Date of Award

2017

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Mark S. George

Second Advisor

Jeffrey J. Borckardt

Third Advisor

Truman R. Brown

Fourth Advisor

Colleen A. Hanlon

Fifth Advisor

Lisa M. McTeague

Sixth Advisor

Donna R. Roberts

Abstract

Cervically implanted vagus nerve stimulation (VNS) is a FDA-approved treatment for epilepsy and major depressive disorder (MDD). Additionally, VNS is a reemerging area of interest, showing promise in numerous animal studies with significant translatable applications. The cost, surgical risk, and human translation difficulty makes noninvasive VNS a highly-desired alternative. We have developed a transcutaneous auricular vagus nerve stimulation (taVNS) system that electrically stimulates the auricular branch of the vagus nerve (ABVN). We aimed to answer the following questions in this body of work: 1) whether taVNS is safe and feasible 2) if taVNS stimulates the vagus system similarly to implanted VNS 3) if the neurobiological effect of taVNS is similar to implanted VNS. We measured physiological recordings in healthy adults during taVNS to determine whether taVNS has vagus-mediated effects. In our first trial (n=15), we explored the physiological effects of 9 various stimulation parameter combinations (various pulse widths and frequencies) as a broad search of the physiological effect. A second, follow up trial was conducted (n=20) to determine the best candidate parameter that optimally activates the parasympathetic nervous system. Lastly, we developed and conducted a novel concurrent taVNS/fMRI trial (n=17) to determine the neurobiological effect of taVNS and its afferent targets. All three trials consisted of 2 visits each, in a randomized, controlled, crossover design in which taVNS was delivered to either the left tragus (active) or earlobe (control). The first physiological trial revealed relevant, immediate heart rate decreases during taVNS followed by a sympathetic rebound upon termination of stimulation. Of the nine parameters tested, two had the largest effect on heart rate (500µs, 10Hz; 500µs, 25Hz). These two parameters were tested in the follow-up trial, which demonstrated that both parameters decrease heart rate, with 500µs 10Hz having the largest physiologic effect. Lastly, findings from the taVNS/fMRI trial demonstrate the neurobiological effect of taVNS mimics that of cervically implanted VNS and targets several cortical and subcortical vagus afferent pathway targets. taVNS in our paradigms was feasible, safe, and demonstrated neurobiological effects that are similar to implantable VNS. Future trials should conduct parametric optimization using the taVNS/fMRI protocol as it reliably targets vagus nerve afferents as well as further explore optimizing taVNS as a possible therapeutic and research tool.

Rights

All rights reserved. Copyright is held by the author.

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