Activation of ganglion cells and axon bundles using epiretinal electrical stimulation.

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 study introduces a method to detect axon bundle activation on the basis of 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 multielectrode system (512 electrodes, 10-μm diameter, 60-μm pitch). Axon bundle signals were identified by their bidirectional 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 expected ganglion cells) over the array. In one recording 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.NEW & NOTEWORTHY Large-scale multielectrode recording and stimulation were used to test how selectively retinal ganglion cells can be electrically activated without activating axon bundles. A novel method was developed to identify axon activation on the basis of its unique electrical signature and was used to find that a subset of ganglion cells can be activated at single-cell, single-spike resolution without producing bundle activity in peripheral and central retina. These findings have implications for the development of advanced retinal prostheses.

[1]  Mark S Humayun,et al.  Frequency and amplitude modulation have different effects on the percepts elicited by retinal stimulation. , 2012, Investigative ophthalmology & visual science.

[2]  Eero P. Simoncelli,et al.  Spatio-temporal correlations and visual signalling in a complete neuronal population , 2008, Nature.

[3]  D. Dacey,et al.  Origins of perception : retinal ganglion cell diversity and the creation of parallel visual pathways , 2011 .

[4]  D. Dacey The mosaic of midget ganglion cells in the human retina , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  E. Callaway,et al.  Anatomical Identification of Extracellularly Recorded Cells in Large-Scale Multielectrode Recordings , 2015, The Journal of Neuroscience.

[6]  Charles P. Ratliff,et al.  Changes in ganglion cell physiology during retinal degeneration influence excitability by prosthetic electrodes , 2016, Journal of neural engineering.

[7]  Piotr Wiącek,et al.  An integrated multichannel waveform generator for large-scale spatio-temporal stimulation of neural tissue , 2008 .

[8]  Mark S Humayun,et al.  Both electrical stimulation thresholds and SMI-32-immunoreactive retinal ganglion cell density correlate with age in S334ter line 3 rat retina. , 2011, Journal of neurophysiology.

[9]  Jessy D. Dorn,et al.  Blind subjects implanted with the Argus II retinal prosthesis are able to improve performance in a spatial-motor task , 2010, British Journal of Ophthalmology.

[10]  Jessy D. Dorn,et al.  Interim results from the international trial of Second Sight's visual prosthesis. , 2012, Ophthalmology.

[11]  Joseph F Rizzo,et al.  Thresholds for activation of rabbit retinal ganglion cells with an ultrafine, extracellular microelectrode. , 2003, Investigative ophthalmology & visual science.

[12]  Joseph F Rizzo,et al.  Encoding visual information in retinal ganglion cells with prosthetic stimulation , 2011, Journal of neural engineering.

[13]  E J Chichilnisky,et al.  Focal Electrical Stimulation of Major Ganglion Cell Types in the Primate Retina for the Design of Visual Prostheses , 2013, The Journal of Neuroscience.

[14]  Eberhart Zrenner,et al.  Functional outcome in subretinal electronic implants depends on foveal eccentricity. , 2013, Investigative ophthalmology & visual science.

[15]  Devyani Nanduri,et al.  Prosthetic vision in blind human patients: Predicting the percepts of epiretinal stimulation , 2011 .

[16]  E J Chichilnisky,et al.  Behavioral / Systems / Cognitive Identification and Characterization of a Y-Like Primate Retinal Ganglion Cell Type , 2007 .

[17]  Keith Mathieson,et al.  Properties and application of a multichannel integrated circuit for low-artifact, patterned electrical stimulation of neural tissue , 2012, Journal of neural engineering.

[18]  Alice K. Cho,et al.  Retinal prostheses: current clinical results and future needs. , 2011, Ophthalmology.

[19]  Ravi S. Jonnal,et al.  Imaging retinal nerve fiber bundles using optical coherence tomography with adaptive optics , 2011, Vision Research.

[20]  S. Kelly,et al.  Perceptual efficacy of electrical stimulation of human retina with a microelectrode array during short-term surgical trials. , 2003, Investigative ophthalmology & visual science.

[21]  Daniel Palanker,et al.  Contrast Sensitivity With a Subretinal Prosthesis and Implications for Efficient Delivery of Visual Information. , 2015, Investigative ophthalmology & visual science.

[22]  E J Chichilnisky,et al.  Changes in physiological properties of rat ganglion cells during retinal degeneration. , 2011, Journal of neurophysiology.

[23]  Hierlemann Andreas,et al.  Electrical Identification and Selective Microstimulation of Neuronal Compartments Based on Features of Extracellular Action Potentials , 2016 .

[24]  Joseph F Rizzo,et al.  Selective activation of neuronal targets with sinusoidal electric stimulation. , 2010, Journal of neurophysiology.

[25]  K. Mathieson,et al.  Spatially patterned electrical stimulation of the retina for improved specificity , 2011, 2011 5th International IEEE/EMBS Conference on Neural Engineering.

[26]  Srinivasan Parthasarathy,et al.  Symmetrizations for clustering directed graphs , 2011, EDBT/ICDT '11.

