|Sharon Kujawa and Charles Liberman|
Hidden Hearing Loss – the Problem and the Promise
Sharon G. Kujawa and M. Charles Liberman
Most adult hearing impairment is sensorineural in nature and arises from inner ear dysfunction. Dogma has long held that hair cells are the most vulnerable cochlear elements and that cochlear neural loss typically occurs only after, and because of, hair cell degeneration. Work from our lab, and others, over the last 10 years has shownthat this is not true for key etiologies of acquired sensorineural hearing loss, including noise, aging, and ototoxic drugs (Kujawa and Liberman 2015). These insults can cause massive (>50%) loss of cochlear nerve peripheral synapses without any hair cell loss (see Figure). This extensive cochlear synaptopathy has remained a “hidden hearing loss”, because 1) diffuse neural degeneration does not significantly elevate cochlear pure-tone thresholds, or the behavioral audiogram, until it reaches 80%, 2) the synaptic connections between cochlear neurons and hair cells are hard to see in routine histological material, and 3) the cell bodies and central axons of cochlear neurons, survive for years to decades despite their loss of functional connection to the hair cells.
Although synaptopathy does not affect the audiogram, which is a highly sensitive measure of outer hair cell function, it likely compromises the ability to understand complex stimuli, especially in difficult listening environments (Bharadwaj, Verhulst et al. 2014). This arises, in part, because the most vulnerable cochlear neurons appear to be those with high thresholds and low spontaneous rates (SRs; (Liberman 1978) (Furman, Kujawa et al. 2013)), and low-SR fibers are especially important to the coding of suprathreshold sounds in the presence of background noise. Cochlear synaptopathy may also be a key initiator of tinnitus or hyperacusis, which is not uncommon in people with normal audiometric thresholds (Schaette and McAlpine 2011, Gu, Herrmann et al. 2012).
In animal models, cochlear synaptopathy can be diagnosed via the suprathreshold amplitude of ABR wave 1, the summed sound-evoked activity of cochlear nerve fibers, so long as there is no outer hair cell dysfunction to reduce cochlear sensitivity (Kujawa and Liberman 2009). Recent studies of human subjects with normal audiograms have shown correlations between reduced electrophysiological responses and deficits in suprathreshold processing and/or performance on speech in noise tests (Epstein, Cleveland et al. 2016, Mehraei, Hickox et al. 2016). Such studies also suggest that synpatopathy can be noise-induced, even among college-age subjects (Epstein, Cleveland et al. 2016). Thus, noise damage may be more widespread than previously thought based on standard audiometric evaluation .
We believe that cochlear synaptopathy is widespread in humans, regardless of the “hearing loss” seen on the audiogram, and that the degree of synaptopathy, or “hidden hearing loss”, is an important determinant of the overall impairment. We also believe that synaptopathy might be reversible, since there is a long therapeutic window during which the hair cells and spiral ganglion cells remain, and since neurotrophins can promote spiral ganglion survival and growth of peripheral axons even in the adult ear (Wise, Richardson et al. 2005). Indeed, in mouse, we have shown that either neurotrophin overexpression (Wan, Gomez-Casati et al. 2014) or neurotrophin delivery to the round window (Suzuki, Corfas et al. 2016) can regenerate lost synapses and provide corresponding functional recovery of ABR wave 1. Of all the regenerative strategies for hearing impairment envisioned in our field today, we believe that treatments for cochlear synaptopathy will be the easiest to achieve.
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