Neural activity shaping in visual prostheses with deep learning.

OBJECTIVE: The visual perception provided by retinal prostheses is limited by the overlapping current spread of adjacent electrodes. This reduces the spatial resolution attainable with unipolar stimulation. Conversely, simultaneous multipolar stimulation guided by the measured neural responses - Neural Activity Shaping (NAS) - can attenuate excessive spread of excitation allowing for more precise control over the pattern of neural activation. However, predicting the results of a multipolar stimulus pattern is a challenging task. Previous attempts focused on analytical solutions based on an assumed linear nonlinear model of retinal response; an Analytical Model Inversion (AMI) approach. Here, we propose a model-free solution for NAS, using Artificial Neural Networks (ANNs) that could be trained with data acquired from the implant. APPROACH: Our method consists of two ANNs trained sequentially. The Measurement Predictor Network (MPN) is trained on data from the implant and is used to predict how the retina responds to multipolar stimulation. The Stimulus Generator Network (STG) is trained on a large dataset of natural images and uses the trained MPN to determine efficient multipolar stimulus patterns by learning its inverse model. We validate our method in silico using a realistic model of retinal response to multipolar stimulation. Main Results: We show that our ANN-based NAS approach produces sharper retinal activations than the conventional unipolar stimulation strategy. As a theoretical bench-mark of optimal NAS results, we implemented AMI stimulation by inverting the model used to simulate the retina. Our ANN strategy produced equivalent results to AMI, while not being restricted to any specific type of retina model and being three orders of magnitude more computationally efficient. SIGNIFICANCE: Our novel protocol provides a method for efficient and personalized retinal stimulation, which may improve the visual experience and quality of life of retinal prosthesis users. .

Photovoltaic, wireless wide-field epiretinal prosthesis to treat retinitis pigmentosa.

PURPOSE: To develop and evaluate a photovoltaic, wireless wide-field epiretinal prosthesis for the treatment of retinitis pigmentosa. METHODS: A mosaic array of thinned silicon-based photodiodes with integrated thin-film stimulation electrodes was fabricated with a flexible polyimide substrate film to form a film-based miniaturized electronic system with wireless optical power and signal transmission and integrated electrostimulation. Manufactured implants were characterized with respect to their optoelectronic performance and biocompatibility following DIN EN ISO 10993. RESULTS: A 14 mm diameter prosthesis containing 1276 pixels with a maximum sensitivity at a near infrared wavelength of 905 nm and maximized stimulation current density 30-50 µm below the electrodes was developed for direct activation of retinal ganglion cells during epiretinal stimulation. Fabricated prostheses demonstrated mucosal tolerance and the preservation of both metabolic activity, proliferation and membrane integrity of human fibroblasts as well as the retinal functions of bovine retinas. Illumination of the prosthesis, which was placed epiretinally on an isolated perfused bovine retina, with infrared light resulted in electrophysiological recordings reminiscent of an a-wave (hyperpolarization) and b-wave (depolarization). CONCLUSIONS: A photovoltaic, wireless wide-field epiretinal prosthesis for the treatment of retinitis pigmentosa using near infrared light for signal transmission was designed, manufactured and its biocompatibility and functionality demonstrated in vitro and ex vivo.

Prosthetic Visual Acuity with the PRIMA Subretinal Microchip in Patients with Atrophic Age-Related Macular Degeneration at 4 Years Follow-up.

Objective: To assess the efficacy and safety of the PRIMA neurostimulation system with a subretinal microchip for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months postimplantation. Design: Feasibility clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.govNCT03333954). Subjects: Five patients with GA, no foveal light perception, and VA of logarithm of the minimum angle of resolution (logMAR) 1.3 to 1.7 (20/400-20/1000) in their worse-seeing "study" eye. Methods: In patients subretinally implanted with a photovoltaic neurostimulation array containing 378 pixels of 100 µm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 m. The system's external components, augmented reality glasses, and pocket computer provide image processing capabilities, including zoom. Main Outcome Measures: Visual acuity using ETDRS charts with and without the system, as well as light sensitivity in the central visual field, measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and OCT up to 48 months postimplantation. Results: All 5 subjects met the primary end point of light perception elicited by the implant in the scotoma area. In 1 patient, the implant was incorrectly inserted into the choroid. One subject died 18 months postimplantation due to study-unrelated reasons. ETDRS VA results for the remaining 3 subjects are reported here. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to a mean logMAR of 1.39, or Snellen of 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (standard error 5.1) 95% confidence intervals (13.4, 49.9; P < 0.0001). Natural peripheral visual function in the treated eye did not decline after surgery or during the 48-month follow-up period (P = 0.08). Conclusions: Subretinal implantation of PRIMA in subjects with GA experiencing profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48 months. Prosthetic central vision provided by photovoltaic neurostimulation enabled patients to reliably recognize letters and sequences of letters, and with zoom, it improved VA of up to 8 ETDRS lines. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

3D electronic implants in subretinal space: Long-term follow-up in rodents.

