The possibility of cochlear synaptopathy in young people using a personal listening device.

OBJECTIVE: To evaluate the association of listening to music loudly through personal listening devices with cochlear synaptopathy in young adults. METHODS: Fifty healthy young adults selected among 109 volunteers were included in the study. Participants of high risk (n=25) and low risk (n=25) groups estimated according to ETDNL (estimated total daily noise level) were evaluated using pure tone audiometry, tympanometry, matrix test, electrocochleography (EcochG) and auditory brainstem response (ABR) to evaluate the occurrence of cochlear synaptopathy. RESULTS: Audiometric thresholds between the groups were not significantly different (p>0.05). High risk group participants showed poorer performance than the low-risk group on the TurMatrix test, in non-adaptive noise with -5 SNR and -7.5 SNR, and at the 50% understanding SNR level with headphones (p<0.01). There was no difference in the adaptive free field in noise test at which 50% understanding was achieved (p>0.05). The AP amplitudes on EcochG and wave V amplitudes on ABR were significantly smaller in the high-risk group (p<0.05). There was no association between ETDNL and I/V ratio on ABR. CONCLUSION: Poorer performance in TurMatrix and other electrophysiologic tests revealed the negative effect of personal listening devices on the auditory system. Our findings support the hypothesis that personal listening devices could cause cochlear synaptopathy. Long-term studies are needed to determine the effects of binaural hearing and duration of noise exposure on the auditory system.

Drug development for noise-induced hearing loss.

INTRODUCTION: Excessive exposure to noise is a common occurrence that contributes to approximately 50% of the non-genetic hearing loss cases. Researchers need to develop standardized preclinical models and identify molecular targets to effectively develop prevention and curative therapies. AREAS COVERED: In this review, the authors discuss the many facets of human noise-induced pathology, and the primary experimental models for studying the basic mechanisms of noise-induced damage, making connections and inferences among basic science studies, preclinical proofs of concept and clinical trials. EXPERT OPINION: Whilst experimental research in animal models has helped to unravel the mechanisms of noise-induced hearing loss, there are often methodological variations and conflicting results between animal and human studies which make it difficult to integrate data and translate basic outcomes to clinical practice. Standardization of exposure paradigms and application of -omic technologies will contribute to improving the effectiveness of transferring newly gained knowledge to clinical practice.

The mechanoelectrical transducer channel is not required for regulation of cochlear blood flow during loud sound exposure in mice.

The mammalian cochlea possesses unique acoustic sensitivity due to a mechanoelectrical 'amplifier', which requires the metabolic support of the cochlear lateral wall. Loud sound exposure sufficient to induce permanent hearing damage causes cochlear blood flow reduction, which may contribute to hearing loss. However, sensory epithelium involvement in the cochlear blood flow regulation pathway is not fully described. We hypothesize that genetic manipulation of the mechanoelectrical transducer complex will abolish sound induced cochlear blood flow regulation. We used salsa mice, a Chd23 mutant with no mechanoelectrical transduction, and deafness before p56. Using optical coherence tomography angiography, we measured the cochlear blood flow of salsa and wild-type mice in response to loud sound (120 dB SPL, 30 minutes low-pass filtered noise). An expected sound induced decrease in cochlear blood flow occurred in CBA/CaJ mice, but surprisingly the same sound protocol induced cochlear blood flow increases in salsa mice. Blood flow did not change in the contralateral ear. Disruption of the sympathetic nervous system partially abolished the observed wild-type blood flow decrease but not the salsa increase. Therefore sympathetic activation contributes to sound induced reduction of cochlear blood flow. Additionally a local, non-sensory pathway, potentially therapeutically targetable, must exist for cochlear blood flow regulation.

Associations between speech recognition at high levels, the middle ear muscle reflex and noise exposure in individuals with normal audiograms.

