the main condition is also shown. eccentricity because scores collected at that eccentricity asymptoted clearly below those collected with central reading. This shows that providing more resolution can improve performance to some extent, but does not entirely compensate for the loss due to eccentricity. 4.4. Influence of familiarisation with the word set Subjects were confronted daily for more than one month with the same finite set of 500 words. One might wonder if they improved their identification performance simply because they were progressively learning the set of possible correct answers. We tested this issue by generating an additional pool of 200 new 4-letter words. None of the words in the new set had been used previously. Fifty word blocks were randomly extracted from this new set and presented to the subjects in testing sessions that occurred after the end of the main experiment. All other aspects of testing were exactly identical to that of the main experiment. Fig. 11 compares mean reading performances using the new word set to the data collected using the old 500 word-set throughout the experiment. For both subjects, reading performance using the new word set was significantly higher (EO: p ¼ 0:002; AR: p < 0:001) than the performance measured at the beginning of the main experiment. Reading performance using unpractised words was only slightly lower than that reached at the end of the main experiment (EO: p ¼ 0:2; AR: p ¼ 0:03). This demonstrates that the benefits derived from training with one set of words could be exploited to decipher new, unpractised words. One can conclude from this additional test that repeatedly using the same pool of words did not significantly bias our results. Thus, observed improvements over time were actually real improvements in accomplishing the demanded task. Interestingly, however, familiarisation with the word pool was important for reading speed. Indeed, pixelised words, familiar to the reader, were recognised slightly more rapidly than unpractised words presented in the same conditions. 4.5. Binocular versus monocular perceptual learning (maximum screen resolution). For both subjects, the progression of performance over time was similar to that observed using 286 pixel stimuli. Fits to the experimental data demonstrate that the performance at maximum screen resolution is about 10%–20% higher, the effect of resolution being apparently slightly more pronounced at the end of the experiment. These results confirm that adaptation to eccentric reading was the principal component of the overall learning process. One can conclude from these control conditions that habituation to eccentricity is presumably a dominant component in the learning process. It is interesting to note that perfect performance was never achieved at 15° Subject EO performed all tests using binocular vision while subject AR performed all tests in monocular vision. The final scores reached by subject EO were about 20% higher than those of subject AR (see Fig. 8). Two important questions can be raised: Is this difference reflecting an advantage of binocular vision? What would reading scores be if subjects would be asked to perform the task in the condition they did not use previously? At the end of experiment 2, we measured on subject EO reading scores in monocular viewing condition, and on subject AR reading scores in binocular viewing condition, using the same testing conditions as in our J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 10 0 EO 100 90 Trained cond. 80 70 60 50 40 30 20 Binocular Untrained cond. 90 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Trained cond. 100 Untrained cond. 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 279 80 70 60 50 40 30 20 10 0 AR At the beginning of the main experiment At the end of the main experiment Fig. 11. Mean reading performance with unpractised 4-letter words compared to results at the beginning and the end of the main experiment. Bars indicate mean values SD in three conditions: (1) first three runs and (2) last three runs of the main experiment compared to (3) three additional runs with unpractised words. Experimental conditions: 15° eccentricity using a viewing area of 10° 3:5° containing 286 pixels. main experiment. No significant differences in reading performance were found for both subjects in such ‘‘reversed’’ conditions (Fig. 12). Inter-individual differences in reading scores were preserved. This indicates that the condition, in which the perceptual learning of eccentric reading was conducted, is not relevant. Training with binocular reading benefits subsequent monocular reading and, conversely, training with monocular reading benefits subsequent binocular reading There was, however, a slight, but un-significant, within-subject trend to better scores with binocular vision. This small advantage was possibly due to effects of binocular summation or inter-ocular suppression. We were also interested to know if perceptual learning gathered with one eye transfers to the non-habituated eye. Subject AR, who did all the tests monocularly with her dominant right eye, was therefore retested using her non-dominant left eye in all three different experimental conditions. Fig. 13 shows clearly that there is no significant difference in monocular reading performance across both eyes. 4.6. Persistence of perceptual learning Finally, we were interested to investigate if the benefits of perceptual learning of eccentric reading could persist after a significant period of non-practice. For a 2 months period after the end of the experiments, subject EO did not participate in any testing. Her reading performance was then re-tested using the main experimental condition. Table 1 demonstrates that there Fig. 12. Effects of using reversed viewing conditions (untrained versus trained). Bars indicate mean values SD. Subject EO: three additional runs in monocular condition (untrained) versus the last three runs of the main experiment in binocular condition (trained). Subject AR: three additional runs in binocular condition (untrained) versus the last three runs of the main experiment in monocular condition (trained). Experimental conditions: 15° eccentricity using a viewing area of 10° 3:5° containing 286 pixels. 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 100 90 80 70 60 50 40 30 20 10 0 0°/286 pixels 15°/max. pixels 15°/286 pixels Trained right eye Fig. 13. Comparison of reading performances between the trained and the untrained eye at the end of the training process for subject AR. Bars indicate mean values SD. For each condition, the last three runs of the main experiment are compared to three additional runs conducted on the untrained eye. was no significant change in performance after 2 months of non-practice. This indicates that perceptual learning of eccentric reading is at least preserved for a certain time. 5. Discussion This first study was designed to explore reading performance in conditions mimicking artificial vision. 280 J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 Table 1 Reading performance after two months of rest compared to the reading performance at the end of training for subject EO Mean reading performance At the end of the experiment (day 36) Two months after completion of the experiment (day 99) 4-Letter words read (EO) Rau SD Percent 87.2 85.6 9.8 1.5 88.0 85.9 Mean values are calculated on the basis of three runs: last three runs of the main experiment (day 36) and three additional runs conducted at day 99, two months after completion of the experiment. Experimental conditions: 15° eccentricity using a viewing area of 10° 3:5° containing 286 pixels in binocular vision. Several aspects of the experimental set-up deserve to be discussed. We used 4-letter word stimuli, because Legge et al. (1985) initially demonstrated that this was the minimum letter-sequence allowing close to normal reading speeds. However, subsequent studies demonstrated that seeing more than 4 letters at a glance could yield better reading speeds (Beckmann & Legge, 1996; Fine, Kirschen, & Peli, 1996; Fine & Peli, 1996). Since the aim of this study was to simulate retinal implants of a relatively small area and containing a finite number of stimulation contacts, the use of a small number of letters was an advantage: (1) A small number of letters permitted to fill the restricted viewing area with large letters. The letter size is an important limiting factor if one wants to investigate eccentric reading (see also Chung et al., 1998). (2) Recent work by Thompson et al. (2000), and Dagnielie et al. (2000), demonstrated that a grid density of about 4 pixels per letter width is needed to allow for accurate character definition. This limited the number of characters that could be presented via a finite number of stimulation contacts. (3) The visual span is another important limiting factor in eccentric reading. In a recent study, Legge, Mansfield, and Chung (2001) estimated that the average visual span decreases from at least 10 letters in central vision to about 1.7 letters at 15° eccentricity, this figure however increasing somewhat with prolonged observation time. For those reasons, 4letter word stimuli represented an adequate compromise for our experimental purpose. We decided to conduct our experiments using a proportionally spaced font. Proportionally spaced fonts, which place letters closer together than equally spaced ones, favour the crowding effect and would therefore be less convenient for readers who are restricted to use eccentric locations of their retina. However, books, journals and most printed matters are almost exclusively printed in such proportional fonts. It was mandatory to adapt our simulations to this reality. Attempts to modify letter spacing might improve performance, as suggested by several authors (Arditi, Knoblauch, & Grunwald, 1990; Latham & Whitaker, 1996; Toet & Levi, 1992). This would however imply additional special hardware, which is too speculative to be considered at this point. Furthermore, Chung (2002) concluded a recent study, in which she used an equally spaced Courier font, with the sentence: ‘‘Increased letter spacing beyond the standard size, which presumably decreases the adverse effect of crowding, does not lead to an increase in reading speed in central or peripheral vision’’. Hence, the effect of letter spacing on eccentric reading is still controversial. Finally, we used fixed text to present the stimuli. The use of different presentation methods (e.g. scrolled text or RSVP) might have increased reading speed. However, none of these methods does really mimic the use of a retinal prosthesis. Fixed text was the simplest condition to be tested and we acknowledge this limitation in our present work. More realistic experiments using full-page navigation, as well as other modes of pixelisation, are underway and will be reported soon. Under these experimental conditions, experiment 1 clearly showed that about 300 pixels were necessary to appropriately code 4-letter words. These data replicate in part the work of Cha et al. (1992), using 4-letter words. They extend their findings, because their experiments were limited to a central visual field of 1.7°, and subjects were allowed to scan the image with eye movements. About 300 pixels appear therefore to be an intrinsic limit that is related to the type of stimulus (4letter words) more than to the presentation protocol. Implantable microelectrode arrays consisting of about 300 active contacts seem feasible using present technology. Zrenner et al. (1997) as well as Peyman et al. (1998) have already manufactured such first prototypes. Our simulations attempted to mimic an implantable chip covering a surface of about 3 1 mm2 on the retina with an electrode-to-electrode separation of approximately 100 lm. Multi-site stimulation measurements on chicken retinae have demonstrated that such closely spaced contacts can selectively activate retinal neurons (Stett, Barth, Weiss, Haemmerle, & Zrenner, 2000). The amount of information that can be transmitted via about 300 stimulation contacts is however really useful only if projected onto the central part of the visual field. As our study demonstrates, reading performance drops severely at eccentricities of 10° and beyond, even if more pixels are used. At high eccentricities, the main factor limiting reading performance is not the pixel number, but the fact that only part of the information content of the stimuli can be grasped by the subject. The smallest character size we used corresponded to a visual acuity of less than 20/250. The visual acuity at eccentricities of 15°–20° is expected to be much better (Cowey & Rolls, 1974; Daniel & Whitteridge, 1961). Hence, the low performance observed at high eccentricities could not be attributed to decreased resolution in the periphery. This was confirmed by the fact J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 that eccentric recognition of single letters was much better than eccentric reading of entire words (experiment 1). Reduced discrimination in presence of surrounding stimuli due to the so-called ‘‘crowding effect’’ seems to be a better explanation for low reading performance at high eccentricities. Strictly speaking, on basis of the results collected in experiment 1, an eccentric position (>10°) of a retinal implant would strongly impair reading performance. There are however strong practical arguments suggesting that it might be required to place these implants at such high eccentricities. As already mentioned, morphological studies of the neuronal architecture of the retina, like those by Sj€ ostrand et al. (1999) and others, show that a direct vertical connection between photoreceptor, bipolar cells and ganglion cells is best realised in retinal areas beyond 10° eccentricity. Close to the fovea, several layers of bipolar and ganglion cells are superimposed. At up to about 10° of eccentricity, one cone may be connected to several ganglion cells, and ganglion cells are displaced radially from the photoreceptors they innervate. This distortion decreases with eccentricity. Beyond 10° of eccentricity the distortion is minimal. Such eccentric regions of the retina are therefore much better suited for retinotopic electrical stimulation. This mapping issue is of special importance for retinal implants that are designed to use in situ light falling on the retina. Such prostheses are presently developed by a German (Zrenner et al., 1999) and a US (Chow & Chow, 1997) consortium. This type of device would be the most elegant approach, if successful, but it does not really afford for pre-processing to prevent nonretinotopic mapping. If other systems using an external camera to capture the stimuli are considered, such as those envisioned in the projects of Humayun et al. (1999) or Rizzo and Wyatt (1997), the transmitting hardware could possibly include remapping routines. Although this is technically conceivable, it might require prohibitive amounts of perceptual tests for adjustment. For these reasons, we are convinced that it would be optimal to try to place a retinal implant beyond 10° of eccentricity in a first attempt. These considerations raised the question, as to whether subjects could adapt to eccentric reading. Improvements in the accomplishment of tasks, involving stimuli presented in peripheral vision, have already been reported by several authors to be task-specific. For example, learning has been observed for vernier acuity and bisection, for stereoscopic orientation and time discrimination tasks, but not for resolution tasks or Landolt C acuities (e.g. Beard, Levi, & Reich, 1995; Crist, Kapadia, Westheimer, & Gilbert, 1997; Schoups, Vogels, & Orban, 1995; Westheimer, 2001). Taken together these findings imply that spatial visual functions, which rely on important processing in higher cortical areas, can be improved by training in the visual periphery. In 281 particular the ‘‘crowding effect’’ seems to be of cortical and not of retinal origin (e.g. Levi, Klein, & Aitsebaomo, 1985). Electrophysiological experiments in the monkey, monitoring the functional properties of the primary visual cortex area V1, suggest that perceptual learning is accompanied by a decrease of the ‘‘crowding effect’’ (Crist, Li, & Gilbert, 2001). Moreover, a paper by Leat, Li, and Epp (1999) states that the ‘‘crowding effect’’ also includes an important component of attention; 8 this component being potentially improved by training, as indicated by experiments on contour interaction (Manny, Fern, Loshin, & Marinez, 1988) or visual search (e.g. Sireteanu & Rettenbach, 1995, 2000). There is also extensive evidence in the low vision literature that educational training (e.g. in the use of optical aids) is an important factor for successful eccentric reading by patients with macular scotoma (see e.g. Peli, 1986). In some cases, greatly improved reading capacities were already observed with as little as about 5 h of training (Nilsson, 1990). However, the conditions encountered by low vision patients are markedly different from those expected from users of retinal implants. Low vision patients are generally able to use large parts of their retina, situated relatively close to the fovea, while the stimuli used in this study were restricted to a small area, stabilised at a high eccentricity in the lower visual field and pixelised. It was therefore important to test if training could improve performance in conditions mimicking retinal implants. Experiment 2 was especially designed to investigate if eccentric reading, under conditions simulating a retinal implant, could be improved by learning or if it would be limited by fundamental properties of the visual system. The two subjects tested in this study, demonstrated clearly that they were able to adapt, and their performance improved impressively over time. While more subjects would be needed to better quantify the average amount of improvements that can be expected, two subject were sufficient to demonstrate the existence of learning. Control measurements revealed that this type of learning: (1) was not an artefact due to the progressive memorisation of the set of possible answers, and (2) it was not specific to the trained eye and could be transferred to the untrained eye. This latter finding is in contrast to observations for which learning was restricted to the trained condition, with little or no transfer to the non-trained aspects of the stimulus or to the other eye (Karni & Sagi, 1991; Poggio, Fahle, & Edelman, 1992). Complete interocular transfer, as observed here, favours perceptual learning mechanisms occurring in higher-order, binocular areas, as for 8 Attention, when directed towards the eccentric retinal locus, reduces attentional effects of crowding. 282 J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 example suggested for motion direction discrimination (e.g. Ball & Sekuler, 1987; Schoups et al., 1995; Schoups & Orban, 1996). An alternative explanation might be the involvement of high-level attentional or other cognitive mechanisms, which modulate the specific levels of early visual processing, as suggested by Ahissar and Hochstein (1993, 1996) or Beard et al. (1995). We also found that perceptual learning of eccentric reading was at least maintained for a period of two months after completion of the training. Persistence of perceptual learning over periods of several months has been found, for example by Fiorentini and Berardi (1981) in grating waveform discrimination, by Ball, Beard, Roenker, Miller, and Griggs (1988) or Sireteanu and Rettenbach (2000) for visual search tasks, or by Beard et al. (1995) for vernier and resolution acuity. On the basis of the present study, it is not possible to determine the importance of the different factors influencing on the learning process. Are better performances mainly due to a better control of undesirable reflexive eye movements during the experiments, or are they due to a decrease in the ‘‘crowding effect’’? Both effects are probably in close relation. Preliminary results on fullpage text reading under conditions simulating an eccentric retinal implant indicate that the suppression of undesirable reflexive eye movements plays a dominant role in the learning process. 