Keith Mathieson

What does the eye tell the brain?: Development of a system for the large-scale recording of retinal output activity

A multielectrode array system has been developed to study how the retina processes and encodes visual images. This system can simultaneously record the extracellular electrical activity from hundreds of retinal output neurons as a dynamic visual image is focused on the input neurons. The retinal output signals detected can be correlated with the visual input to study the neural code used by the eye to send information about the visual world to the brain. The system consists of the following components: (1) a 32 /spl times/ 16 rectangular array of 512 planar microelectrodes with a sensitive area of 1.7 square mm. The electrode spacing is 60 microns and the electrode diameter is 5 microns. (Hexagonal arrays with 519 electrodes are under development); (2) eight 64-channel custom-designed integrated circuits to platinize the electrodes and AC couple the signals; (3) eight 64-channel integrated circuits to amplify, band-pass filter and analog multiplex the signals; (4) a data acquisition system; and (5) data processing software. This paper will describe the design of the system, the experimental and data analysis techniques, and some first results with live retina. The system is based on techniques and expertise acquired in the development of silicon microstrip detectors for high energy physics experiments.

Photovoltaic retinal prosthesis with high pixel density

Retinal degenerative diseases lead to blindness due to loss of the “image capturing” photoreceptors, while neurons in the “image processing” inner retinal layers are relatively well preserved. Electronic retinal prostheses seek to restore sight by electrically stimulating surviving neurons. Most implants are powered through inductive coils, requiring complex surgical methods to implant the coil-decoder-cable-array systems, which deliver energy to stimulating electrodes via intraocular cables. We present a photovoltaic subretinal prosthesis, in which silicon photodiodes in each pixel receive power and data directly through pulsed near-infrared illumination and electrically stimulate neurons. Stimulation was produced in normal and degenerate rat retinas, with pulse durations from 0.5 to 4 ms, and threshold peak irradiances from 0.2 to 10 mW/mm2, two orders of magnitude below the ocular safety limit. Neural responses were elicited by illuminating a single 70 μm bipolar pixel, demonstrating the possibility of a fully-integrated photovoltaic retinal prosthesis with high pixel density.

Functional connectivity in the retina at the resolution of photoreceptors.

To understand a neural circuit requires knowledge of its connectivity. Here we report measurements of functional connectivity between the input and ouput layers of the macaque retina at single-cell resolution and the implications of these for colour vision. Multi-electrode technology was used to record simultaneously from complete populations of the retinal ganglion cell types (midget, parasol and small bistratified) that transmit high-resolution visual signals to the brain. Fine-grained visual stimulation was used to identify the location, type and strength of the functional input of each cone photoreceptor to each ganglion cell. The populations of ON and OFF midget and parasol cells each sampled the complete population of long- and middle-wavelength-sensitive cones. However, only OFF midget cells frequently received strong input from short-wavelength-sensitive cones. ON and OFF midget cells showed a small non-random tendency to selectively sample from either long- or middle-wavelength-sensitive cones to a degree not explained by clumping in the cone mosaic. These measurements reveal computations in a neural circuit at the elementary resolution of individual neurons.

Photovoltaic restoration of sight with high visual acuity.

Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration.

Photovoltaic retinal prosthesis : implant fabrication and performance

The objective of this work is to develop and test a photovoltaic retinal prosthesis for restoring sight to patients blinded by degenerative retinal diseases. A silicon photodiode array for subretinal stimulation has been fabricated by a silicon-integrated-circuit/MEMS process. Each pixel in the two-dimensional array contains three series-connected photodiodes, which photovoltaically convert pulsed near-infrared light into bi-phasic current to stimulate nearby retinal neurons without wired power connections. The device thickness is chosen to be 30 µm to absorb a significant portion of light while still being thin enough for subretinal implantation. Active and return electrodes confine current near each pixel and are sputter coated with iridium oxide to enhance charge injection levels and provide a stable neural interface. Pixels are separated by 5 µm wide trenches to electrically isolate them and to allow nutrient diffusion through the device. Three sizes of pixels (280, 140 and 70 µm) with active electrodes of 80, 40 and 20 µm diameter were fabricated. The turn-on voltages of the one-diode, two-series-connected diode and three-series-connected diode structures are approximately 0.6, 1.2 and 1.8 V, respectively. The measured photo-responsivity per diode at 880 nm wavelength is ∼0.36 A W(-1), at zero voltage bias and scales with the exposed silicon area. For all three pixel sizes, the reverse-bias dark current is sufficiently low (<100 pA) for our application. Pixels of all three sizes reliably elicit retinal responses at safe near-infrared light irradiances, with good acceptance of the photodiode array in the subretinal space. The fabricated device delivers efficient retinal stimulation at safe near-infrared light irradiances without any wired power connections, which greatly simplifies the implantation procedure. Presence of the return electrodes in each pixel helps to localize the current, and thereby improves resolution.