It has been hypothesized that noise-induced cochlear synaptopathy in humans may result in functional deficits such as a weakened middle ear muscle reflex (MEMR) and degraded speech perception in complex environments. Although relationships between noise-induced synaptic loss and the MEMR have been demonstrated in animals, effects of noise exposure on the MEMR have not been observed in humans. The hypothesized relationship between noise exposure and speech perception has also been difficult to demonstrate conclusively. Given that the MEMR is engaged at high sound levels, relationships between speech recognition in complex listening environments and noise exposure might be more evident at high speech presentation levels. In this exploratory study with 41 audiometrically normal listeners, a combination of behavioral and physiologic measures thought to be sensitive to synaptopathy were used to determine potential links with speech recognition at high presentation levels. We found decreasing speech recognition as a function of presentation level (from 74 to 104 dBA), which was associated with reduced MEMR magnitude. We also found that reduced MEMR magnitude was associated with higher estimated lifetime noise exposure. Together, these results suggest that the MEMR may be sensitive to noise-induced synaptopathy in humans, and this may underlie functional speech recognition deficits at high sound levels.

Noise: Acoustic Trauma to the Inner Ear.

Cochlear damage is often thought to result in hearing thresholds shift, whether permanent or temporary. The report of tinnitus in the absence of any clear deficit in cochlear function was believed to indicate that hearing loss and tinnitus, while comorbid, could arise independently from each other. In all likelihood, tinnitus that is not of central nervous system origin is associated with hearing loss. As a correlate, although a treatment of most forms of tinnitus will likely emerge in the years to come, curing tinnitus will first require curing hearing loss.

Effect of hyperbaric oxygen therapy and corticosteroid therapy in military personnel with acute acoustic trauma.

INTRODUCTION: Acute acoustic trauma (AAT) is a sensorineural hearing impairment due to exposure to an intense impulse noise which causes cochlear hypoxia. Hyperbaric oxygen therapy (HBO) could provide an adequate oxygen supply. The aim was to investigate the effectiveness of early treatment with combined HBO and corticosteroid therapy in patients with AAT compared with corticosteroid monotherapy. METHODS: A retrospective study was performed on military personnel diagnosed with AAT between November 2012 and December 2017. Inclusion criteria for HBO therapy were hearing loss of 30 dB or greater on at least one, 25 dB or more on at least two, or 20 dB or more on three or more frequencies as compared with the contralateral ear. RESULTS: Absolute hearing improvements showed significant differences (independent t-test) between patients receiving HBO and the control group at 500 Hz (p=0.014), 3000 Hz (p=0.023), 4000 Hz (p=0.001) and 6000 Hz (p=0.01) and at the mean of all frequencies (p=0.002). Relative hearing improvements were significantly different (independent t-test) at 4000 Hz (p=0.046) and 6000 Hz (p=0.013) and at all frequencies combined (p=0.005). Furthermore, the percentage of patients with recovery to the functional level required by the Dutch Armed Forces (clinical outcome score) was higher in the HBO group. CONCLUSIONS: Early-stage combination therapy for patients with AAT was associated with better audiometric results at higher frequencies and better clinical outcome score.

Long-term evidence of noise-induced permanent threshold shift in a harbor seal (Phoca vitulina).

In psychophysical studies of noise-induced hearing loss with marine mammals, exposure conditions are often titrated from levels of no effect to those that induce significant but recoverable loss of auditory sensitivity [temporary threshold shift (TTS)]. To examine TTS from mid-frequency noise, a harbor seal was exposed to a 4.1-kHz underwater tone that was incrementally increased in sound pressure level (SPL) and duration. The seal's hearing was evaluated at the exposure frequency and one-half octave higher (5.8 kHz) to identify the noise parameters associated with TTS onset. No reliable TTS was measured with increasing sound exposure level until the second exposure to a 60-s fatiguing tone of 181 dB re 1 µPa SPL (sound exposure level 199 dB re 1 µPa2s), after which an unexpectedly large threshold shift (>47 dB) was observed. While hearing at 4.1 kHz recovered within 48 h, there was a permanent threshold shift of at least 8 dB at 5.8 kHz. This hearing loss was evident for more than ten years. Furthermore, a residual threshold shift of 11 dB was detected one octave above the tonal exposure, at 8.2 kHz. This hearing loss persisted for more than two years prior to full recovery.