6. Conclusion Based on these results, it appears that functional retinal implants with a few hundred stimulation contacts might successfully restore some reading abilities to blind patients, even if placed outside the fovea. Optimal performance with such devices will however require a significant adaptation process. As future users of retinal implants will have to wear their prosthesis permanently, we expect them to benefit even more from adaptation than the normal subjects in our simulation experiment. Our present results are in this respect very encouraging for the future. Additional research on eccentric reading of whole page texts in similar conditions is required, as well as studies focusing on other important visual tasks such as spatial orientation (mobility) and spatial localisation (visuo-motor coordination), to get a more complete picture of the potential benefits that could be derived from retinal prostheses. Acknowledgements The presented work was supported by the Swiss National Foundation for Scientific Research (grant 3100-61956.00) and the ProVisu Foundation. The authors thank Dr. Andrew R. Whatham for his critical reviewing of this manuscript. Results of experiment 1 have already partially been presented at ARVO (IOVS 2000; 41/4: S436). References Ahissar, M., & Hochstein, S. (1993). Attentional control of early perceptual learning. Proceedings of the National Academy of Sciences, 90, 5718–5722. Ahissar, M., & Hochstein, S. (1996). Learning pop-out detection: specificities to stimulus characteristics. Vision Research, 36, 3487– 3500. Arditi, A., Knoblauch, K., & Grunwald, I. (1990). Reading with fixed and variable character pitch. Journal of the Optical Society of America A, 7, 2011–2015. Bagnoud, M., Sommerhalder, J., Pelizzone, M., & Safran, A. B. (2001). Information visuelle necessaire a la restauration dÕune lecture au moyen dÕun implant retinien chez un aveugle par degenerescence massive des photorecepteurs. Klinische Monatsbl€atter f€ur Augenheilkunde, 218, 360–362. Ball, K., & Sekuler, R. (1987). Direction-specific improvement in motion discrimination. Vision Research, 27, 953–965. Ball, K. K., Beard, B. L., Roenker, D. L., Miller, R. L., & Griggs, D. S. (1988). Age and visual search: expanding the useful field of view. Journal of the Optical Society of America A, 5, 2210–2219. Beard, B. L., Levi, D. M., & Reich, L. N. (1995). Perceptual learning in parafoveal vision. Vision Research, 35, 1679–1690. Beckmann, P. J., & Legge, G. E. (1996). Psychophysics of reading. XIV. The page navigation problem in using magnifiers. Vision Research, 36, 3723–3733. Buultjens, M., Aitken, S., Ravenscroft, J., & Carey, K. (1999). Size counts: The significance of size, font and style of print for readers with low vision sitting examinations. British Journal of Visual Impairment, 17, 5–10. Cha, K., Horch, K. W., Normann, R. A., & Boman, D. K. (1992). Reading speed with a pixelised vision system. Journal of the Optical Society of America A, 9, 673–677. Chow, A. Y., & Chow, V. Y. (1997). Subretinal electrical stimulation of the rabbit retina. Neuroscience Letters, 225, 13–16. Cowey, A., & Rolls, E. T. (1974). Human cortical magnification factor and its relation to visual acuity. Experimental Brain Research, 21, 447–454. Crist, R. E., Kapadia, M. K., Westheimer, G., & Gilbert, C. D. (1997). Perceptual learning of spatial localization: specificity for orientation, position and context. Journal of Neurophysiology, 78, 2889–2894. Crist, R. E., Li, W., & Gilbert, C. D. (2001). Learning to see: experience and attention in primary visual cortex. Nature Neuroscience, 4, 519–525. Chung, S. T. L. (2002). The effect of letter spacing on reading speed in central and peripheral vision. Investigative Ophthalmology and Visual Science, 43, 1270–1276. Chung, S. T. L., Mansfield, J. S., & Legge, G. E. (1998). Psychophysics of reading. XVIII. The effect of print size on reading speed in normal peripheral vision. Vision Research, 38, 2949–2962. Dagnielie, G., Thompson, R. W., Barnett, G. D., & Zhang, W. Q. (2000). Visual perception and performance under conditions simulating prosthetic vision. Perception, 29, 84 (Abstract). Daniel, P. M., & Whitteridge, D. (1961). The representation of the visual field on the cerebral cortex in monkey. Journal of Physiology, 159, 203–221. Dobelle, W. H. (2000). Artificial vision for the blind by connecting a television camera to the visual cortex. ASAJO Journal, 46, 3–9. J. Sommerhalder et al. / Vision Research 43 (2003) 269–283 Fine, E. M., & Peli, E. (1996). Visually impaired observers require a larger window than normally sighted observers to read from a scroll display. Journal of the American Optometric Association, 67, 390–396. Fine, E. M., Kirschen, M. P., & Peli, E. (1996). The necessary field of view to read with an optimal stand magnifier. Journal of the American Optometric Association, 67, 382–389. Fiorentini, A., & Berardi, N. (1981). Learning in grating waveform discrimination: specificity for orientation and spatial frequency. Vision Research, 21, 1149–1158. Humayun, M. S., & de Juan, E., Jr. (1998). Artificial vision. Eye, 12, 605–607. Humayun, M. S., de Juan, E., Jr., Weiland, J. D., Dagnelie, G., Katona, S., Greenberg, R., & Suzuki, S. (1999). Pattern electrical stimulation of the human retina. Vision Research, 39, 2569– 2576. Karni, A., & Sagi, D. (1991). Where practice makes perfect in texture discrimination: evidence for primary visual cortex plasticity. Proceedings of the National Academy of Science, 88, 4966–4970. Latham, K., & Whitaker, D. (1996). A comparison of word recognition and reading performance in foveal and peripheral vision. Vision Research, 36, 2665–2674. Leat, S. J., Li, W., & Epp, K. (1999). Crowding in central and eccentric vision: the effects of contour interaction and attention. Investigative Ophthalmology and Visual Science, 40, 504–512. Legge, G. E., Ahn, S. J., Klitz, T. S., & Luebker, A. (1997). Psychophysics of reading. XVI. The visual span in normal and low vision. Vision Research, 37, 1999–2010. Legge, G. E., Mansfield, J. S., & Chung, S. T. L. (2001). Psychophysics of reading XX. Linking letter recognition to reading speed in central and peripheral vision. Vision Research, 41, 725–743. Legge, G. E., Parish, D. H., Luebker, A., & Wurm, L. H. (1990). Psychophysics of reading. XI. Comparing color contrast and luminance contrast. Journal of the Optical Society of America A, 7, 2002–2010. Legge, G. E., Pelli, D. G., Rubin, G. S., & Schleske, M. M. (1985). Psychophysics of reading. I. Normal vision. Vision Research, 25, 239–252. Legge, G. E., Ross, J. A., Isenberg, L. M., & La May, J. M. (1992). Psychophysics of reading. XII: Clinical predictors of low-vision reading speed. Investigative Ophthalmology and Visual Science, 33, 677–687. Legge, G. E., & Rubin, G. S. (1986). Psychophysics of reading. IV. Wavelength effects in normal and low vision. Journal of the Optical Society of America A, 3, 40–51. Legge, G. E., Rubin, G. S., & Luebker, A. (1987). Psychophysics of reading. V. The role of contrast in normal vision. Vision Research, 27, 1165–1177. Legge, G. E., Rubin, G. S., Pelli, D. G., & Schleske, M. M. (1985). Psychophysics of reading. II. Low vision. Vision Research, 25, 253– 265. Levi, D. M., Klein, S. A., & Aitsebaomo, A. P. (1985). Vernier Acuity, crowding and cortical magnification. Vision Research, 25, 963–977. Li, L., Nugent, A. K., & Peli, E. (2001). Recognition of jagged (pixelated) letters in the periphery. Visual Impairment Research, 2, 143–154. Manny, R. E., Fern, K. D., Loshin, D. S., & Marinez, A. T. (1988). The effects of practice on contour interaction. Clinical Visual Science, 3, 59–67. Nilsson, U. L. (1990). Visual rehabilitation with and without educational training in the use of optical aids and residual vision. A prospective study of patients with advanced age-related macular degeneration. Clinical Vision Sciences, 6, 3–10. 283 Normann, R. A., Maynard, E. M., Rousche, P. J., & Warren, D. J. (1999). A neural interface for a cortical vision prosthesis. Vision Research, 39, 2577–2587. Peli, E. (1986). Control of eye movements with peripheral vision: implications for training of eccentric viewing. American Journal of Optometry and Physiological Optics, 63, 113–118. Pelizzone, M., Cosendai, G., & Tinembart, J. (1999). Within-patient longitudinal speech reception measures with continuous interleaved sampling processors for Ineraid implanted subjects. Ear and Hearing, 20, 228–237. Peyman, G., Chow, A. Y., Liang, C., Chow, V. C., Perlman, J. I., & Peachey, N. S. (1998). Subretinal semiconductor microelectrode array. Opththalmic Surgery and Lasers, 29, 234–241. Poggio, T., Fahle, M., & Edelman, S. (1992). Fast perceptual learning in visual hyperacuity. Science, 256, 1018–1021. Rizzo, J. F., & Wyatt, J. (1997). Prospects for a visual prosthesis. The Neuroscientist, 3, 251–262. Schoups, A. A., Vogels, R., & Orban, G. A. (1995). Human perceptual learning in identifying the oblique orientation: retinotopy, orientation specificity and monocularity. Journal of Physiology (London), 483, 797–810. Rubin, G. S., & Legge, G. E. (1989). Psychophysics of reading. VI. The role of contrast in low vision. Vision Research, 29, 79–91. Schoups, A. A., & Orban, G. A. (1996). Interocular transfer in perceptual learning of a pop-out discrimination task. Proceedings of the National Academy of Science USA, 93, 7358–7362. Sireteanu, R., & Rettenbach, R. (1995). Perceptual learning in visual search: fast, enduring, but not specific. Vision Research, 35, 2037– 2043. Sireteanu, R., & Rettenbach, R. (2000). Perceptual learning in visual search generalizes over tasks, locations, and eyes. Vision Research, 40, 2925–2949. Sj€ ostrand, J., Olsson, V., Popovic, Z., & Conradi, N. (1999). Quantitative estimations of foveal and extra-foveal retinal circuitry in humans. Vision Research, 39, 2987–2998. Stett, A., Barth, W., Weiss, S., Haemmerle, H., & Zrenner, E. (2000). Electrical multisite stimulation of the isolated chicken retina. Vision Research, 40, 1785–1795. Studebaker, G. A. (1985). A ‘‘rationalized’’ arcsine transform. Journal of Speech and Hearing Research, 28, 455–462. Thompson, R. W., Barnett, D., Humayun, M., & Dagnelie, G (2000). Reading speed and facial recognition using simulated prosthetic vision. Investigative Ophthalmology and Visual Science, 41, S860 (Abstract). Toet, A., & Levi, D. M. (1992). The two-dimensional shape of spatial interaction zones in the parafovea. Vision Research, 32, 1349–1357. Tychsen, L. (1992). Binocular vision. In W. Hart (Ed.), AdlerÕs physiology of the eye (p. 832). St. Louis: Mosby. Veraart, C., Raftopoulos, C., Mortimer, J. T., Delbeke, J., Pins, D., Michaux, G., Vanlierde, A., Parrini, S., & Wanet-Defalque, M. C. (1998). Visual sensations produced by optic nerve stimulation using an implanted self-sizing spiral cuff electrode. Brain Research, 813, 181–186. Westheimer, G. (2001). Is peripheral visual acuity susceptible to perceptual learning in the adult? Vision Research, 41, 47–52. Zrenner, E., Miliczek, K. D., Gabel, V. P., Graf, H. G., Guenther, E., Haemmerle, H., Hoefflinger, B., Kohler, K., Nisch, W., Schubert, M., Stett, A., & Weiss, S. (1997). The development of subretinal microphotodiodes for replacement of degenerated photoreceptors. Ophthalmic Research, 29, 269–280. Zrenner, E., Stett, A., Weiss, S., Aramant, R. B., Guenther, E., Kohler, K., Miliczek, K. D., Seiler, M. J., & Haemmerle, H. (1999). Can subretinal microphotodiodes successfully replace degenerated photoreceptors? Vision Research, 39, 2555–2567. Vision Research 44 (2004) 1693–1706 www.elsevier.com/locate/visres Simulation of artificial vision: II. Eccentric reading of full-page text and the learning of this task J€ org Sommerhalder *, Benjamin Rappaz, Raoul de Haller, Angelica Perez Fornos, Avinoam B. Safran, Marco Pelizzone Ophthalmology Clinic, Geneva University Hospitals, 1211 Geneva 14, Switzerland Received 3 June 2003; received in revised form 13 January 2004 Abstract Reading of isolated words in conditions mimicking artificial vision has been found to be a difficult but feasible task. In particular at relatively high eccentricities, a significant adaptation process was required to reach optimal performances [Vision Res. 43 (2003) 269]. The present study addressed the task of full-page reading, including page navigation under control of subject’s own eye movements. Conditions of artificial vision mimicking a retinal implant were simulated by projecting stimuli with reduced information content (lines of pixelised text) onto a restricted and eccentric area of the retina. Three subjects, na€ıve to the task, were trained for almost two months (about 1 h/day) to read full-page texts. Subjects had to use their own eye movements to displace a 10 · 7 viewing window, stabilised at 15 eccentricity in their lower visual field. Initial reading scores were very low for two subjects (about 13% correctly read words), and astonishingly high for the third subject (86% correctly read words). However, all of them significantly improved their performance with time, reaching close to perfect reading scores (ranging from 86% to 98% correct) at the end of the training process. Reading rates were as low as 1–5 words/min at the beginning of the experiment and increased significantly with time to 14–28 words/min. Qualitative text understanding was also estimated. We observed that reading scores of at least 85% correct were necessary to achieve ‘good’ text understanding. Gaze position recordings, made during the experimental sessions, demonstrated that the control of eye movements, especially the suppression of reflexive vertical saccades, constituted an important part of the overall adaptive learning process. Taken together, these results suggest that retinal implants might restore full-page text reading abilities to blind patients. About 600 stimulation contacts, distributed on an implant surface of 3 · 2 mm2 , appear to be a minimum to allow for useful reading performance. A significant learning process will however be required to reach optimal performance with such devices, especially if they have to be placed outside the foveal area. 2004 Elsevier Ltd. All rights reserved. Keywords: Visual prosthesis; Simulation; Reading performance; Eccentric reading; Learning 1. Introduction Visual prostheses for the blind are currently being developed by several research groups (Chow & Chow, 1997; Dobelle, 2000; Humayun, 2001; Normann, Maynard, Rousche, & Warren, 1999; Rizzo & Wyatt, 1997; Veraart et al., 1998; Zrenner, 2002). Technological advances are impressive, but several fundamental constraints have to be seriously considered before one can hope to restore useful vision. For example, retinal prosthesis will be implanted at a fixed location in the eye and they will, in all likelihood, subtend only a fraction * Corresponding author. Tel.: +41-2238-28420; fax: +41-223828382. E-mail address: [email protected] (J. Sommerhalder). 0042-6989/$ - see front matter 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.visres.2004.01.017 of the entire visual field. Furthermore, all envisioned prosthesis will consist of a finite number of discrete stimulation contacts. The implications of these constraints need to be investigated, in order to establish minimum requirements for useful artificial vision before using such devices on patients. We use simulations of artificial vision on normal subjects to investigate this important issue. Pixelised images are projected in a restricted viewing area, positioned at a fixed location in the visual field. In a previous study (Sommerhalder et al., 2003), we demonstrated that the amount of information conveyed by about 250– 300 pixels (or distinct stimulation spots in a retinal prosthesis) is sufficient to allow close to perfect reading of isolated four-letter words, if the stimulus is projected in the central visual field. When the same images were 1694 J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 projected in eccentric areas, reading performance decreased dramatically with increasing eccentricity. Even when using high pixel resolutions, reading was almost impossible for eccentricities beyond 10. It is important to investigate the effect of stimulus eccentricity on performance, because the anatomophysiology of the retina does not favour a foveal location for retinal prostheses (see e.g. Sj€ ostrand, Olsson, Popovic, & Conradi, 1999). Retinal implants are primarily designed to stimulate neurons of the inner retinal layers (bipolar and/or ganglion cells) in cases of blindness due to photoreceptor loss (e.g. retinitis pigmentosa). In the central fovea, these neurons are not present. In the parafovea, they are arranged in several superimposed layers that make it difficult to activate them in predictable patterns. The best sites, potentially preserving retinotopic activation without major distortion, are located at an eccentricity of 10 and more. This means that the vision of future users of retinal prosthesis will probably be restricted to small peripheral areas of their visual field. Our ability to identify objects in the periphery is however poor. Especially reading words of several letters is very difficult due to contour interaction, the so-called ‘crowding effect’ (see e.g. Toet & Levi, 1992). Although our acute experiments at 15 eccentricity had shown very poor reading of isolated four-letter words, performance could be improved impressively upon systematic training (about 1 h/day for about 1 month––Sommerhalder et al., 2003). Whether this promising result was due to the better control of undesirable reflexive eye movements or to a decrease of the ‘crowding effect’ 1 was unclear, but it suggests that retinal prostheses might successfully restore some reading abilities in blind patients, even if the implant has to be placed outside the fovea. So far, our experiments were conducted using isolated four-letter words and not full pages of text. They did not require page navigation during reading. This means that subjects did not have to move their gaze from one word to the other and from the end of one line to the beginning of the next one. Page navigation implies not only the stabilisation of the gaze on a particular point of interest, but also micro-saccades to read lines of text as well as larger saccades to jump from the end of one line to the beginning of the next one. In previous literature, page navigation has essentially been studied in connection with the use of special field of view magnifiers, intended as reading aids for low vision patients. Beckmann and Legge (1996) measured reading rates of normal and of low vision subjects in two conditions: 1 For a more detailed discussion about ‘crowding’, attention and perceptual learning, see also Sommerhalder et al. (2003) and citations therein. with horizontally drifting text 2 requiring no page navigation and with a closed-circuit television magnifier (CCTV) 3 requiring ‘manual’ page navigation. Manual page navigation resulted in significantly lower reading rates. This effect was more pronounced on normal subjects than on low vision patients, suggesting that overall reading performance was reduced in these patients because of limitations due to other visual factors. A second comparative study of the same research group (Harland, Legge, & Luebker, 1998), including RSVP 4 text presentation and ‘mouse’-controlled page navigation, confirmed their previous findings. The use of RSVP and drifting text presentation resulted in better reading performance than the use of CCTV or ‘mouse’ navigation. Interestingly, they did not observe significant differences in reading rates across the four methods of text presentation in a group of patients with central field loss, i.e. for subjects who were forced to use eccentric fixation for reading. It is difficult to predict from these data how patients using retinal prosthesis would cope with the page navigation problem. The most advanced retinal prostheses, envisioned at present, are devices, which will transform in situ, light falling on the retina into electrical stimulation currents. Such an implant design has the fundamental advantage that the user can scan his/her environment using eye movements, even if the implant might need to be placed extra-foveally. An additional benefit is also the fact that these devices do not require the use of an extra-ocular camera, avoiding the delicate issue of wired connections to the rapidly moving eye. Neither horizontally drifting text nor RSVP do realistically mimic text reading using such retinal implants, since both methods are expressively intended to minimise eye movements. 5 ‘Mouse’-controlled and CCTV reading are both quite unnatural conditions, because they rely on manual page navigation. In this study we used simulations to address the issue of full-page text reading in conditions mimicking artificial vision provided by a retinal implant. On one hand, full-page text reading can be expected to be more difficult than deciphering isolated words, 2 Text is drifting as a single line horizontally over a visualisation screen. Thus the reader does not have to jump from one line to another and can keep his gaze position quite stable. 3 A CCTV consists of a video camera equipped with a magnifying lens and connected to a TV monitor. The reader can thus only see a few characters at a time and has to move the video camera over the lines of text. 4 Rapid serial visual presentation, involving no page navigation and very few eye movements. 5 For other types of retinal implants, which are conceived to use an external camera to capture the stimuli, eye movements will have to be replaced by head movements. J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 because successful reading of several lines of text requires page navigation abilities, i.e. well-controlled eye movements, which can be difficult to achieve with a restricted viewing area, located at a fixed position in the visual field, especially if eccentric retinal locations are used. Future users of retinal implants will have to reference reading eye movements to a non-foveal retinal locus. Patients with central field loss develop one or several preferred retinal loci (PRL), in attempt to compensate for the missing fovea. Fletcher and Schuchard (1997) studied the locations of PRLs relative to the macular scotoma, and how their patients managed to use these PRLs (fixation, pursuit and saccadic ability). 