Non-Invasive Assays of Cochlear Synaptopathy -- Candidates and Considerations

Abstract

Studies in multiple species, including in post-mortem human tissue, have shown that normal aging and/or acoustic overexposure can lead to a significant loss of afferent synapses innervating the cochlea. Hypothetically, this cochlear synaptopathy can lead to perceptual deficits in challenging environments and can contribute to central neural effects such as tinnitus. However, because cochlear synaptopathy can occur without any measurable changes in audiometric thresholds, synaptopathy can remain hidden from standard clinical diagnostics. To understand the perceptual sequelae of synaptopathy and to evaluate the efficacy of emerging therapies, sensitive and specific non-invasive measures at the individual patient level need to be established. Pioneering experiments in specific mice strains have helped identify many candidate assays. These include auditory brainstem responses, the middle-ear muscle reflex, envelope-following responses, and extended high-frequency audiograms. Unfortunately, because these non-invasive measures can be also affected by extraneous factors other than synaptopathy, their application and interpretation in humans is not straightforward. Here, we systematically examine six extraneous factors through a series of interrelated human experiments aimed at understanding their effects. Using strategies that may help mitigate the effects of such extraneous factors, we then show that these suprathreshold physiological assays exhibit across-individual correlations with each other indicative of contributions from a common physiological source consistent with cochlear synaptopathy. Finally, we discuss the application of these assays to two key outstanding questions, and discuss some barriers that still remain.

Individual differences in the attentional modulation of the human auditory brainstem response to speech inform on speech-in-noise deficits

“…This may suggest that either cochlear synaptopathy has little influence on auditory difficulty or that it has no significant prevalence, at least in normal-hearing people. However, in this study we did not test for high-frequency hearing loss above 8 kHz, which may serve an early indicator of hearing loss at lower frequencies and may indicate cochlear synaptopathy in a broader frequency range 73,74 . Moreover, the measures that we have employed may not have been optimal for detecting cochlear synaptopathy: the latency shift of wave V in noise, for instance, has been recently shown to have only moderate test-retest reliability 55 .…”

Cutting Through the Noise: Noise-Induced Cochlear Synaptopathy and Individual Differences in Speech Understanding Among Listeners With Normal Audiograms

“…43,NO. 1,[9][10][11][12][13][14][15][16][17][18][19][20][21][22] employed stimuli to elicit electrophysiological responses that may be better suited to identify CS-related AN degeneration than those utilized by many other human studies [see Table 2 in Supplemental Digital Content 1, http://links.lww.com/EANDH/ A935; Bharadwaj et al 2019;Vasilkov et al 2021; see discussions in Grant et al (2020); Mepani et al (2020);and Mepani et al (2021) for further details]. These findings thus highlight the importance of developing both electrophysiological proxies of CS and speech perception tasks in difficult listening conditions that are sensitive to CS.…”

“…The lack of direct assessments of CS in living humans complicates attempts to link synaptic damage to auditory perceptual impairments. Some proxies of CS may also be more sensitive than others-heterogenous methods to predict CS levels likely contribute to the inconsistent results of prior studies, as has been discussed in several recent reviews (Bharadwaj et al 2019;Bramhall et al 2019;Le Prell et al 2019). Further, individual differences in synapse counts from genetic and/or developmental factors may be a source of variability that obscures correlations between noise exposure history and speech perception in challenging listening conditions.…”

Frequency Following Response and Speech Recognition Benefit for Combining a Cochlear Implant and Contralateral Hearing Aid

“…The human FFR is an auditory-evoked potential that reflects the synchronous neural activity originating in the auditory brainstem. However, it should be noted that recent evidence suggests that the FFR may additionally have a cortical contribution (Coffey, Herholz, Chepesiuk, Baillet, & Zatorre, 2016;Coffey, Musacchia, & Zatorre, 2017) though these contributions are likely weak (Bharadwaj et al, 2019;Bidelman, 2018) and unnecessary for FFR generation (White-Schwoch, Anderson, Krizman, Nicol, & Kraus, 2019). Unlike other electrophysiological measures such as the auditory brainstem response (ABR), the FFR is unique in that it accurately represents auditory characteristics of the stimulus, including temporal and spectral properties below $1500 Hz.…”