Electric stimulation of the retina reliably elicits light percepts in patients blinded by outer retinal diseases. However, individual percepts are highly variable and do not readily assemble into more complex visual images. As a result, the quality of visual information conveyed to patients has been quite limited. To develop more effective stimulation methods that will lead to improved psychophysical outcomes, we are studying how retinal neurons respond to electric stimulation. The situation in the retina is analogous to other neural prosthetic applications in which a better understanding of the underlying neural response may lead to improved clinical outcomes. Here, we determined which element in retinal ganglion cells has the lowest threshold for initiating action potentials. Previous studies suggest multiple possibilities, although all were within the soma/proximal axon region. To determine the actual site, we measured thresholds in a dense two-dimensional grid around the soma/proximal axon region of rabbit ganglion cells in the flat mount preparation. In directionally selective (DS) ganglion cells, the lowest thresholds were found along a small section of the axon, about 40 microm from the soma. Immunochemical staining revealed a dense band of voltage-gated sodium channels centered at the same location, suggesting that thresholds are lowest when the stimulating electrode is closest to the sodium-channel band. The size and location of the low-threshold region was consistent within DS cells, but varied for other ganglion cell types. Analogously, the length and location of sodium channel bands also varied by cell type. Consistent with the differences in band properties, we found that the absolute (lowest) thresholds were also different for different cell types. Taken together, our results suggest that the sodium-channel band is the site that is most responsive to electric stimulation and that differences in the bands underlie the threshold differences we observed.

To improve the quality of prosthetic vision, it is desirable to understand how targeted retinal neurons respond to stimulation. Unfortunately, the factors that shape the response of a single neuron to stimulation are not well understood. A dense band of voltage gated sodium channels within the proximal axon of retinal ganglion cells is the site most sensitive to electric stimulation, suggesting that band properties are likely to influence the response to stimulation. Here, we examined how three band properties influence sensitivity using a morphologically realistic ganglion cell model in NEURON. Longer bands were more sensitive to short-duration pulses than shorter bands and increasing the distance between band and soma also increased sensitivity. Simulations using the known limits of band length and location resulted in a sensitivity difference of approximately two. Additional simulations tested how changes to sodium channel conductance within the band influenced threshold and found that the sensitivity difference increased to a factor of nearly three. This is close to the factor of 5 difference measured in physiological studies suggesting that band properties contribute significantly to the sensitivity differences found between different types of retinal neurons.

Cai C, Ren Q, Desai NJ, Rizzo JF 3rd, Fried SI. Response variability to high rates of electric stimulation in retinal ganglion cells.

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