54% of them showed some pursuit ability; 57% of them were able to stabilise a stationary target within a discrete retinal area; 77% of them were able to move their PRL to separate targets. Most of them made however several saccades when moving from one target to another, having also difficulties with a stable target fixation. Foveating saccades have shorter initiation latencies and are faster than non-foveating saccades. Whittaker, Cummings, and Swieson (1991) compared the saccadic eye movements of patients with macular degeneration with those of normal subjects. They found out, that even if patients were capable to consistently direct images to their PRL, their saccades still kept the characteristics of non-foveating saccades, suggesting that patients with macular scotoma suppress rather than adapt the foveating saccade mechanism. There is very little literature concerning the time course of saccadic adaptation to a non-foveal location. Heinen and Skavenski (1992) studied this issue on monkeys. They introduced bilateral foveal lesions in three adult animals and found that new PRLs were stable within two days, while the saccadic system did not stabilize for at least two weeks. Two of the three animals were not capable to bring the target directly to the new fixation locus. On the other hand, full-page text reading might be expected to be easier than deciphering isolated words, because subjects can make use of context information to facilitate reading. We are better at reading meaningful sentences than random words (Fine & Peli, 1996; Latham & Whitaker, 1996). The benefits of context are however controversial when it comes to peripheral vision. It has been suggested that readers with central field loss would be less efficient in using context to facilitate reading (see Baldasare & Watson, 1986 or Latham & Whitaker, 1996). But this hypothesis is contradicted by other studies. For example, Fine and Peli (1996) compared reading rates for meaningful sentences to reading rates for random words for normally sighted subjects and for subjects with central field loss, they found that speed gains due to context were present and equivalent for both groups of subjects when using RSVP and scrolled text presentation. 1695 2. Methods We conducted two successive experiments. In the first experiment, subjects were asked to read pixelised fullpage texts using a viewing area, stabilised on the fovea. In the second experiment, subjects were asked to perform the same task, but using a viewing area stabilised at 15 eccentricity. In both experiments, we expected that the subjects might adapt progressively to the task and perform better with time. Thus, experimental sessions were repeated daily, until we were sure that scores were stable. In the first experiment, reading scores asymptoted within a few sessions. In the second experiment, an important learning process was observed. A period of almost two months was necessary until eccentric reading scores asymptoted. 2.1. Subjects Three young subjects (AD, female, 24 years old; DV, female, 23 years old; DS, male, 30 years old), working at the Geneva Eye Clinic, participated in both experiments. All of them had normal or corrected to normal vision as well as a normal ophthalmologic status. They were native French speakers and they were familiar with the purpose of the study. All of them knew that two daily sessions over a time period of several weeks would be necessary to complete the experiment. They did not participate in any of the previous studies on eccentric reading. All experiments were conducted according to the ethical recommendations of the Declaration of Helsinki, and were approved by local ethical authorities. 6 2.2. Experimental procedure To simulate the visual percepts produced by a retinal prosthesis (in our case a retinal implant, which transforms in situ incident light into electrical stimulation signals), images were projected on a defined and stabilised area of the retina. Briefly, the position and content of the stimulus were generated on a fast computer display used in association with a SMI EyeLink gaze tracking system (Senso Motoric Instruments GmbH, Teltow/Berlin, Germany) for online monitoring of the gaze position. Gaze position data were used to move a small viewing window over a screen displaying full-page text (Fig. 1). The position of the viewing window relative to the gaze position could be offset arbitrarily. The viewing window was thus projected either onto the central retina (no offset between viewing window and gaze position) or onto a defined eccentric area of retina 6 Comite d’Etique de la Recherche sur l’Etre Humain (CEREH) des H^ opitaux Universitaires de Geneve. 1696 J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 Fig. 1. The experimental set-up used to simulate full-page text reading in conditions mimicking vision with a retinal prosthesis. The subject was asked to read a page of pixelised text, using her own eye movements to move a restricted viewing window on the computer screen. (constant non zero offset). The experimental set-up was described in detail in a previous paper (Sommerhalder et al., 2003). From previous experiments, we knew that a sampling density of 286 pixels, distributed over an area corresponding to 10 · 3.5 of the visual field, would allow for close to perfect recognition of isolated words. We observed however, that the height of such a viewing window was limiting page navigation, because it did not allow to see the preceding or the following line of the text. Therefore, we conducted pilot experiments in central vision to determine a more adequate height of the viewing window. We found that doubling the height of the viewing window to 7 allowed to visualise two lines of the text at once, and this was found to be greatly helpful to orient page navigation. When increasing the viewing area height to 10, more than two lines were visible simultaneously, but this was not experienced as a further improvement by the subjects. We therefore decided to use a 10 · 7 viewing window for the present experiments. Using the same pixel density as in our previous studies, this resulted in an area containing 572 pixels. 7 Such a viewing area would correspond to a surgically manageable implant size of 3 · 2 mm2 as well as to a technically feasible contact to contact spacing of about 100 lm. 2.3. Generation and presentation of the stimuli Stimuli were pre-pixelised bitmap images. The texts used to generate these images were extracted from the Swiss newspaper ‘‘Le Temps’’. This newspaper is written in common French language. It is a good representative 7 This value represents an array of 28.6 · 20 pixels, using the same pixel density as used for our previous study (Sommerhalder et al., 2003). of a common information newspaper, being neither too elementary, nor too sophisticated. One hundred small articles of diverse contents (culture, politics, economics, sports, etc.) were downloaded from the website of the journal. 8 The texts of these articles were presented on the screen using a Helvetica (i.e. Arial) font size as in our previous experiments on single word recognition. At a viewing distance of 57 cm, the height of the small letter ‘x’ corresponded to a visual angle of 1.8. In these conditions, a segment of seven successive lines of text could be displayed on the screen, and about six successive letters could be visualised at once in the 10 width of the viewing window. Hyphenation was used to allow for the presentation of a maximum of words, resulting in an average of about 25 words per text segment. Each article was divided into such successive segments and pixelised 9 using commercial software (Adobe Photoshop 5.5). Fig. 2a shows an example of such a stimulus. Subjects were tested monocularly using their dominant eye. During the experiment, they were comfortably seated facing the stimulation screen, and wearing the headband mounted SMI eye tracking system. At the beginning of each session the eye to screen distance was checked, and a standard nine-point calibration of the eye-tracker was performed. Subjects were requested not to move during the session. Then, the first segment of an article, randomly chosen out of the 100-article library, was presented on the stimulation screen. The subjects could use their own eye movements to scan the stimulation screen, but only a small part of the entire text segment was visible through the 10 · 7 window (see Fig. 2b). During each session, subjects had to read aloud the first four initial text segments (about 100 words) of an article. Their voice and gaze position were recorded for further analysis. After the presentation of each text segment, the calibration was checked for possible drifts or artefactual movements, and if necessary, slightly corrected to insure an exact control of the viewing window position during the entire experimental session. In very rare cases, these controls revealed a significant drift, meaning that the position of the viewing window was not stable during the presentation of the text segment. The results from this segment were discarded and an additional text segment was read. At the end of each session (i.e., after reading four successive text segments), a qualitative comprehension test was performed by questioning the subject on the content of the article. 8 http://www.letemps.ch/ Mosaic pixelisation (i.e., square pixels of uniform grey level) was used. Such simple patterns were adequate to simulate the reduced information content (e.g. finite quantisation) of the stimuli, but do not pretend to mimic exactly percepts elicited by electrical activation of the retina. 9 J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 1697 sessions were performed repeatedly for a period of almost two months. In general, two sessions were conducted each working day of the week (5 days per week). The regular daily flow of sessions was interrupted for weekends, and exceptionally for brief vacations. The duration of each experimental session was variable throughout the experiment, but it never exceeded 30 min. Two sessions represented therefore less than 1 h of daily training. This experiment was stopped when reading scores asymptoted. Between 55 and 68 sessions per subject were necessary to achieve this criterion. 2.4. Data analysis and statistics Fig. 2. (a) A segment of pixelised full-page text as presented on the computer screen. The tree dots, at the beginning and at the end, indicate a text segment situated somewhere in the body of an article. Texts were not justified. (b) The screen viewed by the subject. Only a small part of the test could be seen through a 10 · 7 viewing window. The rest of the screen was blanked by an uniform grey foreground. The gaze position was constantly monitored by the system and the viewing window moved accordingly on the screen. The content of the viewing window was thus permanently projected on the same retinal area at an eccentricity 0 for experiment 1 and, as illustrated, at an eccentricity of 15 for experiment 2. For illustration purposes only, the whole text segment was made slightly visible in this figure. This was not the case during the experiments. A different article was used in each session. None of the subjects read an article twice. In experiment 1, several sessions were conducted using a centrally located viewing window. This experiment lasted until subjects became familiar with the task of reading pixelised text, using a small viewing window for page navigation. A stable percentage of correctly read words was used as criterion to stop the experiment. Experiment 2, testing eccentric reading, began only when the subjects had adapted to central reading. To investigate for possible learning effects, experimental Reading performance was measured in terms of reading scores (expressed in percentage of correctly read words per session) and in terms of reading rate (expressed in number of correctly read words per minute during each session). Reading scores, expressed on a proportional percentage scale are, however, not suitable for statistical analysis. It is well known that with proportional scales, variance is not correlated with the mean. In other words, the data are not normally distributed around the mean and scale values are not linear in relation to the test variability. This problem can be solved by using an arcsine transformation. Studebaker (1985) proposed to use so-called ‘‘rationalised arcsine units’’ (rau), values that are numerically close to the original percentage range, while retaining all of the desirable properties of the arcsine transform. Therefore, reading scores were statistically analysed using scores expressed in rau. For better clarity however, an approximate %-correct scale 10 is indicated on the right ordinates of the graphs. Qualitative comprehension of the text was judged by two examiners using an arbitrary four-grade scale: ‘None’ meaning that the text was not understood at all; ‘insufficient’ meaning very partial comprehension, insufficient to understand the issue reported in the text; ‘good’ meaning that the main issue was grasped but not all details; ‘excellent’ meaning a perfect and detailed comprehension of the text. 11 After each reading session, the subjects had to describe what they had read and were then questioned by the two examiners, who had no difficulties to attribute one of the four comprehension levels. Subjects reported spontaneously to be satisfied, when they reached ‘excellent’ or ‘good’ levels of 10 Note that the %-correct to rau transformation is dependent of sample size (in our case the total number of words used in one session). Therefore, our approximate %-correct scales are based on the average number of words computed across all session presented on the graphs. 11 We used such an uncommon four-level scale, because it is much easier to judge first if a subject understood the main issue of a text and then to ask some questions to determine whether the subjects grasped some parts of the text or if the subject really had a detailed understanding. J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 y ¼ y0 þ að1 ebx Þ: We used a simple linear correlation (Pearson’s correlation) to determine if training (expressed as the number of sessions) had a statistically significant effect on performance. AD 120 110 100 90 DV 120 110 100 100 90 DS 120 110 100 100 90 0 2 4 2 4 (a) Reading rate [words/min] 3. Experiment 1: central reading of full-page text Experiment 1 was dedicated to familiarise normal subjects with the unusual task of reading pixelised fullpage text, using a small viewing window for page navigation. For this easier experiment, subjects read six text segments per session instead of the four segments per session used in the more difficult experiment 2. Fig. 3 presents reading performance in central vision versus session number for each subject. All three subjects performed immediately very well. Perfect, or close to perfect reading scores (i.e. >95% correct) were already achieved in the first sessions. No significant learning effect was observed in the analysis of reading scores versus time. Reading rates improved with time for all three subjects. Analysis of the experimental data, using the exponential function presented in Section 2, revealed that the average reading rate almost doubled from 71 to 122 words per minute for AD. It improved from 65 to 89 words per minute for DV, and from 60 to 72 words per minute for DS. This improvement was however statistically significant only for subject AD (Pearson’s correlation: r ¼ 0:78, p ¼ 0:003). Interestingly, subject AD achieved at the end of this experiment reading rates, which were quite superior to those of the two other subjects. These reading rates can be compared to those achieved by the same subjects in ‘normal’ conditions. Reading rates were measured to be significantly higher, ranging between 160 and 180 words per minute, for articles directly read from the same journal. In conclusion, experiment 1 clearly demonstrates that useful full-page text reading can be obtained under conditions mimicking artificial vision in the central visual field. The relevant information for reading could be transmitted and captured by the visual system. The increased difficulty of page navigation using a restricted viewing window, and the fact, that this viewing window contained pixelised stimuli, resulted in reading rates, significantly below normal values, but almost all words were correctly deciphered. 100 Words correctly read [%] comprehension, associated with a reading rate of about 20 words per minute. From a clinical point of view, these two later levels might be considered as a gratifying and useful performance on full-page text reading. ‘Learning curves’ were established on the basis of the evolution of reading performance versus time. Data were fitted using the non-linear regression function Words correctly read [rau] 1698 120 100 80 60 AD 120 100 80 60 DV 120 100 80 60 DS 0 (b) 6 8 10 Session # 12 14 16 6 12 14 16 8 10 Session # Fig. 3. Reading performance during experiment 1 for three subjects (AD, DV and DS). Full-page texts were read using central vision (10 · 7 viewing window containing 572 pixels). (a) Reading scores as well as (b) reading rates versus session number. The solid lines indicate the best fits to the data. 4. Experiment 2: eccentric reading of full-page text Experiment 2 was started when subjects had adapted to perform the task in central vision. Based on our previous results on eccentric reading of isolated words (Sommerhalder et al., 2003), we expected that eccentric reading of full-page text might also require significant adaptation to reach maximum performance. Fig. 4 presents individual reading scores versus session number for full-page text reading at 15 eccentricity. Experimental data were fitted with the exponential function presented in Section 2, to average session-tosession variability. The performances of two out of the three subjects tested showed massive improvements during the course of the experiment. At the beginning of the experiment, the subjects DV and DS were able to identify only about 13 % of the words and they ended up with scores of 86% and 98% correct respectively. In contrast, subject AD already performed very well in the initial sessions (about 85% correct), and ended up with 80 70 60 50 40 30 20 10 AD 0 0 10 20 30 40 50 60 70 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 100 90 80 70 60 50 40 30 20 10 DV Words correctly read [%] Words correctly read [rau] Session # 0 0 10 20 30 40 50 60 70 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 100 90 80 70 60 50 40 30 20 10 Words correctly read [%] Words correctly read [rau] Session # DS 0 0 10 20 30 40 50 Session # 60 70 Fig. 4. Reading scores during experiment 2 versus session number for three subjects (AD, DV and DS). Full-page texts were read in eccentric vision (15 eccentricity in the lower visual field), using a viewing window of 10 · 7 containing 572 pixels. The solid lines indicate the best fits to the data. almost perfect scores (98% correct). Her learning curve was therefore less spectacular. However, reading score improvements were highly statistically significant for all three subjects (Pearson’s correlation: r ¼ 0:57, p < 0:0001 for AD; r ¼ 0:81, p < 0:0001 for DV and r ¼ 0:77, p < 0:0001 for DS). Reading rate [words/min] 90 1699 The second important parameter indicating the presence of learning is the reading rate. Fig. 5 presents reading rates achieved during experiment 2. Reading rates improved for all three subjects. Subject AD improved from 5 to 26 words per minute (w/m), subject 60 55 50 45 40 35 30 25 20 15 10 5 0 AD 0 Reading rate [words/min] 100 10 20 30 40 50 Session # 60 55 50 45 40 35 30 25 20 15 10 5 0 60 70 DV 0 Reading rate [words/min] 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Words correctly read [%] Words correctly read [rau] J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 10 20 30 40 50 Session # 60 55 50 45 40 35 30 25 20 15 10 5 0 60 70 DS 0 10 20 30 40 50 Session # 60 70 Fig. 5. Reading rates during experiment 2 versus session number for three subjects (AD, DV and DS). Full-page texts were read in eccentric vision (15 eccentricity in the lower visual field), using a viewing window of 10 · 7 containing 572 pixels. The solid lines indicate the best fits to the data. Three subjects: AD, DV and DS. J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 Text comprehension [arbritary units] DV from 3 to 14 w/m, and subject DS from 1 to 28 w/m. In spite of a large session-to-session variability (especially for subject AD), reading rate improvements were statistically significant for all three subjects (Pearson’s correlation: r ¼ 0:74, p < 0:0001 for AD, r ¼ 0:81, p < 0:0001 for DV and r ¼ 0:90, p < 0:0001 for DS). At the end of experiment 2, reading rates for eccentric reading were still significantly below values obtained in similar conditions for central reading, and of course below normal reading rates, but they were remarkable when compared to what subjects achieved at the beginning of experiment 2. It is also important to note that reading rates continued to improve after almost two months of training, (i.e. at the time we terminated the experiment because reading scores had asymptoted). This suggests that higher reading rates could still have been achieved with further practice. Word recognition scores and reading rates can be measured accurately, and are therefore helpful experimental values to demonstrate changes in performance, but they do not reflect to which degree the content of the text was understood. Text comprehension is not easy to quantify, but we tried to assess this parameter using a qualitative four-level scale (see Section 2). Fig. 6 presents the evolution of text comprehension on the three subjects throughout experiment 2. During initial sessions, subjects DV and DS had experienced major problems to understand the texts they read. ‘Good’ understanding could only be achieved after 16 sessions or more. In contrast, subject AD achieved ‘good’ to ‘excellent’ text comprehension from the beginning. At the end of experiment 2, subjects AD and DS systematically achieved ‘excellent’ text comprehension, but not subject DV. These results fit well with