Objective Intra-retinal placement of stimulating electrodes can provide close and stable proximity to target neurons. We assessed improvement in stimulation thresholds and selectivity of the direct and network-mediated retinal stimulation with intraretinal electrodes, compared to epiretinal and subretinal placements. Approach Stimulation thresholds of the retinal ganglion cells (RGCs) in wild-type rat retina were measured using patch-clamp technique. Direct and network-mediated responses were discriminated using various synaptic blockers. Main results Three types of RGC responses were identified: short latency (SL, τ<5ms) originating in RGCs, medium latency (ML, 3<τ<70ms) originating in the inner nuclear layer and long latency (LL, τ>40ms) originating in photoreceptors. Cathodic epiretinal stimulation exhibited the lowest threshold for direct RGC response and the highest direct selectivity (network/direct thresholds ratio), exceeding a factor of 3 with pulse durations below 0.5ms. For network-mediated stimulation, the lowest threshold was obtained with anodic pulses in OPL position, and its network selectivity (direct/network thresholds ratio) increased with pulse duration, exceeding a factor of 4 at 10ms. Latency of all three types of responses decreased with increasing strength of the stimulus. Significance These results define optimal range of pulse durations, pulse polarities and electrode placement for the retinal prostheses aiming at direct or network-mediated stimulation of RGCs.

Boinagrov D, Loudin J, Palanker D. Strength-duration relationship for extracellular neural stimulation: numerical and analytical models. J Neurophysiol 104: 2236 -2248, 2010. First published August 11, 2010 doi:10.1152/jn.00343.2010. The strength-duration relationship for extracellular stimulation is often assumed to be similar to the classical intracellular stimulation model, with a slope asymptotically approaching 1/ at pulse durations shorter than chronaxy. We modeled extracellular neural stimulation numerically and analytically for several cell shapes and types of active membrane properties. The strength-duration relationship was found to differ significantly from classical intracellular models. At pulse durations between 4 s and 5 ms stimulation is dominated by sodium channels, with a slope of Ϫ0.72 in log-log coordinates for the Hodgkin-Huxley ion channel model. At shorter durations potassium channels dominate and slope decreases to Ϫ0.13. Therefore the charge per phase is decreasing with decreasing stimulus duration. With pulses shorter than cell polarization time (ϳ0.1-1 s), stimulation is dominated by polarization dynamics with a classical Ϫ1 slope and the charge per phase becomes constant. It is demonstrated that extracellular stimulation can have not only lower but also upper thresholds and may be impossible below certain pulse durations. In some regimes the extracellular current can hyperpolarize cells, suppressing rather than stimulating spiking behavior. Thresholds for burst stimuli can be either higher or lower than that of a single pulse, depending on pulse duration. The modeled thresholds were found to be comparable to published experimental data. Electroporation thresholds, which limit the range of safe stimulation, were found to exceed stimulation thresholds by about two orders of magnitude. These results provide a biophysical basis for understanding stimulation dynamics and guidance for optimizing the neural stimulation efficacy and safety.

Photovoltaic conversion of pulsed light into pulsed electric current enables optically-activated neural stimulation with miniature wireless implants. In photovoltaic retinal prostheses, patterns of near-infrared light projected from video goggles onto subretinal arrays of photovoltaic pixels are converted into patterns of current to stimulate the inner retinal neurons. We describe a model of these devices and evaluate the performance of photovoltaic circuits, including the electrode-electrolyte interface. Characteristics of the electrodes measured in saline with various voltages, pulse durations, and polarities were modeled as voltage-dependent capacitances and Faradaic resistances. The resulting mathematical model of the circuit yielded dynamics of the electric current generated by the photovoltaic pixels illuminated by pulsed light. Voltages measured in saline with a pipette electrode above the pixel closely matched results of the model. Using the circuit model, our pixel design was optimized for maximum charge injection under various lighting conditions and for different stimulation thresholds. To speed discharge of the electrodes between the pulses of light, a shunt resistor was introduced and optimized for high frequency stimulation.

It is well known that spiking neurons can produce action potentials in response to extracellular stimulation above certain threshold. It is widely assumed that there is no upper limit to somatic stimulation, except for cellular or electrode damage. Here we demonstrate that there is an upper stimulation threshold, above which no action potential can be elicited, and it is below the threshold of cellular damage. Existence of this upper stimulation threshold was confirmed in retinal ganglion cells (RGCs) at pulse durations ranging from 5 to 500 μs. The ratio of the upper to lower stimulation thresholds varied typically from 1.7 to 7.6, depending on pulse duration. Computational modeling of extracellular RGC stimulation explained the upper limit by sodium current reversal on the depolarized side of the cell membrane. This was further confirmed by experiments in the medium with a low concentration of sodium. The limited width of the stimulation window may have important implications in design of the electro-neural interfaces, including neural prosthetics

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