Henri Lorach

Photovoltaic restoration of sight with high visual acuity.

Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration.

Three-dimensional electrode arrays for retinal prostheses: modeling, geometry optimization and experimental validation

Three-dimensional electrode geometries were proposed to increase the spatial resolution in retinal prostheses aiming at restoring vision in blind patients. We report here the results from a study in which finite-element modeling was used to design and optimize three-dimensional electrode geometries. Proposed implants exhibit an array of well-like shapes containing stimulating electrodes at their bottom, while the common return grid electrode surrounds each well on the implant top surface. Extending stimulating electrodes and/or the grid return electrode on the walls of the cavities was also considered. The goal of the optimization was to find model parameters that maximize the focalization of electrical stimulation, and therefore the spatial resolution of the electrode array. The results showed that electrode geometries with a well depth of 30 µm yield a tenfold increase in selectivity compared to the planar structures of similar electrode dimensions. Electrode array prototypes were microfabricated and implanted in dystrophic rats to determine if the tissue would behave as hypothesized in the model. Histological examination showed that retinal bipolar cells integrate the electrode well, creating isolated cell clusters. The modeling analysis showed that the stimulation current is confounded within the electrode well, leading to selective electrical stimulation of the individual bipolar cell clusters and thereby to electrode arrays with higher spatial resolution.

Taurine Provides Neuroprotection against Retinal Ganglion Cell Degeneration

Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases leading to blindness, either as a primary process like in glaucoma, or secondary to photoreceptor loss. However, no commercial drug is yet directly targeting RGCs for their neuroprotection. In the 70s, taurine, a small sulfonic acid provided by nutrition, was found to be essential for the survival of photoreceptors, but this dependence was not related to any retinal disease. More recently, taurine deprivation was incriminated in the retinal toxicity of an antiepileptic drug. We demonstrate here that taurine can improve RGC survival in culture or in different animal models of RGC degeneration. Taurine effect on RGC survival was assessed in vitro on primary pure RCG cultures under serum-deprivation conditions, and on NMDA-treated retinal explants from adult rats. In vivo, taurine was administered through the drinking water in two glaucomatous animal models (DBA/2J mice and rats with vein occlusion) and in a model of Retinitis pigmentosa with secondary RGC degeneration (P23H rats). After a 6-day incubation, 1 mM taurine significantly enhanced RGCs survival (+68%), whereas control RGCs were cultured in a taurine-free medium, containing all natural amino-acids. This effect was found to rely on taurine-uptake by RGCs. Furthermore taurine (1 mM) partly prevented NMDA-induced RGC excitotoxicity. Finally, taurine supplementation increased RGC densities both in DBA/2J mice, in rats with vein occlusion and in P23H rats by contrast to controls drinking taurine-free water. This study indicates that enriched taurine nutrition can directly promote RGC survival through RGC intracellular pathways. It provides evidence that taurine can positively interfere with retinal degenerative diseases.

Performance of photovoltaic arrays in-vivo and characteristics of prosthetic vision in animals with retinal degeneration

Loss of photoreceptors during retinal degeneration leads to blindness, but information can be reintroduced into the visual system using electrical stimulation of the remaining retinal neurons. Subretinal photovoltaic arrays convert pulsed illumination into pulsed electric current to stimulate the inner retinal neurons. Since required irradiance exceeds the natural luminance levels, an invisible near-infrared (915 nm) light is used to avoid photophobic effects. We characterized the thresholds and dynamic range of cortical responses to prosthetic stimulation with arrays of various pixel sizes and with different number of photodiodes. Stimulation thresholds for devices with 140 μm pixels were approximately half those of 70 μm pixels, and with both pixel sizes, thresholds were lower with 2 diodes than with 3 diodes per pixel. In all cases these thresholds were more than two orders of magnitude below the ocular safety limit. At high stimulation frequencies (>20 Hz), the cortical response exhibited flicker fusion. Over one order of magnitude of dynamic range could be achieved by varying either pulse duration or irradiance. However, contrast sensitivity was very limited. Cortical responses could be detected even with only a few illuminated pixels. Finally, we demonstrate that recording of the corneal electric potential in response to patterned illumination of the subretinal arrays allows monitoring the current produced by each pixel, and thereby assessing the changes in the implant performance over time.

Neural stimulation for visual rehabilitation: Advances and challenges

Blindness affects tens of million people worldwide and its prevalence constantly increases along with population aging. In some pathologies leading to vision loss, prosthetic approaches are currently the only hope for the patient to recover some visual perception. Here, we review the latest advances in visual prosthetic strategies with their respective strength and weakness. The principle is to electrically stimulate neurons along the visual pathway. Ocular approaches target the remaining retinal cells whereas brain stimulation aims at stimulating higher visual structures directly. Even though ocular approaches are less invasive and easier to implement, brain stimulation can be applied to diseases where the connection between the retina and the brain is lost such as in glaucoma and could therefore benefit to patients with different pathologies. Today, numbers of groups are investigating these strategies and the first devices start being commercialized. However, critical bottlenecks still impair our scientific efforts towards efficient visual implants. These challenges include electrode miniaturization, material optimization, multiplexing of stimulation channels and encoding of visual information into electrical stimuli.

