PROJECT SUMMARY / ABSTACT Mild traumatic brain injury (mTBI) is a major global public health issue. Following mTBI, individuals commonly report difficulties with hearing quality, tinnitus, hyperacusis, and speech-in-noise intelligibility. In order to understand why patients experience auditory dysfunction after mTBI, new approaches are needed that combine quantitative non-invasive biomarkers in mTBI patients with studies of the underlying neurophysiological and anatomical changes. The overarching hypothesis of the proposal is that many of the neurosensory disorders associated with mTBI share a common root related to a disruption of low-level sensory feature coding. Of all the sensory systems, the auditory system places the highest demand on rapid, high-fidelity temporal coding. We therefore propose that abnormal temporal processing and central gain in the auditory system of mTBI patients and animal models would highlight a neural signature of the auditory behavioral sequalae and may serve as the “canary in the coal mine” for distributed pathophysiology occurring more generally in other brain systems. Thus, the Candidate proposes a mentored training plan to develop non-invasive biomarkers of auditory dysfunction in mTBI subjects and to identify the neurobiological substrates for these deficits in a mouse model of mTBI. The Candidate has assembled a mentorship team that has expertise in a range of relevant areas for the proposal, including psychophysics in human subjects, mTBI mouse models, neurophysiological measures of auditory temporal processing and central gain, and quantitative cochlear histopathology. By integrating complementary levels of analysis through the study of different species it will be possible to generate greater insight into the pathophysiology of mTBI. In Aim 1, the Candidate will use a combination of auditory psychophysical tests and measures of the electroencephalography (EEG) frequency following response to test the hypothesis that mTBI subjects show deficits in coding rapid temporal cues and hyperactivity in sound intensity coding relative to controls. In Aim 2, the Candidate will incorporate a mouse mTBI model to compare EEG recordings against extracellular recordings of local field potentials and single unit spiking from the inferior colliculus (IC) and auditory cortex (ACtx) to test whether: 1) mice exhibit a similar auditory temporal processing and central gain phenotype observed in human subjects, and 2) abnormal temporal processing and coding of sound intensity are more prevalent in the IC or ACtx. In Aim 3, the Candidate will examine sensory and neural pathology in the cochlea of mice that have undergone mTBI, as well as transcriptional changes in Gria2 and Gabra1 mRNA levels in the IC and ACtx. These studies in Aim 3 will address the hypothesis that dysregulation of auditory temporal processing and central gain are linked to cochlear afferent neuropathy and imbalanced markers of excitatory and inhibitory signaling in the central auditory pathway. The K08 award will be a crucial stepping-stone toward the goal of developing into an independent clinician-scientist.

PROJECT NARRATIVE Mild traumatic brain injury (mTBI) is a major public health issue and significant source of disability in the United States. While auditory symptoms are among the most common sequelae of mTBI, the neurobiological mechanisms are not well understood. Rigorous studies of auditory pathophysiology in humans and mice with mTBI could provide a critical step toward addressing two of the most urgent needs in this field: 1) To develop clinical measures in human subjects with mTBI that may eventually evolve into a new class of biomarkers, and 2) To understand the underlying etiology of auditory dysfunction following mTBI in an animal model.