Clinical results with photovoltaic subretinal prosthesis (PRIMA) demonstrated restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution matching the 100 µm pixel size. Since scaling the pixels below 75 µm in the current bipolar planar geometry will significantly limit the penetration depth of the electric field and increase stimulation threshold, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 32-36 weeks post-implantation in aged rats. With both flat and 3D implants, signals elicited in the visual cortex decreased after the day of implantation by more than 3-fold, and gradually recovered over the next 12-16 weeks. With 25 µm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the retina. Retinal thickness and full-field stimulation threshold with 40 µm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10 ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 µm-wide wells, and stimulation threshold increased over 12-16 weeks, before stabilizing at about 0.08 mW/mm2. Such threshold is still significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

Enhanced organic photovoltaic-based retinal prosthesis using a cathode-modified structure with plasmonic silver nanoparticles: a computational study.

Introduction: Organic interfaces have recently emerged as a breakthrough trend in biomedical applications, demonstrating exceptional performance in stimulating retinal neuronal cells owing to their high flexibility and compatibility with tissues. However, the primary challenge associated with organic photovoltaics is their low efficiency compared to that of their inorganic counterparts. Among different approaches, embedding plasmonic metal nanoparticles (NPs) in active or buffer layers can efficiently improve photovoltaic cell performance. Methods: A cathode decorated with silver nanoparticles is introduced to increase the absorption Phenomenon and improve the interface performance as a computational study. In addition to embedding spherical silver nanoparticles in the active layer (A-AgNPs), a monolayer array of spherical AgNPs in the cathode electrode (K-AgNPs) is incorporated. In this configuration, the large K-AgNPs play dual roles: acting as cathode electrode and serving as plasmonic centers to increase light trapping and absorption. The bulk heterojunction PCPDTBT:PCBM is chosen as the active layer due to its favorable electronic properties. Results: Our computational analysis demonstrates a notable 10% enhancement in the photovoltaic cell current density for the developed structure with K-AgNPs in contrast to without them. Additionally, the simulation results reveal that the modeled device achieves a two-fold efficiency of the bare photovoltaic cell (without A-AgNPs and K-AgNPs), which is particularly evident at a low intensity of 0.26 mW/mm2. Discussion: This study aims to propose an efficient epiretinal prosthesis structure using a different strategy for plasmonic effects rather than conventional methods, such as incorporating NPs into the active or buffer layer. This structure can prevent the harmful side effects of using large metal NPs (r > 10 nm) in the active layer during exciton quenching, charge trapping, and recombination, which deteriorate the power conversion efficiency (PCE).

Enhancing Prosthetic Vision by Upgrade of a Subretinal Photovoltaic Implant in situ.

In patients with atrophic age-related macular degeneration, subretinal photovoltaic implant (PRIMA) provided visual acuity up to 20/440, matching its 100µm pixels size. Next-generation implants with smaller pixels should significantly improve the acuity. This study in rats evaluates removal of a subretinal implant, replacement with a newer device, and the resulting grating acuity in-vivo. Six weeks after the initial implantation with planar and 3-dimensional devices, the retina was re-detached, and the devices were successfully removed. Histology demonstrated a preserved inner nuclear layer. Re-implantation of new devices into the same location demonstrated retinal re-attachment to a new implant. New devices with 22µm pixels increased the grating acuity from the 100µm capability of PRIMA implants to 28µm, reaching the limit of natural resolution in rats. Reimplanted devices exhibited the same stimulation threshold as for the first implantation of the same implants in a control group. This study demonstrates the feasibility of safely upgrading the subretinal photovoltaic implants to improve prosthetic visual acuity.

Corrigendum: Electrically-evoked responses for retinal prostheses are differentially altered depending on ganglion cell types in outer retinal neurodegeneration caused by Crb1 gene mutation.

