Sasidhar Madugula

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

  Abstract

  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

• Efficient Modeling and Calibration of Multi-Electrode Stimuli for Epiretinal Implants Vasireddy, P. K., Gogliettino, A. R., Brown, J. B., Vilkhu, R. S., Madugula, S. S., Phillips, A. J., Mitra, S., Hottowy, P., Sher, A., Litke, A., Shah, N. P., Chichilnisky, E. J., IEEE IEEE. 2023

  View details for DOI 10.1109/NER52421.2023.10123907

  View details for Web of Science ID 001009053700189

• 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)

  Abstract

  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

  View details for Web of Science ID 000690761600407

• Automatic Identification of Axon Bundle Activation for Epiretinal Prosthesis IEEE TRANSACTIONS ON NEURAL SYSTEMS AND REHABILITATION ENGINEERING Tandon, P., Bhaskhar, N., Shah, N., Madugula, S., Grosberg, L., Fan, V. H., Hottowy, P., Sher, A., Litke, A. M., Chichilnisky, E. J., Mitra, S. 2021; 29: 2496-2502

  Abstract

  Retinal prostheses must be able to activate cells in a selective way in order to restore high-fidelity vision. However, inadvertent activation of far-away retinal ganglion cells (RGCs) through electrical stimulation of axon bundles can produce irregular and poorly controlled percepts, limiting artificial vision. In this work, we aim to provide an algorithmic solution to the problem of detecting axon bundle activation with a bi-directional epiretinal prostheses.The algorithm utilizes electrical recordings to determine the stimulation current amplitudes above which axon bundle activation occurs. Bundle activation is defined as the axonal stimulation of RGCs with unknown soma and receptive field locations, typically beyond the electrode array. The method exploits spatiotemporal characteristics of electrically-evoked spikes to overcome the challenge of detecting small axonal spikes.The algorithm was validated using large-scale, single-electrode and short pulse, ex vivo stimulation and recording experiments in macaque retina, by comparing algorithmically and manually identified bundle activation thresholds. For 88% of the electrodes analyzed, the threshold identified by the algorithm was within ±10% of the manually identified threshold, with a correlation coefficient of 0.95.This works presents a simple, accurate and efficient algorithm to detect axon bundle activation in epiretinal prostheses.The algorithm could be used in a closed-loop manner by a future epiretinal prosthesis to reduce poorly controlled visual percepts associated with bundle activation. Activation of distant cells via axonal stimulation will likely occur in other types of retinal implants and cortical implants, and the method may therefore be broadly applicable.

  View details for DOI 10.1109/TNSRE.2021.3128486

  View details for Web of Science ID 000730473200002

  View details for PubMedID 34784278

• Epiretinal stimulation with local returns enhances selectivity at cellular resolution. Journal of neural engineering Fan, V. H., Grosberg, L. E., Madugula, S. S., Hottowy, P., Dabrowski, W., Sher, A., Litke, A. M., Chichilnisky, E. J. 2018

  Abstract

  OBJECTIVE: Epiretinal prostheses are designed to restore vision in people blinded by photoreceptor degenerative diseases, by directly activating retinal ganglion cells (RGCs) using an electrode array implanted on the retina. In present-day clinical devices, current spread from the stimulating electrode to a distant return electrode often results in the activation of many cells, potentially limiting the quality of artificial vision. In the laboratory, epiretinal activation of RGCs with cellular resolution has been demonstrated with small electrodes, but distant returns may still cause undesirable current spread. Here, the ability of local return stimulation to improve the selective activation of RGCs at cellular resolution was evaluated. Approach: A custom multi-electrode array (512 electrodes, 10 mum diameter, 60 mum pitch) was used to simultaneously stimulate and record from RGCs in isolated primate retina. Stimulation near the RGC soma with a single electrode and a distant return was compared to stimulation in which the return was provided by six neighboring electrodes. Main Results: Local return stimulation enhanced the capability to activate cells near the central electrode (<30 m) while avoiding cells farther away (>30 m). This resulted in an improved ability to selectively activate ON and OFF cells, including cells encoding immediately adjacent regions in the visual field. Significance: These results suggest that a device that restricts the electric field through local returns could optimize activation of neurons at cellular resolution, improving the quality of artificial vision.

