Implications of Neural Plasticity in Retinal Prosthesis.

Retinal degenerative diseases such as retinitis pigmentosa cause a progressive loss of photoreceptors that eventually prevents the affected person from perceiving visual sensations. The absence of a visual input produces a neural rewiring cascade that propagates along the visual system. This remodeling occurs first within the retina. Then, subsequent neuroplastic changes take place at higher visual centers in the brain, produced by either the abnormal neural encoding of the visual inputs delivered by the diseased retina or as the result of an adaptation to visual deprivation. While retinal implants can activate the surviving retinal neurons by delivering electric current, the unselective activation patterns of the different neural populations that exist in the retinal layers differ substantially from those in physiologic vision. Therefore, artificially induced neural patterns are being delivered to a brain that has already undergone important neural reconnections. Whether or not the modulation of this neural rewiring can improve the performance for retinal prostheses remains a critical question whose answer may be the enabler of improved functional artificial vision and more personalized neurorehabilitation strategies.

Optogenetic therapy: high spatiotemporal resolution and pattern discrimination compatible with vision restoration in non-human primates.

Vision restoration is an ideal medical application for optogenetics, because the eye provides direct optical access to the retina for stimulation. Optogenetic therapy could be used for diseases involving photoreceptor degeneration, such as retinitis pigmentosa or age-related macular degeneration. We describe here the selection, in non-human primates, of a specific optogenetic construct currently tested in a clinical trial. We used the microbial opsin ChrimsonR, and showed that the AAV2.7m8 vector had a higher transfection efficiency than AAV2 in retinal ganglion cells (RGCs) and that ChrimsonR fused to tdTomato (ChR-tdT) was expressed more efficiently than ChrimsonR. Light at 600 nm activated RGCs transfected with AAV2.7m8 ChR-tdT, from an irradiance of 1015 photons.cm-2.s-1. Vector doses of 5 × 1010 and 5 × 1011 vg/eye transfected up to 7000 RGCs/mm2 in the perifovea, with no significant immune reaction. We recorded RGC responses from a stimulus duration of 1 ms upwards. When using the recorded activity to decode stimulus information, we obtained an estimated visual acuity of 20/249, above the level of legal blindness (20/400). These results lay the groundwork for the ongoing clinical trial with the AAV2.7m8 - ChR-tdT vector for vision restoration in patients with retinitis pigmentosa.

Psychosocial assessment of potential retinal prosthesis trial participants.

BACKGROUND: As the field of retinal prostheses advances, volunteers are required for device trials, and optimal participant recruitment is vital for intervention success. The aims of this study were: (i) to select tests that assess the psychosocial aspects of visual impairment and develop a psychosocial assessment protocol for persons who may be eligible for participation in retinal prostheses trials; (ii) to investigate correlations between these tests; and (iii) to determine associations between psychosocial factors and a person's interest in participating in a retinal prosthesis (bionic eye) trial. METHODS: Cross-sectional study of 72 adults with advanced retinal degeneration. Questionnaire assessments included personality, cognitive ability, social-support, self-efficacy, coping, optimism, depression, and quality of life (Impact of Vision Impairment Profile ([IVI], and Vision and Quality of Life Index [VisQoL]). Level of interest in a retinal prosthesis was also evaluated. RESULTS: All questionnaires were completed without floor or ceiling effects and with minimal respondent burden. Depression correlated with decreased quality of life (rho = -0.37 and 0.40, p < 0.001 for IVI and VisQoL, respectively). Together, depression, gender and vision-specific coping explained 35.2 per cent of variance in IVI quality of life (p < 0.001). Forty-nine per cent of participants were interested in a retinal prosthesis now and 77 per cent in the future. Although the personality trait of 'openness' was somewhat predictive of interest in retinal prostheses (odds ratio 0.78, 95% CI 0.62-0.97), neither severity of vision impairment nor any of the psychosocial measures were strong predictors. CONCLUSIONS: Several existing psychosocial questionnaires can be used for patients with advanced retinal degeneration and may be useful in exploring suitability for a retinal prosthesis or evaluating outcomes. However, the questionnaires used in this study were not good predictors of whether or not a person might be interested in a retinal prosthesis.

Retinal and Optic Nerve Degeneration in Patients with Multiple Sclerosis Followed up for 5 Years.