[This corrects the article DOI: 10.3389/fncel.2023.1115703.].

Nanoparticle-based optical interfaces for retinal neuromodulation: a review.

Degeneration of photoreceptors in the retina is a leading cause of blindness, but commonly leaves the retinal ganglion cells (RGCs) and/or bipolar cells extant. Consequently, these cells are an attractive target for the invasive electrical implants colloquially known as "bionic eyes." However, after more than two decades of concerted effort, interfaces based on conventional electrical stimulation approaches have delivered limited efficacy, primarily due to the current spread in retinal tissue, which precludes high-acuity vision. The ideal prosthetic solution would be less invasive, provide single-cell resolution and an ability to differentiate between different cell types. Nanoparticle-mediated approaches can address some of these requirements, with particular attention being directed at light-sensitive nanoparticles that can be accessed via the intrinsic optics of the eye. Here we survey the available known nanoparticle-based optical transduction mechanisms that can be exploited for neuromodulation. We review the rapid progress in the field, together with outstanding challenges that must be addressed to translate these techniques to clinical practice. In particular, successful translation will likely require efficient delivery of nanoparticles to stable and precisely defined locations in the retinal tissues. Therefore, we also emphasize the current literature relating to the pharmacokinetics of nanoparticles in the eye. While considerable challenges remain to be overcome, progress to date shows great potential for nanoparticle-based interfaces to revolutionize the field of visual prostheses.

Axonal stimulation affects the linear summation of single-point perception in three Argus II users.

Objective.Retinal implants use electrical stimulation to elicit perceived flashes of light ('phosphenes'). Single-electrode phosphene shape has been shown to vary systematically with stimulus parameters and the retinal location of the stimulating electrode, due to incidental activation of passing nerve fiber bundles. However, this knowledge has yet to be extended to paired-electrode stimulation.Approach.We retrospectively analyzed 3548 phosphene drawings made by three blind participants implanted with an Argus II Retinal Prosthesis. Phosphene shape (characterized by area, perimeter, major and minor axis length) and number of perceived phosphenes were averaged across trials and correlated with the corresponding single-electrode parameters. In addition, the number of phosphenes was correlated with stimulus amplitude and neuroanatomical parameters: electrode-retina and electrode-fovea distance as well as the electrode-electrode distance to ('between-axon') and along axon bundles ('along-axon'). Statistical analyses were conducted using linear regression and partial correlation analysis.Main results.Simple regression revealed that each paired-electrode shape descriptor could be predicted by the sum of the two corresponding single-electrode shape descriptors (p < .001). Multiple regression revealed that paired-electrode phosphene shape was primarily predicted by stimulus amplitude and electrode-fovea distance (p < .05). Interestingly, the number of elicited phosphenes tended to increase with between-axon distance (p < .05), but not with along-axon distance, in two out of three participants.Significance.The shape of phosphenes elicited by paired-electrode stimulation was well predicted by the shape of their corresponding single-electrode phosphenes, suggesting that two-point perception can be expressed as the linear summation of single-point perception. The impact of the between-axon distance on the perceived number of phosphenes provides further evidence in support of the axon map model for epiretinal stimulation. These findings contribute to the growing literature on phosphene perception and have important implications for the design of future retinal prostheses.

Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.

Objective.Retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables increasing prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigated 3-dimensional (3d) structures on top of photovoltaic arrays for enhanced penetration of the electric field, permitting higher resolution implants.Approach.3D COMSOL models of subretinal photovoltaic arrays were developed to accurately quantify the electrodynamics during stimulation and verified through comparison to flat photovoltaic arrays. Models were applied to optimize the design of 3D electrode structures (pillars and honeycombs). Return electrodes on honeycomb walls vertically align the electric field with bipolar cells for optimal stimulation. Pillars elevate the active electrode, thus improving proximity to target neurons. The optimized 3D structures were electroplated onto existing flat subretinal prostheses.Main results.Simulations demonstrate that despite exposed conductive sidewalls, charge mostly flows via high-capacitance sputtered iridium oxide films topping the 3D structures. The 24µm height of honeycomb structures was optimized for integration with the inner nuclear layer cells in the rat retina, whilst 35µm tall pillars were optimized for penetrating the debris layer in human patients. Implantation of released 3D arrays demonstrates mechanical robustness, with histology demonstrating successful integration of 3D structures with the rat retinain-vivo.Significance. Electroplated 3D honeycomb structures produce vertically oriented electric fields, providing low stimulation thresholds, high spatial resolution, and high contrast for pixel sizes down to 20µm. Pillar electrodes offer an alternative for extending past the debris layer. Electroplating of 3D structures is compatible with the fabrication process of flat photovoltaic arrays, enabling much more efficient retinal stimulation.

