Temporal structure in spiking patterns of ganglion cells defines perceptual thresholds in rodents with subretinal prosthesis

Abstract

Subretinal prostheses are designed to restore sight in patients blinded by retinal degeneration using electrical stimulation of the inner retinal neurons. To relate retinal output to perception, we studied behavioral thresholds in blind rats with photovoltaic subretinal prostheses stimulated by full-field pulsed illumination at 20 Hz, and measured retinal ganglion cell (RGC) responses to similar stimuli ex-vivo. Behaviorally, rats exhibited startling response to changes in brightness, with an average contrast threshold of 12%, which could not be explained by changes in the average RGC spiking rate. However, RGCs exhibited millisecond-scale variations in spike timing, even when the average rate did not change significantly. At 12% temporal contrast, changes in firing patterns of prosthetic response were as significant as with 2.3% contrast steps in visible light stimulation of healthy retinas. This suggests that millisecond-scale changes in spiking patterns define perceptual thresholds of prosthetic vision. Response to the last pulse in the stimulation burst lasted longer than the steady-state response during the burst. This may be interpreted as an excitatory OFF response to prosthetic stimulation, and can explain behavioral response to decrease in illumination. Contrast enhancement of images prior to delivery to subretinal prosthesis can partially compensate for reduced contrast sensitivity of prosthetic vision.

Decoding network-mediated retinal response to electrical stimulation: implications for fidelity of prosthetic vision

“…Figures 2c-e show example receptive fields and time courses (spiketriggered average, STA) for natural visual response, electrical stimulation of the healthy retina, and electrical stimulation of RCS retina, respectively. Electrically stimulated cells generally have faster, but weaker STAs, similar to previous observations (8,11).…”

“…This may be explained by stimulation of rod bipolar cells, which feed into the ON and OFF cone pathways via amacrine cells. Contrast sensitivity of prosthetic vision in rats appears to be about 5 times lower than natural (11), which could be partially compensated by image processing prior to projection into the eye. Clinical trial demonstrated that patients correctly perceive various patterns of lines and letters, demonstrating monochromatic shaped vision with resolution closely matching the pixel size (100 μm in the first trial) (7).…”

Stem Cell Therapies, Gene-Based Therapies, Optogenetics, and Retinal Prosthetics:

“…Preserved features include flicker fusion at high frequencies, 82 antagonistic center-surround organization 83 and nonlinear summation of subunits in receptive fields, 82 as well as ON and OFF responses. 84 Another theoretical advantage of the subretinal placement is that it provides close and stable proximity of electrodes to the target neurons. However, implantation in the subretinal space can be more difficult than the epiretinal approach, and removal of the implant is also more challenging.…”

Photogenerated Electrical Fields for Biomedical Applications

“…Retinal and subretinal inorganic prostheses were developed to restore sight in patients blinded by retinal degeneration by stimulating the inner retinal neurons using 3D pillar electrodes (Figure 1D ) which enhance the cell-chip coupling and the integration the implant in the target tissue (Mathieson et al, 2012 ; Flores et al, 2018 ). In a recent work done by Ho et al ( 2018a ) a photodiode array made of boron-doped silicon-on-insulator (SOI) wafers was used to perform in vivo and in vitro measurements, in which the retina is placed between the recording array (ganglion cell side) and the photodiode array (photoreceptor side). In a recent work, transparent extracellular microelectrode arrays (MEA) were used to characterize the spatial and temporal response properties of retinal ganglion cells (RGCs) to photovoltaic stimulation in the healthy and degenerate rat retina (Ho et al, 2018b ).…”