PURPOSE: To quantify retinal nerve fiber layer (RNFL) changes in patients with multiple sclerosis (MS) and healthy controls with a 5-year follow-up and to analyze correlations between disability progression and RNFL degeneration. DESIGN: Observational and longitudinal study. PARTICIPANTS: One hundred patients with relapsing-remitting MS and 50 healthy controls. METHODS: All participants underwent a complete ophthalmic and electrophysiologic exploration and were re-evaluated annually for 5 years. MAIN OUTCOME MEASURES: Visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), scanning laser polarimetry (SLP), and visual evoked potentials. Expanded Disability Status Scale (EDSS) scores, disease duration, treatments, prior optic neuritis episodes, and quality of life (QOL; based on the 54-item Multiple Sclerosis Quality of Life Scale score). RESULTS: Optical coherence tomography (OCT) revealed changes in all RNFL thicknesses in both groups. In the MS group, changes were detected in average thickness and in the mean deviation using the GDx-VCC nerve fiber analyzer (Laser Diagnostic Technologies, San Diego, CA) and in the P100 latency of visual evoked potentials; no changes were detected in visual acuity, color vision, or visual fields. Optical coherence tomography showed greater differences in the inferior and temporal RNFL thicknesses in both groups. In MS patients only, OCT revealed a moderate correlation between the increase in EDSS and temporal and superior RNFL thinning. Temporal RNFL thinning based on OCT results was correlated moderately with decreased QOL. CONCLUSIONS: Multiple sclerosis patients exhibit a progressive axonal loss in the optic nerve fiber layer. Retinal nerve fiber layer thinning based on OCT results is a useful marker for assessing MS progression and correlates with increased disability and reduced QOL.

[The Subretinal Implant - Clinical Results]. / Das subretinale Implantat ­ klinische Ergebnisse.

Since the end of the last century, subretinal electronic chips have been used to restore vision in patients blinded by degenerative retinal diseases such as retinitis pigmentosa. Various procedures have been suggested by different international scientific groups. The promising were the retinal-based concepts, for which there are now human data. The two distinct retina-based concepts not only differ in the site of stimulation (epi- or subretinal), but in their physiological concept. Whereas in camera-based systems (epiretinal, transchoroidal), eye movements cannot be used to detect objects, this is possible with subretinal access. It is as yet unclear as to whether this is relevant to restoring some kind of useful visual perception. This and other questions can only be answered by carefully designed human studies with sufficient patient numbers. Comparison of the visual results of the different groups is neither simple nor trivial. The implantations in each project need well trained and skilled retinal surgeons.

[Future Developments in Retinal Prostheses]. / Zukünftige Entwicklungen bei implantierbaren Netzhautprothesen.

Implantable retinal prostheses for the blind are already in use. In blind subjects suffering from retinitis pigmentosa (RP), these systems are able to induce phosphenes. However, the measurable gain in vision is limited. This is due to degeneration in the retina itself and to the technology, which is used in the currently available systems. Research groups and companies are working on solutions and prototypes to improve the outcome of electrical stimulation in the visual system. One improvement will be to enlarge the electrode array in order to restore a larger visual field. A second approach is to enlarge the number of electrodes and to place them at a higher density to improve the spatial resolution of the system. A third concept is to develop a recording unit within the electrode array to analyse ganglion cell behaviour underneath the electrode. This information can than be used to optimise the stimulation pattern. Not only retinal prostheses are under development but also systems to stimulate the retina from the suprachoroidal space, to directly stimulate the optic nerve or the lateral geniculate body or even the primary visual cortex.

Optogenetics.

PURPOSE OF REVIEW: In this review, we will discuss the recent developments in optogenetics and their potential applications in ophthalmology to restore vision in retinal degenerative diseases. RECENT FINDINGS: In recent years, we have seen major advances in the field of optogenetics, providing us with novel opsins for potential applications in the retina. Microbial opsins with improved light sensitivity and red-shifted action spectra allow optogenetic stimulation at light levels well below the safety threshold in the human eye. In parallel, remarkable success in the development of highly efficient viral vectors for ocular gene therapy led to new strategies of using these novel optogenetic tools for vision restoration. SUMMARY: These recent findings show that novel optogenetic tools and viral vectors for ocular gene delivery are now available providing many opportunities to develop potential optogenetic strategies for vision restoration.

Light-controlled biphasic current stimulator IC using CMOS image sensors for high-resolution retinal prosthesis and in vitro experimental results with rd1 mouse.

