Spatially patterned bi-electrode epiretinal stimulation for axon avoidance at cellular resolution

Abstract

Objective.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.Approach.In this work, a custom multi-electrode array (512 electrodes, 10μm diameter, 60μm pitch) was used to stimulate and record RGCs in macaque retinaex vivoat 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.Main results.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.Significance.This work suggests that a bi-electrode epiretinal stimulation strategy can reduce inadvertent axonal activation at cellular resolution, for high-fidelity artificial vision.

Keywords: axon activation; cellular resolution; epiretinal prosthesis; retinal electrophysiology; retinal ganglion cells; spatially-patterned stimulation strategy.

Figure 1.. Example electrical image decomposition into axonal and somatic compartments along with biophysical theory.

A. Spatial component of the electrical image for a single cell plotted on the electrode array along with polynomial axon trajectory fit and Gaussian somatic compartment fit. Crosses represent an example bi-electrode stimulation pattern, straddling the axon fit (blue cross, positive polarity electrode; black cross, negative polarity electrode). B. Example of an ideal bi-electrode stimulus: a pair of electrodes perfectly straddling an axon providing equal and opposite currents. The resulting activating function (the second spatial derivative of voltage along the length of the axon) from each active electrode is shown. Linear summation of electric fields implies that these activating functions would cancel perfectly in this idealized case.

Figure 2.. Axonal and somatic activation thresholds from bi-electrode and single-electrode stimulation.

Scatter plots for three preparations show activation threshold of analyzed cells to bi-electrode (BE) and single-electrode (SE) stimulation. Dashed diagonals denote equality. An example of the “surrogate” analysis method (see Results) is illustrated in retina 3: dashed lines show all possible pairings between a non-target axon and all somas; solid line denotes a soma-axon pair targeted by the same set of electrodes. Data are shown from 40 distinct cells and 192 distinct cell-electrode pairs across the three retinal preparations.

Figure 3.. Impact of bi-electrode stimulation on selectivity.

Scatter plots with each point representing selectivity calculated for a target soma (gray points, Fig. 2) and non-target axon (red points, Fig. 2) pair with bi-electrode (BE) and single-electrode (SE) stimulation in three retinas. Red diagonals denote equality. Shaded region represents regions of rescued selectivity (Fig. 4). Open symbols with dotted tails represent scenarios in which the target soma or non-target axon did not spike at the maximum supplied current amplitude. In these cases selectivity was calculated with the threshold set to the largest current amplitude tested, and the tail shows the possible range of true selectivity for larger thresholds.

Figure 4.. Electrical images and activation curves for target somas and non-target axons exhibiting rescued selectivity.

Each panel on the left shows a simplified electrical image of the axonal and somatic compartments of a recorded cell over a region of the electrode array. Each panel on the right shows the observed activation curves for the target and non-target cell, using bi-electrode and single electrode stimulation. In all cases, bi-electrode stimulation resulted in selective activation of the target soma, at a lower current level than the threshold for the non-target axon, which was not possible with single electrode stimulation. Soma-axon pairs A, B, and C were from retina 1, 2, and 3, respectively.