Effects of Selective Inner Hair Cell Loss and Cochlear Synaptopathy on Psychophysical Intensity Increment Detection Tasks in the Chinchilla Animal Model

Intensity coding of sound plays a critical role in the perception of complex auditory stimuli such as speech. These stimuli are considered complex, in part, due to rapid fluctuations along the intensity and temporal domains. These essential temporal and intensity processing abilities are thought to be negatively impacted by age-related hearing loss (Vermiglio et al., 2012) or noise- induced hearing loss (Altschuler et al., 2019) and deficits in these two domains are thought to contribute to speech processing deficits (Kumar et al., 2012). In the periphery, prior to cortical levels of auditory processing, hearing loss is highly correlated with damage to the outer hair cells (OHC) and/or inner hair cells (IHC), the two sensory cell types that reside in the inner ear. At this level, OHC play a critical role in active basilar membrane non-linear gain in the cochlea. However, OHC only transmit about 5% of afferent information to auditory nerve fibers (Spoendlin, 1971). Loss of OHC has been directly correlated with increased thresholds and poorer frequency tuning due to loss of non-linear amplification for low intensity acoustic stimuli. For example, it has been shown that damage to OHC from noise exposure results in reduced hearing sensitivity evidenced by commensurate elevations in auditory thresholds (Boettcher et al., 1992a). IHC on the other hand have extensive auditory nerve fiber innervation and transmit over 95% of afferent acoustic input to the central auditory system. Despite the extensive innervation, selective loss of IHC in animal models has been shown to have little effect on physiological or psychophysical auditory thresholds but has been shown to reduce the neural signal coming from the cochlea. Despite these findings, few studies have evaluated the effects of selective IHC loss or damage on suprathreshold auditory perception. Over the last decade, animal studies have suggested that noise and age-induced IHC deafferentation in mice could play a significant role in auditory temporal processing (Liberman and Kujawa, 2017) and may also impact intensity coding. Other previous studies have shown that selective IHC loss in chinchillas following carboplatin treatment, a commonly used anticancer drug, has little effect on pure tone thresholds in quiet (Lobarinas et al., 2013b; 2016; Salvi et al., 2016), but significantly affects pure-tone thresholds in noise (Lobarinas et al., 2016) and detection of gaps in continuous noise (Lobarinas et al., 2020). In contrast, selective IHC loss has little effect on temporal summation assessed by psychophysical detection of short-duration pure-tones (Trevino et al., 2022). The results of these two studies suggest that the gap detection deficits may be the result of poorer intensity coding given that temporal summation does not change even after IHC losses of over 70%. To assess whether the deficits observed in the gap detection studies stem from poorer intensity coding, I developed software based on previous studies to measure intensity increment detection (IID). This psychophysical task was used to evaluate chinchilla sensitivity to intensity changes before and after carboplatin, a treatment that has been shown to reliably and selectively destroy IHCs in this species. Alternatively, selective damage but not loss of IHCs can occur as a result of exposure to noise at levels that are below those that would cause mechanical and metabolic trauma to OHC (Kujawa and Liberman, 2009). Studies suggest that this noise-induced loss of afferent synaptic connections between IHC and auditory nerve fibers may be a potential cause of suprathreshold hearing deficits (Hickox and Liberman, 2014; Hickox et al., 2017). This pathology has been termed cochlear synaptopathy, and it produces a pattern of change in which auditory thresholds are not affected but suprathreshold deficits such as poorer hearing in noise may be present. To evaluate whether intensity coding, a critical component of hearing in noise, is also affected by noise-induced cochlear synaptopathy, my studies will assess chinchilla IID threshold before and after a noise exposure aimed to induce synaptopathic damage to IHCs. I hypothesized that IID thresholds would increase following both carboplatin treatment and noise exposure, suggesting that IHCs synaptic damage or loss of IHCs is correlated with deficits in intensity coding. If this hypothesis is supported, IID tasks could be used as a suprathreshold assay of IHC cochlear damage. The goal of this study was to investigate the effects of IHC loss or damage on the chinchilla’s ability to detect intensity changes. Each animal completed a battery of baseline assessments, including a psychoacoustic pure tone detection task and an intensity increment detection task. Physiological assays of cochlear function were also obtained. These included distortion product otoacoustic emissions (DPOAEs), a measure associated with OHC function, Auditory Brainstem Response (ABR) thresholds, and ABR wave-1 amplitude measurement, measures associated with the neural output of both the cochlea and the auditory brainstem. These baseline measures were re-assessed following two distinct patterns of cochlear damage induced by (1) selective IHC loss from 75 mg/kg of carboplatin and (2) synaptopathic noise exposure. At the conclusion of data collection, histological analysis of chinchilla cochleae was completed including individual animal IHC, IHC synapses, and OHC counts. The degree of IHC and OHC loss was correlated with post-lesion perceptual test results to assess the effects of cochlear damage on intensity coding. The results from this study suggest that IHC likely play a critical role in the ability to code changes in intensity given that deficits in intensity coding can directly impact an individual’s ability to process speech, especially in the presence of background noise. IID could be used to assess the presence of IHC damage or IHC synapse damage independent of traditional measures of hearing which are primarily sensitive to OHC loss. Identifying the cause of these suprathreshold speech in noise deficits may lead us further in identifying specific solutions for these patients. Unlike most current electrophysiological tests that have been used to estimate cochlear damage, this test is quick to administer and could easily be implemented in clinical audiology practice. In humans, this task would take approximately 5 minutes indicating that a healthcare provider could administer this test in a standard evaluation without having to schedule a separate testing appointment.