Cortical responses elicited by photovoltaic subretinal prostheses exhibit similarities to visually evoked potentials

We have previously developed a wireless photovoltaic retinal prosthesis, in which camera-captured images are projected onto the retina using pulsed near-IR light. Each pixel in the subretinal implant directly converts pulsed light into local electric current to stimulate the nearby inner retinal neurons. Here we report that implants having pixel sizes of 280, 140 and 70μm implanted in the subretinal space in rats with normal and degenerate retina elicit robust cortical responses upon stimulation with pulsed near-IR light. Implant-induced eVEP has shorter latency than visible light-induced VEP, its amplitude increases with peak irradiance and pulse duration, and decreases with frequency in the range of 2-20Hz, similar to the visible light response. Modular design of the arrays allows scalability to a large number of pixels, and combined with the ease of implantation, offers a promising approach to restoration of sight in patients blinded by retinal degenerative diseases.

Thermal and optical characterization of micro-LED probes for in vivo optogenetic neural stimulation

Within optogenetics there is a need for compact light sources that are capable of delivering light with excellent spatial, temporal, and spectral resolution to deep brain structures. Here, we demonstrate a custom GaN-based LED probe for such applications and the electrical, optical, and thermal properties are analyzed. The output power density and emission spectrum were found to be suitable for stimulating channelrhodopsin-2, one of the most common light-sensitive proteins currently used in optogenetics. The LED device produced high light intensities, far in excess of those required to stimulate the light-sensitive proteins within the neurons. Thermal performance was also investigated, illustrating that a broad range of operating regimes in pulsed mode are accessible while keeping a minimum increase in temperature for the brain (0.5°C). This type of custom device represents a significant step forward for the optogenetics community, allowing multiple bright excitation sites along the length of a minimally invasive neural probe.

Efficient coding of spatial information in the primate retina

Sensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (∼30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina.

Charge sharing in silicon pixel detectors

We used a pixellated hybrid silicon X-ray detector to study the effect of the sharing of generated charge between neighbouring pixels over a range of incident X-ray energies, 13–36 keV. The system is a room temperature, energy resolving detector with a Gaussian FWHM of 265 eV at 5.9 keV. Each pixel is 300 μm square, 300 μm deep and is bump bonded to matching read out electronics. The modelling packages MEDICI and MCNP were used to model the complete X-ray interaction and the subsequent charge transport. Using this software a model is developed which reproduces well the experimental results. The simulations are then altered to explore smaller pixel sizes and different X-ray energies. Charge sharing was observed experimentally to be 2% at 13 keV rising to 4.5% at 36 keV, for an energy threshold of 4 keV. The models predict that up to 50% of charge may be lost to the neighbouring pixels, for an X-ray energy of 36 keV, when the pixel size is reduced to 55 μm.

Spatially Patterned Electrical Stimulation to Enhance Resolution of Retinal Prostheses

Retinal prostheses electrically stimulate neurons to produce artificial vision in people blinded by photoreceptor degenerative diseases. The limited spatial resolution of current devices results in indiscriminate stimulation of interleaved cells of different types, precluding veridical reproduction of natural activity patterns in the retinal output. Here we investigate the use of spatial patterns of current injection to increase the spatial resolution of stimulation, using high-density multielectrode recording and stimulation of identified ganglion cells in isolated macaque retina. As previously shown, current passed through a single electrode typically induced a single retinal ganglion cell spike with submillisecond timing precision. Current passed simultaneously through pairs of neighboring electrodes modified the probability of activation relative to injection through a single electrode. This modification could be accurately summarized by a piecewise linear model of current summation, consistent with a simple biophysical model based on multiple sites of activation. The generalizability of the piecewise linear model was tested by using the measured responses to stimulation with two electrodes to predict responses to stimulation with three electrodes. Finally, the model provided an accurate prediction of which among a set of spatial stimulation patterns maximized selective activation of a cell while minimizing activation of a neighboring cell. The results demonstrate that tailored multielectrode stimulation patterns based on a piecewise linear model may be useful in increasing the spatial resolution of retinal prostheses.