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. 2023 Jun 28;43(26):4808-4820.
doi: 10.1523/JNEUROSCI.1023-22.2023. Epub 2023 Jun 2.

Inference of Electrical Stimulation Sensitivity from Recorded Activity of Primate Retinal Ganglion Cells

Sasidhar S Madugula  1   2   3 , Ramandeep Vilkhu  4 , Nishal P Shah  5   4   3 , Lauren E Grosberg  5   3   6 , Alexandra Kling  5   3 , Alex R Gogliettino  7   3 , Huy Nguyen  5 , Paweł Hottowy  8 , Alexander Sher  9 , Alan M Litke  9 , E J Chichilnisky  5   10   3
Affiliations

Inference of Electrical Stimulation Sensitivity from Recorded Activity of Primate Retinal Ganglion Cells

Sasidhar S Madugula et al. J Neurosci. .

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, 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 multielectrode stimulation and recording from retinal ganglion cells (RGCs) of male and female macaque monkeys 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 similar. 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.

Keywords: biophysics; macular degeneration; multielectrode array; primate; retinal electrophysiology; retinal ganglion cells.

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Figures

Figure 1.
Figure 1.
Electrical recording and stimulation of individual cells with a large-scale electrode array. A, ON parasol cell EI superimposed on the ERF. Circle area is proportional to recorded signal strength. Electrode color represents electrical stimulation threshold. Electrodes that recorded spike amplitudes lower than the electrical noise threshold (30 μV) are not plotted, and those that did not evoke spikes over the current range tested are black and open. Electrodes for which the signal could not be analyzed because of axon bundle activity are light blue and open. Top, Examples of recorded dendritic (black), somatic (blue), and axonal (red) spike waveforms (see Materials and Methods). Bottom, Electrical activation probability as a function of current level at selected electrodes from cellular compartment (bottom). B, Similar to A, but for an OFF parasol cell from the same retina.
Figure 2.
Figure 2.
Relationship between activation thresholds, electrode location, and EI amplitudes for peripheral macaque parasol cells. Circular markers represent ON parasol cells. Square markers represent OFF parasol cells. A, B, Electrical activation threshold versus recorded spike amplitude for axonal (red) and somatic (blue) electrodes in two different retinal preparations (see Materials and Methods). Colored dashed lines indicate maximum likelihood curve fits to the aggregated data for somas (blue, fit to data in C) and axons (red, fit to data in D, parameters: axon, Eq. 1, a = 6.5, b = 0.4 μA, and c = 35 μV; soma, Eq. 2, a = 22, b = 0.4 μA, c = 96 μV, d = 0.0146, e = −0.428). Aggregated thresholds versus EI amplitudes for axonal (C) and somatic (D) electrodes, collected from 23 retinas. Dashed lines indicate curve fits to the data. Color represents distance from the AIS location.
Figure 3.
Figure 3.
Relationship between activation curve slopes and thresholds. A, Two somatic (blue) and two axonal (red) measured sigmoidal activation curves. C, Activation curves shown in A along with 10 additional examples for each compartment, after current values were normalized by each curve's activation threshold (see Results). Activation curve slopes versus thresholds for somatic (B) and axonal (D) electrodes, with curve fits (dashed line), with parameters a = 3.94 for somas and 4.91 for axons, b = 0.1 for somas and 0.15 for axons. Fitted activation curves with spuriously high slopes resulting from poorly estimated spiking probabilities were excluded (see Materials and Methods).
Figure 4.
Figure 4.
Relationship between activation thresholds, activation slopes, electrode location, and recorded spike amplitudes for RGCs of different types, eccentricities, and species. A-F, Marker color represents distance from estimated AIS location. Dashed lines indicate fits to parasol cell data from Figure 2. Dotted lines indicate fits to midget cell data in A, D (parameters: a = 94.2, b = 0.23 μA, c = 7 μV for somas; a = 23.4, b = 0.28 μA, and c = 9 μV for axons; Eq. 1). A, D, Thresholds versus spike amplitudes for peripheral midget cell somatic (top) and axonal (bottom) electrodes aggregated from 15 macaque retina recordings (circular markers). B, E, Thresholds versus spike amplitudes for macaque central parasol somatic (top) and axonal (bottom) electrodes collected from 10 different macaque retina recordings. C, F, Thresholds versus spike amplitudes for peripheral human parasol (circles) and midget (triangles) cell somatic (top) and axonal (bottom) electrodes from three human retina recordings. G-I, Relationship between activation curve slopes and activation thresholds for macaque peripheral midget (G), macaque central parasol (H), and human peripheral parasol (circles) and midget (triangles) cells (I). Dotted lines indicate the somatic (blue) and axonal (red) slope-threshold relationships in Figure 3B, D. Dashed lines indicate fits to midget cell data in G (parameters a = 8.44 for somas and 11.41 for axons, b = 0.1 for somas and.15 for axons). Blue represents somatic electrodes. Red represents axonal electrodes.
Figure 5.
Figure 5.
Simulated extracellular activation properties of RGCs. A, Finite-element NEURON model schematic with parasol cell soma (red dashed outline indicates midget cell soma; thickness of all other compartments also differs for midget cells but is not shown; see Materials and Methods), axon hillock, sodium channel band, narrow axon, and distal axon compartments, along with rectangles representing overlying simulated electrode positions, including the somatic (blue) and axonal (red) electrodes used in B, D. Ellipsis indicates spatial discontinuity to allow for visualization of the distal axon. B, Simulated parasol cell ERF with electrode locations corresponding to each electrode x position in A. Circle sizes represent peak recorded spike amplitudes. Colors represent activation thresholds. C, D, Activation thresholds versus recorded spike amplitudes for simulated (triangular markers) and experimentally collected (dashed fit and circular markers) data, for somatic (blue) and axonal (red) electrodes overlying parasol (C) and midget (D) cells. E, Simulated somatic (blue) and axonal (red) activation curves.
Figure 6.
Figure 6.
Comparison of inferred and measured activation properties. A, Measured versus inferred ERFs for a single ON parasol cell. Circle size corresponds to spike amplitude recorded at each electrode. Circle shade corresponds to measured (left) or inferred (right) activation threshold at each electrode. Inferred versus measured somatic (B) and axonal (E) thresholds, and slopes (C,F), pooled across 259 cell-electrode pairs. Circular markers represent ON parasol cells. Square markers represent OFF parasol cells. Dashed line indicates x = y. D, Histograms of the absolute differences between integrals of inferred (green), or fixed (purple) somatic activation curves. Vertical dashed lines indicate respective mean values. G, Histograms of absolute differences between integrals of inferred and measured axonal activation curves.
Figure 7.
Figure 7.
Simulated image reconstruction using inferred, measured, and fixed activation curves. A, Reconstructed images in one retinal recording for two targets (top and bottom rows, respectively, left), using measured (middle left), inferred (middle), and fixed control (middle right), activation curves. B, NMSE image reconstruction for inferred versus fixed (green markers) and measured versus fixed (black markers) across 15 targets and 3 retinal recordings. Data from each recording form a cluster of points. Red dashed line indicates x = y. Green dashed line indicates linear fit to inferred versus fixed points. Black dashed line indicates linear fit to measured versus fixed points.
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