NYMC Student Theses and Dissertations

Date of Award

4-3-2024

Document Type

Doctoral Dissertation - Open Access

Degree Name

Doctor of Philosophy

Department

Physiology

First Advisor

Jonathan A.N. Fisher, Ph.D.

Second Advisor

Christopher S. Leonard, Ph.D.

Third Advisor

William N. Ross, Ph.D.

Abstract

Neurological diseases impose a large health and financial burden for nations worldwide. Current treatments for many conditions are limited to pharmacological or invasive surgical approaches. Neuromodulation is an alternative therapy wherein electrical currents, magnetic fields, or electromagnetic waves are used to noninvasively modify brain function. Focused ultrasound (FUS) has been shown to alter neural activity, theoretically with much higher spatial resolution than other neuromodulation techniques. However, these predictions assume that neuromodulatory effects are constrained to the acoustic focus. Given that the architecture of neural circuitry in the cerebral cortex supports delicately balanced lateral processing on spatial scales that may exceed the acoustic spot size, it is critical to probe spatial effects in vivo.

Here, we used a novel approach that combines wide-field Ca2+ imaging with targeted, random-access sonication to examine the effects of focal neuromodulation in the auditory cortex of transgenic mice expressing the Ca2+ sensor GCaMP6s. We visualized auditory-evoked cortical activity and quantified the effects of low-intensity FUS on the magnitude and spatiotemporal evolution of these sensory responses. We performed immunohistochemical analysis of brain slices as well as in vivo optical coherence tomography-angiography imaging to assess gross changes in microvascular integrity.

Our work provides a preclinical exploration of a promising neuromodulation modality with insight into the acute and persistent effects of targeted sonication in the cerebral cortex. While our results support the assertion that neuromodulatory effects can be localized, they also find evidence in some cases of off-target effects such as altered spatial propagation of sensory evoked responses.

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