It is well known that two people with the same audiogram, whether normal or abnormal, can have different speech discrimination abilities, especially in noisy environments (J Am Acad Audiol. 2012;23:779 http://bit.ly/2ooFzi2). The contribution of cochlear neurodegeneration to this difference in impairment has always been a logical possibility. However, recent research on animals has led to the novel idea that massive deafferentation of surviving inner hair cells (IHCs) may be the rule rather than the exception in acquired sensorineural hearing loss (SNHL), and that significant hair cell deafferentation occurs well before elevation of audiometric thresholds in the noise-exposed ear (Hear Res. 2015;330[Pt B]:191 http://bit.ly/2ooLO5o).
COCHLEAR SYNAPTOPATHY PRECEDES HAIR CELL LOSS
Decades of research on noise-exposed humans and animals have shown that acoustic overexposure leads to hair cell damage, which causes threshold elevation, degraded frequency tuning, and loss of critical cochlear nonlinearities. The general consensus has been that hair cells are the most vulnerable elements to noise and that cochlear neurons only die as a result of hair cell degeneration. According to this view: (1) cochlear neuropathy is a delayed downstream consequence of noise-induced hair cell loss, and (2) an exposure that causes a temporary threshold elevation is benign because there is no permanent impairment. This assumption underlies the damage-risk criteria for workplace noise set by several federal agencies.
Recent animal studies suggest otherwise. Noise exposure can lead to cochlear neuronal degeneration, even when hair cells are preserved and thresholds recover (J Neurosci. 2009;29:14077 http://bit.ly/2geeElv). In a noise-exposed ear showing no acute or chronic hair cell loss, there can be up to 50 percent loss of synapses between IHCs and cochlear neurons. The same primary loss of cochlear synapses occurs in the aging ear (Hear Res. 2015 http://bit.ly/2ooLO5o). This primary cochlear neuropathy has remained “hidden” because (1) the synapse between the nerve and the IHC is invisible when histological material is studied under a traditional optical microscope, (2) the subsequent loss of spiral ganglion cells that can be studied with a light microscope occurs years or decades later, and (3) the diffuse neural degeneration does not elevate behavioral or electrophysiological thresholds until it becomes extreme (Hear Res. 2013;302:113 http://bit.ly/2ooNSKB). Part of the reason for the relative insensitivity of threshold measures to primary neuropathy is that the most vulnerable cochlear neurons, to both noise and aging, are those with high thresholds and low spontaneous rates (SRs; J Neurophysiol. 1996;76:2799 http://bit.ly/2ooGJKD). These low-SR fibers do not contribute to threshold detection in quiet, but, by virtue of their elevated thresholds, are key to the coding of transient stimuli in the presence of continuous background noise that saturates the responses of the sensitive high-SR fibers. Together, these new findings suggest that low-SR neuropathy could be a major contributor to the classic impairment in noise-induced hearing loss (NIHL), i.e., poor speech discrimination in difficult listening environments. It also may be important in limiting psychophysical performance among “normal-hearing” human listeners. Indeed, deficits in binaural temporal processing, seen as a decrease in detectability of interaural phase differences in amplitude-modulated tones, are highly correlated with changes in auditory brainstem responses (ABRs) consistent with selective loss of low-SR fibers. Cochlear synaptopathy may also be key to the genesis of other perceptual anomalies of SNHL, including hyperacusis and tinnitus, via an induction of central gain adjustment secondary to loss of afferent input to the auditory CNS. Indeed, several human studies report that auditory brainstem responses (ABRs) from subjects with tinnitus tend to have reduced wave I amplitude (cochlear nerve response) and enhanced wave V amplitude (generated in the auditory CNS), compared with non-tinnitus sufferers with matched and normal audiograms (J Neurophysiol. 2010;104:3361 http://jn.physiology.org/content/104/6/3361.long).
MEASURING COCHLEAR SYNAPTOPATHY IN HUMANS
In animal studies on noise and aging, cochlear synaptopathy has been diagnosed by suprathreshold amplitude of ABR wave I, the summed activity of cochlear neurons (J Neurosci. 2009 http://bit.ly/2geeElv). This correspondence is only straightforward if uncomplicated by hair cell damage, since disruption of mechano-electric transduction will also reduce ABR amplitudes. The robustness of this correlation in mouse is enhanced by genetic homogeneity and low inter-subject variability. In humans, inter-subject variability in ABR amplitude, due to heterogeneity in head shape/size, tissue conductivity, etc., likely complicates its diagnostic utility.
In a recent pilot study, we hypothesized that variability could be reduced by recording from a site closer to the generators (i.e., tiptrodes in the ear canal) and normalizing ABR wave I (also known as AP) to the hair cell-generated summating potential (SP; PLoS One. 2016;11:e0162726 http://bit.ly/2gefP46). We measured SP/AP ratios in normal-hearing young adults with widely varying ear abuse, including music students who practice and perform in ensembles for hours daily without ear protection, and audiology students, who understand the risks of acoustic overexposure and tend to avoid it. We separated subjects into two groups based on their use of hearing protection devices and compared audiograms, electrocochleography, and word recognition scores. Although group thresholds were perfectly matched at standard audiometric frequencies, our “high-risk” group showed significant threshold elevation at high frequencies (>8 kHz), consistent with early signs of noise damage. Word recognition scores were excellent in quiet for both groups, but with added noise or time compression and reverberation, significant performance decrements emerged in the expected direction. We obtained robust SP and AP recordings from all subjects, and observed a significant intergroup difference in SP/AP ratios, as well as a significant correlation between SP/AP ratio and word recognition performance, both in the predicted direction. We were surprised to see an enhanced SP along with the reduced AP, but noise-induced SP enhancement has been reported in a prior human study (see PLoS One. 2016 http://bit.ly/2gefP46 for further discussion of SP enhancement).
