An Optoelectronic Stimulator for Retinal Prosthesis

Retinal prostheses require the presence of viable population of cells in the inner retina. Evaluations of retina with Age-Related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) have shown a large number of cells remain in the inner retina compared with the outer retina. Therefore, vision loss caused by AMD and RP is potentially treatable with retinal prostheses. Photostimulation based retinal prostheses have shown many advantages compared with retinal implants. In contrary to electrode based stimulation, light does not require mechanical contact. Therefore, the system can be completely external and not does have the power and degradation problems of implanted devices. In addition, the stimulating point is flexible and does not require a prior decision on the stimulation location. Furthermore, a beam of light can be projected on tissue with both temporal and spatial precision. This thesis aims at fi nding a feasible solution to such a system. Firstly, a prototype of an optoelectronic stimulator was proposed and implemented by using the Xilinx Virtex-4 FPGA evaluation board. The platform was used to demonstrate the possibility of photostimulation of the photosensitized neurons. Meanwhile, with the aim of developing a portable retinal prosthesis, a system on chip (SoC) architecture was proposed and a wide tuning range sinusoidal voltage-controlled oscillator (VCO) which is the pivotal component of the system was designed. The VCO is based on a new designed Complementary Metal Oxide Semiconductor (CMOS) Operational Transconductance Ampli er (OTA) which achieves a good linearity over a wide tuning range. Both the OTA and the VCO were fabricated in the AMS 0.35 µm CMOS process. Finally a 9X9 CMOS image sensor with spiking pixels was designed. Each pixel acts as an independent oscillator whose frequency is controlled by the incident light intensity. The sensor was fabricated in the AMS 0.35 µm CMOS Opto Process. Experimental validation and measured results are provided

Retinas artificiales para el tratamiento de la pérdida de visión

Millones de personas en todo el mundo sufren enfermedades degenerativas de retina con distintos grados de pérdida de la visión, incluyendo ceguera total. Entre las más comunes se encuentran la degeneración macular asociada a la edad y la retinosis pigmentaria. A menudo, son condiciones progresivas que limitan cada vez más la vida diaria de los pacientes. Común a todas ellas, es el deterioro de las células fotorreceptoras de la retina. En condiciones normales, estas células son las responsables de captar la luz, iniciando una cascada de impulsos eléctricos que se envían a través de la retina y el nervio óptico a la corteza visual responsable de formar la imagen. Cuando estas células no funcionan correctamente a causa de la patología, la imagen se percibe borrosa, distorsionada o completamente oculta. Dada la magnitud y gravedad del problema, no es de extrañar que se estén investigando nuevas estrategias de tratamiento. Cabe mencionar la terapia génica, la optogenética y los trasplantes celulares. Sin embargo, actualmente la única estrategia aplicable a los diferentes tipos de degeneraciones retinianas son las retinas artificiales. El mecanismo de estas prótesis en relación con los fotorreceptores se basa en utilizar un dispositivo artificial que detecte y transforme la energía lumínica en una señal eléctrica, como en condiciones normales harían éstos, transmitiendo dicho estímulo a las áreas no afectadas de la retina interna y comenzar así la vía visual. Existen tres principales enfoques físicos para implantar quirúrgicamente estas prótesis: el epirretiniano, el subretiniano y el supracoroidal. En el presente trabajo, se identificarán los modelos en ensayos o disponibles en el mercado que siguen las dos primeras aproximaciones. Además, se describirán estos dispositivos, su proceso de implantación y los candidatos más idóneos. Por último, se evaluarán los resultados obtenidos hasta la fecha, incluyendo ventajas e inconvenientes de cada uno de ellos.Universidad de Sevilla. Doble Grado en Farmacia y Óptica y Optometrí

Large scale retinal modeling for the design of new generation retinal prostheses

With the help of modern technology, blindness caused by retinal diseases such as age-related macular degeneration or retinitis pigmentosa is now considered reversible. Scientists from various fields such as Neuroscience, Electrical Engineering, Computer Science, and Bioscience have been collaborating to design and develop retinal prostheses, with the aim of replacing malfunctioning parts of the retina and restoring vision in the blind. Human trials conducted to test retinal prostheses have yielded encouraging results, showing the potential of this approach in vision recovery. However, a retinal prosthesis has several limitations with regard to its hardware and biological functions, and several attempts have been made to overcome these limitations. This thesis focuses on the biological aspects of retinal prostheses: the biological processes occurring inside the retina and the limitations of retinal prostheses corresponding to those processes have been analysed. Based on these analyses, three major findings regarding information processing inside the retina have been presented and these findings have been used to conceptualise retinal prostheses that have the characteristics of asymmetrical and separate pathway stimulations. In the future, when nanotechnology gains more popularity and is completely integrated inside the prosthesis, this concept can be utilized to restore useful visual information such as colour, depth, and contrast to achieve high-quality vision in the blind

