The Effects of Transcranial Focused Ultrasound on Neuronal Subtypes and Pairwise Neuronal Correlation in the In Vivo Rat Brain

<p dir="ltr">Transcranial focused ultrasound (tFUS) is a promising next-gen neuromodulation technique able to target shallow and deep brain structures with high precision. It has been shown to be capable of both exciting and inhibiting neural circuits, inducing connectivity changes, and eliciting cell-type specific effects that are controllable through parameter selection, as well as modulating high level perception and behavior. However, we lack an in depth understanding of how tFUS modulates the ways neurons interact with each other, due to both a vast parameter space and key confounds affecting electrophysiological studies of tFUS including anesthesia effects and vibrational artifacts. This thesis aims to characterize the effects of tFUS on neuronal function and interactions under a wide array of parameters using a rat model, and to tackle these confounds through development of an awake head-fixed model and investigation of the use of flexible electrodes to mitigate vibrational artifacts. We first demonstrate that selection of tFUS stimulation repetition frequency can modulate pairwise correlation between targeted neurons as well as general excitability of the targeted region, inducing increases or decreases at different frequencies. We then used our developed awake head-fixed model to test cell-type specificity to pulse repetition frequency and duty cycle of tFUS in an awake setting. We observed that anesthesia can significantly modulate the magnitude and latency of responses especially in some neuronal subtypes, but that cell-type specificity exists outside of this confound. Finally, we demonstrated that using flexible electrodes eliminates the vibrational artifact that has prevented testing of high pressure levels with rigid silicon electrodes. Using higher pressure levels, we demonstrated how response curves to other parameters vary at different pressure levels, showing how important further testing of different pressure levels is. Together, these studies show the effects of a wide range of parameters, and help provide insights into the mechanism behind tFUS effects. Showing the capability of tFUS to modulate neuronal subtypes as well as connectivity between neurons will help guide future tFUS research, both in systemic investigations on the neuronal mechanisms behind tFUS stimulation as well as towards its use as a therapeutic tool for neurological disorders.</p>