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

People with normal hearing thresholds can nonetheless have difficulty with understanding speech in noisy backgrounds. The origins of such supra-threshold hearing deficits remain largely unclear. Previously we showed that the auditory brainstem response to running speech is modulated by selective attention, evidencing a subcortical mechanism that contributes to speech-in-noise comprehension. We observed, however, significant variation in the magnitude of the brainstem's attentional modulation between the different volunteers. Here we show that this variability relates to the ability of the subjects to understand speech in background noise. In particular, we assessed 43 young human volunteers with normal hearing thresholds for their speech-in-noise comprehension. We also recorded their auditory brainstem responses to running speech when selectively attending to one of two competing voices. To control for potential peripheral hearing deficits, and in particular for cochlear synaptopathy, we further assessed noise exposure, the temporal sensitivity threshold, the middle-ear muscle reflex, and the auditory-brainstem response to clicks in various levels of background noise. These tests did not show evidence for cochlear synaptopathy amongst the volunteers. Furthermore, we found that only the attentional modulation of the brainstem response to speech was significantly related to speech-in-noise comprehension. Our results therefore evidence an impact of top-down modulation of brainstem activity on the variability in speech-in-noise comprehension amongst the subjects.

The TLR-4/NF-κB signaling pathway activation in cochlear inflammation of rats with noise-induced hearing loss.

The TLR-4/NF-κB signaling pathway is involved in innate immunity and inflammation induced by trauma. The present study aimed to investigate possible TLR-4/NF-κB signaling pathway activation in the cochlea associated with acoustic trauma that might induce cochlear inflammation. A total of 72 rats were exposed to white noise at 120 dB SPL for 8 h per day repeated over 2 successive days. Auditory brainstem responses (ABR) were measured in animals before noise exposure and 0 d (PE0), 1 d (PE1), 3 d (PE3), 7 d (PE7), and 14 d (PE14) after noise exposure. At each defined time point, animals were sacrificed, and cochleae were collected to evaluate the expression levels of TLR4, MyD88, cytoplasmic NF-κB p65, IκBα, TNF-α, and IL-1ß using western blotting and NF-κB p65 transcriptional activity using an NF-κB p65 Transcription Factor Assay Kit. Cochlear localizations of TLR-4, TNF-α and IL-1ß were analyzed using immunohistochemistry in paraffin-embedded slices. The nuclear translocation of NF-κB p65 was evaluated using immunofluorescence staining in paraffin-embedded slices. DNA fragmentation was measured with a TUNEL assay in paraffin-embedded slices. We found a stable permanent threshold shift after noise exposure. After noise exposure, expression levels of TLR-4, MyD88, IκBα, TNF-α, and IL-1ß were significantly upregulated (PE3); DNA binding activity of NF-κB p65 was also significantly enhanced (PE3), while the cytoplasmic NF-κB p65 levels were unchanged. TLR-4, TNF-α, and IL-1ß immunostaining intensities were substantially enhanced in spiral ganglion cells and spiral ligament fibrocytes after noise exposure (PE3). In conclusion, the results of this study indicate that the TLR-4/NF-κB signaling pathway is activated in noise-exposed cochleae and that it participates in noise-induced cochlear inflammation.

Hearing differences in Hartley guinea pig stocks from two breeders.