The increased SP/AP ratio strongly supports the idea that peripheral pathology is associated with differences in word recognition performance among normal-hearing young people. Our pilot study further suggests that noise exposure may be a root cause. However, the pilot was small (n=34). Future large-scale investigations will require assessment of noise exposure based on a more rigorous and exhaustive questionnaire, confirmed directly through noise dosimetry. Furthermore, the possible contribution of basal-turn hair cell damage to the test battery results (high-frequency threshold elevation) must also be more rigorously evaluated. In addition, the test battery needs to be expanded to include other tests, which recent animal studies or others’ theoretical considerations suggest that there might be more sensitive metrics of low-SR synaptopathy, including envelope following responses, middle-ear muscle, and medial olivocochlear reflex strength or assays of detection threshold for very short stimuli.
CLASSIC AUDIOLOGICAL TESTS AND HIDDEN HEARING LOSS
The use of ABRs, electrocochleography (SP/AP ratio), and the middle-ear muscle reflex to search for evidence of cochlear synaptopathy highlights the new idea that the variation in audiological test results among people with similar audiograms may represent clinically useful information about the degree of cochlear synaptopathy, rather than simply reflecting inter-subject variability.
Current belief with respect to ABRs has been that suprathreshold amplitudes are not a reliable measure of underlying pathology, in part because two people with normal audiograms can have very different ABR amplitudes. However, when viewed through the lens of hidden hearing loss, the novel interpretation is that some difference in ABR amplitudes is meaningful because it may reflect neuropathy of underlying generators.
The SP/AP ratio has been used to support the diagnosis of Ménière's disease associated with endolymphatic hydrops. We have evidence from both animal and human studies that an enhanced SP/AP ratio may be diagnostic for cochlear synaptopathy. In Ménière's, the altered SP/AP ratio may arise in part because the SP is increased by changes in mechano-electric transduction associated with an enlarged endolymphatic space. However, a reduced AP, due to synaptopathy, may also contribute to Ménière's phenotype (decreased word recognition scores). Indeed, electron microscopic studies showed dramatic deafferentation of IHCs in a case study of unilateral Ménière's (Ann Otol Rhinol Laryngol. 1987;96:449 http://bit.ly/2oouyNW). In that study, about three synapses per IHC were observed in the pathological ear compared with an estimated 12 synapses per IHC in the “normal” ear. Thus, interpretation of the SP/AP ratio and the underlying pathophysiology of Ménière's may be reshaped when hidden hearing loss is factored in.
Finally, the middle-ear muscle (MEM) reflex test was first introduced in the diagnosis of middle-ear pathology. Years later, it was shown that in the absence of conductive hearing loss, the MEM reflex might be useful to assess “retrocochlear pathology” such as vestibular schwannoma and auditory neuropathy. However, its diagnostic power appears limited by the wide range of reflex thresholds and amplitudes in “normal-hearing” people. New data from animal studies suggest that the MEM reflex may be an exceptionally sensitive metric of selective low-SR neuropathy in subjects with normal thresholds (Hear Res. 2016;332:29 http://bit.ly/2ooNHPC).
Establishing diagnostic indicators for cochlear synaptopathy in humans is important if we are to understand the prevalence of primary neural degeneration in clinical and “not-yet-clinical” human populations. Recent animal studies of aging mice show that ear abuse at a young age exacerbates the progression of age-related hearing impairment (Hear Res. 2016 http://bit.ly/2ooNHPC). Thus, early diagnosis is critical to identifying those with “tender ears,” who may already be incurring significant inner ear damage long before there is elevation of standard audiometric thresholds. Furthermore, clarification of the true risks of noise are important to public policy on noise abatement and to raising general awareness of the dangers of ear abuse. Recent animal research suggests that neurotrophin overexpression can elicit synaptogenesis and the regeneration of nerve terminals with inner hair cells in a noise-damaged mouse model. Reconnecting surviving spiral ganglion cells to cochlear hair cells may be on the horizon, as therapies based on local delivery to the round window of neurotrophin can elicit partial hearing recovery (Otol Neurotol. 2016;37:1223 http://bit.ly/2ooOlg2). Characterizing objective measurements of cochlear synaptopathy and defining its time course are key to identifying candidates for future therapies and tracking the efficacy of outcome measures.
Journal Club Highlight
Toward a Differential Diagnosis of Hidden Hearing Loss in Humans
Liberman MC, Epstein MJ, Cleveland SS, Wang H, Maison SF.
PLoS One. 2016 Sep 12;11(9):e0162726. http://bit.ly/2gefP46