Elucidating neural mechanisms of tinnitus generation and persistence: A multimodal neuroimaging investigation

Khan, Rafay Ali

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https://hdl.handle.net/2142/117795 Copy

Description

Title

Elucidating neural mechanisms of tinnitus generation and persistence: A multimodal neuroimaging investigation

Author(s)

Khan, Rafay Ali

Issue Date

2022-11-30

Director of Research (if dissertation) or Advisor (if thesis)

Husain, Fatima T

Doctoral Committee Chair(s)

Husain, Fatima T

Committee Member(s)

• Sutton, Brad P
• Mudar, Raksha
• Lam, Fan

Department of Study

Neuroscience Program

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• tinnitus
• hearing loss
• neuroimaging
• MRI
• network neuroscience

Abstract

Tinnitus, the perception of sound in the absence of an external source, is one of the most common audiological disorders, impacting approximately 10-15% of the general population. It is associated with increases in reports of emotional disturbance, trouble with communication, and general decreases in quality of life. Hearing loss has been proposed as a driver for tinnitus, but discrepancies in their incidence and heterogeneity in the population have presented a unique challenge in the understanding of their relationship. The neural correlates of subjective chronic tinnitus have been studied using a wide range of methodologies and techniques; yet our understanding of tinnitus and its drivers and mechanisms remain unclear. The objectives of the work in this dissertation were to investigate biological markers of tinnitus in the context of hearing loss to help us better understand its generation and chronicity, with the aim of evaluating proposed models and mechanisms underlying it. Three interconnected studies were conducted to investigate the mechanisms underlying tinnitus and its relationship to hearing loss. In Chapter 2, anatomical connectivity was compared between those with tinnitus and hearing loss, tinnitus with normal hearing, controls with hearing loss and controls with normal hearing. Using fractional anisotropy, mean diffusivity, and probabilistic tractography analyses, differences were found in FA and structural connectivity specific to tinnitus, and hearing loss, as well as when both conditions are comorbid. Age was seen to play an important role in the neural plasticity associated with these conditions, and may account for some of the variability of results in the literature. These results suggest underlying tinnitus-specific neural networks, and we propose an updated model of tinnitus, wherein the internal capsule and corpus callosum play important roles in the evaluation of, and neural plasticity in response to tinnitus. Chapter 3 expanded the network connectivity approach. While some consistent patterns associated with tinnitus have been observed in the literature, resting-state functional connectivity studies of tinnitus have shown considerable heterogeneity in findings. In Chapter 3, a novel approach was used to investigate hybrid anatomical and functional connectivity, to better understand structure-function relationships underlying tinnitus and hearing loss. Four participant groups were constructed in a similar fashion to Chapter 2, and a hybrid connectivity analysis pipeline established in the literature was used to extract data-driven components of functional and structural connectivity using independent component analysis. Results suggested a larger impact of hearing loss on structural reorganization than tinnitus. The design of the study allowed for investigation of the relationship between neural architecture and resting-state functional connectivity, revealing that hearing-loss related changes in structural connectivity may be associated with downstream changes in functional connectivity when tinnitus is comorbid. Of particular interest was the relationship between thalamic structural connectivity and cortical frontal and auditory functional connectivity in the tinnitus group, suggesting potential mechanisms for the onset of tinnitus in the presence of hearing loss. Additionally, subtle differences in auditory-frontal and default mode-frontal functional connectivity hint at possible downstream differences in participants who have tinnitus and hearing loss and those who have just hearing loss. Findings may indicate how subcortical structural alterations could impact cortical functional activity, and suggest mechanisms underlying tinnitus when comorbid with hearing loss. Studies of tinnitus and hearing loss have primarily been conducted in animal models, due to limited availability of tools for such investigations in humans. Two recent studies have investigated the concentrations of neurotransmitters in the auditory cortex of humans, with some overlap and some contradiction in findings. However, no human study has investigated the concentration of neurotransmitters in subcortical auditory regions. In Chapter 4, magnetic resonance spectroscopy was used to investigate the relative concentrations of GABA and glutamate/glutamine (or Glx) in the auditory cortex, thalamus, and inferior colliculus. Results were contrary to hypotheses – only hearing loss-related differences were seen in the auditory cortex, while in the thalamus, both hearing loss and tinnitus participants had reduced Glx and increased GABA compared to controls. In the inferior colliculus, reduced Glx and increased GABA was seen in the tinnitus group compared to the control group only. Results may indicate support for the thalamocortical dysrhythmia hypothesis of tinnitus, but a larger study is required. Further, results highlighted the limitations of animal work, which in itself has shown extensive inconsistency in findings relating to the role of neurotransmitters in tinnitus. This study was the first to investigate the neurochemical differences associated with tinnitus and hearing loss at a subcortical level, and provides a strong justification on which to build a larger study. Overall, the studies in this dissertation have provided support for a large range of previous findings in the neuroimaging of tinnitus, while incorporating new findings into proposed models of tinnitus and its relationship to hearing loss. Collectively, these studies suggest a potential mechanism of tinnitus incidence through plasticity in subcortical auditory structures. The amalgamation of literature discussed here also highlights a particular disconnect between tinnitus research in human and animal models, as the findings do not often overlap, leading to an unclear understanding of tinnitus from the view of structural and functional connectivity, as well as at a neurochemical level. Expanding on the studies presented in this dissertation may be helpful in furthering our understanding of tinnitus, and help in the development of more precise and effective therapeutics.

Graduation Semester

2022-12

Type of Resource

Thesis

Copyright and License Information

Copyright 2022 Rafay Khan

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