In the last decade several groups have been developing vision prostheses to restore visual perception to the profoundly blind. Despite some promising results from human trials, further understanding of the neural mechanisms involved is crucial for improving the efficacy of these devices. One of the techniques involves placing stimulating electrodes in the subretinal space between the photoreceptor layer and the pigment epithelium to evoke neural responses in the degenerative retina. This study used cell-attached and whole cell current-clamp recordings to investigate the responses of rabbit retinal ganglion cells (RGCs) following subretinal stimulation with 25-mum-diameter electrodes. We found that direct RGC responses with short latency (

Dendritic spines are the primary site of excitatory synaptic input onto neurons, and are biochemically isolated from the parent dendritic shaft by their thin neck. However, due to the lack of direct electrical recordings from spines, the influence that the neck resistance has on synaptic transmission, and the extent to which spines compartmentalize voltage, specifically excitatory postsynaptic potentials, albeit critical, remains controversial. Here, we use quantum-dot-coated nanopipette electrodes (tip diameters ~15–30 nm) to establish the first intracellular recordings from targeted spine heads under two-photon visualization. Using simultaneous somato-spine electrical recordings, we find that back propagating action potentials fully invade spines, that excitatory postsynaptic potentials are large in the spine head (mean 26 mV) but are strongly attenuated at the soma (0.5–1 mV) and that the estimated neck resistance (mean 420 MΩ) is large enough to generate significant voltage compartmentalization. Nanopipettes can thus be used to electrically probe biological nanostructures.

In traditional electrophysiology, spatially inefficient electronics and the need for tissue-to-electrode proximity defy non-invasive interfaces at scales of more than a thousand low noise, simultaneously recording channels. Using compressed sensing concepts and silicon complementary metal-oxide-semiconductors (CMOS), we demonstrate a platform with 65,536 simultaneously recording and stimulating electrodes in which the per-electrode electronics consume an area of 25.5 μm by 25.5 μm. Application of this platform to mouse retinal studies is achieved with a high-performance processing pipeline with a 1 GB/s data rate. The platform records from 65,536 electrodes concurrently with a ~10 µV r.m.s. noise; senses spikes from more than 34,000 electrodes when recording across the entire retina; automatically sorts and classifies greater than 1700 neurons following visual stimulation; and stimulates individual neurons using any number of the 65,536 electrodes while observing spikes over the entire retina. The approaches developed here are applicable to other electrophysiological systems and electrode configurations.

PURPOSE. Research to restore some degree of vision to patients suffering from retinal degeneration is becoming increasingly more promising. Several groups have chosen electrical stimulation of the remaining network of a degenerate retina as a means to generate discrete light percepts (phosphenes). Approaches vary significantly, with the greatest difference being the location of the stimulating electrode itself.METHODS. Suprachoroidal positioning offers excellent mechanical stability and surgical simplicity; however, at the cost of activation thresholds and focused stimulation due to the distance from the electrodes to the target neurons. Past studies proposed a hexapolar electrode configuration to focus the cortical activation and minimize cross-talk between electrodes during concurrent stimulation. The high impedance nature of the choroid and pigment epithelium, however, cause current to shunt between the stimulating and return electrodes, resulting in even higher activation thresholds. In our study, we analyzed the effect of stimulating the feline retina using a quasimonopolar stimulation by simultaneously stimulating a hexapolar and distant monopolar return configurations. RESULTS.Results of in vivo studies showed that quasimonopolar stimulation can be used to maintain the activation containment properties of hexapolar stimulation, while lowering the activation threshold to values almost equivalent to those of monopolar stimulation.CONCLUSIONS. The optimal stimulus was found to be composed of a subthreshold monopolar stimulus combined with a suprathreshold hexapolar stimulation. This resulted in a decrease of activation threshold of 60% with respect to hexapolar alone, but with no discernible deleterious effect on the charge containment of a pure hexapolar stimulation.