Argus® II Retinal Prosthesis System: Clinical & Functional Outcomes

Developing artificial visual systems to restore sight in blind patients has long been the dream of scientists, clinicians and the public at large. After decades of research, the greatest success in the field has been achieved with electronic retinal prostheses. To date, 3 retinal prosthetic systems have made the transition from laboratory / clinical research to entering the commercial market for clinical use, namely the Argus® II Retinal Prosthesis System (Second Sight), the alpha-IMS system (Retinal Implant AG), and the IRIS® II (Pixium Vision). The following body of work describes the Argus® II Retinal Prosthesis system, which obtained regulatory approval in the European Economic Area in 2011 (CE marking) and later on in the USA (FDA approval in February 2013), based on the results of an international multi-centre clinical feasibility trial (Clinical Trial identifier: NCT 00407602). This thesis aims to examine the long-term clinical and functional outcomes in an early cohort of subjects chronically implanted with the Argus® II system, from the original feasibility study. A further aim is to elucidate the characteristics of the artificial vision that is perceived and its long-term repeatability and reproducibility in individual subjects. These two broad aims will assist in understanding the nature of the visual performance provided by this device, as well as to add to the current data that is defining the feasibility of constructing predictable pixelated patterns to achieve useful artificial vision in the future. Finally, we explored the feasibility of real-time imaging of visual cortex activation in response to electrical retinal stimulation with the Argus® II system, using functional near infra-red spectroscopy (fNIRS). Development of this real-time imaging tool will enable future investigations into the differences in the cortical activities in response to different stimulations and in different subjects. This may in turn help us understand the variability in their visual performance, as well as to further explore the extent and effect of cross-modal plasticity at the cortical level, in this cohort of patients who have been deprived of visual inputs for decades. Visual function was assessed in terms of: a) form recognition and b) spatial localisation under both 2-dimensional (2D) screen-based laboratory settings and 3-dimensional (3D) paradigms simulating real-life settings. A prospective study of 11 Argus® II subjects showed that the subjects could identify distinct geometric shapes presented in high contrast better with the prosthetic system switched on (median % of correct identification = 20.0%, IQR = 18.8), versus off (median = 12.5%, IQR = 5.0). The accuracy of shapes identification could be further improved by enhancing the outlines of the geometric shape (median = 33.1%, IQR = 21.6). A further prospective study from a subset of 7 subjects showed that this 2D shape identification could be translated into improved identification of 3D objects. These subjects could identify 8 common daily-life objects presented in high contrast with the prosthetic system switched on (median = 31.3%, IQR = 20.3) versus off (median = 12.5%, IQR = 12.5). Scrambling of the transmission signals within the prosthetic system in order to separate light information from form information (i.e. “scrambled mode”) hindered the identification in some but not all subjects (median = 25.0%, IQR = 12.5). The accuracy of object identification could also be improved by enhancing the edges of objects (median = 43.8%, IQR = 15.6). Previously published data showed that Argus® II subjects were able to locate and point to white squares presented on touch screens against a black background more accurately with the prosthetic system switched on versus off. We demonstrated with a prospective study of 5 subjects that they could localise an object on the table, reach out and grasp the object (prehension) with great accuracy (66.7 – 100%) when the prosthetic system was switched on, versus no object prehension (0%) with the system switched off. A prospective study of 6 Argus® II subjects illustrated that while there was a wide variation in the shape and size of the phosphenes perceived by individual subjects, the elicited phosphenes were consistently reproducible in each subject using fixed stimulating parameters, with inter-stimuli intervals ranging from 20 minutes apart, down to 1 second. The perceived location of the phosphenes grossly matched retinotopic agreement, with 4 subjects drawing phosphenes in the same visual field quadrant as predicted by the relative stimulus-fovea position, and 2 subjects depicting phosphenes in the same hemi-field as the expected locations. A retrospective study of 3 Argus® II subjects who underwent MRI brain scan (for unrelated medical reasons) showed that MRI brain scans of up to 1.5 Tesla field strength appeared to have no detrimental effect on the subjects and their implant function. The Argus® II implant produced an artefact of around 50mm x 50mm in size which would prevent visualisation of structures within the orbit, but visualisation of surrounding tissues outside this areas are unaffected. The use of functional MRI as a tool of exploring visual cortex activation in Argus® II subjects was discounted, due to concerns of signal interference from the radiofrequency telemetry of Argus® II system with that of MRI. Subsequently, we have demonstrated in a prospective study that an alternative neuro-imaging technique, functional near infra-red spectroscopy (fNIRS), was capable of capturing real-time cortical activation in 5 out of 6 Argus® II subjects, and maybe a feasible tool for future investigation into cortical function and interactions. The work in this thesis has shown that the Argus® II retinal prosthesis system could improve visual function both in terms of form recognition, as well as object localisation in 3D in situations simulating real-life settings, in a cohort of patients with end-stage retinitis pigmentosa or other outer retinal diseases such as choroideremia. The wide variation in the visual performance level observed could in part be attributable to the diversity in the phosphene features perceived by these subjects. Nevertheless, the consistency and reproducibility with which these phosphenes could be elicited, with fixed stimulating parameters within each subject, provides an encouraging basis for the construction of more complicated pixelated images. Future work to determine the underlying factors influencing the perceived phosphene characteristics, may allow for better prediction of functional outcome, which could in turn be useful for patient selection and tailored preoperative counselling. For those subjects already implanted with the Argus® II system, future work into determining the suitable stimulating parameters for each electrode / quad stimulation may be required for individual subjects, to achieve the construction of optimised and useful, pixelated prosthetic vision

