All Publications

  • Inference of Electrical Stimulation Sensitivity from Recorded Activity of Primate Retinal Ganglion Cells. The Journal of neuroscience : the official journal of the Society for Neuroscience Madugula, S. S., Vilkhu, R., Shah, N. P., Grosberg, L. E., Kling, A., Gogliettino, A. R., Nguyen, H., Hottowy, P., Sher, A., Litke, A. M., Chichilnisky, E. J. 2023


    High-fidelity electronic implants can in principle restore the function of neural circuits by precisely activating neurons via extracellular stimulation. However, direct characterization of the individual electrical sensitivity of a large population of target neurons, in order to precisely control their activity, can be difficult or impossible. A potential solution is to leverage biophysical principles to infer sensitivity to electrical stimulation from features of spontaneous electrical activity, which can be recorded relatively easily. Here, this approach is developed and its potential value for vision restoration is tested quantitatively using large-scale multi-electrode stimulation and recording from male and female macaque retinal ganglion cells (RGCs) ex vivo Electrodes recording larger spikes from a given cell exhibited lower stimulation thresholds across cell types, retinas, and eccentricities, with systematic and distinct trends for somas and axons. Thresholds for somatic stimulation increased with distance from the axon initial segment. The dependence of spike probability on injected current was inversely related to threshold, and was substantially steeper for axonal than somatic compartments, which could be identified by their recorded electrical signatures. Dendritic stimulation was largely ineffective for eliciting spikes. These trends were quantitatively reproduced with biophysical simulations. Results from human RGCs were broadly consistent. The inference of stimulation sensitivity from recorded electrical features was tested in a data-driven simulation of visual reconstruction, revealing that the approach could significantly improve the function of future high-fidelity retinal implants.Significance Statement:This study demonstrates that individual in situ primate retinal ganglion cells of different types respond to artificially generated, external electrical fields in a systematic manner, in accordance with theoretical predictions, that allows for prediction of electrical stimulus sensitivity from recorded spontaneous activity. It also provides evidence that such an approach could be immensely helpful in the calibration of clinical retinal implants.

    View details for DOI 10.1523/JNEUROSCI.1023-22.2023

    View details for PubMedID 37268418

  • High-fidelity reproduction of visual signals by electrical stimulation in the central primate retina. The Journal of neuroscience : the official journal of the Society for Neuroscience Gogliettino, A. R., Madugula, S. S., Grosberg, L. E., Vilkhu, R. S., Brown, J., Nguyen, H., Kling, A., Hottowy, P., Dąbrowski, W., Sher, A., Litke, A. M., Chichilnisky, E. J. 2023


    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 stimulation ex 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.

    View details for DOI 10.1523/JNEUROSCI.1091-22.2023

    View details for PubMedID 37188516

  • Focal electrical stimulation of human retinal ganglion cells for vision restoration. Journal of neural engineering Madugula, S. S., Gogliettino, A. R., Zaidi, M., Aggarwal, G., Kling, A., Shah, N. P., Brown, J. B., Vilkhu, R., Hays, M. R., Nguyen, H., Fan, V., Wu, E. G., Hottowy, P., Sher, A., Litke, A. M., Silva, R. A., Chichilnisky, E. J. 2022; 19 (6)


    Objective. Vision restoration with retinal implants is limited by indiscriminate simultaneous activation of many cells and cell types, which is incompatible with reproducing the neural code of the retina. Recent work has shown that primate retinal ganglion cells (RGCs), which transmit visual information to the brain, can be directly electrically activated with single-cell, single-spike, cell-type precision - however, this possibility has never been tested in the human retina. In this study we aim to characterize, for the first time, direct in situ extracellular electrical stimulation of individual human RGCs.Approach. Extracellular electrical stimulation of individual human RGCs was conducted in three human retinas ex vivo using a custom large-scale, multi-electrode array capable of simultaneous recording and stimulation. Measured activation properties were compared directly to extensive results from macaque.Main results. Precise activation was in many cases possible without activating overlying axon bundles, at low stimulation current levels similar to those used in macaque. The major RGC types could be identified and targeted based on their distinctive electrical signatures. The measured electrical activation properties of RGCs, combined with a dynamic stimulation algorithm, was sufficient to produce an evoked visual signal that was nearly optimal given the constraints of the interface.Significance. These results suggest the possibility of high-fidelity vision restoration in humans using bi-directional epiretinal implants.

    View details for DOI 10.1088/1741-2552/aca5b5

    View details for PubMedID 36533865

  • Inferring retinal ganglion cell light response properties from intrinsic electrical feature Zaidi, M., Aggarwal, G., Shah, N. P., Karniol-Tambour, O., Goetz, G., Madugula, S., Gogliettino, A. R., Wu, E. G., Kling, A., Brackbill, N., Sher, A., Litke, A. M., Chichilnisky, E. J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2021
  • Spatially Patterned Bi-electrode Epiretinal Stimulation for Axon Avoidance at Cellular Resolution. Journal of neural engineering Vilkhu, R. S., Madugula, S. S., Grosberg, L. E., Gogliettino, A. R., Hottowy, P., Dabrowski, W., Sher, A., Litke, A. M., Mitra, S., Chichilnisky, E. J. 2021


    Epiretinal prostheses are designed to restore vision to people blinded by photoreceptor degenerative diseases by stimulating surviving retinal ganglion cells (RGCs), which carry visual signals to the brain. However, inadvertent stimulation of RGCs at their axons can result in non-focal visual percepts, limiting the quality of artificial vision. Theoretical work has suggested that axon activation can be avoided with current stimulation designed to minimize the second spatial derivative of the induced extracellular voltage along the axon. However, this approach has not been verified experimentally at the resolution of single cells.In this work, a custom multi-electrode array (512 electrodes, 10 μm diameter, 60 μm pitch) was used to stimulate and record RGCs in macaque retina ex vivo at single-cell, single-spike resolution. RGC activation thresholds resulting from bi-electrode stimulation, which consisted of bipolar currents simultaneously delivered through two electrodes straddling an axon, were compared to activation thresholds from traditional single-electrode stimulation.On average, across three retinal preparations, the bi-electrode stimulation strategy reduced somatic activation thresholds (~21%) while increasing axonal activation thresholds (~14%), thus favoring selective somatic activation. Furthermore, individual examples revealed rescued selective activation of somas that was not possible with any individual electrode.This work suggests that a bi-electrode epiretinal stimulation strategy can reduce inadvertent axonal activation at cellular resolution, for high-fidelity artificial vision.

    View details for DOI 10.1088/1741-2552/ac3450

    View details for PubMedID 34710857