Across the world, dozens of outbred Hartley guinea pig stocks are used for auditory experiments. The genetic makeup of these different stocks will differ due to differences in breeding protocols, history and genetic drift. In fact, outbred breeding protocols are not intended to produce genetically identical animals, neither across breeders, nor across time. For this reason, it is unclear how reproducible experimental results are likely to be using animals from different stocks. We evaluated the consistency of cochlear function using both clicks and tones in Hartley guinea pigs as a function of breeder (Kuiper and Charles River) and sex using archival Auditory Brain Stem Response (ABR) data and tissue from our own laboratory. Sound levels required to reach baseline threshold for click-induced ABRs were similar between male Charles River and male Kuiper guinea pig stocks. However, the median and average thresholds after exposure to high level noise were larger in the Kuiper population than in the Charles River population with corresponding threshold shifts higher in the Kuiper than in the Charles River animals. We evaluated the relationship between pure-tone thresholds and sex, age, breeder stock, left or right cochleas, weight and 5 test frequencies before and after noise exposure using a linear mixed statistical model. Across all frequencies, the effect of breeder on baseline threshold is statistically significant, with effect sizes most pronounced at the lower frequencies before exposure to noise. After noise exposure, the differences are minimal in the model, indicating that differences in threshold shift are chiefly due to differences in initial baseline hearing. However, a contingency calculation comparing response/no response at the highest speaker output at 32 kHz gave a statistically significant difference between the stocks: 28% of Kuiper cochleas responded to the highest output of the speaker as compared with 71.4% of Charles River cochleas, indicating that noise exposure induced a larger threshold shift in a greater proportion of Kuiper animals. Using our archival cochlear tissue from these studies, we confirmed the sex of each animal by PCR, then compared males and females of the Kuiper stock. Across all baseline frequencies, the effect of sex on threshold is statistically significant, with no noticeable difference after exposure. The effect sizes for baseline thresholds are most pronounced at lower frequencies. These data demonstrate that Hartley guinea pig stocks from different breeders are not uniform in their auditory characteristics, and that due to these differences, results and conclusions can differ among laboratories. Moreover, within a single stock, males and females can provide different data, confirming that male and female animals must be individually evaluated in any auditory protocol.

Circadian integration of inflammation and glucocorticoid actions: Implications for the cochlea.

Auditory function has been shown to be influenced by the circadian system. Increasing evidence point towards the regulation of inflammation and glucocorticoid actions by circadian rhythms in the cochlea. Yet, how these three systems (circadian, immune and endocrine) converge to control auditory function remains to be established. Here we review the knowledge on immune and glucocorticoid actions, and how they interact with the circadian and the auditory system, with a particular emphasis on cochlear responses to noise trauma. We propose a multimodal approach to understand the mechanisms of noise-induced hearing loss by integrating the circadian, immune and endocrine systems into the bearings of the cochlea. Considering the well-established positive impact of chronotherapeutic approaches in the treatment of cardiovascular, asthma and cancer, an increased knowledge on the mechanisms where circadian, immune and glucocorticoids meet in the cochlea may improve current treatments against hearing disorders.

Attenuation of adverse effects of noise induced hearing loss on adult neurogenesis and memory in rats by intervention with Adenosine A2A receptor agonist.

Hearing loss and cognitive decline are commonly associated with aging and morbidity. Present clinical interest lies in whether peripheral hearing loss promotes cognitive decline and if prophylaxis with selective adenosine receptor agonist CGS21680 effectively mitigates the adverse effects. In the current study, male Sprague Dawley rats weighing 200-250 g m were randomly allocated into three groups: Group 1) rats exposed to 100 dB SPL white noise, 2 h a day for 15 consecutive days, 2) rats supplemented with an adenosine receptor agonist, CGS21680 at 100 µg/kg/day prior to noise exposure and 3) unexposed control rats. Baseline hearing and cognition assessed by auditory brainstem response (ABR) and water maze respectively was undertaken for all the groups. Phalloidin stain and synaptic ribbons count in cochlea, and, Ki67, DCX and NeuN in hippocampus were observed by immunohistochemistry. It was inferred that noise exposed rats showed elevated thresholds of ABR and poorer performances in spatial working memory when compared with controls. On the contrary, CGS21680 administered group exhibited improved ABR and cognitive functions with shorter mean latency and path-length to reach the platform, significant reduction in the noise induced loss of synaptic ribbons count and increased number of Ki67 and doublecortin (DCX) positive cells compared to their noise exposed counterparts. Pharmacologic intervention with selective A2A receptor agonist CGS21680 provided adequate protection from noise by effectively maintaining hearing threshold levels, cell viability in cochlea and hippocampus & functional/intact reference memory.