[27]  S. Fried,et al.  Axonal sodium-channel bands shape the response to electric stimulation in retinal ganglion cells. , 2009, Journal of neurophysiology.

[28]  E J Chichilnisky,et al.  A simple white noise analysis of neuronal light responses , 2001, Network.

[29]  M E J Newman,et al.  Modularity and community structure in networks. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Nathan D. Shemonski,et al.  Computational high-resolution optical imaging of the living human retina , 2015, Nature Photonics.

[31]  Mark S Humayun,et al.  Imaging the response of the retina to electrical stimulation with genetically encoded calcium indicators. , 2013, Journal of neurophysiology.

[32]  E. Chichilnisky,et al.  Functional Asymmetries in ON and OFF Ganglion Cells of Primate Retina , 2002, The Journal of Neuroscience.

[33]  Timothy A. Machado,et al.  Functional connectivity in the retina at the resolution of photoreceptors , 2010, Nature.

[34]  F. Werblin,et al.  A method for generating precise temporal patterns of retinal spiking using prosthetic stimulation. , 2006, Journal of neurophysiology.

[35]  Angelika Braun,et al.  Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS , 2013, Proceedings of the Royal Society B: Biological Sciences.

[36]  Jonathon Shlens,et al.  Spatial Properties and Functional Organization of Small Bistratified Ganglion Cells in Primate Retina , 2007, The Journal of Neuroscience.

[37]  Georges Goetz,et al.  Recognizing retinal ganglion cells in the dark , 2015, NIPS.

[38]  E. Chichilnisky,et al.  High-Resolution Electrical Stimulation of Primate Retina for Epiretinal Implant Design , 2008, The Journal of Neuroscience.

[39]  J. Weiland,et al.  Improving the spatial resolution of epiretinal implants by increasing stimulus pulse duration , 2015, Science Translational Medicine.

[40]  D. Palanker,et al.  Electronic approaches to restoration of sight , 2016, Reports on progress in physics. Physical Society.

[41]  E. Chichilnisky,et al.  Spatially Patterned Electrical Stimulation to Enhance Resolution of Retinal Prostheses , 2014, The Journal of Neuroscience.

[42]  E J Chichilnisky,et al.  A Polyaxonal Amacrine Cell Population in the Primate Retina , 2014, The Journal of Neuroscience.

[43]  Y. Goo,et al.  The slow wave component of retinal activity in rd/rd mice recorded with a multi-electrode array , 2007, Physiological measurement.

[44]  E. Chichilnisky,et al.  High-Fidelity Reproduction of Spatiotemporal Visual Signals for Retinal Prosthesis , 2014, Neuron.

[45]  Nils J. Nilsson,et al.  A Formal Basis for the Heuristic Determination of Minimum Cost Paths , 1968, IEEE Trans. Syst. Sci. Cybern..

[46]  E. Chichilnisky,et al.  Fidelity of the ensemble code for visual motion in primate retina. , 2005, Journal of neurophysiology.

[47]  B. Boycott,et al.  Dendritic territories of cat retinal ganglion cells , 1981, Nature.

[48]  D. Palanker,et al.  Selectivity of direct and network-mediated stimulation of the retinal ganglion cells with epi-, sub- and intraretinal electrodes , 2014, Journal of neural engineering.

[49]  Socrates Dokos,et al.  Activation and inhibition of retinal ganglion cells in response to epiretinal electrical stimulation: a computational modelling study , 2015, Journal of neural engineering.

[50]  Thomas Euler,et al.  Functional Stability of Retinal Ganglion Cells after Degeneration-Induced Changes in Synaptic Input , 2008, The Journal of Neuroscience.

[51]  D. Baylor,et al.  Mosaic arrangement of ganglion cell receptive fields in rabbit retina. , 1997, Journal of neurophysiology.

[52]  A. Sher,et al.  Photovoltaic restoration of sight with high visual acuity , 2015, Nature Medicine.

[53]  Michael J. Berry,et al.  Recording spikes from a large fraction of the ganglion cells in a retinal patch , 2004, Nature Neuroscience.

[54]  P. Tresco,et al.  Response of brain tissue to chronically implanted neural electrodes , 2005, Journal of Neuroscience Methods.

[55]  A.M. Litke,et al.  What does the eye tell the brain?: Development of a system for the large scale recording of retinal output activity , 2003, 2003 IEEE Nuclear Science Symposium. Conference Record (IEEE Cat. No.03CH37515).

[56]  E J Chichilnisky,et al.  Loss of responses to visual but not electrical stimulation in ganglion cells of rats with severe photoreceptor degeneration. , 2009, Journal of neurophysiology.

[57]  Jonathon Shlens,et al.  Uniform Signal Redundancy of Parasol and Midget Ganglion Cells in Primate Retina , 2009, The Journal of Neuroscience.

[58]  Michalis Vazirgiannis,et al.  Clustering and Community Detection in Directed Networks: A Survey , 2013, ArXiv.

[59]  James D. Weiland,et al.  Physiological response of mouse retinal ganglion cells to electrical stimulation: Effect of soma size , 2011, 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society.