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.

Fabrication and Validation of Sub-Cellular Carbon Fiber Electrodes.

Multielectrode arrays for interfacing with neurons are of great interest for a wide range of medical applications. However, current electrodes cause damage over time. Ultra small carbon fibers help to address issues but controlling the electrode site geometry is difficult. Here we propose a methodology to create small, pointed fiber electrodes (SPFe). We compare the SPFe to previously made blowtorched fibers in characterization. The SPFe result in small site sizes [Formula: see text] with consistently sharp points (20.8 ± 7.64°). Additionally, these electrodes were able to record and/or stimulate neurons multiple animal models including rat cortex, mouse retina, Aplysia ganglia and octopus axial cord. In rat cortex, these electrodes recorded significantly higher peak amplitudes than the traditional blowtorched fibers. These SPFe may be applicable to a wide range of applications requiring a highly specific interface with individual neurons.

Patient-specific computational models of retinal prostheses.

Retinal prostheses stimulate inner retinal neurons to create visual perception for blind patients. Implanted arrays have many small electrodes. Not all electrodes induce perception at the same stimulus amplitude, requiring clinicians to manually establish a visual perception threshold for each one. Phosphenes created by single-electrode stimuli can also vary in shape, size, and brightness. Computational models provide a tool to predict inter-electrode variability and automate device programming. In this study, we created statistical and patient-specific field-cable models to investigate inter-electrode variability across seven epiretinal prosthesis users. Our statistical analysis revealed that retinal thickness beneath the electrode correlated with perceptual threshold, with a significant fixed effect across participants. Electrode-retina distance and electrode impedance also correlated with perceptual threshold for some participants, but these effects varied by individual. We developed a novel method to construct patient-specific field-cable models from optical coherence tomography images. Predictions with these models significantly correlated with perceptual threshold for 80% of participants. Additionally, we demonstrated that patient-specific field-cable models could predict retinal activity and phosphene size. These computational models could be beneficial for determining optimal stimulation settings in silico, circumventing the trial-and-error testing of a large parameter space in clinic.

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.

Patient-specific computational models of retinal prostheses.

Retinal prostheses stimulate inner retinal neurons to create visual perception for blind patients. Implanted arrays have many small electrodes, which act as pixels. Not all electrodes induce perception at the same stimulus amplitude, requiring clinicians to manually establish a visual perception threshold for each one. Phosphenes created by single-electrode stimuli can also vary in shape, size, and brightness. Computational models provide a tool to predict inter-electrode variability and automate device programming. In this study, we created statistical and patient-specific field-cable models to investigate inter-electrode variability across seven epiretinal prosthesis users. Our statistical analysis revealed that retinal thickness beneath the electrode correlated with perceptual threshold, with a significant fixed effect across participants. Electrode-retina distance and electrode impedance also correlated with perceptual threshold for some participants, but these effects varied by individual. We developed a novel method to construct patient-specific field-cable models from optical coherence tomography images. Predictions with these models significantly correlated with perceptual threshold for 80% of participants. Additionally, we demonstrated that patient-specific field-cable models could predict retinal activity and phosphene size. These computational models could be beneficial for determining optimal stimulation settings in silico, circumventing the trial-and-error testing of a large parameter space in clinic.

Full-field, conformal epiretinal electrode array using hydrogel and polymer hybrid technology.

Shape-morphable electrode arrays can form 3D surfaces to conform to complex neural anatomy and provide consistent positioning needed for next-generation neural interfaces. Retinal prostheses need a curved interface to match the spherical eye and a coverage of several cm to restore peripheral vision. We fabricated a full-field array that can (1) cover a visual field of 57° based on electrode position and of 113° based on the substrate size; (2) fold to form a compact shape for implantation; (3) self-deploy into a curvature fitting the eye after implantation. The full-field array consists of multiple polymer layers, specifically, a sandwich structure of elastomer/polyimide-based-electrode/elastomer, coated on one side with hydrogel. Electrodeposition of high-surface-area platinum/iridium alloy significantly improved the electrical properties of the electrodes. Hydrogel over-coating reduced electrode performance, but the electrodes retained better properties than those without platinum/iridium. The full-field array was rolled into a compact shape and, once implanted into ex vivo pig eyes, restored to a 3D curved surface. The full-field retinal array provides significant coverage of the retina while allowing surgical implantation through an incision 33% of the final device diameter. The shape-changing material platform can be used with other neural interfaces that require conformability to complex neuroanatomy.