Retinal prosthetic devices stimulate retinal nerve cells with electrical signals proportional to the incident light intensities. For a high-resolution retinal prosthesis, it is necessary to reduce the size of the stimulator pixels as much as possible, because the retinal nerve cells are concentrated in a small area of approximately 5 mm × 5 mm. In this paper, a miniaturized biphasic current stimulator integrated circuit is developed for subretinal stimulation and tested in vitro. The stimulator pixel is miniaturized by using a complementary metal-oxide-semiconductor (CMOS) image sensor composed of three transistors. Compared to a pixel that uses a four-transistor CMOS image sensor, this new design reduces the pixel size by 8.3%. The pixel size is further reduced by simplifying the stimulation-current generating circuit, which provides a 43.9% size reduction when compared to the design reported to be the most advanced version to date for subretinal stimulation. The proposed design is fabricated using a 0.35 µm bipolar-CMOS-DMOS process. Each pixel is designed to fit in a 50 µ m × 55 µm area, which theoretically allows implementing more than 5000 pixels in the 5 mm × 5 mm area. Experimental results show that a biphasic current in the range of 0 to 300 µA at 12 V can be generated as a function of incident light intensities. Results from in vitro experiments with rd1 mice indicate that the proposed method can be effectively used for retinal prosthesis with a high resolution.

Virtual electrodes by current steering in retinal prostheses.

PURPOSE: Retinal prostheses are an approved treatment for vision restoration in retinal degenerative diseases; however, present implants have limited resolution and simply increasing the number of electrodes is limited by design issues. In cochlear implants, virtual electrodes can be created by simultaneous stimulation of adjacent physical electrodes (current steering). The present study assessed whether this type of current steering can be adapted for retinal implants. METHODS: Suprachoroidal electrode arrays were implanted in four normally sighted cat eyes. Electrode pairs were driven simultaneously at different current levels and current ratios. Multiunit spiking activity in the visual cortex was recorded. Spike distribution across channels enabled generation of cortical activation maps and calculation of centroid positions. For each current configuration, centroid shifts between two virtual electrodes were compared to shifts obtained from physical electrode stimulation. RESULTS: Using current steering, virtual electrodes with different cortical activation maps could be created. Cortical centroids were found to shift as a function of the current ratio used for virtual electrodes and were similar to the centroid shifts seen when using physical electrodes. In addition, the cortical response to stimulation of a physical electrode could be reproduced by applying current steering to electrodes on either side of the physical electrode. CONCLUSIONS: These results suggest that current steering can alter activation patterns in the visual cortex and could enhance visual perception in retinal implants by eliciting phosphene percepts intermediate between those elicited by physical electrodes. These results inform development of new electrode arrays that can take advantage of current steering.

A system verification platform for high-density epiretinal prostheses.

Retinal prostheses have restored light perception to people worldwide who have poor or no vision as a consequence of retinal degeneration. To advance the quality of visual stimulation for retinal implant recipients, a higher number of stimulation channels is expected in the next generation retinal prostheses, which poses a great challenge to system design and verification. This paper presents a system verification platform dedicated to the development of retinal prostheses. The system includes primary processing, dual-band power and data telemetry, a high-density stimulator array, and two methods for output verification. End-to-end system validation and individual functional block characterization can be achieved with this platform through visual inspection and software analysis. Custom-built software running on the computers also provides a good way for testing new features before they are realized by the ICs. Real-time visual feedbacks through the video displays make it easy to monitor and debug the system. The characterization of the wireless telemetry and the demonstration of the visual display are reported in this paper using a 256-channel retinal prosthetic IC as an example.

Interim results from the international trial of Second Sight's visual prosthesis.

PURPOSE: This study evaluated the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, CA) in blind subjects with severe outer retinal degeneration. DESIGN: Single-arm, prospective, multicenter clinical trial. PARTICIPANTS: Thirty subjects were enrolled in the United States and Europe between June 6, 2007, and August 11, 2009. All subjects were followed up for a minimum of 6 months and up to 2.7 years. METHODS: The electronic stimulator and antenna of the implant were sutured onto the sclera using an encircling silicone band. Next, a pars plana vitrectomy was performed, and the electrode array and cable were introduced into the eye via a pars plana sclerotomy. The microelectrode array then was tacked to the epiretinal surface. MAIN OUTCOME MEASURES: The primary safety end points for the trial were the number, severity, and relation of adverse events. Principal performance end points were assessments of visual function as well as performance on orientation and mobility tasks. RESULTS: Subjects performed statistically better with the system on versus off in the following tasks: object localization (96% of subjects), motion discrimination (57%), and discrimination of oriented gratings (23%). The best recorded visual acuity to date is 20/1260. Subjects' mean performance on orientation and mobility tasks was significantly better when the system was on versus off. Seventy percent of the patients did not have any serious adverse events (SAEs). The most common SAE reported was either conjunctival erosion or dehiscence over the extraocular implant and was treated successfully in all subjects except in one, who required explantation of the device without further complications. CONCLUSIONS: The long-term safety results of Second Sight's retinal prosthesis system are acceptable, and most subjects with profound visual loss perform better on visual tasks with system than without it.

