Overall Project Summary Insights from animal studies of noise-induced and age-related hearing loss suggest that the most vulnerable elements in the inner ear are the synaptic connections between hair cells and sensory neurons. This primary cochlear neural degeneration (CND) does not elevate thresholds, thus, it can be widespread in ears with intact hair cell populations and can “hide” behind a normal audiogram. It likely contributes to difficulties understanding speech in a noisy environment and may be an instigating factor in the generation of tinnitus and hyperacusis. CND may also be widespread, and even more severe, in cases of acquired sensorineural hearing loss (SNHL) where there is hair cell damage and threshold elevation. Thus, it may be a major contributor to the well-known differences in auditory performance among people with identical audiometric patterns of overt hearing loss. Our Research Center aims to take these paradigm-shifting ideas from animal models to human subjects. Based on the synthesis of many research threads, we have devised a set of physiological, psychophysical and behavioral assays of cochlear function and hearing that we believe are most powerful in diagnosing CND and understanding its effects on suprathreshold hearing. In Project 1, we apply electrophysiological tests to animals exposed to noise or ototoxic drugs and validate their utility in predicting the underlying CND and apply behavioral approaches to assess the role of CND in generating tinnitus and hyperacusis. In Project 2, we study human autopsy material from subjects with SNHL to directly assess the prevalence and patterns of CND in humans and to evaluate its role in compromising word-recognition scores and as a risk factor for tinnitus. In Project 3, we study patients with SNHL to characterize the effects of CND, as inferred from “bottom-up” electrophysiological measures of peripheral auditory function, on word identification in difficult listening environments and to probe the role of CND in the generation of tinnitus and hyperacusis. In Project 4, we further study the same subjects, probing the effects of CND on neural hyperactivity in central pathways, and its “top-down” effects on the hyper-reactivity to sound that dominates the clinical burden of tinnitus and hyperacusis. In our Research Center, we leverage the P50 mechanism to combine research perspectives from auditory neuroscience and audiology in a coordinated study of the most handicapping aspects of SNHL. Progress in understanding the effects of CND and how to effectively diagnose it, are of increasing importance as the progress in regenerative therapies for hair cells and cochlear neurons move from laboratories to clinical trials.