Mediating Retinal Ganglion Cell Spike Rates Using High-Frequency Electrical Stimulation

Recent retinal studies have directed more attention to sophisticated stimulation strategies based on high-frequency (>1.0 kHz) electrical stimulation (HFS). In these studies, each retinal ganglion cell (RGC) type demonstrated a characteristic stimulus-strength-dependent response to HFS, offering the intriguing possibility of focally targeting retinal neurons to provide useful visual information by retinal prosthetics. Ionic mechanisms are known to affect the responses of electrogenic cells during electrical stimulation. However, how these mechanisms affect RGC responses is not well understood at present, particularly when applying HFS. Here, we investigate this issue via an in silico model of the RGC. We calibrate and validate the model using an in vitro retinal preparation. An RGC model based on accurate biophysics and realistic representation of cell morphology, was used to investigate how RGCs respond to HFS. The model was able to closely replicate the stimulus-strength-dependent suppression of RGC action potentials observed experimentally. Our results suggest that spike inhibition during HFS is due to local membrane hyperpolarization caused by outward membrane currents near the stimulus electrode. In addition, the extent of HFS-induced inhibition can be largely altered by the intrinsic properties of the inward sodium current. Finally, stimulus-strength-dependent suppression can be modulated by a wide range of stimulation frequencies, under generalized electrode placement conditions. In vitro experiments verified the computational modeling data. This modeling and experimental approach can be extended to further our understanding on the effects of novel stimulus strategies by simulating RGC stimulus-response profiles over a wider range of stimulation frequencies and electrode locations than have previously been explored

Direct activation of retinal ganglion cells with subretinal stimulation

Recent advances in the design and implementation of vision prostheses have made these devices a promising therapeutic option for restoring sight to blind patients in the near future. The success of vision prostheses in providing clinically useful vision, however, depends critically on our understanding of the retinal neural mechanisms evoked during electrical stimulation, and how these mechanisms can be controlled precisely to elicit the desired visual percept. We demonstrate here that subretinal stimulation can reliably elicit stimulus-locked short latency (les 2 ms) responses. To our knowledge, this is the first report of such responses using the subretinal paradigm. These responses could be readily distinguished from within the stimulus artifacts using cell-attached extracellular recording or whole-cell patch clamp. The thresholds for these short latency responses were determined for ON, OFF and ON- OFF type retinal ganglion cell classes across cathodic biphasic pulses of 0.1-5.0 ms. No significant difference was found for the mean latency and the threshold for the different cell types over the pulse range tested

A wearable real-time image processor for a vision prosthesis

Rapid progress in recent years has made implantable retinal prostheses a promising therapeutic option in the near future for patients with macular degeneration or retinitis pigmentosa. Yet little work on devices that encode visual images into electrical stimuli have been reported to date. This paper presents a wearable image processor for use as the external module of a vision prosthesis. It is based on a dual-core microprocessor architecture and runs the Linux operating system. A set of image-processing algorithms executes on the digital signal processor of the device, which may be controlled remotely via a standard desktop computer. The results indicate that a highly flexible and configurable image processor can be built with the dual-core architecture. Depending on the image-processing requirements, general-purpose embedded microprocessors alone may be inadequate for implementing image-processing strategies required by retinal prostheses

Direct activation and temporal response properties of rabbit retinal ganglion cells following subretinal stimulation

In the last decade several groups have been developing vision prostheses to restore visual perception to the profoundly blind. Despite some promising results from human trials, further understanding of the neural mechanisms involved is crucial for improving the efficacy of these devices. One of the techniques involves placing stimulating electrodes in the subretinal space between the photoreceptor layer and the pigment epithelium to evoke neural responses in the degenerative retina. This study used cell-attached and whole cell current-clamp recordings to investigate the responses of rabbit retinal ganglion cells (RGCs) following subretinal stimulation with 25-μm-diameter electrodes. We found that direct RGC responses with short latency (≤2 ms using 0.1-ms pulses) could be reliably elicited. The thresholds for these responses were reported for on, off, and on–off RGCs over pulse widths 0.1–5.0 ms. During repetitive stimulation these direct activation responses were more readily elicited than responses arising from stimulation of the retinal network. The temporal spiking characteristics of RGCs were characterized as a function of stimulus configurations. We found that the response profiles could be generalized into four classes with distinctive properties. Our results suggest that for subretinal vision prostheses short pulses are preferable for efficacy and safety considerations, and that direct activation of RGCs will be necessary for reliable activation during high-frequency stimulation

