Jennifer R. Melcher - US grants

neuroanatomy; neural information processing; binaural hearing; auditory pathways; auditory cortex; olivary body; inferior colliculus; medial geniculate body; auditory nuclei; functional magnetic resonance imaging; auditory stimulus; human subject; clinical research;

DESCRIPTION (provided by applicant): Attempts to relate structure and function in human auditory cortex have been seriously impeded by our inability to discern the internal architecture of cortical gray matter in living humans. Here, we propose exploiting and extending recent advances in structural MRI to resolve features of human gray matter myeloarchitecture and thickness in vivo. High-field scanning, specially-designed imaging coils, and state-of the-art 3D analysis and visualization techniques will be used to resolve - on a submillimeter scale - features of gray matter architecture (i.e., laminar structure, myelin density, thickness) that would normally be discernable only in postmortem tissue. By spatially mapping these gray matter features, we propose to delineate anatomical areas that define auditory cortical organization at a fundamental level (e.g., core, belt), but have never before been distinguished in the living human brain. Combined with functional neuroimaging, this work will enable cortical neuroanatomy and function to be related in individual humans, in ways that have so far only been possible in animals. By providing unprecedented access to the cortical neuroanatomy of living humans, the proposed work promises to open new avenues for understanding the structural underpinnings of hearing, speech, and language processes, both normal and abnormal.

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (06): Enabling Technologies and specific Challenge Topic, 06-DC-103: Understanding the Neural Mechanisms Responsible for Tinnitus. The proposed work will investigate a completely new brain mechanism for tinnitus directly in people. This mechanism - abnormal coordination, or coupling, between brain centers - is manifested strikingly in our preliminary analyses of functional magnetic resonance (fMRI) data: Tinnitus subjects, but not non-tinnitus controls, demonstrate an abnormal coupling of activity between non-primary auditory cortex and frontal areas known to mediate emotions. This abnormal coupling is strongly suggestive of one of the most clinically perplexing aspects of the tinnitus condition, the "vicious cycle" whereby the tinnitus percept causes distress and distress exacerbates the percept. The possibility that aberrant coupling between brain areas may be the tie that binds tinnitus percept and affect is, by itself, strong motivation for the present proposal. The possibility that our initial observations are only the tip of the iceberg is all the more reason to examine a brain mechanism that may prove to be a crucial aspect of the physiology of tinnitus. Here, we propose behavioral, fMRI, magneto- and electro-encephalographic (MEG, EEG) measurements in tinnitus subjects and non-tinnitus controls to test for, quantify, and establish the behavioral significance of aberrant coordination between brain centers in tinnitus subjects. We expect this work will fundamentally change how the field conceptualizes the brain mechanisms of tinnitus. It promises to also bring us closer to the day when every one of the millions of Americans plagued by tinnitus can enter a clinic and walk away cured. PUBLIC HEALTH RELEVANCE: This proposal investigates a novel abnormality of brain function that may underlie the most clinically significant aspect of tinnitus, the "vicious cycle": tinnitus causes distress;distress causes tinnitus. The nature of the abnormality - to be studied directly in people - is an unusually strong coupling of activity between brain centers such as those processing sound and emotions. If our work shows that this abnormal coupling is indeed operative in tinnitus patients, there are existing treatments that may be able to reverse it and thereby provide relief from a condition that is all too often debilitating.

DESCRIPTION (provided by applicant): This proposal to examine classic indicators of sensorimotor gating - the acoustic startle response (ASR) and prepulse inhibition (PPI) - in humans with tinnitus and hyperacusis is both important and timely. It is motivated by (i) the almost complete absence of data on either ASR or PPI in relation to human tinnitus or hyperacusis, despite the success of these measures in objectifying and elucidating a variety of other conditions also thought to involve failures of inhibition and over-excitation, including schizophrenia, obsessive compulsive disorder and Tourette's syndrome, (ii) suggestions that enhanced ASR in animal models indicates hyperacusis, but a lack of data testing this hypothesis and, (iii) the recent surge of interest in a gap-detection startle reflex (GDSR) test fo tinnitus in animals, which has yet to be validated in humans and is reliant on the ASR and neural circuitry mediating PPI. The proposed experiments measuring ASR, PPI and GDSR in human subjects will test (1) whether insights into the mechanisms of tinnitus and hyperacusis might be leveraged from other more heavily studied neurological conditions for which the ASR and PPI are already well-characterized, and (2) whether ASR and GDSR measures thought to indicate hyperacusis and tinnitus in animals actually do. The proposed work is crucial to understanding clinical tinnitus and hyperacusis and, specifically, relating it to animal data on th underlying neural mechanisms of these increasingly prevalent disorders. PUBLIC HEALTH RELEVANCE: The proposed work moves into largely unexplored territory by examining the acoustic startle response (ASR) and prepulse inhibition (PPI) in humans with tinnitus and hyperacusis. The work will test whether insights into the mechanisms of tinnitus and hyperacusis might be leveraged from other more heavily studied neurological conditions for which the ASR and PPI are already well-characterized. ASR/PPI-based measures thought to indicate tinnitus and hyperacusis in animals will be tested in humans, thus building a bridge between clinical tinnitus/hyperacusis and animal data on the underlying neural mechanisms of these disorders.