Objective. This study focused on characterising the response of four major functionally-different retinal ganglion cells (RGCs) to a high frequency stimulus (HFS) paradigm. Approach. We used in vitro patch clamp experiments to assess the viability of evoking a differential response between different RGC types—OFF-Sustained, OFF-Transient, ON-Sustained and ON-Transient—under a wide range of HFS and stimulation amplitude combinations. Main results . Of the four types, we found that the OFF-Sustained, OFF-Transient and ON-Transient RGCs could be differentially activated at various frequency and amplitude combinations, in particular, OFF-Sustained cells can be differentially targeted between 20–100 µ A at all frequencies, OFF-Transient cells between 150–240 µ A at 1 kHz and ON-Transient between 180–240 µ A and 4–6 kHz. We further found that this differential activation held true when the stimulus duration was reduced from 300 ms to 50 ms. Finally, we found that the cell spiking response was not primarily dependent on total charge contained in the pulse train or current amplitude alone, but a combination of amplitude and frequency. Significance. These results indicate that HFS may be a promising method to target functionally-distinct neural pathways in the retina in an effort to improve the vision quality with retinal prostheses.

Purpose.: To investigate the spatiotemporal properties of the cortical responses elicited by intraorbital optic nerve (ON) stimulation with penetrating electrodes as means of designing optimal stimulation strategies for an ON visual prosthesis. Methods.: The ON of rabbits was exposed by orbital surgery for electrical stimulation. Craniotomy was performed to expose the visual cortex contralateral to the operated eye. Electrically evoked potentials (EEPs) were recorded by an electrode array positioned on the visual cortex. Results.: There were primarily four components (N1, P1, P2, P3) in EEPs with implicit times of 8.0 ± 0.6, 11.3 ± 1.3, 20.5 ± 1.4, and 26.9 ± 1.5 ms, respectively, when the ON was stimulated by penetrating electrodes. The thresholds to elicit these components were different, and the higher thresholds were seen with slower cortical components. The corresponding thresholds were 13.8 ± 3.1 μA for N1, 21.8 ± 4.7 μA for P1, 36.4 ± 11.4 μA for P2, and 68.4 ± 17.2 μA for P3. The time courses of the EEP components were also distinct. The locations of EEPs with the maximum P1 amplitude showed a spatial correspondence to the ON stimulation sites. Different profiles of cortical responses could be discriminated when the ON stimulation sites were separated by 150 μm. Conclusions.: Multiple components with different properties were elicited in EEPs when the ON was stimulated by penetrating electrodes. Retinotopic and localized stimulation could be achieved with this stimulating approach.

Epiretinal prostheses have been greatly successful in helping restore the vision of patients blinded by retinal degenerative diseases. The design of stimulating electrodes plays a crucial role in the performance of epiretinal prostheses. The objective of this study was to investigate, through computational modeling analysis, the effects on the excitation of retinal ganglion cells (RGCs) when different three-dimensional (3-D) electrodes were placed in the epiretinal space. 3-D finite element models of retinal electrical stimulation were created in COMSOL using a platinum microelectrode, a vitreous body, multi-layered retinal tissue, and retinal pigment epithelium (RPE). Disk and non-planar electrodes with different 3-D structures were used in the epiretinal electrical stimulation. In addition, a multi-RGC model including ionic mechanisms was constructed in NEURON to study the excitability of RGCs in response to epiretinal electrical stimulation by different types of electrodes. Threshold current, threshold charge density, and the activated RGC area were the three key factors used to evaluate the stimulating electrode’s performance. As the electrode-retina distance increased, both threshold current and threshold charge density showed an approximately linear relationship. Increasing the disk electrode’s diameter resulted in an increase in threshold current and a decrease in threshold charge density. Non-planar electrodes evoked different activation responses in RGCs than the disk electrode. Concave electrodes produced superior stimulation localization and electrode safety while convex electrodes performed relatively poorly. Investigation of epiretinal electrical stimulation using different 3-D electrodes would further the optimization of electrode design and help improve the performance of epiretinal prostheses. The combination of finite element analysis in COMSOL and NEURON software provides an efficient way to evaluate the influences of various 3-D electrodes on epiretinal electrical stimulation. Non-planar electrodes had larger threshold currents than disk electrodes. Of the five types of electrodes, concave hemispherical electrodes may be the ideal option, considering their superior stimulation localization and electrode safety.