the performance curves in Figs. 4 and 5 where subject AD achieved high reading scores from the beginning and subject DV finished with the lowest performances. AD excellent good insufficient none DV excellent good insufficient none DS excellent good insufficient none 0 10 20 30 40 50 60 70 Session # Fig. 6. Text comprehension estimates during experiment 2 versus session number for the three subjects (AD, DV and DS). All subjects Words correctly read [%] 0 20 40 60 80 100 excellent Text comprehension [arbitrary units] 1700 good insufficient none 0 20 40 60 80 100 120 Words correctly read [rau] excellent good insufficient none 0 10 20 30 Reading rate [words/min] 40 Fig. 7. Text comprehension estimates versus reading scores and reading rate. All the data collected on the three subjects were merged. Box plots indicate median values, 25th and 75th percentile values (grey box) as well as 10th and 90th percentile values (vertical bars). Circles indicate outliners. It is interesting to plot the results of text comprehension versus reading scores and reading rates (Fig. 7). Reading scores of 85% correct or more were required to reach ‘excellent’ or ‘good’ levels of text comprehension. Below 60% correct, text understanding seemed to be impossible. The distribution of comprehension levels versus reading rates was more variable. For example, ‘excellent’ or ‘good’ comprehension levels were reached over a large range of reading rates, and even occasionally at reading rates below 10 w/m. Good text comprehension appeared thus to be more closely associated to high reading scores than to high reading rates. Taken together, results from experiment 2 demonstrate that an important learning process occurred for eccentric reading of full-page text. This process was however expressed differently across subjects. Subject DS, for example, improved impressively in each of the three measured parameters throughout the experiment. In contrast, subject AD begun the experiment with relatively high reading scores and good text comprehension. In her case, the learning process was best expressed by a major improvement of reading rates. Both subjects, AD and DS, achieved clearly functionally useful eccentric full-page reading after almost two months of daily training. Subject DV, while showing significant improvements in all aspects, did not achieve the same level of performance in the same period of time. J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 1701 4.1. Analysis of eye movements During initial sessions, full-page text reading using an eccentric part of the retina was reported by the subjects to be ‘‘very difficult’’. The same task became however ‘‘much easier’’ with time. As the gaze position on the stimulation screen was recorded every 4 ms throughout all experiments, we were able to analyse how subjects used their eye movements to perform the task. Fig. 8 illustrates such data with an example, comparing on the same subject gaze position recordings made during the first and the last experimental session. During the first session, the subject experienced major difficulties in controlling her eye movements. The viewing window wandered across the whole screen, irrespective of the positions of the lines of text. During the last session, the subject had learned to control her eye movements, and the viewing window focussed quite accurately on the successive lines of text. Occasionally the subject traced back on the same line, to visualise again specific words. We quantified gaze stability by computing histograms of the vertical position of the viewing area during the test (plotted on the right side of Fig. 8). For the first session, this histogram is broad, roughly centred on the screen. There is no evidence for successful focusing on single lines of the text. Numerous uncontrolled reflexive vertical saccades (i.e., an automatic foveation of the stimuli) could not be prevented. For the last session, the histogram is completely different. A series of small peaks, with a vertical spacing corresponding to that of the lines of text, can be observed in the histogram. This analysis also revealed that the subject had the tendency to place the centre of the viewing area slightly below the lines to read, probably minimising in this way the eccentricity of the relevant part of the target image. How did the overall control of eye movements improve during the experiment? On-line recordings of the gaze position were used to compute the mean cumulative length of vertical eye movements for each experimental session. Fig. 9 presents fits to these data for each subject. The mean cumulative length of vertical eye movements decreased dramatically during the course of the experiment for all subjects. Initial values ranged between 35 and 48 m per text segment, while final values dropped to 5–9 m per text segment; a fivefold decrease. For subjects DV and AD, they asymptoted within the 10–20 initial sessions. For subject DS, they were still decreasing when experiment 2 terminated. This quantitative analysis demonstrates clearly, that the control of eye movements under such unusual reading conditions was one prominent factor in the entire learning process. However, this was only one factor affecting performance, since reading scores and reading rates continued to progress after vertical eye movements had stabilised in two out of the three subjects. Fig. 8. Trajectory of the centre of the viewing window (solid line) relative to the text during (a) the first, and (b) the last experimental session of experiment 2 for subject AD. The panels on the right represent frequency histograms of the vertical coordinates of the trajectory recorded every 4 ms. Grey bars indicate the position of the lines of text. 4.2. Control experiments Two of the three subjects (AD and DS) participated in additional control experiments. Immediately after completion of experiment 2, eight successive experimental sessions were dedicated to tests using the untrained (non-dominant) contra-lateral eye, and eight additional sessions were conducted using stimuli presented with maximum screen resolution. After a rest period of three months for subject DS, and six months for subject AD, both subjects were tested again. Fig. 10 summarises the results of these control experiments, which were conducted to address three different issues: (1) Could the benefits of learning gathered with one eye be transferred to the other eye? No significant difference in performance was found for fullpage text reading using the untrained contra-lateral eye. Thus, learning accumulated during experiment 2 appeared to be fully transferred to the contra-lateral eye. 1702 J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 significant change in reading scores was found after several months of non-practice. We observed a tendency towards lower reading rates (about 20% reduction), but this trend was not statistically significant. This indicates that learning of eccentric full-page text reading was generally preserved, at least for a period of several months. 5. Discussion 55 50 45 40 35 30 25 20 15 10 5 0 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 AD DS AD Reading rate [words/min] Words correctly read [rau] Fig. 9. Mean cumulative length of vertical eye movements per text segment versus session number in experiment 2. Lines are representing best fits to individual data for subjects AD, DV and DS. Note that absolutely all vertical eye movements, including saccades and microsaccades, are summed up in this computation. DS Trained eye at the end of experiment 2 Non-trained contralateral eye Trained eye using stimuli at full screen resolution Trained eye 6 months (AD) or 3 months (DS) after completion of experiment 2 Fig. 10. Mean performances (reading scores and reading rates) observed in the control experiments conducted on subjects AD and DS. Mean reading scores and reading rates were computed on the basis of eight experimental sessions for the conditions 1–3. For condition 4, four experimental sessions were conducted on AD, and two on DS. Errors bars indicate SDs. (2) Could increased image resolution increase performance? The use of full-screen resolution did not improve reading accuracy (expressed in % of correctly read words), but it improved reading rates. For subject DS, this improvement was highly statistically significant (p < 0:0001); for subject AD it was at the limit of significance (p ¼ 0:013). (3) Would the benefits of learning persist after a significant period of non-practice? No In the present study, subjects had to move, under the control of their own eye movements, a small viewing window on a computer screen to read full pages of pixelised text. When the window was placed in the centre of the visual field, reading performances were (almost immediately) close to perfect. In contrast, when the window was placed at 15 eccentricity in the lower visual field, reading performances dropped markedly and were much poorer in two of the three subjects. However, all subjects improved spectacularly after almost two months of daily training. At the end of the study, two out of the three subjects reached very high percentages of correctly read words, reading rates of 25–30 w/m 12 and repeatedly ‘‘excellent’’ or ‘‘good’’ levels of text comprehension. The third subject improved impressively during the course of the study, but terminated the experiments at a lower performance level, perhaps because her learning process was not yet completed. Control measurements demonstrated inter-ocular transfer as well as persistence of learning for this difficult task. Taken together, these results indicate that useful full-page text reading can be achieved in conditions mimicking a retinal implant. During their adaptation to full-page reading using an eccentric area of the visual field subjects had to cope with several difficulties: suppression of unwanted reflexive eye movements; scanning several lines of text using an eccentric and restricted viewing window; focussing attention to this peripheral region of the visual field; extracting a maximum of information out of low resolution (pixelised) stimuli; reconstructing meaningful sentences out of words and phrase fragments; and this list is surely not exhaustive. Although all these difficulties had to be surmounted to achieve the task, it is impossible to analyse them in an isolated way. It is however interesting to discuss in more details some 12 Reading rates of 25 w/m seem to be very low compared to ‘normal’ values of more than 100 w/m. Very few people would want to read a novel at 25 w/m, but greatly reduced reading rates are still useful for daily-living reading tasks, such as reading price tags or correspondence (see e.g. Whittaker & Lovie-Kitchin, 1993, or Rumney, 1995, who estimate that 40 w/m would be a reasonable value). To our clinical experience, low vision patients (e.g. with central scotoma) appreciate to be able to read even at lowest reading rates. J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 factors potentially contributing to the learning process as well as others, limiting reading performance. 5.1. Analysis of the learning process Monitoring of eye movements throughout the learning process indicated clearly that an important part of the overall learning process could be attributed to progressive suppression of uncontrolled reflexive eye movements. Subjects learned to reference their eye movements for reading to a non-foveal and even highly eccentric retinal locus. The temporal evolution of vertical saccades (Fig. 9) was however not perfectly correlated with the evolution of other measures, such as reading scores (Fig. 4), reading rate (Fig. 5), or text comprehension (Fig. 6). This is most evident for subject DV. While she could already control her vertical eye movements after about five sessions, her reading scores required more than 30 sessions to asymptote and both, her reading rate and her text comprehension still progressed slightly after 60 sessions. This mismatch, also observed for the two other subjects, suggests that other factors were influencing reading performance during the overall learning process. In a previous study, we observed significant learning effects for eccentric reading of pixelised isolated words (Sommerhalder et al., 2003). Similar to the present results, these improvements took a time period of about 70 experimental learning sessions. These experiments did not require page navigation, which implies that one important component of the overall learning process seems to be independent of the accurate control of eye movements and that it is likely to be associated with performance improvements in deciphering eccentric low-resolution stimuli. Crist, Li, and Gilbert (2001) suggested that this kind of perceptual learning is accompanied by a concomitant decrease of the ‘‘crowding effect’’. The decrease of crowding has been found to be related to attention (Leat, Li, & Epp, 1999), which in turn can be improved by learning (see e.g. Sireteanu & Rettenbach, 2000). This would mean that a significant decrease of the ‘‘crowding effect’’ is very likely to be an important part of the overall learning process. 5.2. Text comprehension and influence of context It is interesting to retain that subjects had to achieve relatively high reading scores above 85% of correctly read words, to reach ‘‘good’’ or ‘‘excellent’’ text comprehension levels, i.e. to achieve useful text comprehension. Lower reading scores were almost always paired with insufficient text comprehension. This finding, based on a very simple qualitative comprehension test, has to be considered with prudence, but it indicates that 1703 reading scores, which can be measured in a quantitative way, have to be at high levels to allow for useful reading. The influence of context information on performance remains a difficult issue to assess. The comparison of the present data on full-page text reading to those of our previous study using isolated words is interesting in this respect. After training, we observed mean reading scores of about 75% correct for isolated words (two subjects in Sommerhalder et al., 2003) and mean reading scores of about 94% correct for full-page text reading (three subjects in this study). While this difference is not statistically significant for such a small number of subjects, it is in agreement with the results reported by Fine and Peli (1996) and Fine, Hazel, Latham, and Rubin (1999), supporting the hypothesis that the use of context information helps reading performance, even in eccentric reading. 5.3. Eccentric versus central full-page text reading At the end of experiment 2, all subjects had reached relatively efficient full-page text reading. It was therefore interesting to compare, quantitatively and qualitatively, their performances to those achieved with central reading in similar experimental conditions. Table 1 compares ‘final’ reading performances, averaged across the last four sessions of experiment 1 (central reading) to those averaged across the last four sessions of experiment 2 (eccentric reading). Final reading scores across the two conditions were not statistically different for two of the three subjects. Only subject DV presented significantly lower scores for eccentric reading (p ¼ 0:0004). The pattern of results was however quite different for reading rates. Average reading rates using eccentric vision were considerably lower (by a factor of 2.5–5.8) than those achieved with central vision, confirming that target eccentricity was one major factor limiting the reading rate. Other authors already reported low reading rates for eccentric vision. Wensveen, Bedell, and Loshin (1995), for example, found that simulated central scotoma produced dramatic decrements of reading rates. Simulated 8 central scotomata resulted in a threefold reduction of the reading rates for their younger subjects. The experimental conditions in their study were however markedly different from those used in the present study. It is therefore difficult to compare results quantitatively. In this context should also be noted, that, when experiment 2 was terminated, reading rates had not really asymptoted. We believe, however, that only subject DS would have been able to further increase his reading rate with prolonged training (see Fig. 5). It is also interesting to compare, for the same subject, eye movements when scanning full-page text using either a central or an eccentric viewing window. Fig. 11 presents the trajectory of the centre of the viewing area 1704 J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 Table 1 Mean reading scores and reading rates at the end of experiment 1 (central vision) compared to those at the end of experiment 2 (eccentric vision) Subject Central vision Mean reading scores rau % Eccentric vision (15) rau % p AD DV DS 116.5 113.6 117.8 99.9 99.4 100 113.0 89.8 109.1 99.3 88.2 98.2 ns 0.0004 ns words/min words/min p 117.7 87.4 71.8 27.6 14.9 29.0 <0.0001 0.0002 <0.0001 Mean reading rates AD DV DS Means are calculated on the basis of the four last experimental sessions in each condition. p values indicate the statistical significance for the difference between means. ns: non-significant. Fig. 11. Trajectory of the centre of the viewing window (solid line) relative to the text during the last experimental session of experiment 1 (central reading) for subject AD. The panel on the right represents the frequency histogram of the vertical coordinate of the gaze position recorded every 4 ms. Grey bars indicate the position of the lines of text. relative to the lines of text during the last session of experiment 1 (central reading) for subject AD. Equivalent data on the same subject, but collected for eccentric reading at the end of experiment 2 were presented in Fig. 8b. While similitudes are striking, there are noticeable differences. The subject traced backwards much less frequently when using a central viewing area, the vertical gaze position was better controlled, and finally, the viewing window appeared to be more accurately centred on the lines, not slightly below. Central reading remained obviously more efficient than eccentric reading, even after a prolonged twomonth period of adaptation to the task. This difference might have several foundations. The width of the viewing window used in this study limited the maximum visual span to about 6 letters. Legge, Mansfield, and Chung (2001) proposed that the average visual span shrinks from at least 10 letters in central vision to about 1.7 letters at 15 eccentricity; this low value being however increased upon prolonged observation times. As a consequence, the visual span experienced by the subjects was artificially limited to 6 letters in central vision, thus reducing reading rates for central vision. At 15 eccentricity, this effect was even more pronounced, not because of this experimental limitation, but because of the ‘natural’ reduction of the visual span at high eccentricity. Subjects had therefore either to increase the number of saccades to decipher a given word, or to increase fixation time to extend the visual span; both strategies leading to lower reading rates, which is consistent with our experimental observations. Finally, one can wonder to which extent lower reading rates, observed with eccentric vision, could be attributed to the decreased spatial resolution in peripheral regions of the retina. The visual acuity at an eccentricity of 15 is expected to be about 20/125 (Cowey & Rolls, 1974; Daniel & Whitteridge, 1961). Whittaker and Lovie-Kitchin (1993) proposed to use font sizes, several times bigger than the acuity threshold, to reach optimal reading rates. Bowers and Reid (1997) suggested print sizes of at least four times the acuity threshold. The character size we used corresponds to a visual acuity of about 20/400. This size was thus just adequate, and did not, in our view, significantly limit reading rates for eccentric reading in this study. 5.4. Other factors limiting reading performance At the end of experiment 1 (central reading), subjects achieved reading rates ranging between 72 and 118 w/m, which was considerably lower than the 160–180 w/m, they achieved when reading the same newspaper under ‘normal’ reading conditions. This speed reduction of about a factor two must be associated with constraints of the experimental set-up. One probable reason for this reduction of reading rates is the spatial limitation of the viewing window. Several authors, such as Fine, Kirschen, and Peli (1996) or Beckmann and Legge (1996), have reported that the reading rate in central vision can increase for visual J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 spans up to 13–14 characters. As stated above, the visual span was artificially limited to a maximum of about six letters in this study. This is considerably smaller than the optimal visual span required to achieve maximum reading rates with central vision. Additionally, the use of a restricted viewing window was certainly also affecting page navigation since peripheral vision was not available to orient saccades, which probably also contributed to a further decrease of reading rates. Another experimental factor reducing reading rates was certainly the use of target pixelisation. The pixel resolution we used for our experiments (572 pixels in a viewing window of 10 · 7) was high enough to transmit the necessary information for full-page text reading. This was demonstrated by close to perfect reading scores in central vision. However, one of our control measurements, conducted at 15 eccentricity, revealed that the use of non-pixelised text could significantly improve the reading rate (see Fig. 10). This implies that performing this task using pixelised stimuli, containing a close to threshold information content (which is pertinent in view of the development of retinal prosthesis), does put some significant load on the visual system in order to extract the relevant information. Using stimuli largely exceeding this lowest limit does facilitate reading, probably through the use of redundancy. One could relate this issue to findings, obtained by Legge, Ahn, Klitz, and Luebker (1997) when using low contrast text, or to those of Whittaker and Lovie-Kitchin (1993) or Bowers and Reid (1997) who suggested that print size and contrast should be at least several times the threshold values to achieve optimal reading rates. 