Large scale retinal modeling for the design of new generation retinal prostheses

With the help of modern technology, blindness caused by retinal diseases such as age-related macular degeneration or retinitis pigmentosa is now considered reversible. Scientists from various fields such as Neuroscience, Electrical Engineering, Computer Science, and Bioscience have been collaborating to design and develop retinal prostheses, with the aim of replacing malfunctioning parts of the retina and restoring vision in the blind. Human trials conducted to test retinal prostheses have yielded encouraging results, showing the potential of this approach in vision recovery. However, a retinal prosthesis has several limitations with regard to its hardware and biological functions, and several attempts have been made to overcome these limitations. This thesis focuses on the biological aspects of retinal prostheses: the biological processes occurring inside the retina and the limitations of retinal prostheses corresponding to those processes have been analysed. Based on these analyses, three major findings regarding information processing inside the retina have been presented and these findings have been used to conceptualise retinal prostheses that have the characteristics of asymmetrical and separate pathway stimulations. In the future, when nanotechnology gains more popularity and is completely integrated inside the prosthesis, this concept can be utilized to restore useful visual information such as colour, depth, and contrast to achieve high-quality vision in the blind

FPGA design and implementation of a framework for optogenetic retinal prosthesis

PhD ThesisThere are 285 million people worldwide with a visual impairment, 39 million of whom are completely blind and 246 million partially blind, known as low vision patients. In the UK and other developed countries of the west, retinal dystrophy diseases represent the primary cause of blindness, especially Age Related Macular Degeneration (AMD), diabetic retinopathy and Retinitis Pigmentosa (RP). There are various treatments and aids that can help these visual disorders, such as low vision aids, gene therapy and retinal prosthesis. Retinal prostheses consist of four main stages: the input stage (Image Acquisition), the high level processing stage (Image preparation and retinal encoding), low level processing stage (Stimulation controller) and the output stage (Image displaying on the opto-electronic micro-LEDs array). Up to now, a limited number of full hardware implementations have been available for retinal prosthesis. In this work, a photonic stimulation controller was designed and implemented. The main rule of this controller is to enhance framework results in terms of power and time. It involves, first, an even power distributor, which was used to evenly distribute the power through image sub-frames, to avoid a large surge of power, especially with large arrays. Therefore, the overall framework power results are improved. Second, a pulse encoder was used to select different modes of operation for the opto-electronic micro-LEDs array, and as a result of this the overall time for the framework was improved. The implementation is completed using reconfigurable hardware devices, i.e. Field Programmable Gate Arrays (FPGAs), to achieve high performance at an economical price. Moreover, this FPGA-based framework for an optogenetic retinal prosthesis aims to control the opto-electronic micro-LED array in an efficient way, and to interface and link between the opto-electronic micro-LED array hardware architecture and the previously developed high level retinal prosthesis image processing algorithms.University of Jorda

Zur Invertierbarkeit von durch spatio-temporale Filter erzeugten Abbildungen mit besonderem Bezug zur Entwicklung einer lernfähigen Sehprothese

