Experimental and Computational Investigation of Metabolic Demands on Neuronal Responses to Focused Ultrasound Stimulation



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Focused ultrasound (FUS) presents the ability to non-invasively modulate neuronal activity with greater resolution and penetration than other methods, making it an attractive mode of stimulation both in basic research and clinically. Yet no one has investigated the local metabolic demands of neuronal response to FUS. Subtle changes in metabolism have profound effects on neuronal activity ranging from enhanced excitability to quiescence. Understanding the metabolic landscape of neuronal stimulation can lead to enhanced methods of modulation including greater safety and efficacy. This dissertation presents the first experiments characterizing ionic and metabolic responses to increased energy demands in acoustic stimulation of neuronal tissue. It also presents a novel model of neuronal tissue that incorporates conductance-based membrane dynamics with electric, diffusive, volumetric, and metabolic dynamics. The model investigates the coupling between these mechanisms and acoustic radiation force as a source of neuronal response to acoustic stimulation with respect to energy dissipation and ionic redistribution in cellular electrochemical gradients. We performed extracellular measurements of potassium and oxygen in response to both electrical and acoustic stimulation, then validated the model against the experimental results. The experiments revealed a disparity between oxygen and potassium changes in response to FUS and electrical stimulation, indicating different metabolic demands between both modalities. We further applied model predictions to modulate neuronal responses to electrical stimulation ultrasonically, yielding a statistically significant pulse repetition frequency-dependent increase in local field potentials. Additionally, our computational model indicates that ionic redistribution due to acoustic radiation force is largely responsible for the observed effects, thereby opening a new avenue of investigation for mechanisms.