Seeing the Future: A Review of Ocular Therapy.

Ocular diseases present a unique challenge and opportunity for therapeutic development. The eye has distinct advantages as a therapy target given its accessibility, compartmentalization, immune privilege, and size. Various methodologies for therapeutic delivery in ocular diseases are under investigation that impact long-term efficacy, toxicity, invasiveness, and delivery range. While gene, cell, and antibody therapy and nanoparticle delivery directly treat regions that have been damaged by disease, they can be limited in the duration of the therapeutic delivery and have a focal effect. In contrast, contact lenses and ocular implants can more effectively achieve sustained and widespread delivery of therapies; however, they can increase dilution of therapeutics, which may result in reduced effectiveness. Current therapies either offer a sustained release or a broad therapeutic effect, and future directions should aim toward achieving both. This review discusses current ocular therapy delivery systems and their applications, mechanisms for delivering therapeutic products to ocular tissues, advantages and challenges associated with each delivery system, current approved therapies, and clinical trials. Future directions for the improvement in existing ocular therapies include combination therapies, such as combined cell and gene therapies, as well as AI-driven devices, such as cortical implants that directly transmit visual information to the cortex.

Focal stimulation of retinal ganglion cells using subretinal 3D microelectrodes with peripheral electrodes of opposite current.

Subretinal prostheses have been developed to stimulate survived retinal ganglion cells (RGCs), indirectly following the physiological visual pathways. However, current spreading from the prosthesis electrode causes the activation of unintended RGCs, thereby limiting the spatial resolution of artificial vision. This study proposes a strategy for focal stimulation of RGCs using a subretinal electrode array, in which six hexagonally arranged peripheral electrodes surround a stimulating electrode. RGCs in an in-vitro condition were subretinally stimulated using a fabricated electrode array coated with iridium oxide, following the three different stimulation configurations (with no peripheral, six electrodes of opposite current, and six ground). In-vitro experiments showed that the stimulation with six electrodes of opposite current was most effective in controlling RGC responses with a high spatial resolution. The results suggest that the effective utilization of return electrodes, such as by applying an opposite current to them, could help reduce current spreading beyond the local area targeted for stimulation and elicit RGC responses only in the vicinity of the stimulating electrode. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-023-00342-3.

Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.

Objective: High-resolution retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables an increase in prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigate 3-dimensional structures on top of the photovoltaic arrays for enhanced penetration of electric field to permit higher-resolution implants. Approach: We developed 3D COMSOL models of subretinal photovoltaic arrays that accurately quantify the device electrodynamics during stimulation and verified it experimentally through comparison with the standard (flat) photovoltaic arrays. The models were then applied to optimise the design of 3D electrode structures (pillars and honeycombs) to efficiently stimulate the inner retinal neurons. The return electrodes elevated on top of the honeycomb walls surrounding each pixel orient the electric field inside the cavities vertically, aligning it with bipolar cells for optimal stimulation. Alternatively, pillars elevate the active electrode into the inner nuclear layer, improving proximity to the target neurons. Modelling results informed a microfabrication process of electroplating the 3D electrode structures on top of the existing flat subretinal prosthesis. Main results: Simulations demonstrate that despite the conductive sidewalls of the 3D electrodes being exposed to electrolyte, most of the charge flows via the high-capacitance sputtered Iridium Oxide film that caps the top of the 3D structures. The 24 µm height of the electroplated honeycomb structures was optimised for integration with the inner nuclear layer cells in rat retina, while 35 µm height of the pillars was optimized for penetrating the debris layer in human patients. Release from the wafer and implantation of the 3D arrays demonstrated that they are mechanically robust to withstand the associated forces. Histology demonstrated successful integration of the 3D structures with the rat retina in-vivo. Significance: Electroplated 3D honeycomb structures produce a vertically oriented electric field that offers low stimulation threshold, high spatial resolution and high contrast for the retinal implants with pixel sizes down to 20µm in width. Pillar electrodes offer an alternative configuration for extending the stimulation past the debris layers. Electroplating of the 3D structures is compatible with the fabrication process of the flat photovoltaic arrays, thereby enabling much more efficient stimulation than in their original flat configuration.