Purpose: Current steering is a neural stimulation strategy that uses simultaneous stimulation of adjacent electrodes to produce additional intermediate stimulation sites and thus improves spatial resolution. We investigated the feasibility of current steering using electrophysiological and computational methods after implanting paired penetrating electrodes into the rabbit's optic nerve (ON). Methods: Penetrating electrodes at different interelectrode distances were implanted into the ON and electrically evoked cortical potentials (EEPs) in V1 recorded with a 6 × 8 array. The current thresholds, EEP amplitudes, and spatial distributions were analyzed during current steering. Computational simulation studies were performed based on finite element models to calculate the area and spatial distribution of recruited ON fibers using a current steering stimulation strategy. Results: Threshold reduction and EEP amplitude enhancement were found with simultaneous stimulation of closely spaced electrode pairs. Spatially shifted cortical responses were achieved using current steering, whereas the amplitudes and spatial spreads of the responses were similar to that elicited by a single electrode. Computational simulations suggested that the centroid of the ON recruitment area could be modulated by current steering while the total recruitment area did not show any appreciable variability at a fixed current intensity. Conclusions: Current steering is a useful strategy to enhance the spatial resolution of an ON prosthesis without increasing the number of physical electrodes. This study provides useful information for optimizing the design of stimulation strategies with a penetrating ON prosthesis.

Objective . Visual outcomes provided by present retinal prostheses that primarily target retinal ganglion cells (RGCs) through epiretinal stimulation remain rudimentary, partly due to the limited knowledge of retinal responses under electrical stimulation. Better understanding of how different retinal regions can be quantitatively controlled with high spatial accuracy, will be beneficial to the design of micro-electrode arrays and stimulation strategies for next-generation wide-view, high-resolution epiretinal implants. Approach . A computational model was developed to assess neural activity at different eccentricities (2 mm and 5 mm) within the human retina. This model included midget and parasol RGCs with anatomically accurate cell distribution and cell-specific morphological information. We then performed in silico investigations of region-specific RGC responses to epiretinal electrical stimulation using varied electrode sizes (5–210 µ m diameter), emulating both commercialized retinal implants and recently developed prototype devices. Main results . Our model of epiretinal stimulation predicted RGC population excitation analogous to the complex percepts reported in human subjects. Following this, our simulations suggest that midget and parasol RGCs have characteristic regional differences in excitation under preferred electrode sizes. Relatively central (2 mm) regions demonstrated higher number of excited RGCs but lower overall activated receptive field (RF) areas under the same stimulus amplitudes (two-way analysis of variance (ANOVA), p < 0.05). Furthermore, the activated RGC numbers per unit active RF area (number-RF ratio) were significantly higher in central than in peripheral regions, and higher in the midget than in the parasol population under all tested electrode sizes (two-way ANOVA, p < 0.05). Our simulations also suggested that smaller electrodes exhibit a higher range of controllable stimulation parameters to achieve pre-defined performance of RGC excitation. An empirical model: I = a · exp ( b · D ) + c of the stimulus amplitude ( I )–electrode diameter ( D ) relationship was constructed to achieve the pre-defined objective function values in different retinal regions, indicating the ability of controlling retinal outputs by fine-tuning the stimulation amplitude with different electrode sizes. Finally, our multielectrode simulations predicted differential neural crosstalk between adjacent electrodes in central temporal and peripheral temporal regions, providing insights towards establishing a non-uniformly distributed multielectrode array geometry for wide-view retinal implants. Significance. Stimulus–response properties in central and peripheral retina can provide useful information to estimate electrode parameters for region-specific activation by retinal stimulation. Our findings support the possibility of improving the performance of epiretinal prostheses by exploring the influence of electrode array geometry on activation of different retinal regions.

Objective. Trans-corneal electrical stimulation (TcES) produces therapeutic effects on many ophthalmic diseases non-invasively. Existing clinical TcES devices use largely variable design of electrode distribution and stimulation parameters. Better understanding of how electrode configuration paradigms and stimulation parameters influence the electric field distribution on the retina, will be beneficial to the design of next-generation TcES devices. Approach. In this study, we constructed a realistic finite element human head model with fine eyeball structure. Commonly used DTL-Plus and ERG-Jet electrodes were simulated. We then conducted in silico investigations of retina observation surface (ROS) electric field distributions induced by different return electrode configuration paradigms and different stimulus intensities. Main results. Our results suggested that the ROS electric field distribution could be modulated by re-designing TcES electrode settings and stimulus parameters. Under far return location paradigms, either DTL-Plus or ERG-Jet approach could induce almost identical ROS electric field distribution regardless where the far return was located. However, compared with the ERG-Jet mode, DTL-Plus stimulation induced stronger nasal lateralization. In contrast, ERG-Jet stimulation induced relatively stronger temporal lateralization. The ROS lateralization can be further tweaked by changing the DTL-Plus electrode length. Significance. These results may contribute to the understanding of the characteristics of DTL-Plus and ERG-Jet electrodes based electric field distribution on the retina, providing practical implications for the therapeutic application of TcES.