Modeling extracellular stimulation of retinal ganglion cells: theoretical and practical aspects.

Objective.Retinal prostheses use electric current to activate inner retinal neurons, providing artificial vision for blind people. Epiretinal stimulation primarily targets retinal ganglion cells (RGCs), which can be modeled with cable equations. Computational models provide a tool to investigate the mechanisms of retinal activation, and improve stimulation paradigms. However, documentation of RGC model structure and parameters is limited, and model implementation can influence model predictions.Approach.We created a functional guide for building a mammalian RGC multi-compartment cable model and applying extracellular stimuli. Next, we investigated how the neuron's three-dimensional shape will influence model predictions. Finally, we tested several strategies to maximize computational efficiency.Main results.We conducted sensitivity analyses to examine how dendrite representation, axon trajectory, and axon diameter influence membrane dynamics and corresponding activation thresholds. We optimized the spatial and temporal discretization of our multi-compartment cable model. We also implemented several simplified threshold prediction theories based on activating function, but these did not match the prediction accuracy achieved by the cable equations.Significance.Through this work, we provide practical guidance for modeling the extracellular stimulation of RGCs to produce reliable and meaningful predictions. Robust computational models lay the groundwork for improving the performance of retinal prostheses.

Post-explant profiling of subcellular-scale carbon fiber intracortical electrodes and surrounding neurons enables modeling of recorded electrophysiology.

Objective.Characterizing the relationship between neuron spiking and the signals that electrodes record is vital to defining the neural circuits driving brain function and informing clinical brain-machine interface design. However, high electrode biocompatibility and precisely localizing neurons around the electrodes are critical to defining this relationship.Approach.Here, we demonstrate consistent localization of the recording site tips of subcellular-scale (6.8µm diameter) carbon fiber electrodes and the positions of surrounding neurons. We implanted male rats with carbon fiber electrode arrays for 6 or 12+ weeks targeting layer V motor cortex. After explanting the arrays, we immunostained the implant site and localized putative recording site tips with subcellular-cellular resolution. We then 3D segmented neuron somata within a 50µm radius from implanted tips to measure neuron positions and health and compare to healthy cortex with symmetric stereotaxic coordinates.Main results.Immunostaining of astrocyte, microglia, and neuron markers confirmed that overall tissue health was indicative of high biocompatibility near the tips. While neurons near implanted carbon fibers were stretched, their number and distribution were similar to hypothetical fibers placed in healthy contralateral brain. Such similar neuron distributions suggest that these minimally invasive electrodes demonstrate the potential to sample naturalistic neural populations. This motivated the prediction of spikes produced by nearby neurons using a simple point source model fit using recorded electrophysiology and the mean positions of the nearest neurons observed in histology. Comparing spike amplitudes suggests that the radius at which single units can be distinguished from others is near the fourth closest neuron (30.7 ± 4.6µm,X-± S) in layer V motor cortex.Significance.Collectively, these data and simulations provide the first direct evidence that neuron placement in the immediate vicinity of the recording site influences how many spike clusters can be reliably identified by spike sorting.

Integration of artificial vision with non-visual peripheral cues to guide mobility.

Visual prostheses can improve vision for people with severe vision loss, but low image resolution and lack of peripheral vision limit their effectiveness. To address both problems, we developed a prototype advanced video processing system with a headworn depth camera and feature detection capabilities. We used computer vision algorithms to detect landmarks representing a goal and plan a path towards the goal, while removing unnecessary distractors from the video. If the landmark fell outside the visual prosthesis's field-of-view (20 degrees central vision) but within the camera's field-of-view (70 degrees), we provided vibrational cues to the left or right temple to guide the user in pointing the camera. We evaluated an Argus II retinal prosthesis participant with significant vision loss who could not complete the task (finding a door in a large room) with either his remaining vision or his retinal prosthesis. His success rate improved to 57%, 37.5%, and 100% while requiring 52.3, 83.0, and 58.8 seconds to reach the door using only vibration feedback, retinal prosthesis with modified video, and retinal prosthesis with modified video and vibration feedback, respectively. This case study demonstrates a possible means of augmenting artificial vision. Clinical Relevance- Retinal prostheses can be enhanced by adding computer vision and non-visual cues.

