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High-resolution electrical stimulation of primate retina for epiretinal implant design - PubMed

  • ️Tue Jan 01 2008

Comparative Study

High-resolution electrical stimulation of primate retina for epiretinal implant design

Chris Sekirnjak et al. J Neurosci. 2008.

Abstract

The development of retinal implants for the blind depends crucially on understanding how neurons in the retina respond to electrical stimulation. This study used multielectrode arrays to stimulate ganglion cells in the peripheral macaque retina, which is very similar to the human retina. Analysis was restricted to parasol cells, which form one of the major high-resolution visual pathways in primates. Individual cells were characterized using visual stimuli, and subsequently targeted for electrical stimulation using electrodes 9-15 microm in diameter. Results were accumulated across 16 ON and 9 OFF parasol cells. At threshold, all cells responded to biphasic electrical pulses 0.05-0.1 ms in duration by firing a single spike with latency lower than 0.35 ms. The average threshold charge density was 0.050 +/- 0.005 mC/cm(2), significantly below established safety limits for platinum electrodes. ON and OFF ganglion cells were stimulated with similar efficacy. Repetitive stimulation elicited spikes within a 0.1 ms time window, indicating that the high temporal precision necessary for spike-by-spike stimulation can be achieved in primate retina. Spatial analysis of observed thresholds suggests that electrical activation occurred near the axon hillock, and that dendrites contributed little. Finally, stimulation of a single parasol cell produced little or no activation of other cells in the ON and OFF parasol cell mosaics. The low-threshold, temporally precise, and spatially specific responses hold promise for the application of high-density arrays of small electrodes in epiretinal implants.

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Figures

Figure 1.
Figure 1.

White noise visual stimulation. A, The average stimulus observed 50 ms before a spike in two primate retinal ganglion cells in one retina. Dots represent the location of each electrode in the 61-electrode array. The primary (recording) electrode is marked with a circle, the site of electrical stimulation with a radiating symbol. Lighter-than-background pixels describe the receptive field of an ON parasol cell (left), whereas the region of darker pixels indicates the receptive field of an OFF parasol cell (right). Scale bar, 65 μm. B, Average time course of STA (spike-triggered average) contrast of the red, green, and blue display phosphors in the 300 ms preceding a spike, summed over several pixels in the center of the receptive field (same cells as in A). Black dashed line shows the best-fit curve to the green signal (Chichilnisky and Kalmar, 2002). The ON cell (left) shows a dominant positive lobe whereas the OFF cell (right) exhibits a dominant negative peak. C, Receptive fields of nine ON parasol ganglion cells and 13 OFF parasol ganglion cells recorded simultaneously in this retina. Ellipses represent 1 SD of the Gaussian fit to the spatial profile of each receptive field. The shaded fields indicate cells electrically stimulated in this retina. The small circles mark the cells shown in the above panels (same scale as in A). D, Electrical images of two ON and two OFF cells in this retina. Colored lines represent the interpolated amplitudes of the electrical signal measured at all nearby electrodes, normalized to the largest spike signal. Black ellipses are 1 SD of the Gaussian fits to the amplitude data and were used to describe the electrical image size of each cell (same scale as in A).

Figure 2.
Figure 2.

Spike responses to electrical stimulation. A, Spikes recorded in the same ON cell shown in Figure 1A, stimulated using a neighboring electrode. A superposition of responses to 65 repeated pulses of 50 μs duration is shown. Near threshold, the electrical stimulus (large artifact) evoked either successful spikes (black traces) or no spikes (gray traces). Occasional spontaneous spikes also occurred before and after the stimulation. B, The average evoked spike, obtained by subtracting failures from successes in A. The evoked spike resembles the spontaneous spikes in A. The arrow points to the onset of the stimulation pulse. C, Response rate (fraction of pulses that evoked a spike) as a function of stimulus strength. Threshold was defined as a 50% response rate. Data from 18 parasol cells were pooled for this plot; open and closed symbols denote ON and OFF cells, respectively. The dashed line is an error function fit to the data (see Materials and Methods).

Figure 3.
Figure 3.

Precision of submillisecond latency responses to electrical stimulation. A, Top, Superposition of responses of a primate retinal ganglion cell to 244 stimulus pulses delivered at 5 Hz near threshold (pulse duration, 0.05 ms). The stimulation artifact has been subtracted as shown in Figure 2. Bottom, Latencies of each spike shown in A. Bin size, 15 μs. The dotted gray line is a fit to the data. B, Normalized latency histograms of nine ganglion cells such as the one shown in A. Only the fit lines are shown. Black lines indicate ON cells; gray lines indicate OFF cells.

Figure 4.
Figure 4.

Sensitivity to spatial location of stimulation. A, Threshold charge plotted against the square of the distance between stimulation electrode and estimated soma location. Most data are from stimulating at a neighboring electrode (circles), but several cells stimulated directly at the primary electrode were included (diamonds). The dashed line is a linear fit to the data (R2 = 0.58) and denotes a squared dependence of charge on distance from soma. B, Stimulation sites (circles) plotted relative to the soma center (filled square). Data from all cells were aligned at the soma center and rotated so that the direction of the axon (dotted arrow) points to the right. Circle diameter is proportional to the threshold charge minus an offset (minimum 26 pC, maximum 103 pC). The lowest thresholds are found near the soma and the proximal portion of the axon. The filled circle indicates the center of a Gaussian fit to the data and the gray dots denote the expected error around this center (resampled 950 times with replacement; see Materials and Methods). This location of maximal sensitivity to electrical stimulation is situated ∼13 μm to the right of the soma center.

Figure 5.
Figure 5.

Relationship between stimulation parameters. A, Dependence of threshold charge on receptive field size. Open circles, ON cells; closed circles, OFF cells. No significant correlation was found (R2 = 0.001). B, Dependence of threshold charge on electrical image size. No significant correlation was found (R2 = 0.03). Nine cells were omitted because their location near the edge of the array precluded the calculation of complete electrical images. C, Dependence of evoked spike latency on electrical image size. The dashed line is a linear fit (R2 = 0.43).

Figure 6.
Figure 6.

Spatial specificity. Receptive field outlines for ON and OFF parasol mosaics. Numbers denote response rates (in percent) to stimulation at the primary electrode (outlined in bold). Dots indicate cells that were stimulated in this retina. A and B are from the same retina as shown in Figure 1. C and D, are from a different retina. To emphasize that the vast majority of cells were definitely alive at the time of stimulation, spontaneous firing rates were not subtracted.

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