Lysine acetyltransferase 8-mediated histone acetylation, regulated by GBA1, is associated with lysosomal function related to α-Synuclein pathology.

Hyperacusis is a debilitating auditory condition characterized by an abnormal sensitivity to everyday sounds, resulting in discomfort, pain, emotional distress, and functional impairment (). It frequently co-occurs with sensorineural hearing loss, where damage to cochlear structures, particularly auditory nerve fibers, is thought to trigger compensatory increases in central auditory gain, thereby exaggerating the loudness of sounds that are not normally perceived as uncomfortable (, ; ; ). Animal models of sensorineural hearing loss have shown that reduced cochlear nerve output can paradoxically lead to elevated spontaneous and sound-evoked activity across multiple levels of the central auditory system (, ; ; ; ). This central hyperactivity is thought to reflect maladaptive plasticity triggered by decreased afferent input and disrupted inhibitory signaling within central auditory circuits (), ultimately resulting in exaggerated neural responses to sound (; ). Notably, both hyperacusis and tinnitus are frequently observed in individuals with clinically normal audiometric thresholds (; ), challenging the assumption that these perceptual disturbances are exclusively linked to outer hair cell dysfunction. The recognition that cochlear nerve degeneration (CND) can occur without audiometric threshold elevation offers a compelling explanation for these findings (); ). Early evidence suggested that CND may preferentially affect high-threshold, low-spontaneous rate (SR) auditory nerve fibers, which are less susceptible to threshold shifts but play a key role in suprathreshold coding in complex listening environments (; ; ). Loss of these fibers could leave tone detection in quiet relatively intact while degrading auditory processing under more challenging conditions. Computational modeling and behavioral validation support the functional impact of SR-specific deafferentation, demonstrating declines in speech recognition as low- and medium-SR fibers are progressively lost (). Of note, prior studies suggest that SR selectivity may vary by species, cochlear location, and noise exposure paradigm, and that synaptic loss may not always be confined to low- and medium-SR fibers (). CND, defined as the loss of synaptic connections between inner hair cells and spiral ganglion neurons, has been shown in animal models to increase spontaneous or sound-evoked activity in central auditory structures (; ; ; ). These central changes have been linked to behavioral correlates of both hyperacusis (; ; ) and tinnitus (; ; ). In humans, individual variability in loudness perception, even among listeners with normal audiograms, has been associated with electrophysiological markers of cochlear nerve loss and with self-reported sound aversion (). Recent electrocochleographic evidence further shows that chronic subjective tinnitus may be accompanied by reduced peripheral auditory nerve responses coupled with enhanced brainstem activity, independent of sex and hearing thresholds across both standard and extended high-frequencies (EHFs) (). However, that analysis did not account for comorbid sound-level intolerance, which is frequently observed in tinnitus patients (; ).