Für die Entwicklung wahrnehmungsbasierter Dialogverfahren für das Training lernfähiger Retina Encoder (RE) wird ein Inverter Modul benötigt, welches die spatio-temporale Abbildung, die durch den RE geleistet wird, umkehrt. In der vorliegenden Arbeit wird, ausgehend von einem speziellen Modell der visuellen Informationsverarbeitung beim Menschen, der Sehvorgang als Sequenz zweier Abbildungen betrachtet, die auf zueinander invers sein müssen. Mit der mathematischen Beschreibung dieser spatio-temporalen Filterung war es möglich, zwei unterschiedliche Inversionsverfahren, die Matrix-Methode und die Entscheidungsbaum-Methode, zu entwickeln, die einen Eingangsreiz perfekt aus dem RE-Filterergebnis rekonstruieren können. Die Matrix-Methode wurde durch Übertragung geeigneter Inversionsverfahren aus anderen Wissenschaftsdisziplinen auf die Retina Encoder Problemstellung realisiert. Die Entwicklung der Entscheidungsbaum-Methode basierte auf Erkenntnissen und Annahmen über die visuelle Informationsverarbeitung im Zentralen Sehsystem des Menschen sowie auf künstlich generierten Augenbewegung. Es stellte sich dabei heraus, dass die Invertierung der ST-Filterung typischerweise auf ein schlecht gestelltes Problem (ill-posed problem) bzw. schlecht konditioniertes Problem (ill-conditioned problem) führt. Aus diesem Grund musste die Matrix Methode durch Regularisierungsverfahren erweitert werden. Die Eignung der Inversionsverfahren für das wahrnehmungsbasierte RE-Training mit normalsichtigen Versuchspersonen wurde in Dialogverfahren unter Einsatz evolutionärer Algorithmen mit automatischer Selektion untersucht. Es stellte sich heraus, dass die Entscheidungsbaum-Methode der Matrix-Methode im Falle schlecht konditionierter RE-Abbildungen bei der Rekonstruktion reiner schwarz-weißer Reizmuster überlegen ist. Der Einsatz der Entscheidungsbaum-Methode im Inverter Modul zusammen mit einem ebenfalls neu entwickelten Lerndialogverfahren mit ortspezifischem Feedback (Position Sensitive Tuning) ermöglichte normalsichtigen Versuchspersonen ein schnelles und erfolgreiches RE-Training. </p

Rehabilitación visual con implantes o prótesis de visión artificial

En el presente trabajo se realiza una revisión bibliográfica enfocada a entender los implantes o prótesis de visión artificial que existen en el mercado como alternativas para el tratamiento de las personas con ceguera secundaria a un daño en los fotorreceptores o células del epitelio pigmentario de la retina. Se explica la función de los fotorreceptores en el sistema visual humano así como el procesamiento de la información visual normal como base para entender lo que una prótesis que suple los fotorreceptores debe ser capaz de realizar. Se describe brevemente la historia de la estimulación neuronal en las distintas porciones del sistema visual. Se explica la composición general de las prótesis retinianas, se hace mención de las diversas prótesis retinianas que se han desarrollado como prototipos y a nivel investigación y se habla mas a detalle de las únicas dos prótesis retinianas que cuentan con aprobación para su uso en humanos. Finalmente se mencionan los requisitos mínimos para poder hablar de una visión funcional útil y los resultados visuales que se obtienen con las prótesis, así como los candidatos susceptibles a ser implantados y gozar de los beneficios de las prótesis retinianas.Máster en Rehabilitación Visua

Information transmission in normal vision and optogenetically resensitised dystrophic retinas

Phd ThesisThe retina is a sophisticated image processing machine, transforming the visual scene as detected by the photoreceptors into a pattern of action potentials that is sent to the brain by the retinal ganglion cells (RGCs), where it is further processed to help us understand and navigate the world. Understanding this encoding process is important on a number of levels. First, it informs the study of upstream visual processing by elucidating the signals higher visual areas receive as input and how they relate to the outside world. Second, it is important for the development of treatments for retinal blindness, such as retinal prosthetics. In this thesis, I present work using multielectrode array (MEA) recordings of RGC populations from ex-vivo retinal wholemounts to study various aspects of retinal information processing. My results fall into two main themes. In the rst part, in collaboration with Dr Geo rey Portelli and Dr Pierre Kornprobst of INRIA, I use ashed gratings of varying spatial frequency and phase to compare di erent coding strategies that the retina might use. These results show that information is encoded synergistically by pairs of neurons and that, of the codes tested, a Rank Order Code based on the relative order of ring of the rst spikes of a population of neurons following a stimulus provides information about the stimulus faster and more e ciently than other codes. In the later parts, I use optogenetic stimulation of RGCs in congenitally blind retinas to study how visual information is corrupted by the spontaneous hyperactivity that arises as a result of photoreceptor degeneration. I show that by dampening this activity with the gap junction blocker meclofenamic acid, I can improve the signal-to-noise ratio, spatial acuity and contrast sensitivity of prosthetically evoked responses. Taken together, this work provides important insights for the future development of retinal prostheses