Enhanced Central Neural Gain Compensates Acoustic Trauma-induced Cochlear Impairment, but Unlikely Correlates with Tinnitus and Hyperacusis.

For successful future therapeutic strategies for tinnitus and hyperacusis, a subcategorization of both conditions on the basis of differentiated neural correlates would be of invaluable advantage. In the present study, we used our refined operant conditioning animal model to divide equally noise-exposed rats into groups with either tinnitus or hyperacusis, with neither condition, or with both conditions co-occurring simultaneously. Using click stimulus and noise burst-evoked Auditory Brainstem Responses (ABR) and Distortion Product Otoacoustic Emissions, no hearing threshold difference was observed between any of the groups. However, animals with neither tinnitus nor hyperacusis responded to noise trauma with shortened ABR wave I and IV latencies and elevated central neuronal gain (increased ABR wave IV/I amplitude ratio), which was previously assumed in most of the literature to be a neural correlate for tinnitus. In contrast, animals with tinnitus had reduced neural response gain and delayed ABR wave I and IV latencies, while animals with hyperacusis showed none of these changes. Preliminary studies, aimed at establishing comparable non-invasive objective tools for identifying tinnitus in humans and animals, confirmed reduced central gain and delayed response latency in human and animals. Moreover, the first ever resting state functional Magnetic Resonance Imaging (rs-fMRI) analyses comparing humans and rats with and without tinnitus showed reduced rs-fMRI activities in the auditory cortex in both patients and animals with tinnitus. These findings encourage further efforts to establish non-invasive diagnostic tools that can be used in humans and animals alike and give hope for differentiated classification of tinnitus and hyperacusis.

Avocado Oil Extract Modulates Auditory Hair Cell Function through the Regulation of Amino Acid Biosynthesis Genes.

Sensorineural hearing loss (SNHL) is one of the most common causes of disability, affecting over 466 million people worldwide. However, prevention or therapy of SNHL has not been widely studied. Avocado oil has shown many health benefits but it has not yet been studied in regards to SNHL. Therefore, we aimed to investigate the efficacy of avocado oil on SNHL in vitro and in vivo and elucidate its mode of action. For the present study, we used enhanced functional avocado oil extract (DKB122). DKB122 led to recovery of otic hair cells in zebrafish after neomycin-induced otic cell damage. Also, DKB122 improved auditory sensory transmission function in a mouse model of noise induced-hearing loss and protected sensory hair cells in the cochlea. In addition, RNA sequencing was performed to elucidate the mechanism involved. KEGG pathway enrichment analysis of differentially expressed genes showed that DKB122 protected House Ear Institute-Organ of Corti 1 (HEI-OC1) cells against neomycin-related alterations in gene expression due to oxidative stress, cytokine production and protein synthesis.

Acoustic Middle-Ear-Muscle-Reflex Thresholds in Humans with Normal Audiograms: No Relations to Tinnitus, Speech Perception in Noise, or Noise Exposure.

The acoustic middle-ear-muscle reflex (MEMR) has been suggested as a sensitive non-invasive measure of cochlear synaptopathy, the loss of synapses between inner hair cells and auditory nerve fibers. In the present study, clinical MEMR thresholds were measured for 1-, 2-, and 4-kHz tonal elicitors, using a procedure shown to produce thresholds with excellent reliability. MEMR thresholds of 19 participants with tinnitus and normal audiograms were compared to those of 19 age- and sex-matched controls. MEMR thresholds did not differ significantly between the two groups at any frequency. These 38 participants were included in a larger sample of 70 participants with normal audiograms. For this larger group, MEMR thresholds were compared to a measure of spatial speech perception in noise (SPiN) and a detailed self-report estimate of lifetime noise exposure. MEMR thresholds were unrelated to either SPiN or noise exposure, despite a wide range in both measures. It is possible that thresholds measured using a clinical paradigm are less sensitive to synaptopathy than those obtained using more sophisticated measurement techniques; however, we had good sensitivity at the group level, and even trends in the hypothesized direction were not observed. To the extent that MEMR thresholds are sensitive to cochlear synaptopathy, the present results provide no evidence that tinnitus, SPiN, or noise exposure are related to synaptopathy in the population studied.