00 Finally, it is important to recall, that on the 22 PC monitor we used in this study, the pages of text consisted of seven lines, made of two to five words per line. Scanning such a text is certainly less optimal than scanning normal text in a newspaper. However, such optimal conditions are unfortunately difficult to conceive in the present stage of development of retinal implants. 6. Conclusion On the basis of the results reported in the present work, we can conclude that retinal implants might be able to restore full-page text reading abilities to blind patients. About 600 electrodes equally distributed on an implant surface of 3 · 2 mm2 , appear to be a minimum to restore useful function. 13 A significant learning process will however be required to reach optimal performance with such devices, especially if the implant has to be placed outside the fovea. Future users of retinal im13 Prototypes of highly integrated retinal prosthesis, reaching this level of contact density, have already been realised by Zrenner et al. (1997) and Peyman et al. (1998). 1705 plants will wear their prosthesis permanently in daily life. They will have much more time to adapt to their new vision than the normal subjects who participated in these simulation experiments. One might therefore expect them to benefit even more from learning, as well as from other possible brain plasticity mechanisms. Our present results are in this respect very encouraging for the future. Additional research using similar simulations to assess the potential feasibility of other important visual tasks, such as spatial orientation (mobility) and spatial localisation (visuo-motor coordination) are required to get a more complete picture of the potential benefits that could be derived from retinal prostheses. Multidisciplinary research is also needed to determine, if prototype chips can actually reach the required spatial selectivity in neural excitation, as well as if they can preserve to some extent retinotopic mapping. Acknowledgements This work was supported by the Swiss National Foundation for Scientific Research (grant 310061956.00 and grant 3152-063915.00) and the ProVisu Foundation. References Baldasare, J., & Watson, G. (1986). Observations from the psychology of reading relevant to low vision research. In G. C. Woo (Ed.), Low vision principles and applications (pp. 272–286). New York: Springer Verlag. Beckmann, P. J., & Legge, G. E. (1996). Psychophysics of reading. XIV. The page navigation problem in using magnifiers. Vision Research, 36, 3723–3733. Bowers, A. R., & Reid, V. M. (1997). Eye movements and reading with simulated visual impairment. Ophthalmic and Physiological Optics, 17, 392–402. Chow, A. Y., & Chow, V. Y. (1997). Subretinal electrical stimulation of the rabbit retina. Neuroscience Letters, 225, 13–16. Cowey, A., & Rolls, E. T. (1974). Human cortical magnification factor and its relation to visual acuity. Experimental Brain Research, 21, 447–454. Crist, R. E., Li, W., & Gilbert, C. D. (2001). Learning to see: experience and attention in primary visual cortex. Nature Neuroscience, 4, 519–525. Daniel, P. M., & Whitteridge, D. (1961). The representation of the visual field on the cerebral cortex in monkey. Journal of Physiology, 159, 203–221. Dobelle, W. H. (2000). Artificial vision for the blind by connecting a television camera to the visual cortex. ASAJO Journal, 46, 3–9. Fine, E. M., & Peli, E. (1996). The role of context in reading with central field loss. Optometry and Vision Science, 73, 533–539. Fine, E. M., Kirschen, M. P., & Peli, E. (1996). The necessary field of view to read with an optimal stand magnifier. Journal of the American Optometric Association, 67, 382–389. Fine, E. M., Hazel, C. A., Latham, K., & Rubin, G. S. (1999). Are benefits of sentence context different in central and peripheral vision? Optometry and Vision Science, 76, 764–769. 1706 J. Sommerhalder et al. / Vision Research 44 (2004) 1693–1706 Fletcher, D. C., & Schuchard, R. A. (1997). Preferred retinal loci. Relationship to macular scotomas in a low-vision population. Ophthalmology, 104, 632–638. Harland, S., Legge, G. E., & Luebker, A. (1998). Psychophysics of reading. XVII. Low-vision performance with four types of electronically magnified text. Optometry and Vision Science, 75, 183–190. Heinen, S. J., & Skavenski, A. A. (1992). Adaptation of saccades and fixation to bilateral foveal lesions in adult monkey. Vision Research, 32, 365–373. Humayun, M. S. (2001). Intraocular retinal prosthesis. Transcations of the American Ophtalmological Society, 99, 271–300. Latham, K., & Whitaker, D. (1996). A comparison of word recognition and reading performance in foveal and peripheral vision. Vision Research, 36, 2665–2674. Leat, S. J., Li, W., & Epp, K. (1999). Crowding in central and eccentric vision: the effects of contour interaction and attention. Investigative Ophthalmology and Visual Science, 40, 504–512. Legge, G. E., Ahn, S. J., Klitz, T. S., & Luebker, A. (1997). Psychophysics of reading. XVI. The visual span in normal and low vision. Vision Research, 37, 1999–2010. Legge, G. E., Mansfield, J. S., & Chung, S. T. L. (2001). Psychophysics of reading XX. Linking letter recognition to reading speed in central and peripheral vision. Vision Research, 41, 725–743. Normann, R. A., Maynard, E. M., Rousche, P. J., & Warren, D. J. (1999). A neural interface for a cortical vision prosthesis. Vision Research, 39, 2577–2587. Peyman, G., Chow, A. Y., Liang, C., Chow, V. C., Perlman, J. I., & Peachey, N. S. (1998). Subretinal semiconductor microelectrode array. Opththalmic Surgery and Lasers, 29, 234–241. Rizzo, J. F., & Wyatt, J. (1997). Prospects for a visual prosthesis. The Neuroscientist, 3, 251–262. Rumney, N. J. (1995). Using visual thresholds to establish vision performance. Ophthalmic & Physiological Optics, 15, S18–S24. Sireteanu, R., & Rettenbach, R. (2000). Perceptual learning in visual search generalizes over tasks, locations, and eyes. Vision Research, 40, 2925–2949. Sj€ ostrand, J., Olsson, V., Popovic, Z., & Conradi, N. (1999). Quantitative estimations of foveal and extra-foveal retinal circuitry in humans. Vision Research, 39, 2987–2998. Sommerhalder, J., Oueghlani, E., Bagnoud, M., Leonards, U., Safran, A. B., & Pelizzone, M. (2003). Simulation of artificial vision: I. Eccentric reading of isolated words, and perceptual learning. Vision Research, 43, 269–283. Studebaker, G. A. (1985). A rationalized arcsine transform. Journal of Speech and Hearing Research, 28, 455–462. Toet, A., & Levi, D. M. (1992). The two-dimensional shape of spatial interaction zones in the parafovea. Vision Research, 32, 1349–1357. Veraart, C., Raftopoulos, C., Mortimer, J. T., Delbeke, J., Pins, D., Michaux, G., Vanlierde, A., Parrini, S., & Wanet-Defalque, M. C. (1998). Visual sensations produced by optic nerve stimulation using an implanted self-sizing spiral cuff electrode. Brain Research, 813, 181–186. Wensveen, J. M., Bedell, H. E., & Loshin, D. S. (1995). Reading rates with artificial central scotoma with and without special remapping of print. Optometry and Vision Science, 72, 100–114. Whittaker, S. G., Cummings, R. W., & Swieson, L. R. (1991). Saccade control without a fovea. Vision Research, 31, 2209–2218. Whittaker, S. G., & Lovie-Kitchin, J. (1993). Visual requirements for reading. Optometry and Vision Science, 70, 54–65. Zrenner, E., Miliczek, K. D., Gabel, V. P., Graf, H. G., Guenther, E., Haemmerle, H., Hoefflinger, B., Kohler, K., Nisch, W., Schubert, M., Stett, A., & Weiss, S. (1997). The development of subretinal microphotodiodes for replacement of degenerated photoreceptors. Ophthalmic Research, 29, 269–280. Zrenner, E. (2002). Will retinal implants restore vision? Science, 295, 1022–1025. Processes Involved in Oculomotor Adaptation to Eccentric Reading Angélica Pérez Fornos, Jörg Sommerhalder, Benjamin Rappaz, Marco Pelizzone, and Avinoam B. Safran PURPOSE. Adaptation to eccentric viewing in subjects with a central scotoma remains poorly understood. The purpose of this study was to analyze the adaptation stages of oculomotor control to forced eccentric reading in normal subjects. METHODS. Three normal adults (25.7 ⫾ 3.8 years of age) were trained to read full-page texts using a restricted 10° ⫻ 7° viewing window stabilized at 15° eccentricity (lower visual field). Gaze position was recorded throughout the training period (1 hour per day for approximately 6 weeks). RESULTS. In the first sessions, eye movements appeared inappropriate for reading, mainly consisting of reflexive vertical (foveating) saccades. In early adaptation phases, both vertical saccade count and amplitude dramatically decreased. Horizontal saccade frequency increased in the first experimental sessions, then slowly decreased after 7 to 15 sessions. Amplitude of horizontal saccades increased with training. Gradually, accurate line jumps appeared, the proportion of progressive saccades increased, and the proportion of regressive saccades decreased. At the end of the learning process, eye movements mainly consisted of horizontal progressions, line jumps, and a few horizontal regressions. CONCLUSIONS. Two main adaptation phases were distinguished: a “faster” vertical process aimed at suppressing reflexive foveation and a “slower” restructuring of the horizontal eye movement pattern. The vertical phase consisted of a rapid reduction in the number of vertical saccades and a rapid but more progressive adjustment of remaining vertical saccades. The horizontal phase involved the amplitude adjustment of horizontal saccades (mainly progressions) to the text presented and the reduction of regressions required. (Invest Ophthalmol Vis Sci. 2006;47:1439 –1447) DOI:10.1167/iovs.05-0973 I n humans, selective attention is mainly focused around the fovea, the retinal area providing the highest spatial resolution. The oculomotor system is constructed essentially to subserve foveal function by directing and stabilizing images of interest to that retinal location. When the fovea is lost as a result of disease, affected subjects strive to use optimally spared retinal areas as a replacement. Adaptation to this viewing condition may involve several processes. Spared retinal areas with best visual acuity and/or appropriate visual field From the Ophthalmology Clinic, Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland. Supported by the Swiss National Foundation for Scientific Research Grants 3100-61956.00 and 3152-063915.00, by the ProVisu Foundation, and by the Fondation en Faveur des Aveugles, Geneva, Switzerland. Submitted for publication July 26, 2005; revised November 23, 2005; accepted February 14, 2006. Disclosure: A. Pérez Fornos, None; J. Sommerhalder, None; B. Rappaz, None; M. Pelizzone, None; A.B. Safran, None The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement ” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Corresponding author: Jörg Sommerhalder, Ophthalmology Clinic, Geneva University Hospitals, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland; [email protected]. Investigative Ophthalmology & Visual Science, April 2006, Vol. 47, No. 4 Copyright © Association for Research in Vision and Ophthalmology (“visual span”) should be identified. Such eccentric retinal locations are commonly known as preferred retinal loci (PRL).1,2 Selective attention must be transferred to these eccentrically located PRL.3 In addition, oculomotor control mechanisms should be reorganized to allow shifting images of interest directly to the PRL.4 There is no simple rule by which patients select a particular PRL,5,6 but it appears that PRL location can be influenced by several factors (e.g., attentional3,7). Multiple PRL with specific complementary functions can be used in combination.8 –14 The development of eccentric fixation seems to appear before the ability to perform saccades shifting the image of interest onto that new fixation area. An experimental study where bilateral foveal lesions were made in three adult monkeys showed that while both fixation and saccadic mechanisms may adapt to foveal loss, saccadic adaptation requires a much lengthier process.4 In that experiment, eccentric fixation occurred as early as 1 day after the lesion, and new PRL stabilized within 2 days. In contrast, numerous reflexive saccades inappropriately projecting visual stimuli onto the damaged fovea were still observed the first days after the lesion. Saccades gradually adapted to reference the newly developed PRL over a period that lasted several weeks. Two months after the lesions were induced, two of the three animals were able to generate saccades, bringing the PRL directly or close to the target image. In a clinical report of a patient who had the sudden development of a large central scotoma, the first stages of oculomotor adaptation to the field defect have been analyzed.15 Impressively, target fixation attempts evolved from large, apparently poorly controlled saccades to small, mainly horizontal saccades centered on defined retinal areas in a rapid (⬍20 seconds) and structured process. In another clinical study involving patients with central field defects, various refixation strategies were identified.16 One of these patients had a central monocular scotoma and therefore presumably had not used his affected eye for fixation. With that eye, he showed a striking foveating– defoveating strategy: to fixate a stimulus appearing in the peripheral visual field, he first performed a foveating saccade (inappropriately projecting the target image onto the central scotoma) and subsequently generated an additional saccade projecting the image onto the PRL. This distinction between the development of eccentric fixation and the adaptation of eccentric (non-foveating) saccades suggests that oculomotor adaptation to peripheral viewing relies on multiple mechanisms. In our laboratory, we are conducting a series of psychophysical experiments to determine, for a variety of tasks, the minimum requirements for a retinal prosthesis to restore useful artificial vision to blind patients. In this context, we recently published a study17 focusing on full-page text reading. Tested subjects were requested to read entire pages of text presented on a computer screen, using a restricted viewing area that was stabilized at a defined, first central and then eccentric visual field location. After systematic training, useful reading was achieved with a viewing area stabilized at high eccentricity. Our paper focused on issues essential to the development of visual prostheses, and most of the data collected on the oculomotor adaptation process are not reported. These results, 1439 1440 Pérez Fornos et al. IOVS, April 2006, Vol. 47, No. 4 They had normal ophthalmic status and normal or corrected to normal visual acuity. The experiments were designed according to the guidelines of the Declaration of Helsinki and were approved by the local ethical authorities. Experimental Procedure FIGURE 1. Example of a pixelized full-page text. Hyphenation was used to maximize words and texts were not justified. The image covered the whole screen, subtending a visual angle of 40° ⫻ 30°. however, also offer a unique opportunity to study the overall process through which subjects adapt to eccentric viewing. In the present study we further analyze these data, to better define the processes of oculomotor adaptation to eccentric reading. To our knowledge, this is the first attempt at describing such processes in human subjects. The restricted and stabilized viewing area used in our experiments can be considered an artificial, suddenly imposed PRL. In this setting, we found that one of the main issues involved in the learning process was the adjustment of oculomotor control, to reference as accurately as possible the eccentric viewing area used to navigate across text pages. We observed that the adaptation of eye movements includes several distinct processes. This analysis is presented herein. METHODS Subjects Three normal subjects (AD, DV, and DS; respective ages: 23, 24, and 30 years) participated in the study. All of them were native French speakers, naı̈ve to the task but familiar with the purpose of the experiment. Stimuli consisted of full pages of text presented to the subjects in bitmap image format. A pool of 100 articles was downloaded from the Internet Web site of the popular Swiss newspaper Le Temps (http:// www.letemps.ch). Each article was divided in 10 text segments, each containing seven lines of text (⬃25 words). The Arial font was used and the height of the lowercase letter x was 1.8° at a 57-cm viewing distance. These text segments were transformed to bitmap images and processed (pixelized) with commercial software (Photoshop ver. 5.5; Adobe, Mountain View, CA). Figure 1 displays an example of such a text. Subjects sat in front of a 22-in. screen, at a viewing distance of 57 cm. In each experimental session, subjects were requested to read the first four pages of a newspaper article displayed on the screen. The text page was visible only through a 10 ⫻ 7° rectangular viewing area, stabilized at a determined location of the visual field. Stabilization of the viewing window on the retina was achieved by online gaze position compensation. Eye movements were monitored with a fast videobased eye and head-tracking system (SMI EyeLink; SensoMotoric Instruments GmbH, Teltow/Berlin, Germany). A photograph of one of the subjects sitting in front of the stimulation screen and wearing the eye-tracking system is shown in Figure 2a. Gaze position data captured by the eye-tracking system were used to move the viewing window with respect to the page of text and to update its contents accordingly (see Fig. 2b). The maximum delay between the actual eye movement and the subsequent update of the position and content of the viewing window was 14 ms. The viewing window contained 572 pixels (minimum information content required for useful reading18), and at least four characters were visible inside it at a glance (minimum required for efficient reading19). In the first phase of the experiment, the center of the viewing window was stabilized on the fovea. Once subject became accustomed to the experimental setup and reached stable reading performances (i.e., after 8 to 16 experimental sessions) the training period for eccentric reading began. For this second phase, the center of the viewing window was stabilized at 15° eccentricity in the lower visual field. Two experimental sessions were conducted each working day of the week. An experimental session never lasted more than 30 minutes, to avoid fatiguing the subject, resulting thus in approximately 1 h/day FIGURE 2. Experimental setup. (a) A tested subject is wearing the head-mounted eye tracker. (b) Illustration of the screen as viewed by the subject during an experimental session. The page of text was only visible through a 10° ⫻ 7° viewing window that shifted to follow the subject’s eye movements (arrows). This window was stabilized either in central vision or at 15° eccentricity in the lower visual field (as shown in the illustration). Please note that the cross marking of the foveal fixation point is only schematic (there was no foveal fixation point present during the task). IOVS, April 2006, Vol. 47, No. 4 Oculomotor Adaptation to Eccentric Reading 1441 FIGURE 3. Saccade categorization. (a) Saccadic eye movements were categorized as horizontal (oriented between ⫺20° and ⫹20° around the horizontal axis and directed either forward or backward), vertical (oriented between 70° and 110° around the vertical axis and directed either up or down), and oblique. (b) According to their direction and amplitude, horizontal saccades were further subcategorized into progressions, regressions, and line jumps. of training. Experiments stopped once reading scores became asymptotic (between 55 and 68 sessions). Tests were performed monocularly, with the dominant eye. Eye movements were recorded throughout the experiment and stored for further analysis. Please refer to our previous papers17,18 for more details on the experimental setup and procedure. Data Analysis and Statistics Saccades detected online by the automatic parser of the eye-tracking system were analyzed to define the various stages of the oculomotor adaptation process for eccentric reading. For a saccade to be detected by the system, several criteria had to be fulfilled: a minimum eye displacement of 0.1°, a velocity threshold of at least 30 deg/s, and a minimum acceleration threshold of 8000 deg/s2. Detected saccades were categorized into three main groups according to their orientation (Fig. 3a): horizontal saccades (those with an angle of ⫾20° around the horizontal axis, and directed either right or left), vertical saccades (those with angles between 70° and 110° around the vertical axis, and directed either up or down), and oblique saccades (those not fitting into any of the preceding categories). Horizontal