Spatial Transcriptomics as a Novel Approach to Redefine Electrical Stimulation Safety.

Current standards for safe delivery of electrical stimulation to the central nervous system are based on foundational studies which examined post-mortem tissue for histological signs of damage. This set of observations and the subsequently proposed limits to safe stimulation, termed the "Shannon limits," allow for a simple calculation (using charge per phase and charge density) to determine the intensity of electrical stimulation that can be delivered safely to brain tissue. In the three decades since the Shannon limits were reported, advances in molecular biology have allowed for more nuanced and detailed approaches to be used to expand current understanding of the physiological effects of stimulation. Here, we demonstrate the use of spatial transcriptomics (ST) in an exploratory investigation to assess the biological response to electrical stimulation in the brain. Electrical stimulation was delivered to the rat visual cortex with either acute or chronic electrode implantation procedures. To explore the influence of device type and stimulation parameters, we used carbon fiber ultramicroelectrode arrays (7 µm diameter) and microwire electrode arrays (50 µm diameter) delivering charge and charge density levels selected above and below reported tissue damage thresholds (range: 2-20 nC, 0.1-1 mC/cm2). Spatial transcriptomics was performed using Visium Spatial Gene Expression Slides (10x Genomics, Pleasanton, CA, United States), which enabled simultaneous immunohistochemistry and ST to directly compare traditional histological metrics to transcriptional profiles within each tissue sample. Our data give a first look at unique spatial patterns of gene expression that are related to cellular processes including inflammation, cell cycle progression, and neuronal plasticity. At the acute timepoint, an increase in inflammatory and plasticity related genes was observed surrounding a stimulating electrode compared to a craniotomy control. At the chronic timepoint, an increase in inflammatory and cell cycle progression related genes was observed both in the stimulating vs. non-stimulating microwire electrode comparison and in the stimulating microwire vs. carbon fiber comparison. Using the spatial aspect of this method as well as the within-sample link to traditional metrics of tissue damage, we demonstrate how these data may be analyzed and used to generate new hypotheses and inform safety standards for stimulation in cortex.

Retinal ganglion cell desensitization is mitigated by varying parameter constant excitation pulse trains.

Retinal prostheses partially restore vision in patients blinded by retinitis pigmentosa (RP) and age-related macular degeneration (AMD). One issue that limits the effectiveness of retinal stimulation is the desensitization of the retina response to repeated pulses. Rapid fading of percepts is reported in clinical studies. We studied the retinal output evoked by fixed pulse trains vs. pulse trains that have variable parameters pulse-to-pulse. We used the current clamp to record RGC spiking in the isolated mouse retina. Trains of biphasic current pulses at different frequencies and amplitudes were applied. The main results we report are: (1) RGC desensitization was induced by increasing stimulus frequency, but was unrelated to stimulus amplitude. Desensitization persisted when the 20 Hz stimulation pulses were applied to the retinal ganglion cells at 65 µA, 85 µA, and 105 µA. Subsequent pulses in the train evoked fewer spikes. There was no obvious desensitization when 2 Hz stimulation pulse trains were applied. (2) Blocking inhibitory GABAA receptor increased spontaneous activity but did not reduce desensitization. (3) Pulse trains with constant charge or excitation (based on strength-duration curves) but varying pulse width, amplitude, and shape increased the number of evoked spikes/pulse throughout the pulse train. This suggests that retinal desensitization can be partially overcome by introducing variability into each pulse.

Progressive Retinal Degeneration Increases Cortical Response Latency of Light Stimulation but Not of Electric Stimulation.

