David Tsai

Direct activation and temporal response properties of rabbit retinal ganglion cells following subretinal stimulation.

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 (</=2 ms using 0.1-ms pulses) could be reliably elicited. The thresholds for these responses were reported for on, off, and on-off RGCs over pulse widths 0.1-5.0 ms. During repetitive stimulation these direct activation responses were more readily elicited than responses arising from stimulation of the retinal network. The temporal spiking characteristics of RGCs were characterized as a function of stimulus configurations. We found that the response profiles could be generalized into four classes with distinctive properties. Our results suggest that for subretinal vision prostheses short pulses are preferable for efficacy and safety considerations, and that direct activation of RGCs will be necessary for reliable activation during high-frequency stimulation.

Responses of Retinal Ganglion Cells to Extracellular Electrical Stimulation, from Single Cell to Population: Model-Based Analysis

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.

Current Steering in Retinal Stimulation via a Quasimonopolar Stimulation Paradigm

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.

Targeted intracellular voltage recordings from dendritic spines using quantum-dot-coated nanopipettes

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.

A wearable real-time image processor for a vision prosthesis

Rapid progress in recent years has made implantable retinal prostheses a promising therapeutic option in the near future for patients with macular degeneration or retinitis pigmentosa. Yet little work on devices that encode visual images into electrical stimuli have been reported to date. This paper presents a wearable image processor for use as the external module of a vision prosthesis. It is based on a dual-core microprocessor architecture and runs the Linux operating system. A set of image-processing algorithms executes on the digital signal processor of the device, which may be controlled remotely via a standard desktop computer. The results indicate that a highly flexible and configurable image processor can be built with the dual-core architecture. Depending on the image-processing requirements, general-purpose embedded microprocessors alone may be inadequate for implementing image-processing strategies required by retinal prostheses.

Cell-specific modeling of retinal ganglion cell electrical activity

Variations in ionic channel expression and anatomical properties can influence how different retinal ganglion cell (RGC) types process synaptic information. Computational modeling approaches allow us to precisely control these biophysical and physical properties and isolate their effects in shaping RGC firing patterns. In this study, three models based on realistic representations of RGC morphologies were used to simulate the contribution of spatial structure of neurons and membrane ion channel properties to RGC electrical activity. In all simulations, the RGC models shared common ionic channel kinetics, differing only in their regional ionic channel distributions and cell morphology.

High-channel-count, high-density microelectrode array for closed-loop investigation of neuronal networks.

We present a system for large-scale electrophysiological recording and stimulation of neural tissue with a planar topology. The recording system has 65,536 electrodes arranged in a 256 × 256 grid, with 25.5 μm pitch, and covering an area approximately 42.6 mm2. The recording chain has 8.66 μV rms input-referred noise over a 100 ~ 10k Hz bandwidth while providing up to 66 dB of voltage gain. When recording from all electrodes in the array, it is capable of 10-kHz sampling per electrode. All electrodes can also perform patterned electrical microstimulation. The system produces ~ 1 GB/s of data when recording from the full array. To handle, store, and perform nearly real-time analyses of this large data stream, we developed a framework based around Xilinx FPGAs, Intel x86 CPUs and the NVIDIA Streaming Multiprocessors to interface with the electrode array.

Direct activation of retinal ganglion cells with subretinal stimulation

Recent advances in the design and implementation of vision prostheses have made these devices a promising therapeutic option for restoring sight to blind patients in the near future. The success of vision prostheses in providing clinically useful vision, however, depends critically on our understanding of the retinal neural mechanisms evoked during electrical stimulation, and how these mechanisms can be controlled precisely to elicit the desired visual percept. We demonstrate here that subretinal stimulation can reliably elicit stimulus- locked short latency (≤ 2 ms) responses. To our knowledge, this is the first report of such responses using the subretinal paradigm. These responses could be readily distinguished from within the stimulus artifacts using cell-attached extracellular recording or whole-cell patch clamp. The thresholds for these short latency responses were determined for ON, OFF and ON- OFF type retinal ganglion cell classes across cathodic biphasic pulses of 0.1–5.0ms. No significant difference was found for the mean latency and the threshold for the different cell types over the pulse range tested.

Matching the Power, Voltage, and Size of Biological Systems: A nW-Scale, 0.023-

This paper explores the extent to which a solid-state transmitter can be miniaturized, while still using RF for wireless information transfer and working with power densities and operating voltages comparable to what could be harvested from a living system. A 3.1 nJ/bit pulsed millimeter-wave transmitter, 300 μm by 300 μm by 250 μm in size, designed in 32-nm SOI CMOS, operates on an electric potential of 130 mV and 3.1 nW of dc power. Far-field data transmission at 33 GHz is achieved by supply-switching an LC-oscillator with a duty cycle of 10-6. The time interval between pulses carries information on the amount of power harvested by the radio, supporting a data rate of ~ 1 bps. The inductor of the oscillator also acts as an electrically small (λ/30) on-chip antenna, which, combined with millimeter-wave operation, enables the extremely small form factor.

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Exploration into electrical stimulation of the retina has thus far focussed primarily upon the development of prostheses targeted at one of two sites of intervention - the epi- and sub-retinal surfaces. These two approaches have sound, logical merit owing to their proximity to retinal neurons and their potential to deliver stimuli via the surviving retinal neural networks respectively. There is increasing evidence, however, that electric field effects, electrode engineering limitations, and electrode-tissue interactions limit the spatial resolution that once was hoped could be elicited from electrical stimulation at epi- and sub-retinal sites. An alternative approach has been proposed that places a stimulating electrode array within the supra-choroidal space - that is, between the sclera and the choroid. Here we investigate whether discrete, cortical activity patterns can be elicited via electrical stimulation of a feline retina using a custom, 14 channel, silicone rubber and Pt electrode array arranged in two hexagons comprising seven electrodes each. Cortical responses from Areas 17/18 were acquired using a silicon-based, multi-channel, penetrating probe developed at IMTEK, University of Freiburg, within the European research project NeuroProbes. Multi-unit spike activity was recorded in synchrony with the presentation of electrical stimuli. Results show that distinct cortical response patterns could be elicited from each hexagon separated by 1.8 mm (center-to-center) with a center-to-center electrode spacing within each hexagon of 0.55 mm. This lends support that higher spatial resolution may also be discerned.