saccades were further subcategorized (Fig. 3b) into progressions (horizontal saccades directed right and ⬍10° in amplitude), regressions (horizontal saccades directed left and ⬍10° in amplitude), and line jumps (horizontal saccades directed left and ⬎20° in amplitude). Saccade frequency was calculated as the total number of saccades performed during an experimental session (i.e., four full pages of text). Saccade amplitude was computed as the total absolute eye displacement (length) between the eye position at the beginning of the saccade and its end position. Average saccade amplitude for a given experimental session was calculated on the basis of the absolute amplitude of all saccades performed during the session. Significant changes in oculomotor behavior throughout the learning process were determined with Pearson’s correlation (linear regression). In addition, whenever the results allowed it, we computed learning curves to average intersession variability and better highlight the time course of the learning process. These learning curves were obtained by fitting the data to an exponential function. Stabilization times were determined based on the exponential time constant (), which corresponds to the time required for the function to vary by a factor of 1/e (approximately 0.368). The stabilization time of an exponential function is generally estimated as 3. RESULTS When using central vision, performance increased and stabilized after 8 to 16 experimental sessions. Detailed reading performance results have already been reported in our previous paper.17 Briefly, when using central vision, initial reading scores were already higher than 95%. Reading rates increased from 60 to 70 words per minute to stabilize at approximately 72 to 122 words per minute. For eccentric reading, two subjects (DV and DS) started the experiment with reading scores that were nearly 13% correct and reached final scores between 86% to 98% correct. Subject AD, who had already attained good scores (⬎85% correct) in the first sessions, achieved final scores higher than 98% correct. Reading rates improved impressively: from 5 to 26 words per minute for subject AD, from 3 to 14 words per minute for subject DV, and from 1 to 28 words per minute for subject DS. Samples of successive gaze position recordings obtained during a choice of experimental sessions, superimposed to the corresponding text page presented, are displayed in Figures 4 (central reading) and 5 (eccentric reading). During the first training sessions for eccentric reading, oculomotor behavior appeared quite inappropriate for the reading task: large vertical saccades predominated. Subjects seemed unable to fixate presented words or to follow a line of text. Oculomotor behavior evolved gradually. Eye movements intended to decipher single words were already visible as early as in the 5th session, especially for subject DV. At the end of the training period, all subjects developed a structured page navigation strategy. When comparing final eccentric reading strategies with those observed by the end of the previous central vision reading tasks (compare Figs. 4, 5), it appears that, after training, both eye movement patterns were roughly similar. The viewing window focused on consecutive words and across successive lines of text. Forward-directed saccades shifting fixation from one word to the next (progressions) and saccades shifting fixation from the end of one line to the beginning of the next (line jumps) were clearly distinguishable. Occasionally, subjects traced back on the same line (regressions), to visualize specific words again. However, differences could also be noted between central and eccentric reading. In eccentric vision, 1442 Pérez Fornos et al. IOVS, April 2006, Vol. 47, No. 4 FIGURE 4. Gaze position recorded for the three normal subjects while they performed the reading task in central vision (last session). Solid line: trajectory of the center of the viewing window relative to the text (see Fig. 2b). regressions occurred more frequently. Moreover, horizontal saccades seemed less precise; therefore, more small corrective saccades were required. These considerations were based on a qualitative assessment of the oculomotor adaptation process observed in our subjects. To provide an objective evaluation of the changes that occurred in the reading strategy, a quantified analysis of our data was conducted. The characteristics of the recorded saccades will be described in the following section. Saccadic Adaptation The distribution of saccades performed during the 1st, 5th, 15th, and last eccentric reading sessions is plotted in Figure 6. During the first training session, bundles of large vertical saccades were observed. Many of these eye movements were between 10° and 20° in amplitude, probably reflecting recurring (reflexive) attempts to bring the stimulus image onto the fovea (foveating saccades), followed by an equivalent saccade of opposite direction attempting to bring the viewing window back on the stimulation screen. In the fifth session, these movements were no longer visible in subjects AD and DV, and only a few of them were still observed in subject DS. The remaining vertical saccades gradually decreased in amplitude, to become hardly visible at the end of training. In contrast, structured patterns of horizontal eye movements developed in the 5th session in two subjects (AD and DV). From the 15th session on, horizontal saccades predominated over the initially prevailing vertical pattern. In the last training session, eye movements essentially consisted of progressions, regressions, line jumps, and other small corrective saccades. Changes in saccade counts (frequencies) by category, are plotted in Figure 7. The total number of vertical saccades decreased significantly over time in all subjects (Pearson’s correlation: r ⫽ 0.58, P ⬍ 0.0001 for AD; r ⫽ 0.39, P ⬍ 0.01 for DV; and r ⫽ 0.72, P ⬍ 0.0001 for DS). An approximate 15-fold drop was observed after 3, 20, and 25 sessions in subjects DV, AD, and DS, respectively. Slighter (approximately 5-fold) but significant (Pearson’s correlation: r ⫽ 0.72, P ⬍ 0.0001 for AD; r ⫽ 0.73, P ⬍ 0.0001 for DV; and r ⫽ 0.82, P ⬍ 0.0001 for DS) frequency decays were observed for oblique saccades. In subjects AD and DS, the process was slower (33 and 38 sessions, respectively) than for vertical saccades. In subject DV, values were still decreasing when the experiment ended. Evolution of horizontal saccade counts was more complex, and data could not be fitted with an exponential curve. In AD and DV, these increased significantly during the first 15 sessions (respectively, Pearson’s correlation: r ⫽ 0.60, P ⬍ 0.05 and r ⫽ 0.72, P ⬍ 0.01) and then significantly decreased (respectively, Pearson’s correlation: r ⫽ 0.48, P ⬍ 0.001 and r ⫽ 0.31, P ⬍ 0.05). In subject DS, horizontal saccade counts increased significantly during the first seven sessions (Pear- son’s correlation: r ⫽ 0.91, P ⬍ 0.01) and then decreased significantly (Pearson’s correlation: r ⫽ 0.82, P ⬍ 0.0001). Additional results were obtained after horizontal saccade subcategorization (Fig. 8). The proportion of progressions increased significantly in all three subjects, from average values ranging between 45% and 60% in the first sessions up to approximately 65% by the end of training (Pearson’s correlation: r ⫽ 0.74, P ⬍ 0.0001 for AD; r ⫽ 0.43, P ⬍ 0.001 for DV; and r ⫽ 0.74, P ⬍ 0.0001 for DS). Only subject AD reached an asymptote (after 50 sessions). Regressions behaved inversely. In the beginning of training, they represented approximately 41%, 34%, and 43% of the total number of horizontal saccades in AD, DV, and DS, respectively. These proportions significantly decreased to 17%, 26%, and 27%, respectively (Pearson’s correlation: r ⫽ 0.70, P ⬍ 0.0001 for AD; r ⫽ 0.65, P ⬍ 0.0001 for DV; and r ⫽ 0.81, P ⬍ 0.001 for DS). At the end of the experiment, the proportion of regressions was still decreasing in subjects DV and DS, whereas in subject AD, values stabilized after approximately 30 sessions. The total number of line jumps increased significantly with training in DV and DS (Pearson’s correlation: r ⫽ 0.64, P ⬍ 0.0001 and r ⫽ 0.61, P ⬍ 0.0001, respectively). Line jump counts in AD were more variable, but also tended to increase over time (Pearson’s correlation: r ⫽ 0.20, P ⫽ 0.1). Values in subjects AD and DV stabilized after approximately 16 and 27 sessions. In the case of subject DS, line jump counts had not reached an asymptote when the experiment ended. Average amplitude of the different saccade categories was also modulated throughout the training period (Fig. 9). For vertical saccades, amplitudes dropped significantly from initial values of 5° to 8° down to final values of around 3° (Pearson’s correlation: r ⫽ 0.56, P ⬍ 0.0001 for AD; r ⫽ 0.69, P ⬍ 0.0001 for DV; and r ⫽ 0.72, P ⬍ 0.0001 for DS). Asymptotes were reached after 13, 20, and 27 sessions in subjects DV, AD, and DS, respectively. Average amplitude of oblique saccades remained stable in subject DS, and decreased very slightly but significantly in subjects AD and DV (respectively, Pearson’s correlation: r ⫽ 0.34, P ⬍ 0.01 and r ⫽ 0.47, P ⬍ 0.0001). In contrast, average amplitude of horizontal saccades significantly increased from values ranging between 5°, 4°, and 2.5°, up to 7°, 6°, and 4° in subjects AD, DV, and DS (correspondingly, Pearson’s correlation: r ⫽ 0.42, P ⬍ 0.001; r ⫽ 0.51, P ⬍ 0.001; and r ⫽ 0.80, P ⬍ 0.0001). In subject DS, amplitudes did not stabilize, whereas in subjects AD and DV, curves reached asymptote after 20 and 23 sessions, respectively. DISCUSSION Eccentric vision requires adaptation of oculomotor control to such specific viewing conditions. Reflexive foveating mecha- IOVS, April 2006, Vol. 47, No. 4 Oculomotor Adaptation to Eccentric Reading 1443 FIGURE 5. Gaze position recorded for the three normal subjects during the 1st, 5th, 15th, and last eccentric reading sessions. Solid line: trajectory of the center of the viewing window relative to the text (see Fig. 2b). nisms must be suppressed and saccadic eye movements must be redirected to the new fixation locus. Our data demonstrate that the pattern of eye movements changed impressively throughout the learning process. Certain oculomotor adaptation stages appeared consistently in all tested subjects. Two essential adaptation processes were distinguishable: a faster, vertical phase aimed at suppressing reflexive foveation, and a slower, horizontal phase dedicated to the restructuring of the horizontal eye-movement pattern. During the first sessions, numerous vertical foveating saccades were observed. Interestingly, the first rapid, vertical adaptation process appeared to include two relatively distinct, parallel phases: one consisting of the reduction of the vertical saccade count, the second of the reduction of both the oblique saccade count and vertical saccade amplitude. According to our results, the former occurred promptly, and the latter, although rapid, was more progressive. It is reasonable to presume that both aim at reducing reflexive foveation, but each relies on distinct mechanisms, as suggested by their different time course. The second, slower adaptation phase concerned the restructuring of the horizontal eye movement pattern. In the initial sessions, no structured reading sequence was distinguishable. Frequency of horizontal saccades increased during the first 7 to 15 sessions and then slowly decreased, whereas their average amplitude increased all through the learning process. The proportion of progressions increased gradually. It has been demonstrated that, in eccentric vision, the visual span 1444 Pérez Fornos et al. IOVS, April 2006, Vol. 47, No. 4 FIGURE 6. Angular and amplitude (polar) distribution of the saccades performed during the 1st, 5th, 15th, and last eccentric reading sessions, for each of the three subjects. can increase with training.20 This should result in fewer but longer saccades, as observed in our data. A significant reduction in the proportion of regressive saccades was also observed in all subjects. As a rule, when reading difficulty decreases, saccade length increases, and the frequency of regressions diminishes.21,22 Subjects spontaneously reported that the task became easier with training, resulting in better word recognition during eccentric fixation (see also our previous publications17,18). Thus, fewer regressions were necessary for deciphering. Line jumps developed gradually, and better calibration of progressive saccades was achieved with training. Hence, as better eccentric oculomotor control was developed, fewer corrective saccades were needed. Two parallel, presumably related phenomena may therefore be distinguished during the development of horizontal saccade control. The first one corresponded to the adaptation of the amplitude of horizontal saccades (mainly progressions) to the text presented. The second one consisted of the reduction in number of regressions. Our results showed that, even when optimal eccentric reading performance has been attained, oculomotor behavior was not optimal compared with that observed in central vision (compare results for central and eccentric reading in Figs. 7, 8, 9). Although subjects adapted to the eccentric reading task, IOVS, April 2006, Vol. 47, No. 4 Oculomotor Adaptation to Eccentric Reading 1445 FIGURE 7. Changes in saccade frequency versus session number for the three subjects during training of eccentric reading, by saccade category. Average values in central vision (black dashed lines) are also shown for comparison. vertical saccades did not disappear completely. More horizontal and oblique saccades were necessary in eccentric vision than in central vision. In two of the three subjects, more line jumps were performed and horizontal saccades were smaller during eccentric reading. In general, oblique saccades were smaller for eccentric than central viewing conditions. These results clearly demonstrate that, even after extensive training, the characteristics of saccades performed during eccentric and central reading differed. A previous investigation23 in patients with central scotoma described similar behavior. Even when these patients had adapted to direct images consistently onto the PRL, characteristics of eccentric saccades differed from those of foveating saccades. Typically, foveating saccades have shorter latencies and are more accurate than eccentric, nonfoveating saccades.24 –26 Taken together, these findings confirm that subjects suppress foveating saccades and then adapt nonfoveating saccades to reference the new fixation locus, in accordance with previous reports.23 Limitations and Implications of the Present Study Our experimental setting obviously does not fully simulate the functional constraints and remaining retinal capacities found in conditions associated with central scotomas and eccentric reading. Furthermore, the results presented herein were cer- tainly influenced by the artificial constraints imposed by our experimental setting. Unlike most patients with macular disease, our subjects were also confronted with artificial tunnel-vision conditions. As a consequence, page navigation was not only limited by eccentric viewing, but also, because of the lack of peripheral information (restricted by the size of the viewing window). It is therefore possible that subjects learned to make stereotyped patterns of horizontal forward and return saccades to move the viewing window along the text. Another possibility is that subjects achieved horizontal page navigation by performing saccades to “meaningful” portions of the text that were already visible in the viewing window. Both strategies limit the amplitude and timing of the resultant eye movements, therefore restricting the maximum reading speed that the subjects attained. Furthermore, patients with central scotoma can develop multiple PRL that may be used in combination to improve reading performance,12 whereas, in our experimental setting, subjects had to cope with a single and fixed PRL. The retinal location of our artificial PRL and the choice of the task to be performed (reading) also influenced the oculomotor adaptation pattern. The orientation of foveating saccades obviously depends on the absolute position of the restricted viewing window relative to the fovea. In our case, FIGURE 8. Evolution of the different horizontal saccade subcategories versus session number for the three subjects during training of eccentric reading. The proportions (%) of progressions and regressions were calculated on the basis of the total number of horizontal saccades. Average values for central vision (black dashed lines) are also shown for comparison. 1446 Pérez Fornos et al. IOVS, April 2006, Vol. 47, No. 4 FIGURE 9. Changes in average saccade amplitude (in degrees) versus session number for the three subjects during training of eccentric reading, by saccade category. Average values for central vision (black dashed lines) are also shown for comparison. foveating saccades were vertical because the restricted viewing window was stabilized at a given position along the vertical meridian. Furthermore, for this reading task, the page navigation strategy essentially consisted of horizontal saccades (saccades performed from one word to the next, and from the end of one line to the beginning of another). Therefore, because of the nature and requirements of the task, subjects essentially optimized the horizontal oculomotor pattern once foveating saccades were controlled. Moreover, Peli27 suggested that an orthogonal paradigm (where eccentricity direction is perpendicular to direction of gaze or target movement), as used in our experiments, might favor eccentric oculomotor adaptation. Despite these methodological limitations, our experimental setting simulated the fundamental constraints faced by patients with central scotoma. In these patients, at least one new fixation locus must be developed to compensate for the missing fovea, and eye movements should be recalibrated accordingly. We therefore believe the present results offer useful indications of how mechanisms for eccentric reading are constructed, at least in certain circumstances. Additional Considerations Even after extensive training, eccentric reading remained a difficult task resulting in low reading rates, as consistently observed in clinical practice.6,19,20 As already discussed, suboptimal control of eccentric, non-foveating saccades might limit the maximum reading performance that can be achieved in eccentric viewing conditions. However, optimal peripheral reading rates were approximately five times slower than those obtained by the same subjects in the initial central viewing experiments. Oculomotor deficits observed at the end of training can hardly account for such a slowdown. Previous research18,28 –30 demonstrated that peripheral reading remains slow, even when no eye movements are necessary (i.e., the RSVP paradigm). Similar to these investigations, in our experiments, maximum reading rates were essentially limited because of the spatial constraint of the viewing area. Such visual span restrictions are known to be even more important in peripheral than in central vision.17,31,32 Other possible factors have already been discussed in our companion publication.17 When considering the analysis reported herein, together with the reading performance results reported in our previous paper,17 no consistent correlation could be established between reading performance and the course of oculomotor adaptation to eccentric reading. Furthermore, significant learning effects have been demonstrated in previous eccentric reading studies18,20 where page navigation (i.e., the development of precise eccentric oculomotor control) was not required. This suggests the existence of additional adaptation mechanisms that were difficult to analyze in this study, such as learning to shift attention from the foveal region toward the eccentric retinal area stimulated.3,7 The learning effects reported in this article, altogether with those described in our companion publication,17 might appear surprising because experiments were performed in normal subjects interleaving short eccentric viewing sessions with much longer periods of normal foveal viewing. Similar learning effects, however, have also been reported elsewhere.18,33 One possibility is that learning effects acquired within a single experimental session are somehow retained in the next one. Another explanation could be that learning results from some kind of perceptual assimilation occurring between sessions. Our experience suggests us that it could be a combination of both. This issue would be an interesting line of investigation for future research efforts. In conclusion, our results demonstrate that oculomotor adaptation to eccentric reading involves at least two parallel processes: a faster suppression of the mechanisms generating reflexive foveating saccades and a lengthier process aimed at optimizing the remaining saccades (especially in the horizontal plane in the case of reading). Even after systematic training, eccentric reading remains a difficult task resulting in low reading rates. References 1. Von Noorden GK, Mackensen G. Phenomenology of eccentric fixation. Am J Ophthalmol. 1962;53:642– 660. 2. Cummings RW, Whittaker SG, Watson GR, Budd JM. Scanning characters and reading with a central scotoma. Am J Optom Physiol Opt. 1985;62:833– 843. 3. Altpeter E, Mackeben M, Trauzettel-Klosinski S. The importance of sustained attention for patients with maculopathies. Vision Res. 2000;40:1539 –1547. 