Taurine Is a Crucial Factor to Preserve Retinal Ganglion Cell Survival

Retinal ganglion cells (RGCs) are spiking neurons, which send visual information to the brain, through the optic nerve. RGC degeneration occurs in retinal diseases, either as a primary process or secondary to photoreceptor loss. Mechanisms involved in this neuronal degeneration are still unclear and no drugs directly targeting RGC neuroprotection are yet available. Here, we show that taurine is one factor involved in preserving the RGC survival. Indeed, a taurine depletion induced by the antiepileptic drug, vigabatrin, was incriminated in its retinal toxicity leading to the RGC loss. Similarly, we showed that RGC degeneration can be induced by pharmacologically blocking the taurine-transporter with the chronic administration of a selective inhibitor, which results in a decrease in the taurine levels both in the plasma and in the retinal tissue. Finally, we found that taurine can directly prevent RGC degeneration, occurring either in serum-deprived pure RGC cultures or in animal models presenting an RGC loss (glaucomatous rats and the P23H rats, a model for retinitis pigmentosa). These data suggest that the retinal taurine level is a crucial marker to prevent RGC damage in major retinal diseases.

Development of Animal Models of Local Retinal Degeneration

PURPOSE Development of nongenetic animal models of local retinal degeneration is essential for studies of retinal pathologies, such as chronic retinal detachment or age-related macular degeneration. We present two different methods to induce a highly localized retinal degeneration with precise onset time, that can be applied to a broad range of species in laboratory use. METHODS A 30-μm thin polymer sheet was implanted subretinally in wild-type (WT) rats. The effects of chronic retinal separation from the RPE were studied using histology and immunohistochemistry. Another approach is applicable to species with avascular retina, such as rabbits, where the photoreceptors and RPE were thermally ablated over large areas, using a high power scanning laser. RESULTS Photoreceptors above the subretinal implant in rats degenerated over time, with 80% of the outer nuclear layer disappearing within a month, and the rest by 3 months. Similar loss was obtained by selective photocoagulation with a scanning laser. Cells in the inner nuclear layer and ganglion cell layer were preserved in both cases. However, there were signs of rewiring and decrease in the size of the bipolar cell terminals in the damaged areas. CONCLUSIONS Both methods induce highly reproducible degeneration of photoreceptors over a defined area, with complete preservation of the inner retinal neurons during the 3-month follow-up. They provide a reliable platform for studies of local retinal degeneration and development of therapeutic strategies in a wide variety of species.

Retinal safety of near infrared radiation in photovoltaic restoration of sight

Photovoltaic restoration of sight requires intense near-infrared light to effectively stimulate retinal neurons. We assess the retinal safety of such radiation with and without the retinal implant. Retinal damage threshold was determined in pigmented rabbits exposed to 880nm laser radiation. The 50% probability (ED50) of retinal damage during 100s exposures with 1.2mm diameter beam occurred at 175mW, corresponding to a modeled temperature rise of 12.5°C. With the implant, the same temperature was reached at 78mW, close to the experimental ED50 of 71mW. In typical use conditions, the retinal temperature rise is not expected to exceed 0.43°C, well within the safety limits for chronic use.

Photovoltaic Restoration of Sight with High Visual Acuity in Rats with Retinal Degeneration

Patients with retinal degeneration lose sight due to gradual demise of photoreceptors. Electrical stimulation of the surviving retinal neurons provides an alternative route for delivery of visual information. Subretinal photovoltaic arrays with 70μm pixels were used to convert pulsed near-IR light (880-915nm) into pulsed current to stimulate the nearby inner retinal neurons. Network-mediated responses of the retinal ganglion cells (RGCs) could be modulated by pulse width (1-20ms) and peak irradiance (0.5-10 mW/mm2). Similarly to normal vision, retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images, and non-linear spatial summation. Spatial resolution was assessed in-vitro and in-vivo using alternating gratings with variable stripe width, projected with rapidly pulsed illumination (20-40Hz). In-vitro, average size of the electrical receptive fields in normal retina was 248±59μm – similar to their visible light RF size: 249±44μm. RGCs responded to grating stripes down to 67μm using photovoltaic stimulation in degenerate rat retina, and 28μm with visible light in normal retina. In-vivo, visual acuity in normally-sighted controls was 29±5μm/stripe, vs. 63±4μm/stripe in rats with subretinal photovoltaic arrays, corresponding to 20/250 acuity in human eye. With the enhanced acuity provided by eye movements and perceptual learning in human patients, visual acuity might exceed the 20/200 threshold of legal blindness. Ease of implantation and tiling of these wireless arrays to cover a large visual field, combined with their high resolution opens the door to highly functional restoration of sight.

Interactions of prosthetic and natural vision in animals with local retinal degeneration

PURPOSE Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration. METHODS Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns. RESULTS We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina. CONCLUSIONS Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration.