Temporal properties of network-mediated responses to repetitive stimuli are dependent upon retinal ganglion cell type

Abstract

Objective To provide artificially-elicited vision that is temporally dynamic, retinal prosthetic devices will need to repeatedly stimulate retinal neurons. However, given the diversity of physiological types of retinal ganglion cells (RGCs) as well as the heterogeneity of their responses to electric stimulation, temporal properties of RGC responses have not been adequately investigated. Here, we explored the cell type dependence of network-mediated RGC responses to repetitive electric stimulation at various stimulation rates. Approach We examined responses of ON and OFF types of RGCs in the rabbit retinal explant to five consecutive stimuli with varying inter-stimulus intervals (10–1000 ms). Each stimulus was a 4-ms-long monophasic sinusoidal cathodal current, which was applied epiretinally via a conical electrode. Spiking activity of targeted RGCs was recorded using a cell-attached patch electrode. Main results ON and OFF cells had distinct responses to repetitive stimuli. Consistent with earlier studies, OFF cells always generated reduced responses to subsequent stimuli compared to responses to the first stimulus. In contrast, a new stimulus to ON cells suppressed all pending/ongoing responses from previous stimuli and initiated its own response that was remarkably similar to the response from a single stimulus in isolation. This previously unreported ‘reset’ behavior was observed exclusively and consistently in ON cells. These contrasts between ON and OFF cells created a range of stimulation rates (4–7 Hz) that maximized the ratio of the responses arising in ON vs. OFF cells. Significance Previous clinical testing reported that subjects perceive bright phosphenes (ON responses) and also prefer stimulation rates of 5–7 Hz. Our results suggest that responses of ON cells are weak at high rates of stimulation (> ~7 Hz) due to the reset while responses of OFF cells are strong at low rates (< ~4 Hz) due to reduced desensitization, both reducing the ratio of ON to OFF responses. In combination with previous results indicating that responses in ON cells more closely match physiological patterns (Im and Fried, 2015), our results offer a potential reason for the user preference of intermediate rates (5–7 Hz).

Spike-triggered average electrical stimuli as input filters for bionic vision—a perspective

“…They found that visual ON cells tended to respond during the anodal phase of a slow (5 Hz) sine wave while OFF cells responded during the cathodal phase. Other recent contributions to growing evidence of cell-type selective stimulation include (Twyford & Fried 2016;Guo et al 2014;Im & Fried 2016;Goetz et al 2015;Im et al 2018;Guo et al 2018;Qin et al 2017).…”

Probing and predicting ganglion cell responses to smooth electrical stimulation in healthy and blind mouse retina

“…The clinical relevance of sinusoidal stimulation thus appears to be limited 25 . Varying stimulus parameters such as shape, repetition rate, duration and charge allowed to identify stimulus regimes that maximize the response ratio of ON and OFF RGCs [27][28][29][30][31] .…”

Stimulation Strategies for Improving the Resolution of Retinal Prostheses

“…The desensitization phenomenon has been observed experimentally in both direct and network mediated responses of RGCs. For network mediated responses, in the low frequency range (below 10 Hz), Im and Fried (2016) showed desensitization in OFF RGCs, but not in ON RGCs. However, Walston et al (2018) observed desensitizing responses in ON bipolar cells at frequencies greater than 6 Hz.…”

“…Also, the stimuli that activated photoreceptors yielded better correlations than those activating bipolar cells. In a following study (Im and Fried, 2016), they examined the network-mediated responses to repetitive stimulation and also found differences between ON and OFF cells. In both brisk transient and brisk sustained ON cells, they showed a reset phenomenon, in which each new stimulus elicited a brief burst of spikes.…”