Noise-induced vestibular-mediated motor impairment and restorative therapies

Balance, gait, agility, and related sensory disorders affect millions of Americans and are among the most common service-related disabilities. Despite the impact of vestibular associated disorders on such large portion of the general public and Veterans, there remain challenges to effective detection and diagnosis. Due to their anatomical proximity to the cochlea and shared fluid pathway, the vestibular portion of the inner ear, particularly the saccule and utricle, is exposed to sound pressure and is at risk for noise overstimulation. There is now evidence that noise contributes to vestibular dysfunction, however understanding of underlying mechanisms and thus the available treatments and rehabilitative strategies are limited. Our previous studies in the rat model have shown that noise exposure causes pathological changes that lead to significant decreases in vestibular short latency evoked potential (VsEP) responses and loss of calretinin immunoreactivity of calyx-only afferent terminals, resulting in vestibular hypofunction (VH) (Stewart et al., 2018, 2020a, 2021) and impaired motor performance (Bartikofsky et al., 2023). The proposed studies will assess the cumulative impact of continuous and impulse noise exposures that are commonly encountered during service, explore functional consequences of peripheral vestibular injury, and evaluate treatment with 7,8- dihydroxyflavone, a compound that treats peripheral vestibular damage. The proposed studies will increase our understanding of how Military-relevant continuous and impulse noise exposures cumulatively damage the vestibular periphery and examine how and why some vestibular associated functions recover when VH persists. Specifically, we will explore vestibular-mediated dynamic motor performance in the absence of sensory reweighting that may increase reliance on vision after vestibular injury by using a dark condition that removes visual information in a balance beam crossing task. Although our data suggest that continuous noise exerts the most significant impact on the saccule and utricle, it is known that impulse noise also produces a measurable impact on semicircular canal cristae function. We will explore this impact and the impact of continuous noise exposure on head (vestibulocollic reflex) and eye movement (vestibulo-ocular reflex) using on- and off-axis rotary stimulation. We will correlate measured deficits with changes in VsEP and with cellular changes in vestibular end organs. We will also test treatment with 7,8- dihydroxyflavone, a compound that acts on tyrosine receptor kinase B receptors, similar to brain-derived neurotrophic factor, and has shown promise in the vestibular system to determine if this compound restores vestibular function after noise exposure. Due to their significant noise exposure histories and higher risk for VH due to service-related noise exposures, this work is of particular relevance to Veterans. Development of restorative therapies will hold significant clinical relevance for Veterans, who incur cumulative damage to the vestibular periphery over time and might not experience the consequences of noise exposure until this damage reaches a critical level. Identifying, addressing, and treating VH will ensure Veterans receive accurate diagnoses and interventions that increase independence and quality of life by preserving mobility and preventing fall risk. Studying vestibular- mediated mobility issues in rats will allow us to identify markers of VH that contribute to falls in compensated Veterans that may otherwise have a missed diagnosis. Results of this work will provide data that will guide rehabilitative treatments that enhance visual compensation and restorative therapies that deal with mobility issues when visual compensation is not possible. The results of the proposed studies will provide clinical impact for Veterans (1) by characterizing the progression of VH due to repeated exposure to noise, (2) by evaluating behavioral chang Project Number: 1I01RX005007-01A2 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Courtney Stewart | Institution: VETERANS HEALTH ADMINISTRATION, ANN ARBOR, MI | Activity Code: I01 | Study Section: Sensory Systems & Communication Disorders[RRD3] View on NIH RePORTER: https://reporter.nih.gov/project-details/11103541