4. Heinen SJ, Skavenski AA. Adaptation of saccades and fixation to bilateral foveal lesions in adult monkey. Vision Res. 1992;32:365– 373. 5. Timberlake GT, Peli E, Essock EA, Augliere RA. Reading with a macular scotoma. II. Retinal locus for scanning text. Invest Ophthalmol Vis Sci. 1987;28:1268 –1274. 6. Fletcher DC, Schuchard RA, Watson G. Relative locations of macular scotomas near the PRL: effect on low vision reading. J Rehabil Res Dev. 1999;36:356 –364. 7. Mackeben M. Sustained focal attention and peripheral letter recognition. Spat Vis. 1999;12:51–72. 8. Whittaker SG, Budd J, Cummings RW. Eccentric fixation with macular scotoma. Invest Ophthalmol Vis Sci. 1988;29:268 –278. IOVS, April 2006, Vol. 47, No. 4 9. Lei H, Schuchard RA. Using two preferred retinal loci for different lighting conditions in patients with central scotomas. Invest Ophthalmol Vis Sci. 1997;38:1812–1818. 10. Duret F, Issenhuth M, Safran AB. Combined use of several preferred retinal loci in patients with macular disorders when reading single words. Vision Res. 1999;39:873– 879. 11. Safran AB, Duret F, Issenhuth M, Mermoud C. Full text reading with a central scotoma: pseudo regressions and pseudo line losses. Br J Ophthalmol. 1999;83:1341–1347. 12. Deruaz A, Whatham AR, Mermoud C, Safran AB. Reading with multiple preferred retinal loci: implications for training a more efficient reading strategy. Vision Res. 2002;42:2947–2957. 13. Deruaz A, Matter M, Whatham AR, et al. Can fixation instability improve text perception during eccentric fixation in patients with central scotomas? Br J Ophthalmol. 2004;88:461– 463. 14. Crossland MD, Kabanarou SA, Rubin GS. An unusual strategy for fixation in a patient with bilateral advanced age related macular disease. Br J Ophthalmol. 2004;88:1479 –1480. 15. Safran AB, Landis T. Plasticity in the adult visual cortex: implications for the diagnosis of visual field defects and visual rehabilitation. Curr Opin Ophthalmol. 1996;7:53– 64. 16. Duret F, Buquet C, Charlier J, Mermoud C, Viviani P, Safran AB. Refixation strategies in four patients with macular disorders. Neuroophthalmology. 1999;22:209 –220. 17. Sommerhalder J, Rappaz B, de Haller R, Pérez Fornos A, Safran AB, Pelizzone M. Simulation of artificial vision: II. Eccentric reading of full-page text and the learning of this task. Vision Res. 2004;44: 1693–1706. 18. Sommerhalder J, Oueghlani E, Bagnoud M, Leonards U, Safran AB, Pelizzone M. Simulation of artificial vision: I. Eccentric reading of isolated words, and perceptual learning. Vision Res. 2003;43:269 – 283. 19. Legge GE, Rubin GS, Pelli DG, Schleske MM. Psychophysics of reading II. Low vision. Vision Res. 1985;25:253–265. Oculomotor Adaptation to Eccentric Reading 1447 20. Chung ST, Legge GE, Cheung SH. Letter-recognition and reading speed in peripheral vision benefit from perceptual learning. Vision Res. 2004;44:695–709. 21. Pirozzolo FJ. Eye movements and reading disability. In: Rayner K, ed. Eye Movements in Reading. Perceptual and Language Processes. New York: Academic Press; 1983:499 –509. 22. Rayner K. Eye movements in reading and information processing: 20 years of research. Psychol Bull. 1998;124:372– 422. 23. Whittaker SG, Cummings RW, Swieson LR. Saccade control without a fovea. Vision Res. 1991;31:2209 –2218. 24. Hallett PE. Primary and secondary saccades to goals defined by instructions. Vision Res. 1978;18:1279 –1296. 25. Zeevi YY, Peli E. Latency of peripheral saccades. J Opt Soc Am. 1979;69:1274 –1279. 26. Whittaker SG, Cummings RW. Foveating saccades. Vision Res. 1990;30:1363–1366. 27. Peli E. Control of eye movement with peripheral vision: implications for training of eccentric viewing. Am J Optom Physiol Opt. 1986;63:113–118. 28. Latham K, Whitaker D. A comparison of word recognition and reading performance in foveal and peripheral vision. Vision Res. 1996;36:2665–2674. 29. Rubin GS, Turano K. Low vision reading with sequential word presentation. Vision Res. 1994;34:1723–1733. 30. Chung ST, Mansfield JS, Legge GE. Psychophysics of reading. XVIII. The effect of print size on reading speed in normal peripheral vision. Vision Res. 1998;38:2949 –2962. 31. Beckmann PJ, Legge GE. Psychophysics of reading: XIV. The page navigation problem in using magnifiers. Vision Res. 1996;36:3723– 3733. 32. Fine EM, Kirschen MP, Peli E. The necessary field of view to read with an optimal stand magnifier. J Am Optom Assoc. 1996;67:382– 389. 33. Beard BL, Levi DM, Reich LN. Perceptual learning in parafoveal vision. Vision Res. 1995;35:1679 –1690. Simulation of Artificial Vision, III: Do the Spatial or Temporal Characteristics of Stimulus Pixelization Really Matter? Angélica Pérez Fornos, Jörg Sommerhalder, Benjamin Rappaz, Avinoam B. Safran, and Marco Pelizzone PURPOSE. In preceding studies, simulations of artificial vision were used to determine the basic parameters for visual prostheses to restore useful reading abilities. These simulations were based on a simplified procedure to reduce stimuli information content by preprocessing images with a block-averaging algorithm (square pixelization). In the present study, how such a simplified algorithm affects reading performance was examined. METHODS. Five to six volunteers with normal vision were asked to read full pages of text with a 10° ⫻ 7° viewing window stabilized in central vision. In a first experiment, reading performance with off-line and real-time square pixelizations was compared at different resolutions. In a second experiment, off-line square pixelization was compared with off-line Gaussian pixelization with various degrees of overlap. In a third experiment, real-time square pixelization was compared with real-time Gaussian pixelization. RESULTS. Results from the first experiment showed that realtime square pixelization required approximately 30% less information (pixels) than its off-line counterpart. Results from the second experiment, using off-line processing, revealed a restricted range of Gaussian widths for which performances were equivalent or significantly better than that obtained with square pixelization. The third experiment demonstrated, however, that reading performances were similar in both real-time pixelization conditions. CONCLUSIONS. This study reveals that real-time stimulus pixelization favors reading performance. Performance gains were moderate, however, and did not allow for a significant (e.g., twofold) reduction of the minimum resolution (400 –500 pixels) needed to achieve useful reading abilities. (Invest Ophthalmol Vis Sci. 2005;46:3906 –3912) DOI:10.1167/iovs.04-1173 C urrently, several research groups are working toward the development of visual prostheses for the blind.1–7 Despite fundamental design differences (implantation site, image acquisition, and processing techniques), these approaches share common features that lead to several major constraints on the From the Ophthalmology Clinic, Department of Clinical Neurosciences, Geneva University Hospitals, Geneva, Switzerland. Supported by Swiss National Foundation for Scientific Research Grants 3100-61956.00 and 3152-063915.00 and by the ProVisu Foundation. Submitted for publication October 4, 2004; revised February 14, May 24, and June 2, 2005; accepted August 1, 2005. Disclosure: A. Pérez Fornos, None; J. Sommerhalder, None; B. Rappaz, None; A.B. Safran, None; M. Pelizzone, None The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact. Corresponding author: Jörg Sommerhalder, Ophthalmology Clinic, Geneva University Hospitals, 24 rue Micheli-du-Crest, 1211 Geneva 14, Switzerland; [email protected]. 3906 visual percepts that can be elicited. Envisioned devices consist of a finite number of discrete stimulation contacts, will be implanted at a fixed location in the eye, and will subtend only a fraction of the entire visual field. If one expects to restore useful vision to blind patients, these constraints have to be thoroughly considered. Our research group is part of a larger multidisciplinary research effort aiming to develop a subretinal implant. Our CMOS-Retina8 –10 is built to transform incident light on the retina into electric stimulation currents “in situ.” In this context, we have developed special experimental conditions (simulations) to explore the minimum requirements to restore useful artificial vision. Our simulations use low-resolution (pixelized) images that are projected in a “small” viewing area, stabilized at a fixed location in the visual field. We attempt to mimic the type of visual information provided by a retinal implant, using photodiode technology to transform incident light into an electric signal. With this methodological approach we explored, in a first study,11 the reading of isolated four-letter words. In central vision, accurate recognition was possible with pixelizations down to 286 pixels, distributed over a 10° ⫻ 3.5° viewing window. After a period of systematic training, comparable results were achieved with the same viewing window stabilized at 15° eccentricity in the lower visual field. In a second study,12 we explored full-page text reading under similar conditions. Tests were performed with a larger viewing window of 10° ⫻ 7° containing 572 pixels, that moved across the page of text under control of the subject’s eye movements. Performance was close to perfect with central vision. With eccentric vision, subjects achieved reading scores between 86% and 98% after a period of methodical training. In earlier studies, we used a simplified technique to simulate the limited number of stimulation contacts available in a visual prosthesis. Stimulus images were decomposed into a finite number of pixels with a simple block-averaging algorithm. This resulted in a mosaic of square pixels of various gray levels, the gray level within each pixel being constant (square pixelization). However, electrophysiological research13–15 revealed that the patterns of neural activity elicited by electric stimulation of the retina depend on the strength of the stimulation current and that neural activation diminishes progressively with increasing electrode-to-neural target distance. These findings imply that phosphenes elicited by electrical stimulation of the retina should not be of constant luminosity and not of square shape. Furthermore, depending on the strength of the stimulation current, the percepts may develop from a collection of isolated phosphenes toward more continuous patterns with different degrees of overlap across neighboring phosphenes. One could argue that square pixelization is adequate to simulate the reduced information content of the stimuli transmitted by a retinal implant. In a given condition, the detailed shape of each pixel does not alter the overall information content of the image. However, studies on face recognition Investigative Ophthalmology & Visual Science, October 2005, Vol. 46, No. 10 Copyright © Association for Research in Vision and Ophthalmology Simulation of Artificial Vision IOVS, October 2005, Vol. 46, No. 10 have demonstrated that detection is considerably hampered when images are decomposed into uniform square pixels. Harmon and Julesz16 suggested that the oriented high-frequency noise introduced at block borders masks certain image features essential for recognition. Gestalt psychologists17,18 further proposed that square pixelization distorts the image to the point of modifying its intrinsic gestalt properties.19 Bachmann and Kahusk20 also suggest that the “block” constituents or pixels of the processed image compete for attention with the particular features of the image, thus affecting recognition. If one wants to avoid these drawbacks, square pixelization should be replaced by other types of image quantization featuring softer borders and allowing for variable amounts of overlap. Another shortcoming of our previous studies is that the pixelization algorithm was applied off-line over the entire original image (e.g., seven lines of full-page text). Subjects were allowed to scan this preprocessed image through a viewing window containing a subset of 572 pixels, the gray level of these “frozen” pixels being independent of the point of gaze on the image. This would not be the case in artificial vision systems, since stimulation intensity at each electrode contact would depend on the exact point of gaze relative to the image observed. For retinal implants transforming light falling on the retina into stimulation currents “in situ,”4,7,10 this would happen due to eye movements. Head movements would act similarly in systems using an external head-mounted camera for stimulus generation.1–3,5,6 In the case of reading, when focusing on a string of a few characters, its appearance would change on small eye (or camera) movements. Temporal cues seem to play a significant role in visual perception: the human visual system is optimized for detecting structural changes in dynamic images. A dynamic sequence of slightly different pixelized images may contain more information than one frozen pixelized image; therefore, dynamic (real-time) pixelization is likely to enhance information transmission to the visual system. Major object identification features (such as shape or location) are extracted from different spatial patterns (such as local contrast changes or relative position changes) resulting from image motion. Improved sensitivity for moving contrast changes, compared to their static equivalents, has previously been demonstrated.21 Moreover, it has already been established that dynamic presentations lead to better performance in tasks like facial recognition.22–24 Hence, if one wants more accurate simulations of artificial vision, pixelization should be performed in real-time and the intensity of each pixel should vary dynamically, according to gaze position. To our knowledge, psychophysical research using simulations of prosthetic vision has not been extensive so far. Reading and mobility were first studied by a group at the University of Utah.25,26 Their head-mounted experimental setup consisted of a video camera sending images to a monochrome monitor that projected to the subject’s right eye (maximum viewing angle of 1.7°). Pixelization was achieved by overlaying the monitor with opaque masks containing a variable number of square perforations (pixels). Recently, another group at The Johns Hopkins University presented a series of experiments that used simulations specifically designed to mimic percepts evoked by retinal implants.27–29 Different pixelization algorithms were used: a square pixelizing filter similar to the one presented in this article, a constant luminosity circular pixelizing filter, and a nonoverlapping Gaussian filter. Unfortunately, no direct comparison of the different pixelizing algorithms has been reported. Moreover, all these experiments neglected a fundamental aspect of artificial vision with a retinal implant: Viewing areas were not stabilized at fixed (eccentric) retinal positions. In more recent studies, the latter authors acknowledged that the stabilization of the viewing area on the 3907 retina can significantly affect performance (Dagnelie G, et al. IOVS 2004;45:ARVO E-Abstract 4223; Kelley AJ, et al. IOVS 2004;45:ARVO E-Abstract 5436), especially in visually demanding tasks such as reading. To validate our previous studies as well as to improve our simulation methods for future studies, we decided to investigate specifically the influence of the spatial and temporal characteristics of stimulus pixelization on reading performance. In the present study, we report a series of three paired comparisons of the effects of different pixelization methods on fullpage reading. We compared reading performance: (1) between off-line square pixelization and real-time square pixelization of the image, (2) between off-line square pixelization and off-line Gaussian pixelization of the image, and (3) between real-time square pixelization and real-time Gaussian pixelization of the image. METHODS Subjects Ten subjects aged between 23 and 41 years were recruited from the staff of the Geneva University Ophthalmology Clinic. All of them had perfect command of French, corrected visual acuity of 20/20 or better, and normal ophthalmic status. They were familiar with the purpose of the study and signed appropriate consent forms. All experiments were conducted according to the ethical recommendations of the Declaration of Helsinki and were approved by local ethics authorities. Experimental Setup The stabilized projection of a 10° ⫻ 7° viewing window on the retina was achieved with a high-speed video-based eye and head-tracking system (EyeLink; SensoMotor Instruments GmbH, Berlin, Germany) and a high-refresh-rate monitor (Fig. 1). Please refer to our preceding publications11,12 for a more detailed description of the experimental setup. Generation and Presentation of the Stimuli Stimuli consisted of full-page texts generated by the same procedure as was used in our previous study on full-page text reading.14 Articles were extracted from the Internet Web site of the Swiss newspaper Le Temps (http://www.letemps.ch) and cut into seven-line text segments of approximately 25 words. Arial font (Helvetica) was used. At a viewing distance of 57 cm, the height of the lowercase letter x corresponded to a visual angle of 1.8°. The information content of the stimuli was reduced using one of two pixelization algorithms, square or Gaussian, which differed in the resultant shape of the pixels. These FIGURE 1. Experimental setup used for prosthetic vision simulations. Subjects were asked to read full-page texts by using their eye movements to move a stabilized, restricted viewing window on a computer screen. 3908 Pérez Fornos et al. IOVS, October 2005, Vol. 46, No. 10 algorithms were applied either off-line, yielding images with “frozen” pixels, or in real-time, yielding “dynamic” pixels that changed with gaze position. Square pixelization was performed with a simple block-averaging algorithm, in which matrices of n ⫻ n pixels of the original image are fused into single uniform pixels with luminance values corresponding to the mean gray scale levels of the original n ⫻ n matrices (Fig. 2a). Gaussian pixelization was performed by applying a two-dimensional (2-D) Gaussian function to each pixel of the stimulus image (Fig. 2b): I共x,y兲 ⫽ A共 x, y兲 䡠 G共x,y兲. I(x,y) represents the light intensity (gray scale level) at the coordinates (x,y) of the stimulus image. A(x,y) is the mean gray scale level of the original n ⫻ n pixel matrix with center coordinates (x,y). G(x,y) stands for the 2-D Gaussian function calculated as: G共x,y兲 ⫽ 共x ⫺ x兲2 ⫹ 共y ⫺ y兲2 1 2 2 , 2 e 2 where denotes the SD of the particular Gaussian function around its horizontal (x) and vertical (y) means. In our case, determines the amount of overlap of each pixel onto its neighbors (Gaussian width), whereas x and y correspond to the center coordinates for each pixel (Fig. 3). Off-Line Pixelization. All text segment images (seven lines of full-page text) used for static presentations were processed off-line, during the preparation phase of the experiment. Subjects could scan these prepixelized images through the 10° ⫻ 7° viewing window, under control of their gaze position on the screen. Real-Time Pixelization. In this condition, only the small portion of the entire text segment image displayed in the 10° ⫻ 7° viewing window (determined by the subject’s gaze position on the screen) was pixelized in real-time. Gaze position data were used to reposition the viewing window and to display its newly pixelized content on the screen. To achieve adequate image stabilization on the retina, the maximum image-processing time (stimulus pixelization and display) was kept below 10 ms. To fulfill this condition, enormous processing power is needed when large Gaussian widths are used, due to significant amounts of overlap across neighboring pixels. For real-time pixelization, the processing power of our equipment limited us to Gaussian widths up to 0.14 pixels. Testing Procedure The remaining aspects of the experimental procedure were exactly the same as described in our preceding study on full-page text reading.12 Briefly, tests were performed monocularly (using the dominant eye) FIGURE 3. Gaussian pixelization. A 2-D Gaussian function was applied to each pixel. Block averaging was used to determine the peak of the Gaussian function. represents the SD used in the Gaussian function (Gaussian width); x and y are the center coordinates of the stimulus pixel to which the function is applied. and in central vision. For each run, subjects had to read aloud several text segments of an article, randomly chosen out of a pool of 50 (none of the subjects read an article twice). Test sessions frequently included several runs, but they never lasted longer than 30 minutes, to avoid fatiguing the subjects. The programs and algorithms used for image processing and experiment control were developed in commercial software (Visual C⫹⫹ 6.0 SP5; Microsoft, Redmond, WA) and the latest Platform SDK libraries available at the time of the experiment. Some functions of the EyeLink Windows API library (v. 1.0; SensoMotor Instruments, GmbH) were also used. Data Analysis and Statistics Two variables were measured to assess reading performance: reading scores, expressed in percentage of correctly read words (gender and conjugation mistakes were considered as errors), and reading rates, expressed in the number of correctly read words per minute. Since percentage scales are not adequate for statistical analysis,30 reading scores were transformed to rationalized arcsine units (rau). Nevertheless, for better clarity, an approximate percentage scale is shown on the right axes of the figures and is also used in the text. Results