Purpose: The brain is known to change functionally and structurally in response to blindness, but less is known about the effects of restoration of cortical input on brain function. Here, we present a preliminary study to observe alterations in visual and electrical evoked cortical potentials as a function of age in a clinically relevant animal model of retinitis pigmentosa. Methods: We recorded brain potentials elicited by light (visual evoked potentials [VEPs]) or corneal electrical stimulation (electrical evoked response [EER]) in retinal degenerate animal model LE-P23H-1. We used a linear mixed model to examine the effects of age on latency and amplitude of VEP and EER age groups P120, P180, and P360. Results: VEP N1, P1, and N2 latency and amplitude were analyzed across animal age. For 1 Hz VEP, N1 latency increased significantly with animal age (slope = 0.053 ± 0.020 ms/day, P < 0.01). For 10 Hz VEP, N1, P1, and N2 latency increased significantly with animal age (slope = 0.104 ± 0.011, 0.135 ± 0.011, 0.087 ± 0.023 ms/day, and P < 0.001 for all VEP peaks). Conversely, EER latency did not change with age. Signal amplitude of VEP or EER did not change with age. Conclusions: Cortical potentials evoked by electrical stimulation of the retina do not diminish in spite of continued retinal degeneration in P23H rats. Translational Relevance: These findings suggest that retinal bioelectronic treatments of retinitis pigmentosa will activate cortex consistently despite variations in outer retinal degeneration. Clinical studies of retinal stimulation should consider varying retinitis pigmentosa genotypes as part of the experimental design.

Visual-tactile shape perception in the visually restored with artificial vision.

Retinal prostheses partially restore vision to late blind patients with retinitis pigmentosa through electrical stimulation of still-viable retinal ganglion cells. We investigated whether the late blind can perform visual-tactile shape matching following the partial restoration of vision via retinal prostheses after decades of blindness. We tested for visual-visual, tactile-tactile, and visual-tactile two-dimensional shape matching with six Argus II retinal prosthesis patients, ten sighted controls, and eight sighted controls with simulated ultra-low vision. In the Argus II patients, the visual-visual shape matching performance was significantly greater than chance. Although the visual-tactile shape matching performance of the Argus II patients was not significantly greater than chance, it was significantly higher with longer duration of prosthesis use. The sighted controls using natural vision and the sighted controls with simulated ultra-low vision both performed the visual-visual and visual-tactile shape matching tasks significantly more accurately than the Argus II patients. The tactile-tactile matching was not significantly different between the Argus II patients and sighted controls with or without simulated ultra-low vision. These results show that experienced retinal prosthesis patients can match shapes across the senses and integrate artificial vision with somatosensation. The correlation of retinal prosthesis patients' crossmodal shape matching performance with the duration of device use supports the value of experience to crossmodal shape learning. These crossmodal shape matching results in Argus II patients are the first step toward understanding crossmodal perception after artificial visual restoration.

Real-Time Optimization of Retinal Ganglion Cell Spatial Activity in Response to Epiretinal Stimulation.

Retinal prostheses aim to improve visual perception in patients blinded by photoreceptor degeneration. However, shape and letter perception with these devices is currently limited due to low spatial resolution. Previous research has shown the retinal ganglion cell (RGC) spatial activity and phosphene shapes can vary due to the complexity of retina structure and electrode-retina interactions. Visual percepts elicited by single electrodes differ in size and shapes for different electrodes within the same subject, resulting in interference between phosphenes and an unclear image. Prior work has shown that better patient outcomes correlate with spatially separate phosphenes. In this study we use calcium imaging, in vitro retina, neural networks (NN), and an optimization algorithm to demonstrate a method to iteratively search for optimal stimulation parameters that create focal RGC activation. Our findings indicate that we can converge to stimulation parameters that result in focal RGC activation by sampling less than 1/3 of the parameter space. A similar process implemented clinically can reduce time required for optimizing implant operation and enable personalized fitting of retinal prostheses.

Carbon fiber electrodes for intracellular recording and stimulation.