Prosthetic Visual Acuity with the PRIMA System in Patients with Atrophic Age-related Macular Degeneration at 4 years follow-up.

Objective: To assess the efficacy and safety of the PRIMA subretinal neurostimulation system 48-months post-implantation for improving visual acuity (VA) in patients with geographic atrophy (GA) due to age-related macular degeneration (AMD) at 48-months post-implantation. Design: First-in-human clinical trial of the PRIMA subretinal prosthesis in patients with atrophic AMD, measuring best-corrected ETDRS VA (Clinicaltrials.gov NCT03333954). Subjects: Five patients with GA, no foveal light perception and VA of logMAR 1.3 to 1.7 in their worse-seeing "study" eye. Methods: In patients implanted with a subretinal photovoltaic neurostimulation array containing 378 pixels of 100 µm in size, the VA was measured with and without the PRIMA system using ETDRS charts at 1 meter. The system's external components: augmented reality glasses and pocket computer, provide image processing capabilities, including zoom. Main Outcome Measures: VA using ETDRS charts with and without the system. Light sensitivity in the central visual field, as measured by Octopus perimetry. Anatomical outcomes demonstrated by fundus photography and optical coherence tomography up to 48-months post-implantation. Results: All five subjects met the primary endpoint of light perception elicited by the implant in the scotoma area. In one patient the implant was incorrectly inserted into the choroid. One subject died 18-months post-implantation due to study-unrelated reason. ETDRS VA results for the remaining three subjects are reported herein. Without zoom, VA closely matched the pixel size of the implant: 1.17 ± 0.13 pixels, corresponding to mean logMAR 1.39, or Snellen 20/500, ranging from 20/438 to 20/565. Using zoom at 48 months, subjects improved their VA by 32 ETDRS letters versus baseline (SE 5.1) 95% CI[13.4,49.9], p<0.0001. Natural peripheral visual function in the treated eye did not decline after surgery compared to the fellow eye (p=0.08) during the 48 months follow-up period. Conclusions: Subretinal implantation of PRIMA in subjects with GA suffering from profound vision loss due to AMD is feasible and well tolerated, with no reduction of natural peripheral vision up to 48-months. Using prosthetic central vision through photovoltaic neurostimulation, patients reliably recognized letters and sequences of letters,and with zoom it provided a clinically meaningful improvement in VA of up to eight ETDRS lines.

Multiple consecutive-biphasic pulse stimulation improves spatially localized firing of retinal ganglion cells in the degenerate retina.

Retinal prostheses have shown some clinical success in restoring vision in patients with retinitis pigmentosa. However, the post-implantation visual acuity does not exceed that of legal blindness. The reason for the poor visual acuity might be that (1) degenerate retinal ganglion cells (RGCs) are less responsive to electrical stimulation than normal RGCs, and (2) electrically-evoked RGC spikes show a more widespread not focal response. The single-biphasic pulse electrical stimulation, commonly used in artificial vision, has limitations in addressing these issues. In this study, we propose the benefit of multiple consecutive-biphasic pulse stimulation. We used C57BL/6J mice and C3H/HeJ (rd1) mice for the normal retina and retinal degeneration model. An 8 × 8 multi-electrode array was used to record electrically-evoked RGC spikes. We compared RGC responses when increasing the amplitude of a single biphasic pulse versus increasing the number of consecutive biphasic pulses at the same stimulus charge. Increasing the amplitude of a single biphasic pulse induced more RGC spike firing while the spatial resolution of RGC populations decreased. For multiple consecutive-biphasic pulse stimulation, RGC firing increased as the number of pulses increased, and the spatial resolution of RGC populations was well preserved even up to 5 pulses. Multiple consecutive-biphasic pulse stimulation using two or three pulses in degenerate retinas induced as much RGC spike firing as in normal retinas. These findings suggest that the newly proposed multiple consecutive-biphasic pulse stimulation can improve the visual acuity in prosthesis-implanted patients.

Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision.

In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 µm and reaches the 27 µm limit of natural resolution in rats with 20 µm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.

The Variation of Electrical Pulse Duration Elicits Reliable Network-Mediated Responses of Retinal Ganglion Cells in Normal, Not in Degenerate Primate Retinas.