Electric field stimulation of bipolar cells in a degenerated retina--a theoretical study.

Subretinal implants are the subject of clinical investigation for their ability to evoke useful visual sensations in blind individuals via electrical stimulation of the diseased retina. We investigated the spatial characteristic of the retinal polarization obtained by electric field stimulation through a subretinally located monopolar electrode array and bipolar electrode array. By combining electric potential simulation through a boundary element method with a segmented cell model, we computed the membrane voltage at the axon terminal of the bipolar cells as a function of the axon length (50-110 microm) and the electrode diameter. We found that short OFF bipolar cells are predominantly addressed by small bipolar electrodes (diameter between 60 and 100 microm) and by using a short duration ( < 150 micros) of the stimulating voltage pulse. Long ON cells are best addressed by large monopolar electrodes (diameter > 100 microm) and a long pulse duration ( > 150 micros). However, the low selectivity of the electric field stimulation with regard to the cell length does not enable the individual depolarization of long OFF cells and short ON cells. When the stimulation must take place at multiple retinal sites simultaneously, the bipolar electrode arrays allow for higher spatial modulation of the polarization of the axon terminal than the monopolar arrays.

[Development of a minimally invasive retinal implant system]. / Entwicklung eines minimal-invasiven Retinaimplantats.

PURPOSE: It was the aim of this project to develop a minimally invasive prosthetic retinal implant system for the rehabilitation of blind patients suffering from distal retinal degenerations. For this purpose, encoded image information will be transferred to surviving retinal neurons by electrical stimulation applied via intraretinal microelectrodes. METHODS: The technological concept was generated in a feasibility study of alternative approaches to minimally invasive retinal prostheses. Then two series of test implants were fabricated and applied in different in vitro- and in vivo- studies before a long-term implantation trial was initiated. RESULTS: The conceptual design process was resulting in a system with stimulating microelectrodes penetrating the sclera and choroid ab externo, and with all other implant components in episcleral position. Microelectrode penetration and surgical application techniques were successfully tested in several series of experiments. Finally, a long-term application of test devices was successfully initiated. CONCLUSION: Results so far demonstrate the conceptual feasibility, easy-to-perform surgical application, and long-term biocompatibility of the newly designed minimally invasive retinal implant system.

Tinted contact lenses in Bothnia dystrophy.

PURPOSE: To determine whether tinted contact lenses can improve visual function in patients with Bothnia dystrophy (BD), a genetically defined retinal dystrophy with prolonged dark adaptation. METHODS: Twelve patients with BD were fitted with the same type of soft contact lenses tinted dark brown. Visual acuity (VA), contrast vision, near vision and visual fields were tested before and 1 month after contact lens fitting. The patients completed a visual function questionnaire. The physical properties of the contact lenses were tested using spectrophotometry. RESULTS: The patients with the lowest VA described the most obvious improvement in visual function. This group of patients preferred darker contact lenses and continued wearing their contact lenses after the study ended. The patients with the best VA preferred lighter contact lenses and a few patients in this group discontinued contact lens wear upon completion of the study. CONCLUSIONS: Visual function in BD patients was improved by dark tinted contact lenses. The optimal colour for lenses varies, depending on the season and the individual. Other patient groups with retinal dystrophies associated with prolonged dark adaptation or dysfunction of the cone system, such as cone dystrophies or achromatopsia, may also benefit from this type of contact lens.

A method for generating precise temporal patterns of retinal spiking using prosthetic stimulation.

The goal of retinal prosthetic devices is to generate meaningful visual information in patients that have lost outer retinal function. To accomplish this, these devices should generate patterns of ganglion cell activity that closely resemble the spatial and temporal components of those patterns that are normally elicited by light. Here, we developed a stimulus paradigm that generates precise temporal patterns of activity in retinal ganglion cells, including those patterns normally generated by light. Electrical stimulus pulses (> or =1-ms duration) elicited activity in neurons distal to the ganglion cells; this resulted in ganglion cell spiking that could last as long as 100 ms. However, short pulses, <0.15 ms, elicited only a single spike within 0.7 ms of the leading edge of the pulse. Trains of these short pulses elicited one spike per pulse at frequencies < or =250 Hz. Patterns of short electrical pulses (derived from normal light elicited spike patterns) were delivered to ganglion cells and generated spike patterns that replicated the normal light patterns. Finally, we found that one spike per pulse was elicited over almost a 2.5:1 range of stimulus amplitudes. Thus a common stimulus amplitude could accommodate a 2.5:1 range of activation thresholds, e.g., caused by differences arising from cell biophysical properties or from variations in electrode-to-cell distance arising when a multielectrode array is placed on the retina. This stimulus paradigm can generate the temporal resolution required for a prosthetic device.

