Graduation Year

2018

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Engineering

Major Professor

Joseph P. Walton, Ph.D.

Committee Member

Ann Eddins, Ph.D.

Committee Member

Timothy Fawcett, Ph.D.

Committee Member

Robert Frisina, Ph.D.

Committee Member

Christopher Passaglia, Ph.D.

Keywords

electrophysiology, maladaptive plasticity, modification of the acoustic startle response, mouse model, proteomics

Abstract

Millions of people suffer from tinnitus, a disorder for which there is currently no effective treatment or cure. My dissertation work provides insight into the neural correlates of this pervasive hearing disorder and examines how a newly emerging therapy, transcranial magnetic stimulation (TMS), affects the central auditory system in the generation of the tinnitus percept. This work has a multifold focus of: i) developing and modeling the function of a miniature magnetic coil that can be used for TMS in rodents, ii) establishing a reliable mouse model of tinnitus that can be used for assessing TMS treatment-induced changes, iii) measuring the behavioral alterations and neural changes induced by TMS throughout the auditory system in mice with tinnitus, and iv) to assay underling molecular changes in the auditory cortex (AC) related to TMS and tinnitus. Chapter 1 gives an overview of the current research on tinnitus and TMS. Chapter 2 establishes a reliable neural and behavioral assay of verifying tinnitus in a mouse model and provides further evidence that the underlying hyperactivity associated with tinnitus is initiated in the brainstem following reduced afferent input. The remainder of the dissertation examines the modulation of tinnitus in the auditory central nervous system using a miniature TMS coil. Chapter 3 of the dissertation details the creation and evaluation of a rodent-sized TMS coil, which could increase the overall effectiveness and applicability for human treatment. TMS is currently an FDA approved treatment of depression and has been shown to decrease tinnitus perception in human clinical trials, albeit with variable results. There have been few published studies of tinnitus modulation by TMS using animal models and therefore little is known about the molecular and neural bases of this potential tinnitus treatment. TMS is thought to be therapeutic because the magnetic flux generated from the electromagnetic coil induces an electric field in the brain, altering ion flow and subsequently neural function, as the excitation and inhibition of cortical networks become synchronized to the magnetic pulse. Chapter 4 demonstrates that TMS with our custom-designed miniature rodent coil can successfully reduce behavioral evidence of tinnitus in a mouse model, mainly through activating inhibitory networks in the AC. It also shows that presynaptic activity is altered in the upper layers of the AC responsible for intralaminar processing and sound perception. Finally, chapter 5 describes an in-depth proteomic analysis of over 3000 proteins from the AC, which shows that TMS and noise-induced tinnitus alter the expression of several key proteins and pathways that play a critical role in cortical excitatory and inhibitory activation. The results of this work are also important because they are the first animal model to demonstrate neural changes during TMS-treated tinnitus, creating a paradigm that can be used for optimizing parameters to improve clinical outcomes in human trials.

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