Paul Werginz

Modeling the response of ON and OFF retinal bipolar cells during electric stimulation

Highlights • Biphasic stimuli with opposed polarity activate ON and OFF BP cells differently.• Synaptic [Ca]i reaches levels to initiate synaptic activity during stimulation.• Axonal length influences de- and hyperpolarization of ON and OFF BP cell compartments.

The impact of calcium current reversal on neurotransmitter release in the electrically stimulated retina.

OBJECTIVE In spite of intense theoretical and experimental investigations on electrical nerve stimulation, the influence of reversed ion currents on network activity during extracellular stimulation has not been investigated so far. APPROACH Here, the impact of calcium current reversal on neurotransmitter release during subretinal stimulation was analyzed with a computational multi-compartment model of a retinal bipolar cell (BC) that was coupled with a four-pool model for the exocytosis from its ribbon synapses. Emphasis was laid on calcium channel dynamics and how these channels influence synaptic release. MAIN RESULTS Stronger stimulation with anodic pulses caused transmembrane voltages above the Nernst potential of calcium in the terminals and, by this means, forced calcium ions to flow in the reversed direction from inside to the outside of the cell. Consequently, intracellular calcium concentration decreased resulting in a reduced vesicle release or preventing release at all. This mechanism is expected to lead to a pronounced ring-shaped pattern of exocytosis within a group of neighbored BCs when the stronger stimulated cells close to the electrode fail in releasing vesicles. SIGNIFICANCE Stronger subretinal stimulation causes failure of synaptic exocytosis due to reversal of calcium flow into the extracellular space in cells close to the electrode.

Investigating the Influence of 3D Cell Morphology on Neural Response During Electrical Stimulation

Neuronal compartment models are a basic and often used method to investigate the effect of electrical stim- ulation on the cell. As the outcome of the model heavily de- pends on the cells morphology and its position relative to the electrode, a realistic representation of the cell structure and its variations is of great importance. A method is pre- sented which allows the quick and easy creation of a three dimensional neuron morphology on the basis of a single two dimensional image. Basic properties of this morphology like local diameters, cell size or the amount of branching can easily be changed.

Electric stimulus duration alters network-mediated responses depending on retinal ganglion cell type

OBJECTIVE To improve the quality of artificial vision that arises from retinal prostheses, it is important to bring electrically-elicited neural activity more in line with the physiological signaling patterns that arise normally in the healthy retina. Our previous study reported that indirect activation produces a closer match to physiological responses in ON retinal ganglion cells (RGCs) than in OFF cells (Im and Fried 2015 J. Physiol. 593 3677-96). This suggests that a preferential activation of ON RGCs would shape the overall retinal response closer to natural signaling. Recently, we found that changes to the rate at which stimulation was delivered could bias responses towards a stronger ON component (Im and Fried 2016a J. Neural Eng. 13 025002), raising the possibility that changes to other stimulus parameters can similarly bias towards stronger ON responses. Here, we explore the effects of changing stimulus duration on the responses in ON and OFF types of brisk transient (BT) and brisk sustained (BS) RGCs. APPROACH We used cell-attached patch clamp to record RGC spiking in the isolated rabbit retina. Targeted RGCs were first classified as ON or OFF type by their light responses, and further sub-classified as BT or BS types by their responses to both light and electric stimuli. Spiking in targeted RGCs was recorded in response to electric pulses with durations varying from 5 to100 ms. Stimulus amplitude was adjusted at each duration to hold total charge constant for all experiments. MAIN RESULTS We found that varying stimulus durations modulated responses differentially for ON versus OFF cells: in ON cells, spike counts decreased significantly with increasing stimulus duration while in OFF cells the changes were more modest. The maximum ratio of ON versus OFF responses occurred at a duration of ~10 ms. The difference in response strength for BT versus BS cells was much larger in ON cells than in OFF cells. SIGNIFICANCE The stimulation rates preferred by subjects during clinical trials are similar to the rates that maximize the ON/OFF response ratio in in vitro testing (Im and Fried 2016a J. Neural Eng. 13 025002). Here, we determine the stimulus duration that produces the strongest bias towards ON responses and speculate that it will further enhance clinical effectiveness.