The Effects and Interactions of Epiretinal Electrical Stimulation Parameters on Direct and Network-Mediated Activation of Retinal Ganglion Cells

Neuromodulation efficacy and efficiency hinge on optimization of stimulation parameters like charge, phase width (PW), pulse rate, and waveform shape. Studies have pursued optimization of stimulation for retinal prostheses, but were largely performed under isolated, differing conditions. Given the multi-faceted parameter space of stimulation, it remains unclear how specific parameters (and their interactions) affect the spiking output of retinal ganglion cells (RGCs), particularly for direct versus network-mediated activation. We patch-clamped RGCs in ex vivo Long Evans retinae and applied a variety of epiretinal stimuli before and after synaptic blockage to stratify activation as direct or network-mediated. A systematic analysis identified that pulse rate, charge, PW, and waveform shape significantly affected RGC activation, though there were significant interactions. Increasing pulse rate led to response depression, particularly for network-mediated spiking. Increasing PW reduced charge efficiency and increased network-mediated spiking. At 20 ms PW, there was differential activation of ON and OFF RGCs that persisted after synaptic blockage. For stimuli delivered at 1 and 25 pps, waveform shape had a weaker effect on spiking, heavily subject to interactions, but significant for certain conditions. For high-rate (500 pps) stimulation, where varying shape involved amplitude-modulation, spiking decreased with modulation frequency, indicating frequency-dependent temporal filtering. Our results highlight parameter-specific effects, interactions, and trade-offs. Since the retinal network was implicated in the effects of many parameters (like PW and waveform shape), outcomes may differ for degenerating retinae where inner retinal remodeling has occurred. We surmise that stimulation optimized for direct activation will yield greater consistency across contexts.