Frequency-dependent reduction of voltage-gated sodium current modulates retinal ganglion cell response rate to electrical stimulation

The ability to elicit visual percepts through electrical stimulation of the retina has prompted numerous investigations examining the feasibility of restoring sight to the blind with retinal implants. The therapeutic efficacy of these devices will be strongly influenced by their ability to elicit neural responses that approximate those of normal vision. Retinal ganglion cells (RGCs) can fire spikes at frequencies greater than 200 Hz when driven by light. However, several studies using isolated retinas have found a decline in RGC spiking response rate when these cells were stimulated at greater than 50 Hz. It is possible that the mechanism responsible for this decline also contributes to the frequency-dependent 'fading' of electrically evoked percepts recently reported in human patients. Using whole-cell patch clamp recordings of rabbit RGCs, we investigated the causes for the spiking response depression during direct subretinal stimulation of these cells at 50-200 Hz. The response depression was not caused by inhibition arising from the retinal network but, instead, by a stimulus-frequency-dependent decline of RGC voltage-gated sodium current. Under identical experimental conditions, however, RGCs were able to spike at high frequency when driven by light stimuli and intracellular depolarization. Based on these observations, we demonstrated a technique to prevent the spiking response depression

Responses of starburst amacrine cells to prosthetic stimulation of the retina

Recent advances in the design and development of retinal implants have made these devices a promising therapeutic strategy for restoring sight to the blind. Over the last decade a plethora of studies have investigated the responses of the retinal ganglion cells (RGCs) to electrical stimulation under a variety of stimulus configurations. Similar to the RGCs, the amacrine cells also survive in large numbers following retinal neural degeneration. However, with the exception of two previous reports, where the responses of the amacrine cells were measured indirectly, these cells have thus far received little attention in the context of prosthetic stimulation. In this study we focused on the starburst amacrine cells (SACs), a particularly well-characterized amacrine cell among the approximately two-dozen types known to exist in the retina. Using whole-cell patch clamp recordings in the whole-mount rabbit retina, we investigated the temporal responses of the SACs following subretinal biphasic pulse stimulation. These cells responded to the stimuli with oscillatory membrane potentials that lasted for tens to hundreds of milliseconds, with the response amplitude increasing as a function of stimulus strength. Furthermore, the SAC responses originated primarily from the presynaptic inputs they receive, rather than through direct activation of these cells by the electrical stimuli

Simulating prosthetic vision : I. visual models of phosphenes

With increasing research advances and clinical trials of visual prostheses, there is significant demand to better understand the perceptual and psychophysical aspects of prosthetic vision. In prosthetic vision a visual scene is composed of relatively large, isolated, spots of light so-called “phosphenes”, very much like a magnified pictorial print. The utility of prosthetic vision has been studied by investigators in the form of virtual–reality visual models (simulations) of prosthetic vision administered to normally sighted subjects. In this review, the simulations from these investigations are examined with respect to how they visually render the phosphenes and the virtual–reality apparatus involved. A comparison is made between these simulations and the actual descriptions of phosphenes reported from human trials of visual prosthesis devices. For the results from these simulation studies to be relevant to the experience of visual prosthesis recipients, it is important that, the simulated phosphenes must be consistent with the descriptions from human trials. A standardized simulation and reporting framework is proposed so that future simulations may be configured to be more realistic to the experience of implant recipients, and the simulation parameters from different investigators may be more readily extracted, and study results more fittingly compared