Objective.To understand neural circuit dynamics, it is critical to manipulate and record many individual neurons. Traditional recording methods, such as glass microelectrodes, can only control a small number of neurons. More recently, devices with high electrode density have been developed, but few of them can be used for intracellular recording or stimulation in intact nervous systems. Carbon fiber electrodes (CFEs) are 8µm-diameter electrodes that can be assembled into dense arrays (pitches ⩾ 80µm). They have good signal-to-noise ratios (SNRs) and provide stable extracellular recordings both acutely and chronically in neural tissuein vivo(e.g. rat motor cortex). The small fiber size suggests that arrays could be used for intracellular stimulation.Approach.We tested CFEs for intracellular stimulation using the large identified and electrically compact neurons of the marine molluskAplysia californica. Neuron cell bodies inAplysiarange from 30µm to over 250µm. We compared the efficacy of CFEs to glass microelectrodes by impaling the same neuron's cell body with both electrodes and connecting them to a DC coupled amplifier.Main results.We observed that intracellular waveforms were essentially identical, but the amplitude and SNR in the CFE were lower than in the glass microelectrode. CFE arrays could record from 3 to 8 neurons simultaneously for many hours, and many of these recordings were intracellular, as shown by simultaneous glass microelectrode recordings. CFEs coated with platinum-iridium could stimulate and had stable impedances over many hours. CFEs not within neurons could record local extracellular activity. Despite the lower SNR, the CFEs could record synaptic potentials. CFEs were less sensitive to mechanical perturbations than glass microelectrodes.Significance.The ability to do stable multi-channel recording while stimulating and recording intracellularly make CFEs a powerful new technology for studying neural circuit dynamics.

The effect of axon trajectory on retinal ganglion cell activation with epiretinal stimulation.

For epiretinal prostheses, disc electrodes stimulate retinal ganglion cells (RGCs) with electric current to create visual percepts. Prior studies have determined that the sodium channel band (SOCB), located on the RGC axon (30-50 µm from the soma) is the most sensitive site to extracellular stimulation because of its high sodium channel density. Biophysical cable models used to study RGC activation in silico often rely on simplified axon trajectories, disregarding the non-uniform paths that axons follow to the optic disc. However, since axonal activation is a critical mechanism in epiretinal stimulation, it is important to investigate variable RGC axon trajectories. In this study, we use a computational model to perform a sensitivity analysis examining how the morphology of an RGC axon affects predictions of retinal activation. We determine that RGC cable models are sensitive to changes in the ascending axon trajectory between the soma and nerve fiber layer. On the other hand, RGC cable models are relatively robust to trajectory deviations in the plane parallel to the disc electrode's surface. Overall, our results suggest that incorporating natural variations of soma depth and nerve fiber layer entry angle could result in a more realistic model of the retina's response to epiretinal stimulation and a better understanding of elicited visual percepts.

Compositional and morphological properties of platinum-iridium electrodeposited on carbon fiber microelectrodes.

Objective. Neural interfaces based on carbon fiber (CF) electrodes have demonstrated key positive attributes such as minimal foreign body response and mechanical strength to self-insert in brain tissue. However, carbon does not form a low impedance electrode interface with neural tissue. Electrodeposited platinum iridium (PtIr) has been used to improve electrode interface properties for metallic bioelectrodes.Approach. In this study, a PtIr electrodeposition process has been performed on CF microelectrode arrays to improve the interfacial properties of these arrays. We study the film morphology and composition as well as electrode durability and impedance.Results. A PtIr coating with a composition of 70% Pt, 30% Ir and a thickness of ∼400 nm was observed. Pt and Ir were evenly distributed within the film. Impedance was decreased by 89% @ 1 kHz. Accelerated soak testing in a heated (T= 50∘C) saline solution showed impedance increase (@ 1 kHz) of ∼12% after 36 days (89 equivalent) of soaking.

Multisensory perception in Argus II retinal prosthesis patients: Leveraging auditory-visual mappings to enhance prosthesis outcomes.

