Cross-species experiments reveal widespread cochlear neural damage in normal hearing

Abstract

Animal models suggest that cochlear afferent nerve endings may be more vulnerable than sensory hair cells to damage from acoustic overexposure and aging. Because neural degeneration without hair-cell loss cannot be detected in standard clinical audiometry, whether such damage occurs in humans is hotly debated. Here, we address this debate through co-ordinated experiments in at-risk humans and a wild-type chinchilla model. Cochlear neuropathy leads to large and sustained reductions of the wideband middle-ear muscle reflex in chinchillas. Analogously, human wideband reflex measures revealed distinct damage patterns in middle age, and in young individuals with histories of high acoustic exposure. Analysis of an independent large public dataset and additional measurements using clinical equipment corroborated the patterns revealed by our targeted cross-species experiments. Taken together, our results suggest that cochlear neural damage is widespread even in populations with clinically normal hearing.

Perceptual Consequences of Cochlear Deafferentation in Humans

“…Non-invasive physiological measures that have been shown to be sensitive to synaptopathy in animal models include the amplitude of wave 1 of the auditory brainstem response (ABR; Hickox et al, 2017 ; Kujawa & Liberman, 2009 ; Lin et al, 2011 ; Parthasarathy & Kujawa, 2018 ), the envelope following response (EFR; Parthasarathy & Kujawa, 2018 ; Shaheen et al, 2015 ), and the middle ear muscle reflex (MEMR; Bharadwaj et al, 2022 ; Valero et al, 2018 ). These physiological measures can all be obtained in living humans, although some differences in stimulus parameters and methodology are required.…”

“…The second uses a wideband probe, such as a click or chirp. A wideband probe was used in the animal studies relating MEMR strength to synapse numbers ( Bharadwaj et al, 2022 ; Valero et al, 2018 ). The advantage of using the wideband probe is that it provides information about MEMR-related middle ear impedance changes across a broad range of frequencies.…”

“…No animal study has explicitly compared all three physiological measures in the same animals to evaluate their relative value as indicators of cochlear synaptopathy. However, Shaheen et al (2015) measured both ABR wave 1 amplitude and EFR strength in mice with noise-induced synaptopathy, Valero et al (2018) measured both ABR wave 1 amplitude and wideband MEMR in mice with noise-induced synaptopathy, Parthasarathy and Kujawa (2018) measured ABR wave 1 amplitude and EFR strength in mice with age-related synaptopathy, and Bharadwaj et al (2022) measured ABR wave 1/5 amplitude ratio and wideband MEMR in chinchillas with noise-induced synaptopathy. Shaheen et al found larger noise-exposure related effect sizes for EFR strength relative to ABR wave 1 amplitude.…”

“…They found that of these three measures, EFR magnitude provided the clearest differences between Veterans with high noise exposure and non-Veterans with minimal noise exposure after statistical adjustment for DPOAE levels and sex. Bharadwaj et al (2022) measured wideband MEMR and ABR wave I/V amplitude ratio in young adults with noise exposure from firearm use/playing in a marching band, middle-aged adults, and young adults controls and found that the wideband MEMR was better than ABR wave I/V ratio at differentiating the controls from the noise exposed and middle-aged groups. These human studies suggest that the EFR and wideband MEMR are more sensitive to expected age- and noise exposure-related cochlear synaptopathy than the ABR, similar to what has been shown in animal models.…”

A data-driven approach to identify a rapid screener for auditory processing disorder testing referrals in adults

“…Clinical management for adult patients with normal audiograms is complicated by the lack of consensus on possible underlying conditions 3 , with varying terms used to refer to these conditions including central auditory processing disorder 22 , central presbycusis 23 , King–Koptezky Syndrome 24 , idiopathic discriminatory dysfunction 25 and auditory neuropathy 26 . Additionally, recent anatomical evidence from human temporal bones and animal models suggests a loss of cochlear synapses between the inner hair cells and the auditory nerve, which is not reflected in the audiogram, and is hypothesized to cause hearing difficulties in challenging listening conditions 12 , 27 – 34 . This heterogeneity in presentation and terminology further complicates clinical management in this patient population.…”