An ‘Unhidden’ Perspective on Hidden Hearing Loss

An unconventional but emerging view of hidden hearing loss (HHL) is that it could occur due to outer hair cell dysfunction in humans. This notion is grounded on human studies that highlight the mechanisms and prevalence of this auditory disorder and how it may affect speech-in-noise perception in adults and children—a population typically excluded in HHL studies.FigureFigure 1: Audiogram, Distortion Product Otoacoustic Emissions and Speech-in-Noise Recognition. A. Mean hearing thresholds as a function of frequency; error bars show standard errors of the mean (N = 374 EHF-normal and 70 EHF-impaired ears). B. Violins with box and whisker plots showing overall DPOAE magnitudes averaged across 2 to 5 kHz (N = 15 EHF-normal and 34 EHF-impaired). C. Speech recognition threshold measured using the digit-triplets test for EHF-normal and EHF-impaired groups (N = 374 EHF-normal and 70 EHF-impaired ears). Data were replotted from Mishra et al. (26). Note, both groups had normal hearing thresholds ( 20 dB HL) for standard audiometric frequencies (0.25 through 8 kHz). The mean hearing threshold for standard audiometric frequencies for EHF-normal and EHF-impaired groups were 5 (SD = 3) and 9 dB HL (SD = 3), respectively. Hidden hearing loss, cochlear synaptopathy, outer hair cellHHL BEYOND COCHLEAR SYNAPTOPATHY In the past decade, there has been a tremendous interest in HHL among auditory scientists following papers from two groups across the Atlantic. 1,2 A quick search with the keywords “hidden hearing loss” in PubMed resulted in nearly 300 journal papers. The original use of the term HHL by Schaette and McAlpine was in the context of neural gain alteration in the auditory brainstem. Likewise, synaptopathy was originally described by Kujawa and Liberman, 2 but they did not use the term HHL until 2015. 3 The terms cochlear synaptopathy and HHL are often used interchangeably in the literature, with the implicit assumption that synaptopathy is the whole and sole cause of HHL. In the age of precision medicine, it is essential to distinguish these two terms because the implications for pathophysiology, prevention, assessment, and treatment could differ. Cochlear synaptopathy is the degeneration of synaptic contacts between inner hair cells and auditory nerve fibers. 2 In contrast, HHL has been defined inconsistently between studies and is often used colloquially. HHL has been described as auditory dysfunction that hides underneath the standard audiogram and is thought to be associated with perceptual deficits, including speech understanding in noisy backgrounds. From a clinical standpoint, it is unclear how HHL differs from myriad terms for listening difficulties with a normal audiogram, e.g., King-Kopetzky syndrome, obscure auditory dysfunction, idiopathic discriminatory dysfunction, hidden auditory neuropathy and (arguably) certain forms of auditory processing disorder. Perhaps, HHL was originally intended for referring to the perceptual consequences of cochlear synaptopathy, although this is not explicit in the relevant literature. 1,2 In congruence with Pienkowski, 4 we argue that HHL can be described as hearing problems not captured by the conventional audiogram, excluding cognitive deficits. Thus, HHL is an umbrella term to indicate difficulty in hearing-in-noise with cochlear synaptopathy as one potential cause. Regardless of the definition of HHL, it alludes to a serious public health issue that the standard audiometric procedures miss a significant proportion of individuals with hearing difficulty. Using a stricter criterion for normal audiometric hearing thresholds for adults ( 20 dB HL for 0.5 through 8 kHz), Tremblay et al 5 reported that 12% (82 out of 682) of a cross-section population of the Beaver Dam Offspring Study had self-reported hearing difficulty. Based on this, Edwards 6 estimated that 25.3 million Americans have hearing difficulty but no hearing impairment in contrast to the 12.1 million Americans who had hearing loss and hearing difficulty. An important question is: Do these individuals voluntarily seek professional help? In a survey, most audiologists (208 out of 209) responded that they see at least one normal-hearing patient per month who report significant communication difficulties. 7 Therefore, the scale of this issue—hearing difficulty despite normal audiograms—provides the context to discuss potential contributors to HHL through the lens of a clinician. Although possible, it is highly unlikely that the entire population reporting hearing difficulty despite normal audiograms (~ 25 million U.S. adults) have HHL due to a single cause—cochlear synaptopathy. Cochlear synaptopathy offers a robust mechanism for HHL. However, the search for diagnostic markers for synaptopathy in humans is far from over, 8 despite more than a decade-long effort since the first use of the term. 2 Although electrocochleography or auditory brainstem responses have been found to correlate with self-reported noise exposure 9–12 and hearing-in-noise performance, 9,10,13 many others failed to replicate these findings. 14–22 These discrepancies are often complicated by methodological differences among the studies. 