Crossmodal mappings associate features (such as spatial location) between audition and vision, thereby aiding sensory binding and perceptual accuracy. Previously, it has been unclear whether patients with artificial vision will develop crossmodal mappings despite the low spatial and temporal resolution of their visual perception (particularly in light of the remodeling of the retina and visual cortex that takes place during decades of vision loss). To address this question, we studied crossmodal mappings psychophysically in Retinitis Pigmentosa patients with partial visual restoration by means of Argus II retinal prostheses, which incorporate an electrode array implanted on the retinal surface that stimulates still-viable ganglion cells with a video stream from a head-mounted camera. We found that Argus II patients (N = 10) exhibit significant crossmodal mappings between auditory location and visual location, and between auditory pitch and visual elevation, equivalent to those of age-matched sighted controls (N = 10). Furthermore, Argus II patients (N = 6) were able to use crossmodal mappings to locate a visual target more quickly with auditory cueing than without. Overall, restored artificial vision was shown to interact with audition via crossmodal mappings, which implies that the reorganization during blindness and the limitations of artificial vision did not prevent the relearning of crossmodal mappings. In particular, cueing based on crossmodal mappings was shown to improve visual search with a retinal prosthesis. This result represents a key first step toward leveraging crossmodal interactions for improved patient visual functionality.

The effect of waveform asymmetry on perception with epiretinal prostheses.

Objective: Retinal prosthetic implants have helped improve vision in patients blinded by photoreceptor degeneration. Retinal implant users report improvements in light perception and performing visual tasks, but their ability to perceive shapes and letters is limited due to the low precision of retinal activation, which is exacerbated by axonal stimulation and high perceptual thresholds. A previous in vitro study in our lab used calcium imaging to measure the spatial activity of mouse retinal ganglion cells (RGCs) in response to electrical stimulation. Based on this study, symmetric anodic-first (SA) stimulation effectively avoided axonal activation and asymmetric anodic-first stimulation (AA) with duration ratios (ratio of the anodic to cathodic phase) greater than 10 reduced RGC activation thresholds significantly. Applying these novel stimulation strategies in clinic may increase perception precision and improve the overall patient outcomes. Approach: We combined human subject testing and computational modeling to further examine the effect of SA and AA stimuli on perception shapes and thresholds for epiretinal stimulation of RGCs. Main results: Threshold measurement in three Argus II participants indicated that AA stimulation could increase perception probabilities compared to a standard symmetric cathodic-first (SC) pulse, and this effect can be intensified by addition of an interphae gap (IPG). Our in silico RGC model predicts lower thresholds with AA and asymmetric cathodic-first (AC) stimuli compared to a SC pulse. This effect was more pronounced at shorter pulse widths. The most effective pulse for threshold reduction with short pulse durations (≤0.12 ms) was AA stimulation with small duration ratios (≤5) and long IPGs (≥2 ms). For the 0.5 ms pulse duration, SC stimulation with IPGs longer than 0.5 ms, or asymmetric stimuli with large duration ratios (≥20) were most effective in threshold reduction. Phosphene shape analysis did not reveal a significant change in percept elongation with SA stimulation. However, there was a significant increase in percept size (P < 0.01) with AA stimulation compared to the standard pulse in one participant. Significane: Including asymmetric waveform capability will provide more flexible options for optimization and personalized fitting of retinal implants.

Shape Morphable Hydrogel/Elastomer Bilayer for Implanted Retinal Electronics.

Direct fabrication of a three-dimensional (3D) structure using soft materials has been challenging. The hybrid bilayer is a promising approach to address this challenge because of its programable shape-transformation ability when responding to various stimuli. The goals of this study are to experimentally and theoretically establish a rational design principle of a hydrogel/elastomer bilayer system and further optimize the programed 3D structures that can serve as substrates for multi-electrode arrays. The hydrogel/elastomer bilayer consists of a hygroscopic polyacrylamide (PAAm) layer cofacially laminated with a water-insensitive polydimethylsiloxane (PDMS) layer. The asymmetric volume change in the PAAm hydrogel can bend the bilayer into a curvature. We manipulate the initial monomer concentrations of the pre-gel solutions of PAAm to experimentally and theoretically investigate the effect of intrinsic mechanical properties of the hydrogel on the resulting curvature. By using the obtained results as a design guideline, we demonstrated stimuli-responsive transformation of a PAAm/PDMS flower-shaped bilayer from a flat bilayer film to a curved 3D structure that can serve as a substrate for a wide-field retinal electrode array.