were calculated as the mean of the cumulative performance of each subject ⫾ SEM. Statistically significant differences in reading performance were determined by standard (paired) t-tests with a significance level of 0.05. RESULTS Real-Time Square Pixelization Versus Off-Line Square Pixelization FIGURE 2. Pixelization methods: (a) square pixelization (block averaging); (b) Gaussian pixelization. Five normal volunteers (22, 23, 24, 26, and 28 years of age) were requested to read full-page texts using off-line and realtime square pixelization. Five resolution levels were tested: 28,000, 1,750, 572, 280, and 166 pixels in the viewing window. These resolution levels were identical with those used in our previous study on reading of isolated four-letter words.11 All subjects started with the easiest (highest) resolution and progressed toward the most difficult (lowest) one. The first four text segments of an article (approximately 100 words) had to be read in each run. Three runs were performed per each pixelization condition. Off-line and real-time pixelization conditions alternated. It is important to note that the first resolution level (28,000 pixels) corresponded to maximum screen resolution (no pixelization had to be performed). Off-line and real-time pixelization conditions were thus identical in this particular case. IOVS, October 2005, Vol. 46, No. 10 Figure 4 compares mean reading performances versus number of pixels in the viewing window for off-line and real-time pixelizations. Individual performances in each experimental condition were established on the basis of 12 text segments and data were fitted with psychometric functions. Down to a target resolution of 572 pixels, average reading scores were close to perfect (above 95% correct) and statistically equivalent for both conditions. At 280 pixels, subjects achieved reading scores of 94.3% with real-time pixelization, but of only 76.4% with off-line pixelization. This difference was statistically significant (P ⫽ 0.0017), and persisted at the lowest resolution (166 pixels; 56.1% versus 29.3%; P ⫽ 0.013). It is interesting to estimate the critical target resolution for subjects to reach useful reading performances. In our previous study on full-page reading,12 we Simulation of Artificial Vision 3909 FIGURE 5. Pixelization with various Gaussian widths (pixel overlapping). Gaussian pixelizations with: (a) ⫽ 0.071 pixels (little overlap), (b) ⫽ 0.286 pixels (medium overlap), and (c) ⫽ 1.143 pixels (large overlap). found that adequate (good to excellent) text comprehension correlated closely with high reading scores. This criterion was fulfilled at median scores of 96.8%. In the present case, the fits to the data indicate that this score is reached at 498 pixels in the case of off-line pixelization and at 322 pixels for real-time pixelization (Fig. 4a). Reading rates appeared to be even more sensitive to the number of pixels in the viewing window (Fig. 4b). At the highest resolutions, subjects reached an average reading rate of 93 words/min. At 572 pixels, mean reading rates had significantly (P ⬍ 0.0001) decreased to 80 words/min for real-time and to 64 words/min for off-line pixelization. The difference between both pixelization conditions was also statistically significant (P ⬍ 0.0001) and persisted at 280 pixels (34 words/min for real-time pixelization versus 18 words/min for off-line pixelization; P ⫽ 0.002). The lowest pixelization condition (166 pixels) was so difficult that reading rates were very low (four to six words/min) in both cases. Taken together, these results indicate that equivalent reading performances could be reached at a significantly lower resolution with real-time pixelization. Off-Line Gaussian Pixelization Versus Off-Line Square Pixelization FIGURE 4. Reading performance versus number of pixels in the 10° ⫻ 7° viewing window for five normal subjects. Two stimuli generation procedures are compared in central vision: real-time pixelization and off-line pixelization. (a) Mean reading scores expressed in rau ⫾ SEM (left scale) and in % (right scale). Dashed line: indicates reading scores corresponding to good-to-excellent text comprehension. (b) Mean reading rates expressed in words per minute ⫾ SEM. Six normal subjects (26, 29, 29, 33, 34, and 41 years of age) participated in the second experiment. Pixelizations with six different Gaussian widths ( of 0.036, 0.071, 0.143, 0.286, 0.571, and 1.143 pixels) were tested and compared with square pixelization. The effect of varying the Gaussian width for image pixelization is illustrated in Figure 5. In all conditions, the 10° ⫻ 7° viewing window contained 572 pixels (resolution shown to provide enough information for useful full-page text reading12). Each subject had to read an article of approximately 250 words (i.e., 10 consecutive text segments, per condition). Three subjects started the experiment with Gaussian pixelization at the smallest value, progressed toward the larger Gaussian widths, to finish with square pixelization. The remaining three subjects conducted the experiment inversely. Mean reading performances versus Gaussian function width () are shown in Figure 6 and compared to results obtained with square pixelization. Four Gaussian widths ( ⫽ 0.071, 0.143, 0.286, and 0.571 pixels) resulted in reading scores above 94% correctly read words. These scores were very close to those obtained with square pixelization (Fig. 6a). Mean reading scores with ⫽ 0.143 and 0.286 pixels were found to be significantly better than those obtained with square pixelization (P ⫽ 0.04 and 0.009, respectively). Reading scores declined markedly below 80% for the two extreme Gaussian widths tested ( ⫽ 0.036 and 1.143 pixels). Mean reading rates displayed a similar picture. A maximum reading rate of 70 words/min was achieved at ⫽ 0.286 pixels. This value is significantly higher (P ⬍ 0.001) than the reading 3910 Pérez Fornos et al. IOVS, October 2005, Vol. 46, No. 10 Taken together, these data reveal that Gaussian pixelization can lead to slightly, but significantly better reading performance than can its square counterpart. This suggests that some degree of image smoothing resulting from overlapping between neighboring pixels can be beneficial for reading. This benefit is, however, only observed for a restricted range of overlapping. Real-Time Gaussian Pixelization Versus Real-Time Square Pixelization Results of the second experiment demonstrated that off-line Gaussian pixelization could lead to significantly better reading performance than off-line square pixelization. A third experiment was thus dedicated to extend this comparison to realtime mode. For this evaluation we would have rather used the “optimal” Gaussian width ( ⫽ 0.286 pixels) determined in the second experiment. However, the total processing time needed to simulate this condition turned out to be too important to ensure adequate image stabilization on the retina. Using the second best condition ( ⫽ 0.143 pixels) allowed us to keep processing time below 10 ms. The same six normal volunteers who had participated in the second experiment were requested to read 10 text segments in each of two conditions: (1) real-time Gaussian pixelization at ⫽ 0.143 pixels and (2) real-time square pixelization. In both conditions, the 10° ⫻ 7° viewing window contained 572 pixels. Three subjects started with real-time square pixelization and then switched to realtime Gaussian pixelization. The remaining three subjects performed the experiment inversely. The results of this experiment are summarized in Table 1. No significant difference in performance was recorded between both types of pixelization. However, reading scores and reading rates tended to be slightly higher with square pixelization. Comparing those real-time scores with their off-line counterparts gathered in the second experiment reveals that both real-time conditions yielded better performance. This performance gain was significant for square pixelization (reading scores: P ⫽ 0.003; reading rates: P ⫽ 0.008), but not for Gaussian pixelization (reading scores: P ⫽ 0.12; reading rates: P ⫽ 0.25). DISCUSSION FIGURE 6. Reading performance versus Gaussian function width () used for stimulus pixelization in six normal subjects. Results are compared with reading performances obtained with square-pixelized stimuli (dashed line, ⫾ SEM). The resolution of the 10° ⫻ 7° viewing window in central vision was kept constant at 572 pixels. (a) Mean reading scores expressed in rau ⫾ SEM (left scale) and in % (right scale). (b) Mean reading rates expressed in words per minute ⫾ SEM (left scale). rate of 57 words/min achieved with square pixelization. Reading rates with ⫽ 0.143 and 0.571 pixels were not significantly different from those obtained with square pixelization. For ⫽ 0.036, 0.071, and 1.143 pixels, reading rates declined markedly (below 40 words/min). The first experiment clearly shows that at low stimulus resolutions (below approximately 1000 pixels in a 10° ⫻ 7° viewing area) real-time square pixelization yields better reading performances than its off-line equivalent. The major reason for this performance improvement lies probably in the capability of the visual system to integrate various low-resolution images, enhancing stimulus contrast and resolution21 to improve perception. This effect is also used in standard video: when several low-resolution images are presented in a rapid sequence, the resultant perception is that of a continuous, higher-resolution motion picture. In our experiments, at constant pixel resolution, the readability of pixelized text images depends on the exact position of the pixelization grid relative to the original stimulus image. Therefore, the image can be modified with TABLE 1. Mean Reading Performances with Real-Time Stimulus Pixelization in Six Normal Subjects Gaussian Pixelization Mean Reading Scores (rau ⫾ SEM) Mean Reading Rates (words/min ⫾ SEM) 115.8 ⫾ 3.6 69 ⫾ 12 (99.6%) Square Pixelization 117.2 ⫾ 3.4 74 ⫾ 15 Gaussian pixelization compared to square pixelization using a 10°⫻7° viewing area containing 572 pixels. (99.8%) P 0.22 (ns) 0.35 (ns) Simulation of Artificial Vision IOVS, October 2005, Vol. 46, No. 10 minor eye movements to optimize viewing conditions. Figure 7 illustrates this effect for a series of minor changes in grid position. We observed that subjects quickly adopted this strategy: When resolution decreased, they increased the number of small saccades around the word they were trying to decipher. Other effects are also likely to influence reading performance. Previous research on face recognition16 –18,20,31 revealed that blocked images lead to poorer performance than images filtered using other techniques, mainly because these add artifactual high-frequency components to the target image that may mask essential features for identification. Real-time pixelization does not have the same artifactual bias because pixel movement acts as a low-pass filter that subtracts some of these parasitic frequencies. This could also explain why in the second experiment off-line Gaussian pixelization yielded better reading performance than off-line square pixelization (for a restricted range of Gaussian widths of approximately ⫽ 0.286 pixels). Additional research, especially at lower resolutions, would be necessary to investigate other factors. It should also be stressed that extreme Gaussian widths noticeably impaired performance. When very small Gaussian widths were used, pixels appeared as isolated small points of light, making it almost impossible to extract a cohesive picture. With large Gaussian widths, overlap was too pronounced, leading to verylow-contrast stimuli. Results of experiment 3 might appear surprising in light of the findings of experiment 2: When using real-time processing, the benefits of Gaussian pixelization vanished. In fact, this outcome is not astonishing. Real-time processing had already eliminated the major handicap of square pixelization. The distracting high-frequency noise introduced at pixel borders is low-pass filtered by pixel movement. We believe that the use of the optimal Gaussian width ⫽ 0.286 pixels (instead of 0.143) would not change this result fundamentally. Implications of the Results for Simulations of Artificial Vision The exact characteristics of the electrophysiological response of the retina to patterned electrical stimulation remain undetermined to this date. However, the use of 2-D Gaussian functions for stimulus pixelization is certainly a more physiologically pertinent approach than the use of square pixels (pixel borders are smoother and it allows for overlapping between neighboring pixels). As soon as the results of electrophysiological experiments on retinal tissue become available, the parameters of such 2-D Gaussian (or more adequate) functions should be adapted. Our experiments also revealed that Gaussian width is an important factor for readability, suggesting that stimulating current strength and electrode spacing might have to be further “tuned” (within safe and comfortable limits) to achieve the most efficient image transmission possible. Real-time processing also allows for more realistic simulations of the visual information provided by retinal prostheses. Our results demonstrated that it yields significantly better performance than its off-line counterpart. However, this benefit FIGURE 7. Illustration of the effect of the initial position of the pixelization grid on the readability of the pixelized word. A single position does not provide enough information to identify the word unambiguously, but by integrating all three of them, the French word “niveau” can be easily recognized. 3911 was relatively moderate, not allowing for a significant reduction (e.g., a factor of two) of the number of stimulation points. Most probably, this advantage will be even less important in visual prostheses with external head-mounted cameras, since head movements are larger and less frequent than eye movements. Recurring head movements could also result in an abnormal vestibulo-ocular reflex. The first visual prosthesis prototypes have been recently implanted in humans with encouraging results.5–7 Yet, several important challenges still need to be overcome before these devices can provide benefits similar to those of cochlear implants in cases of deafness. The basic notion of patterned vision resulting from the continuous stimulation of several electrodes has not been fully confirmed. An appropriate method of selective stimulation eliciting the adequate psychophysical response has not been developed yet. Another major problem is to achieve efficient electrical stimulation within safe charge density limits.32 To reduce the total electrical charge injected on the retina, the use of relatively large stimulation electrodes (fundamentally limiting interelectrode spacing) as well as alternate solutions (such as inverted polarity, interleaved stimulation, and/or increasing the total area of the retinal array within feasible limits) may be mandatory. A substantial research effort is therefore still needed to solve these and other open issues before realizing the level of electrode integration suggested by our studies. In conclusion, these results demonstrate that the spatial and temporal characteristics of image pixelization play a role in artificial vision simulations. Equivalent performance could be reached with a resolution reduction of approximately 30%, if stimulation parameters were adequate. This effect is not strong enough, however, to change fundamentally the minimum requirements determined in our previous studies on the basis of simplified processing:11,12 Four to five hundred contacts covering a 2 ⫻ 3-mm2 retinal area are necessary to transmit sufficient visual information for full-page text reading. Reading is particularly important because it is strongly associated with vision-related estimates of quality of life and represents one of the main goals of low vision patients seeking rehabilitation.33–35 It is thus important to be aware of such minimal conditions when developing visual prostheses, even if less sophisticated devices might already bring some clinical benefits to patients. Acknowledgments The authors thank Andrew Whatham, PhD, for insightful contributions and a critical review of the manuscript. References 1. Rizzo JF, Wyatt J. Prospects for a visual prosthesis. Neuroscientist. 1997;3:251–262. 2. Normann RA, Maynard EM, Rousche PJ, Warren DJ. A neural interface for a cortical vision prosthesis. Vision Res. 1999;39: 2577–2587. 3. Dobelle WH. Artificial vision for the blind by connecting a television camera to the visual cortex. ASAIO J. 2000;46:3–9. 4. Zrenner E. Will retinal implants restore vision? Science. 2002;295: 1022–1025. 5. Humayun MS, Weiland JD, Fujii GY, et al. Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res. 2003;43:2573–2581. 6. Veraart C, Wanet-Defalque MC, Gerard B, Vanlierde A, Delbeke J. Pattern recognition with the optic nerve visual prosthesis. Artif Organs. 2003;27:996 –1004. 7. Chow AY, Chow VY, Packo KH, Pollack JS, Peyman GA, Schuchard R. The artificial silicon retina microchip for the treatment of vision loss from retinitis pigmentosa. Arch Ophthalmol. 2004;122:460 – 469. 3912 Pérez Fornos et al. 8. Lecchi M, Marguerat A, Ionescu A, et al. Ganglion cells from chick retina display multiple functional nAChR subtypes. Neuroreport. 2004;15:307–311. 9. Linderholm P, Bertsch A, Renaud P. Resistivity probing of multilayered tissue phantoms using microelectrodes. Physiol Meas. 2004;25:645– 658. 10. Ziegler D, Linderholm P, Mazza M, et al. An active microphotodiode array of oscillating pixels for retinal stimulation. Sensors and Actuators A: Physical. 2004;110:11–17. 11. Sommerhalder J, Oueghlani E, Bagnoud M, Leonards U, Safran AB, Pelizzone M. Simulation of artificial vision: I. Eccentric reading of isolated words, and perceptual learning. Vision Res. 2003;43:269 – 283. 12. Sommerhalder J, Rappaz B, de Haller R, Pérez Fornos A, Safran AB, Pelizzone M. Simulation of artificial vision: II. Eccentric reading of full-page text and the learning of this task. Vision Res. 2004;44: 1693–1706. 13. Weiland JD, Humayun MS, Dagnelie G, De Juan E, Greenberg RJ, Iliff NT. Understanding the origin of visual percepts elicited by electrical stimulation of the human retina. Graefes Arch Clin Exp Ophthalmol. 1999;237:1007–1013. 14. Stett A, Barth W, Weiss S, Haemmerle H, Zrenner E. Electrical multisite stimulation of the isolated chicken retina. Vision Res. 2000;40:1785–1795. 15. Rizzo JF, Wyatt J, Loewenstein J, Kelly S, Shire D. Perceptual efficacy of electrical stimulation of human retina with a microelectrode array during short-term surgical trials. Invest Ophthalmol Vis Sci. 2003;44:5362–5369. 16. Harmon LD, Julesz B. Masking in visual recognition: effects of two-dimensional filtered noise. Science. 1973;180:1194 –1197. 17. Bachmann T. Identification of spatially quantised tachistoscopic images of faces: how many pixels does it take to carry identity? Eur J Cogn Psychol. 1991;3:87–107. 18. Uttal WR, Baruch T, Allen LA parametric study of face recognition when image degradations are combined. Spat Vis. 1997;11:179 – 204. 19. Leeuwenberg E. Miracles of perception. Acta Psychol (Amst). 2003;114:379 –396. 20. Bachmann T, Kahusk N. The effects of coarseness of quantisation, exposure duration, and selective spatial attention on the percep- IOVS, October 2005, Vol. 46, No. 10 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. tion of spatially quantised (‘blocked’) visual images. Perception. 1997;26:1181–1196. Lappin JS, Tadin D, Whittier EJ. Visual coherence of moving and stationary image changes. Vision Res. 2002;42:1523–1534. Christie F, Bruce V. The role of dynamic information in the recognition of unfamiliar faces. Mem Cognit. 1998;26:780 –790. Lander K, Christie F, Bruce V. The role of movement in the recognition of famous faces. Mem Cognit. 1999;27:974 –985. Thornton IM, Kourtzi Z. A matching advantage for dynamic human faces. Perception. 2002;31:113–132. Cha K, Horch KW, Normann RA. Mobility performance with a pixelized vision system. Vision Res. 1992;32:1367–1372. Cha K, Horch KW, Normann RA, Boman DK. Reading speed with a pixelized vision system. J Opt Soc Am A. 1992;9:673– 677. Humayun MS. Intraocular retinal prosthesis. Trans Am Ophthalmol Soc. 2001;99:271–300. Hayes JS, Yin VT, Piyathaisere D, Weiland JD, Humayun MS, Dagnelie G. Visually guided performance of simple tasks using simulated prosthetic vision. Artif Organs. 2003;27:1016 –1028. Thompson RW, Barnett GD, Humayun MS, Dagnelie G. Facial recognition using simulated prosthetic pixelized vision. Invest Ophthalmol Vis Sci. 2003;44:5035–5042. Studebaker GA. A “rationalized” arcsine transform. J Speech Hear Res. 1985;28:455– 462. Costen NP, Parker DM, Craw I. Spatial content and spatial quantisation effects in face recognition. Perception. 1994;23:129 –146. Brummer SB, Robblee LS, Hambrecht FT. Criteria for selecting electrodes for electrical stimulation: theoretical and practical considerations. Ann N Y Acad Sci. 1983;405:159 –171. Wolffsohn JS, Cochrane AL. The changing face of the visually impaired: the Kooyong low vision clinic’s past, present, and future. Optom Vis Sci. 1999;76:747–754. Hazel CA, Petre KL, Armstrong RA, Benson MT, Frost NA. Visual function and subjective quality of life compared in subjects with acquired macular disease. Invest Ophthalmol Vis Sci. 2000;41: 1309 –1315. McClure ME, Hart PM, Jackson AJ, Stevenson MR, Chakravarthy U. Macular degeneration: do conventional measurements of impaired visual function equate with visual disability? Br J Ophthalmol. 2000;84:244 –250.