  View details for PubMedID 30523958

• Electrical stimulus artifact cancellation and neural spike detection on large multi-electrode arrays PLOS COMPUTATIONAL BIOLOGY Mena, G. E., Grosberg, L. E., Madugula, S., Hottowy, P., Litke, A., Cunningham, J., Chichilnisky, E. J., Paninski, L. 2017; 13 (11): e1005842

  Abstract

  Simultaneous electrical stimulation and recording using multi-electrode arrays can provide a valuable technique for studying circuit connectivity and engineering neural interfaces. However, interpreting these measurements is challenging because the spike sorting process (identifying and segregating action potentials arising from different neurons) is greatly complicated by electrical stimulation artifacts across the array, which can exhibit complex and nonlinear waveforms, and overlap temporarily with evoked spikes. Here we develop a scalable algorithm based on a structured Gaussian Process model to estimate the artifact and identify evoked spikes. The effectiveness of our methods is demonstrated in both real and simulated 512-electrode recordings in the peripheral primate retina with single-electrode and several types of multi-electrode stimulation. We establish small error rates in the identification of evoked spikes, with a computational complexity that is compatible with real-time data analysis. This technology may be helpful in the design of future high-resolution sensory prostheses based on tailored stimulation (e.g., retinal prostheses), and for closed-loop neural stimulation at a much larger scale than currently possible.

  View details for PubMedID 29131818

  View details for PubMedCentralID PMC5703587

• Optimizing Selectivity of Epiretinal Stimulation using Local Returns Fan, V., Grosberg, L. E., Madugula, S., Hottowy, P., Dabrowski, W., Sher, A., Litke, A. M., Chichilnisky, E. J. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2017

  View details for Web of Science ID 000432176302326

• Activation of ganglion cells and axon bundles using epiretinal electrical stimulation. Journal of neurophysiology Grosberg, L. E., Ganesan, K., Goetz, G. A., Madugula, S. S., Bhaskhar, N., Fan, V., Li, P., Hottowy, P., Dabrowski, W., Sher, A., Litke, A. M., Mitra, S., Chichilnisky, E. J. 2017: jn 00750 2016-?

  Abstract

  Epiretinal prostheses for treating blindness activate axon bundles, causing large, arc-shaped visual percepts that limit the quality of artificial vision. Improving the function of epiretinal prostheses therefore requires understanding and avoiding axon bundle activation. This paper introduces a method to detect axon bundle activation based on its electrical signature, and uses the method to test whether epiretinal stimulation can directly elicit spikes in individual retinal ganglion cells without activating nearby axon bundles. Combined electrical stimulation and recording from isolated primate retina were performed using a custom multi-electrode system (512 electrodes, 10 μm diameter, 60 μm pitch). Axon bundle signals were identified by their bi-directional propagation, speed, and increasing amplitude as a function of stimulation current. The threshold for bundle activation varied across electrodes and retinas, and was in the same range as the threshold for activating retinal ganglion cells near their somas. In the peripheral retina, 45% of electrodes that activated individual ganglion cells (17% of all electrodes) did so without activating bundles. This permitted selective activation of 21% of recorded ganglion cells (7% of all ganglion cells) over the array. In the central retina, 75% of electrodes that activated individual ganglion cells (16% of all electrodes) did so without activating bundles. The ability to selectively activate a subset of retinal ganglion cells without axon bundles suggests a possible novel architecture for future epiretinal prostheses.

  View details for DOI 10.1152/jn.00750.2016

  View details for PubMedID 28566464