Effects of Electric Stimulation on Physiology and Anatomy of Visual Pathway

Abstract

Retinal degenerative diseases that progressively lead to severe blindness impact the affected individual’s quality-of-life. Visual prosthesis technology aims to provide an individual a potential means of obtaining visual information lost to them by blindness. Since the proof-of-concept success in 1968 of a device implanted in a human, visual prostheses have had sustained academic research and commercial interest. However, commercial failure of two retinal prosthesis device have raised concerns for the visual prosthesis field. To learn from this experience, research in this dissertation is aimed at understanding the impact of electric stimulation on the target neural tissue and investigating technology for a visual cortex prosthesis, which can reach a larger patient population (compared to a retinal prosthesis). My first set of experiments assessed, in an animal model of retinal degeneration, the condition of the brain and its ability to receive artificial vision information. Retinitis Pigmentosa has been proven to impact the human brain. My study investigated the extent to which this was replicated in a rat animal model of a single genetic mutation of Retinitis Pigmentosa. The P23H-1 rat was investigated with electrophysiology and immunohistochemistry to understand the brain’s function and structural condition. Visually evoked potentials changed as a result of blindness progression and electrically evoked response was maintained during retinal degeneration. Histology images show a relatively stable macrostructure of the blind rat brain. Neural activity measure using c-Fos saw a change due to weekly stimulation, but the results may be spurious when put next to an auxiliary analysis using high magnification VGluT2 images. I also created a rodent retinal implant procedure to test newly developed visual prosthesis devices. A retinal device with Parylene-C as its main component was tested and its feasibility in the small eye of a rat animal model was investigated. The device can survive 4-weeks of implantation and is mechanically stable within the eye. In support of the development of a novel cortical visual prosthesis device that fits the need of blind individuals, I used a rat animal model to prove the efficacy and safety of a novel neurostimulation device in preclinical development (StiMote). I worked to characterize the full ability of the neural interface, High-density carbon fiber arrays with electrodeposited Platinum-Iridium. The ability of PtIr-HDCF as a simultaneous recording and stimulation neural interface device was verified with nominal electrochemical measurements before, during, and after a long-duration 7-hour electric stimulation session that simulated a full day of device use. Based on my previous work and prior literature of HDCF as a neural interface that reduces neuroinflammatory response compared to other microelectrode array archetypes, PtIr-HDCF can be used as a device to monitor the brain and can better extract the effect of electric stimulation on the brain alone. I recorded neural electrophysiology to verify the rat brain’s sensitivity to stimuli before and after 7-hour stimulation. Based on the visually evoked potential and intracortical microstimulation data, possible increase in cortical sensitivity to stimuli was hypothesized. To add another layer of information, Spatial Transcriptomics as a novel method was used to define electric stimulation safety. Spatial Transcriptomics showed that PtIr-HDCF, when compared to a conventional microwire array, performs better in reducing proinflammatory cytokines. Findings of this dissertation can be used to better inform future investigations into brain electrophysiology and transcriptomics projects aimed to assist cortical visual prosthesis device development.