High-Fidelity Reproduction of Visual Signals by Electrical Stimulation in the Central Primate Retina

Abstract

Electrical stimulation of retinal ganglion cells (RGCs) with electronic implants provides rudimentary artificial vision to people blinded by retinal degeneration. However, current devices stimulate indiscriminately and therefore cannot reproduce the intricate neural code of the retina. Recent work has demonstrated more precise activation of RGCs using focal electrical stimulation with multi-electrode arrays in the peripheral macaque retina, but it is unclear how effective this can be in the central retina, which is required for high-resolution vision. This work probes the neural code and effectiveness of focal epiretinal stimulation in the central macaque retina, using large-scale electrical recording and stimulationex vivo. The functional organization, light response properties, and electrical properties of the major RGC types in the central retina were mostly similar to the peripheral retina, with some notable differences in density, kinetics, linearity, spiking statistics and correlations. The major RGC types could be distinguished by their intrinsic electrical properties. Electrical stimulation targeting parasol cells revealed similar activation thresholds and reduced axon bundle activation in the central retina, but lower stimulation selectivity. Quantitative evaluation of the potential for image reconstruction from electrically-evoked parasol cell signals revealed higher overall expected image quality in the central retina. An exploration of inadvertent midget cell activation suggested that it could contribute high spatial frequency noise to the visual signal carried by parasol cells. These results support the possibility of reproducing high-acuity visual signals in the central retina with an epiretinal implant.SIGNIFICANCE STATEMENT:Artificial restoration of vision with retinal implants is a major treatment for blindness. However, present-day implants do not provide high-resolution visual perception, in part because they do not reproduce the natural neural code of the retina. Here we demonstrate the level of visual signal reproduction that is possible with a future implant by examining how accurately responses to electrical stimulation of parasol retinal ganglion cells (RGCs) can convey visual signals. Although the precision of electrical stimulation in the central retina was diminished relative to the peripheral retina, the quality of expected visual signal reconstruction in parasol cells was greater. These findings suggest that visual signals could be restored with high fidelity in the central retina using a future retinal implant.

Avoidance of axonal stimulation with sinusoidal epiretinal stimulation

“…A possible explanation could be the recording technique, with calcium imaging requiring the generation of multiple spikes for reaching detection threshold. Other studies, using MEA recordings, with stimulation currents in the range of the one applied here do not show any difference between axonal and focal threshold, or even a bias towards axonal stimulation (Madugula et al 2022, Gogliettino et al 2023. In case of non-selective stimulation, focal activation could be achieved with the use of small electrodes on bidirectional implants (Shah and Chichilnisky 2020).…”

“…In the absence of selective stimulation, axons of passage are activated, creating misleading elongated percepts in the patients (Nanduri et al 2012, Beyeler et al 2019. The problem of activation of passing axons may be tackled via closed-loop stimulus optimization algorithms (Grosberg et al 2017, Madugula et al 2022, Gogliettino et al 2023. However, the simplest way to avoid axonal stimulation would be a stimulation waveform capable of activating only the soma or the axon initial segment (AIS) of a target cell, here defined as focal stimulation, without activating nearby distal axons of passage and without requiring prior knowledge of RGC location.…”

Spike sorting in the presence of stimulation artifacts: a dynamical control systems approach

“…Eyes were obtained from terminally anesthetized macaque monkeys (Macaca mulatta, Macaca fascicularis) used by other researchers, in accordance with Institutional Animal Care and Use Committee guidelines. Further details on the experimental preparation have been described previously [21,22,44].…”

“…A custom spike sorting procedure [42] was applied to the recordings to identify and segregate spikes from individual RGCs. The spike-triggered average (STA) stimulus was then computed for each RGC to classify functionally-distinct cell types [10,11,21,61]. For each cell, the electrical image (EI), or the average spatiotemporal pattern of activity associated with a cell's spike, was computed by averaging the voltage traces during the time of each cell's spike [42,57].…”

“…To characterize RGC responses to epiretinal electrical stimulation, the retina was electrically stimulated by injecting a brief current pulse (charge balanced, positive first, triphasic, 50 µs per phase in relative ratios of 2:-3:1) through one electrode at a time in a random sequence while recording on all electrodes simultaneously [21,22,33,44]. Thus, 39 current amplitudes (0.1-4.1 µA on the second phase, log spacing) were applied, with each amplitude repeated 25 times.…”