Functional verification of pulse frequency modulation-based image sensor for retinal prosthesis by in vitro electrophysiological experiments using frog retina.

The functioning of a 16 x 16 pixel pulse frequency modulation (PFM) image sensor for retinal prosthesis is verified through in vitro electrophysiological experiments using detached frog retinas. This image sensor is a prototype for demonstrating the application to in vitro electrophysiological experiments. Each pixel of the image sensor consists of a pulse generator (PFM photosensor), a stimulus circuit, and a stimulus electrode (Al bonding pad). The image sensor is fabricated using standard 0.6 microm CMOS technology. For in vitro electrophysiological experiments, a Pt/Au stacked electrode is formed on the Al bonding pad of each pixel and the entire sensor is fixed in epoxy resin. The PFM image sensor is confirmed experimentally to provide electrical stimulus to the retinal cells in a detached frog retina.

[Retinal implants. Patients' expectations]. / Retinaimplantate. Erwartungen aus Patientensicht.

The "Pro Retina" Society and the "Retina Implant" Foundation, two patients associations with the goal of "preventing blindness," view the "Retina Implant" project as a possibility for providing blind individuals a modicum of restored vision. Both patients associations cultivated a cooperative relationship with researchers and policy makers already during the research phase, introducing the wishes and concerns of patients into considerations and providing information and the groundwork for acceptance in society and among those who may potentially benefit from the method. An initial survey of patients, the visually impaired, and blind people revealed that recovery of sight not only represents a medical and technical problem but that it also involves numerous psychosocial implications. By adhering to ethical standards in implantations, in particular by taking patient autonomy into consideration, anxieties and fears can be reduced. It would appear from early positive results in a short-term clinical study that soon successful chronic retinal implantation can be expected. The dedication displayed by physicians, researchers, and the industry as well as the willingness of the Federal Ministry for Research to take the risk are appreciated and greatfully accepted by the patients and their relatives.

[Electronic visual prostheses]. / Elektronische Sehprothesen.

BACKGROUND: Currently, no treatment is available for progressive retinal dystrophies. The fabrication of an implantable visual prosthesis seems to be possible now as a result of advances in the fabrication of extremely small micro-systems and their encapsulation in biocompatible materials. MATERIALS AND METHODS: The development of implantable visual prostheses is based on the fabrication of remotely controlled microelectrode arrays which have to be implanted in different target regions of the visual system. Prototypes of such systems have already been implanted in animal experiments and also in pilot trials in humans. RESULTS: Four concepts are pursued: 1. epiretinal implant -- fixation onto the inner retinal surface; 2. subretinal implant -- implantation within the subretinal space; 3. optic nerve stimulator -- cuff electrode placed around the optic nerve; 4. cortical prosthesis -- implantation of surface electrodes in the region of the visual cortex. All these concepts have already been applied in pilot trials in humans. The results show some promising visual perception. CONCLUSIONS: The use of implantable electronic visual prostheses will become a possible option in the treatment of currently untreatable retinal dystrophies. Further basic research initiatives are necessary as well as further human trials to characterize the stimulation parameters and to improve the currently available devices.

Long-term stimulation by active epiretinal implants in normal and RCD1 dogs.

An epiretinal prosthesis, consisting of an extraocular microelectronic stimulator and an intraocular electrode array, was implanted in one eye of three blind and three sighted dogs. Three dogs (2 blind, 1 normal) were stimulated for 120 days, and two dogs (both normal) for 60 and 103 days respectively for 8-10 h/day at levels of 0.1 mC cm(-2) and 0.05 mC cm(-2), with each stimulus level presented to half of the array. One blind dog was kept as an inactive implant control. During the study period, electroretinograms (ERG) and fundus photographs were recorded. At the end of the study period, the dogs were sacrificed and histological and morphometric evaluation was made of the retina. No inflammatory reaction, neovascularization or hemorrhage was observed during the follow-up examinations. ERGs were unchanged. Stimulus levels used were of sufficient amplitude to elicit cortical evoked potentials. Histological evaluation showed no inflammatory infiltrates or changes in retina morphometry related to electrical stimulation when compared to the unstimulated control eye. Morphometric analysis revealed no consistent differences relating to electrical stimulation. In summary, chronic electrical stimulation of the dog retina at up to 0.1 mC cm(-2) with an epiretinal prosthesis does not appear to adversely affect the retina.