22 Further, subtle outer hair cell (OHC) dysfunction despite a normal audiogram could alter compound action potentials 18,19 and, in turn, can confound the diagnosis of cochlear synaptopathy in humans. The observation of synaptopathy is perhaps better described as an animal model of HHL rather than a definitive mechanism for HHL in human patients. It is also likely that synaptopathy coexists with other peripheral damage, which would be difficult to disentangle in humans. Recently, Kohrman et al. 23 summarized two other mechanisms of HHL: cochlear demyelination and subclinical hair cell dysfunction. Here, we focus on the less popular yet (likely) more prevalent source—cochlear OHC dysfunction—of hidden hearing loss, specifically in humans. OUTER HAIR CELL DYSFUNCTION AND HHL Several recent studies provide evidence for OHC dysfunction as a potential mechanism for HHL. 18,19,24,25 Hoben et al. 19 showed altered distortion product otoacoustic emissions (DPAOEs) in adults with clinically normal hearing (< 25 dB HL) but with slightly elevated high-frequency thresholds (16-25 dB HL; 1-4 kHz). Further, the DPOAE outcomes significantly correlated with speech-in-noise recognition scores. In contrast, the compound action potential amplitude was unaffected and did not predict speech-in-quiet or speech-in-noise performance when controlled for the OHC function. These results demonstrate that OHC dysfunction could contribute to HHL. In a follow-up study, Parker 18 reported that individuals with normal hearing may exhibit hearing-in-noise difficulties, and their difficulties are primarily determined by the OHC function rather than the auditory nerve function. Some individuals with normal audiograms may have subclinical OHC dysfunction. Recently, Mishra et al. 26 demonstrated that DPOAEs measured for the 2-5 kHz region were absent in one-third of the EHF-impaired ears (20/60) despite normal thresholds in the standard audiometric frequencies (0.25 through 8 kHz). When DPOAEs were present, the magnitudes were significantly lower (effect size = medium) for adults with elevated EHF thresholds but normal audiograms ( 20 dB HL). Besides, individuals with higher EHF thresholds performed relatively poorly on a speech-in-noise task (effect size = small) regardless of the normal audiogram. These results suggests that EHF impairment, potentially due to basal cochlear damage, is associated with subtle OHC deficits in the lower frequencies, where hearing thresholds are normal and may lead to speech-in-noise deficits. Figure 1, based on the data from Mishra et al., 26 shows the audiogram, DPOAEs, and speech-in-noise performance for the elevated EHF hearing and the control groups; both had normal audiograms. Similar findings have been reported using chirp-evoked-OAEs and DPOAEs for children with normal audiograms yet elevated EHF thresholds. 25 Elevated EHF thresholds may be a reasonable proxy of far basal OHC damage and could be a sign of HHL in individuals with normal audiograms. In fact, Bharadwaj et al. 27 argue that high-frequency OHC damage could occur concurrently with cochlear synaptopathy in lower-frequency regions, although experimental evidence supporting this notion in humans is not direct. Also lacking is the evidence for cochlear synaptopathy in the absence of impaired EHF hearing. It is probable that cochlear synaptopathy precedes subtle OHC dysfunction; however, this hypothesis remains to be tested. Subtle OHC insults may manifest as slightly elevated high-frequency or EHF thresholds. 19,24,25 Individuals with such deficits have significantly lower DPOAEs in the standard frequencies and poorer speech-in-noise performance, 26 and some may have altered cochlear tuning. 28 Remarkably, these effects can be observed for a group of adults with a mean pure-tone average of 9 dB HL (SD = 3) for standard frequencies. 26 Since these subtle deficits cannot be detected using a standard audiogram even with a stricter criterion of normal hearing for adults (20 instead of 25 dB HL, or even 15 dB HL), these findings are suggestive of the OHC origin of some forms of HHL. ESTIMATES OF OHC-RELATED HHL Several claims of a high prevalence of HHL are in the literature without empirical evidence. Unlike other forms of HHL, HHL due to OHC dysfunction—manifested as elevated EHF thresholds—is widespread among young adults with normal audiograms and can be easily identified. Estimates of EHF loss vary between 19 to 56% among young adults with normal audiograms (42 out of 222 in Mishra et al. 26 and 44 out of 78 in Motlagh Zadeh at al. 29). Interestingly, 25 out of 39 (64%) adults with self-reported hearing difficulty had elevated EHF thresholds even when the mean pure-tone average for audiometric frequencies was less than 10 dB HL. 29 Likewise, Mishra et al. 26 found that 10 out of 42 (24%) individuals with EHF impairment but normal audiograms had measurable deficits in speech-in-noise recognition. HHL IN CHILDREN To date, not a single study addressed HHL in children, perhaps partly due to the inadvertent assumption that noise-induced synaptic damage is exclusive to adults. If a relatively lesser degree or moderate levels of noise exposure can cause synaptopathy in humans, then children should also develop synaptopathy because their acoustic environment is nearly as noisy as adults. 30–32 However, given that compelling evidence for synaptopathy in humans is non-existent, we argue, based on our recent findings 24 and others 25 that subtle OHC dysfunction associated with elevated EHF hearing undetected in a standard audiogram illustrates an example of HHL in children. LOOKING FORWARD There could be multiple pathophysiology of HHL, just like those of sensory neural hearing loss. The view that OHC dysfunction can contribute to the pathogenesis of HHL provides an opportunity for exploring diagnostic tools to distinguish different forms of HHL. The differential diagnosis of HHL will stimulate the research for pharmacological intervention. However, further exploration of the OHC origins of HHL in humans, including children, is necessary and probably rewarding.