Retinal ganglion cells (RGCs), which survive in large numbers following neurodegenerative diseases, could be stimulated with extracellular electric pulses to elicit artificial percepts. How do the RGCs respond to electrical stimulation at the sub-cellular level under different stimulus configurations, and how does this influence the whole-cell response? At the population level, why have experiments yielded conflicting evidence regarding the extent of passing axon activation? We addressed these questions through simulations of morphologically and biophysically detailed computational RGC models on high performance computing clusters. We conducted the analyses on both large-field RGCs and small-field midget RGCs. The latter neurons are unique to primates. We found that at the single cell level the electric potential gradient in conjunction with neuronal element excitability, rather than the electrode center location per se, determined the response threshold and latency. In addition, stimulus positioning strongly influenced the location of RGC response initiation and subsequent activity propagation through the cellular structure. These findings were robust with respect to inhomogeneous tissue resistivity perpendicular to the electrode plane. At the population level, RGC cellular structures gave rise to low threshold hotspots, which limited axonal and multi-cell activation with threshold stimuli. Finally, due to variations in neuronal element excitability over space, following supra-threshold stimulation some locations favored localized activation of multiple cells, while others favored axonal activation of cells over extended space.

The ability for visual prostheses to preferentially activate functionally-distinct retinal ganglion cells (RGCs) is important for improving visual perception. This study investigates the use of high frequency stimulation (HFS) to elicit RGC activation, using a closed-loop algorithm to search for optimal stimulation parameters for preferential ON and OFF RGC activation, resembling natural physiological neural encoding in response to visual stimuli. We evaluated the performance of a wide range of electrical stimulation amplitudes and frequencies on RGC responses in vitro using murine retinal preparations. It was possible to preferentially excite either ON or OFF RGCs by adjusting amplitudes and frequencies in HFS. ON RGCs can be preferentially activated at relatively higher stimulation amplitudes (>150 μA) and frequencies (2–6.25 kHz) while OFF RGCs are activated by lower stimulation amplitudes (40–90 μA) across all tested frequencies (1–6.25 kHz). These stimuli also showed great promise in eliciting RGC responses that parallel natural RGC encoding: ON RGCs exhibited an increase in spiking activity during electrical stimulation while OFF RGCs exhibited decreased spiking activity, given the same stimulation amplitude. In conjunction with the in vitro studies, in silico simulations indicated that optimal HFS parameters could be rapidly identified in practice, whilst sampling spiking activity of relevant neuronal subtypes. This closed-loop approach represents a step forward in modulating stimulation parameters to achieve appropriate neural encoding in retinal prostheses, advancing control over RGC subtypes activated by electrical stimulation.

The resulting models were used to study the contribution of different ion channel properties and spatial structure of neurons to RGC activation. The techniques of this study are generally applicable to other excitable cell models, increasing the utility of theoretical models in accurately predicting the response of real biological neurons.

Recent retinal studies have directed more attention to sophisticated stimulation strategies based on high-frequency (>1.0 kHz) electrical stimulation (HFS). In these studies, each retinal ganglion cell (RGC) type demonstrated a characteristic stimulus-strength-dependent response to HFS, offering the intriguing possibility of focally targeting retinal neurons to provide useful visual information by retinal prosthetics. Ionic mechanisms are known to affect the responses of electrogenic cells during electrical stimulation. However, how these mechanisms affect RGC responses is not well understood at present, particularly when applying HFS. Here, we investigate this issue via an in silico model of the RGC. We calibrate and validate the model using an in vitro retinal preparation. An RGC model based on accurate biophysics and realistic representation of cell morphology, was used to investigate how RGCs respond to HFS. The model was able to closely replicate the stimulus-strength-dependent suppression of RGC action potentials observed experimentally. Our results suggest that spike inhibition during HFS is due to local membrane hyperpolarization caused by outward membrane currents near the stimulus electrode. In addition, the extent of HFS-induced inhibition can be largely altered by the intrinsic properties of the inward sodium current. Finally, stimulus-strength-dependent suppression can be modulated by a wide range of stimulation frequencies, under generalized electrode placement conditions. In vitro experiments verified the computational modeling data. This modeling and experimental approach can be extended to further our understanding on the effects of novel stimulus strategies by simulating RGC stimulus-response profiles over a wider range of stimulation frequencies and electrode locations than have previously been explored.