Use of non-invasive measures to predict cochlear synapse counts.

Cochlear synaptopathy, the loss of synaptic connections between inner hair cells (IHCs) and auditory nerve fibers, has been documented in animal models of aging, noise, and ototoxic drug exposure, three common causes of acquired sensorineural hearing loss in humans. In each of these models, synaptopathy begins prior to changes in threshold sensitivity or loss of hair cells; thus, this underlying injury can be hidden behind a normal threshold audiogram. Since cochlear synaptic loss cannot be directly confirmed in living humans, non-invasive assays will be required for diagnosis. In animals with normal auditory thresholds, the amplitude of wave 1 of the auditory brainstem response (ABR) is highly correlated with synapse counts. However, synaptopathy can also co-occur with threshold elevation, complicating the use of the ABR alone as a diagnostic measure. Using an age-graded series of mice and a partial least squares regression approach to model structure-function relationships, this study shows that the combination of a small number of ABR and distortion product otoacoustic emission (DPOAE) measurements can predict synaptic ribbon counts at various cochlear frequencies to within 1-2 synapses per IHC of their true value. In contrast, the model, trained using the age-graded series of mice, overpredicted synapse counts in a small sample of young noise-exposed mice, perhaps due to differences in the underlying pattern of damage between aging and noise-exposed mice. These results provide partial validation of a noninvasive approach to identify synaptic/neuronal loss in humans using ABRs and DPOAEs.

Little evidence for a chronotolerance effect for impulse noise exposure in the C57BL/6J mouse.

Noise-induced hearing loss affects a large number of adults and children worldwide, and continues to be a major public health problem. The cochlea is an organ that maintains delicate metabolic homeostasis and precise mechanical architecture. Disruption of either can cause temporary or permanent injury. Impulse noises, which are short-duration, high-level bursts of sound caused by explosions, such as gunfire, can injure the cochlea through combinations of mechanical and metabolic injury. Susceptibility to the metabolic component of noise injury may vary with the circadian rhythm, a phenomenon known as chronotolerance. Chronotolerance to noise injury has been demonstrated for a one-hour noise exposure at a fixed level, but chronotolerance for impulse noise-induced hearing loss has never been studied. Forty-four mice were exposed to 500 short-duration clicks at 137 dB peSPL at one of four hours after light onset: 2, 8, 14, or 20. Auditory brainstem response threshold shifts were measured at 3, 7, and 21 days after the exposure to measure hearing loss, and post mortem outer hair cell counts were used to confirm cochlear injury. The testing revealed no significant differences between the four exposure times for hearing threshold shifts, but did detect a small, but statistically significant, difference in outer hair cell loss, in which the loss was greatest for the mice exposed two hours after light offset. Therefore, a weak chronotolerance effect for impulse noise was detected, though the functional significance of the effect is low. Further investigation is required to more fully understand the relationship between circadian rhythm and hearing loss from different types of noise exposure.

Effects of lifetime noise exposure on the middle-age human auditory brainstem response, tinnitus and speech-in-noise intelligibility.