This study aims to investigate the efficacy of electrical stimulation by comparing network-mediated RGC responses in normal and degenerate retinas using a N-methyl-N-nitrosourea (MNU)-induced non-human primate (NHPs) retinitis pigmentosa (RP) model. Adult cynomolgus monkeys were used for normal and outer retinal degeneration (RD) induced by MNU. The network-mediated RGC responses were recorded from the peripheral retina mounted on an 8 × 8 multielectrode array (MEA). The amplitude and duration of biphasic current pulses were modulated from 1 to 50 µA and 500 to 4000 µs, respectively. The threshold charge density for eliciting a network-mediated RGC response was higher in the RD monkeys than in the normal monkeys (1.47 ± 0.13 mC/cm2 vs. 1.06 ± 0.09 mC/cm2, p < 0.05) at a 500 µs pulse duration. The monkeys required a higher charge density than rodents among the RD models (monkeys; 1.47 ± 0.13 mC/cm2, mouse; 1.04 ± 0.09 mC/cm2, and rat; 1.16 ± 0.16 mC/cm2, p < 0.01). Increasing the pulse amplitude and pulse duration elicited more RGC spikes in the normal primate retinas. However, only pulse amplitude variation elicited more RGC spikes in degenerate primate retinas. Therefore, the pulse strategy for primate RD retinas should be optimized, eventually contributing to retinal prosthetics. Given that RD NHP RGCs are not sensitive to pulse duration, using shorter pulses may potentially be a more charge-effective approach for retinal prosthetics.

Current Assistive Devices Usage and Recommendations for a Future Artificial Vision Prosthesis among Patients with Severe Visual Impairment Due to Inherited Retinal Diseases.

Patients with inherited retinal diseases (IRDs) utilize various adaptive techniques and devices designed to assist them with activities of daily living (ADLs). The purpose of this study was to assess the assistive devices used by patients with IRDs, the difficulties they face despite these devices, and their recommendations for a future visual prosthesis. In collaboration with blind patients, an online survey was developed and administered to adults with IRDs and visual acuities of 20/400 to no light perception in the better-seeing eye. We analyzed data from 121 survey respondents (aged 18 to >80 years). Five respondents were Argus II prosthesis recipients. The most commonly used aids were cellular phones/tablets for reading (63.6%) as well as a sighted guide (75.0%) and a cane (71.4%) for mobility. Despite current assistive devices, participants reported continued difficulty with ADLs. Improved navigation, reading, and facial recognition were ranked the most desirable features for future visual prostheses. Argus II recipients suggested technology with improved ability to recognize objects and obstacles, detect movement, and cut out busy backgrounds. These insights are valuable in shaping the design of future prosthetic devices tailored to the needs of IRD patients.

Axonal stimulation affects the linear summation of single-point perception in three Argus II users.

Purpose: Retinal implants use electrical stimulation to elicit perceived flashes of light ("phosphenes"). Single-electrode phosphene shape has been shown to vary systematically with stimulus parameters and the retinal location of the stimulating electrode, due to incidental activation of passing nerve fiber bundles. However, this knowledge has yet to be extended to paired-electrode stimulation. Methods: We retrospectively analyzed 3548 phosphene drawings made by three blind participants implanted with an Argus II Retinal Prosthesis. Phosphene shape (characterized by area, perimeter, major and minor axis length) and number of perceived phosphenes were averaged across trials and correlated with the corresponding single-electrode parameters. In addition, the number of phosphenes was correlated with stimulus amplitude and neuroanatomical parameters: electrode-retina and electrode-fovea distance as well as the electrode-electrode distance to ("between-axon") and along axon bundles ("along-axon"). Statistical analyses were conducted using linear regression and partial correlation analysis. Results: Simple regression revealed that each paired-electrode shape descriptor could be predicted by the sum of the two corresponding single-electrode shape descriptors (p < .001). Multiple regression revealed that paired-electrode phosphene shape was primarily predicted by stimulus amplitude and electrode-fovea distance (p < .05). Interestingly, the number of elicited phosphenes tended to increase with between-axon distance (p < .05), but not with along-axon distance, in two out of three participants. Conclusions: The shape of phosphenes elicited by paired-electrode stimulation was well predicted by the shape of their corresponding single-electrode phosphenes, suggesting that two-point perception can be expressed as the linear summation of single-point perception. The notable impact of the between-axon distance on the perceived number of phosphenes provides further evidence in support of the axon map model for epiretinal stimulation. These findings contribute to the growing literature on phosphene perception and have important implications for the design of future retinal prostheses.