ABSTRACT The audiogram is the cornerstone of clinical hearing assessment, but individual differences in speech perception, especially in noisy environments, cannot be explained by audibility alone. People with normal hearing thresholds often complain of difficulty understanding speech-in-noise, and listeners with sensorineural hearing loss (SNHL) show significant variability in speech perception, even when audibility is restored. Animal models of SNHL and temporal bone histology suggest that peripheral pathology missed by the audiogram may explain some of this variance. Outer hair cell (OHC) dysfunction elevates hearing thresholds, but inner hair cell (IHC) and auditory nerve (AN) dysfunction may be hidden from the audiogram despite their impact on neural encoding of sound. The presence of specific cochlear pathologies and their relative contribution to perception, however, cannot be directly tested in humans. Instead, non-invasive biomarkers of pathology are used. Though diagnostics have been developed for identifying hidden pathologies in people with normal hearing, an individual metric is unlikely to be enough when SNHL results from a combination of peripheral dysfunctions. To address this gap, we use a battery of non-invasive diagnostic tools to determine a biomarker profile for individual subjects and assess its relationship to cochlear anatomy and speech-in-noise perception when there are varying degrees of OHC and non-OHC dysfunctions. This proposal tests our central hypothesis that identifying subtypes of SNHL from integration of biomarkers sensitive to both OHC and non-OHC pathologies significantly improves prediction of suprathreshold hearing over the audiogram alone. Using a cross-species approach, three synergistic specific aims test our hypothesis. First, we assess the differences in biomarker profiles of two chinchilla models of distinct SNHL subtypes, OHC-only hearing loss and complex SNHL (e.g., a combination of OHC, IHC, and AN dysfunction), to measure the effect of non-OHC pathologies when they co-occur with OHC dysfunction. Second, we measure physiological biomarker profiles in humans with SNHL and test whether they better predict speech understanding than the audiogram. Third, using our coordinated physiological test battery as a link between species, we make predictions about the underlying cochlear pathology distributions in humans with complex SNHL based on our histology from chinchillas with known exposures. Whether our hypotheses are supported or refuted, this cross-species dataset will advance our understanding of the factors important for everyday communication and establish a quantitative framework for developing more detailed diagnostic profiles. Greater diagnostic precision that recognizes the multifactorial physiological underpinnings of SNHL will support personalization of hearing healthcare and treatment, especially pharmaceutical interventions for hearing loss. Additionally, the quantitative, cross-species, and professional training received through completion of these aims complements my clinical training in audiology and will be foundational to my career as a translational auditory neuroscientist.

PROJECT NARRATIVE People with similar degrees of sensorineural hearing loss, as defined by the audiogram, often have varying levels of difficulty understanding speech in noisy environments. To assess the relationship between dysfunction in the auditory periphery and perception, the proposed project uses coordinated non-invasive biomarkers sensitive to multiple sites of cochlear dysfunction in both humans and chinchillas with sensorineural hearing loss to estimate profiles of peripheral pathology and predict hearing outcomes in background noise. Results from this cross- species study will provide valuable insight into the dysfunctions that underlie common auditory complaints and improve personalization of treatments for sensorineural hearing loss.