Recent animal studies have shown that the synapses between inner hair cells and the dendrites of the spiral ganglion cells they innervate are the elements in the cochlea most vulnerable to excessive noise exposure. Particularly in rodents, several studies have concluded that exposure to high level octave-band noise for 2 h leads to an irreversible loss of around 50% of synaptic ribbons, leaving audiometric hearing thresholds unaltered. Cochlear synaptopathy following noise exposure is hypothesized to degrade the neural encoding of sounds at the subcortical level, which would help explain certain listening-in-noise difficulties reported by some subjects with otherwise 'normal' hearing. In response to this peripheral damage, increased gain of central stages of the auditory system has been observed across several species of mammals, particularly in association with tinnitus. The auditory brainstem response (ABR) wave I amplitude and waves I-V amplitude ratio have been suggested as non-invasive indicators of cochlear synaptopathy and central gain activation respectively, but the evidence for these hearing disorders in humans is inconclusive. In this study, we evaluated the influence of lifetime noise exposure (LNE) on the human ABR and on speech-in-noise intelligibility performance in a large cohort of adults aged 29 to 55. Despite large inter-subject variability, results showed a moderate, but statistically significant, negative correlation between the ABR wave I amplitude and LNE, consistent with cochlear synaptopathy. The results also showed (a) that central gain mechanisms observed in animal studies might also occur in humans, in which higher stages of the auditory pathway appear to compensate for reduced input from the cochlea; (b) that tinnitus was associated with activation of central gain mechanisms; (c) that relevant cognitive and subcortical factors influence speech-in-noise intelligibility, in particular, longer ABR waves I-V interpeak latencies were associated with poorer performance in understanding speech in noise when central gain mechanisms were active; and (d) absence of a significant relationship between LNE and tinnitus, central gain activation or speech-in-noise performance. Although this study supports the possible existence of cochlear synaptopathy in humans, the great degree of variability, the lack of uniformity in central gain activation and the significant involvement of attention in speech-in-noise performance suggests that noise-induced cochlear synaptopathy is, at most, one of several factors that play a role in humans' speech-in-noise performance.

Impaired speech perception in noise with a normal audiogram: No evidence for cochlear synaptopathy and no relation to lifetime noise exposure.

In rodents, noise exposure can destroy synapses between inner hair cells and auditory nerve fibers ("cochlear synaptopathy") without causing hair cell loss. Noise-induced cochlear synaptopathy usually leaves cochlear thresholds unaltered, but is associated with long-term reductions in auditory brainstem response (ABR) amplitudes at medium-to-high sound levels. This pathophysiology has been suggested to degrade speech perception in noise (SPiN), perhaps explaining why SPiN ability varies so widely among audiometrically normal humans. The present study is the first to test for evidence of cochlear synaptopathy in humans with significant SPiN impairment. Individuals were recruited on the basis of self-reported SPiN difficulties and normal pure tone audiometric thresholds. Performance on a listening task identified a subset with "verified" SPiN impairment. This group was matched with controls on the basis of age, sex, and audiometric thresholds up to 14 kHz. ABRs and envelope-following responses (EFRs) were recorded at high stimulus levels, yielding both raw amplitude measures and within-subject difference measures. Past exposure to high sound levels was assessed by detailed structured interview. Impaired SPiN was not associated with greater lifetime noise exposure, nor with any electrophysiological measure. It is conceivable that retrospective self-report cannot reliably capture noise exposure, and that ABRs and EFRs offer limited sensitivity to synaptopathy in humans. Nevertheless, the results do not support the notion that noise-induced synaptopathy is a significant etiology of SPiN impairment with normal audiometric thresholds. It may be that synaptopathy alone does not have significant perceptual consequences, or is not widespread in humans with normal audiograms.

Evidence of noise-induced subclinical hearing loss using auditory brainstem responses and objective measures of noise exposure in humans.

Exposure to loud sound places the auditory system at considerable risk, especially when the exposure is routine. The current study examined the impact of routine auditory overexposure in young human adults with clinically-normal audiometric thresholds by measuring the auditory brainstem response (ABR), an electrophysiological measure of peripheral and central auditory processing. Sound exposure was measured objectively with body-worn noise dosimeters over a week. Participants were divided into low-exposure and high-exposure groups, with the low-exposure group having an average daily noise exposure dose of ∼11% of the recommended exposure limit compared to the high-exposure group average of nearly 500%. Compared to the low-exposure group, the high-exposure group had delayed ABRs to suprathreshold click stimuli and this prolongation was evident at ABR waves I and III but strongest for V. When peripheral differences were corrected using the I-V interpeak latency, the high-exposure group showed greater taxation at faster stimulus presentation rates than the low-exposure group, suggestive of neural conduction inefficiencies within central auditory structures. Our findings are consistent with the hypothesis that auditory overexposure affects peripheral and central auditory structures even before changes are evident on standard audiometry. We discuss our findings within the context of the larger debate on the mechanisms and manifestations of subclinical hearing loss.