Gap detection ability declines with central auditory neurodegeneration following age-related cochlear synaptopathy.

Age-related hearing impairment (ARHI) is commonly associated with decreased auditory temporal resolution caused by auditory neurodegeneration. Age-related deterioration in gap detection ability, resulting in poor temporal auditory processing, is often attributed to pathophysiological changes in both the peripheral and central auditory systems. This study aimed to investigate whether the gap detection ability declines in the early stages of ageing and to determine its usefulness in detecting peripheral and central auditory degeneration. The study used 1-month-old (1 M), 6-month-old (6 M) and 12-month-old (12 M) mice to examine changes in gap detection ability and associated auditory pathophysiology. Although hearing thresholds did not significantly differ between the groups, the amplitude of auditory brainstem response (ABR) wave I decreased significantly in an age-dependent manner, consistent with age-related cochlear synaptopathy. The relative ABR amplitude ratio of waves 2 and 5 to wave 1 was significantly increased in 12 M mice, indicating that the central auditory system had increased in relative neuroactivity. A significant increase in gap detection thresholds was observed in 12 M mice compared to 1 M mice. Although cochlear synaptopathy and central hyperactivity were positively correlated with gap detection thresholds, central hyperactivity strongly influenced gap detection ability. In the cochlear nucleus and auditory cortex, the inhibitory synaptic expression of GAD65 and the expression of parvalbumin were significantly decreased in 12 M mice, consistent with central hyperactivity. Evaluating gap detection performance may allow the identification of decreased auditory temporal resolution in the early stages of ARHI, which is strongly associated with auditory neurodegeneration.

Subcortical auditory system in tinnitus with normal hearing: insights from electrophysiological perspective.

PURPOSE: The mechanism of tinnitus remains poorly understood; however, studies have underscored the significance of the subcortical auditory system in tinnitus perception. In this study, our aim was to investigate the subcortical auditory system using electrophysiological measurements in individuals with tinnitus and normal hearing. Additionally, we aimed to assess speech-in-noise (SiN) perception to determine whether individuals with tinnitus exhibit SiN deficits despite having normal-hearing thresholds. METHODS: A total 42 normal-hearing participants, including 22 individuals with chronic subjective tinnitus and 20 normal individuals, participated in the study. We recorded auditory brainstem response (ABR) and speech-evoked frequency following response (sFFR) from the participants. SiN perception was also assessed using the Matrix test. RESULTS: Our results revealed a significant prolongation of the O peak, which encodes sound offset in sFFR, for the tinnitus group (p < 0.01). The greater non-stimulus-evoked activity was also found in individuals with tinnitus (p < 0.01). In ABR, the tinnitus group showed reduced wave I amplitude and prolonged absolute wave I, III, and V latencies (p ≤ 0.02). Our findings suggested that individuals with tinnitus had poorer SiN perception compared to normal participants (p < 0.05). CONCLUSION: The deficit in encoding sound offset may indicate an impaired inhibitory mechanism in tinnitus. The greater non-stimulus-evoked activity observed in the tinnitus group suggests increased neural noise at the subcortical level. Additionally, individuals with tinnitus may experience speech-in-noise deficits despite having a normal audiogram. Taken together, these findings suggest that the lack of inhibition and increased neural noise may be associated with tinnitus perception.

The curvature quantification of wave I in auditory brainstem responses detects cochlear synaptopathy in human beings.

PURPOSE: Patients with age-related hearing loss complain often about reduced speech perception in adverse listening environment. Studies on animals have suggested that cochlear synaptopathy may be one of the primary mechanisms responsible for this phenomenon. A decreased wave I amplitude in supra-threshold auditory brainstem response (ABR) can diagnose this pathology non-invasively. However, the interpretation of the wave I amplitude in humans remains controversial. Recent studies in mice have established a robust and reliable mathematic algorithm, i.e., curve curvature quantification, for detecting cochlear synaptopathy. This study aimed to determine whether the curve curvature has sufficient test-retest reliability to detect cochlear synaptopathy in aging humans. METHODS: Healthy participants were recruited into this prospective study. All subjects underwent an audiogram examination with standard and extended high frequencies ranging from 0.125 to 16 kHz and an ABR with a stimulus of 80 dB nHL click. The peak amplitude, peak latency, curvature at the peak, and the area under the curve of wave I were calculated and analyzed. RESULTS: A total of 80 individuals with normal hearing, aged 18 to 61 years, participated in this study, with a mean age of 26.4 years. Pearson correlation analysis showed a significant negative correlation between curvature and age, as well as between curvature and extended high frequency (EHF) threshold (10-16 kHz). Additionally, the same correlation was observed between age and area as well as age and EHF threshold. The model comparison demonstrated that the curvature at the peak of wave I is the best metric to correlate with EHF threshold. CONCLUSION: The curvature at the peak of wave I is the most sensitive metric for detecting cochlear synaptopathy in humans  and may be applied in routine diagnostics to detect early degenerations of the auditory nerve.

C-Phycocyanin Attenuates Noise-Induced Cochlear Synaptopathy via the Inhibition of Oxidative Stress and Intercellular Adhesion Molecule-1 in the Cochlea.

The synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) are the most vulnerable structures in the noise-exposed cochlea. Cochlear synaptopathy results from the disruption of these synapses following noise exposure and is considered the main cause of poor speech understanding in noisy environments, even when audiogram results are normal. Cochlear synaptopathy leads to the degeneration of SGNs if damaged IHC-SGN synapses are not promptly recovered. Oxidative stress plays a central role in the pathogenesis of cochlear synaptopathy. C-Phycocyanin (C-PC) has antioxidant and anti-inflammatory activities and is widely utilized in the food and drug industry. However, the effect of the C-PC on noise-induced cochlear damage is unknown. We first investigated the therapeutic effect of C-PC on noise-induced cochlear synaptopathy. In vitro experiments revealed that C-PC reduced the H2O2-induced generation of reactive oxygen species in HEI-OC1 auditory cells. H2O2-induced cytotoxicity in HEI-OC1 cells was reduced with C-PC treatment. After white noise exposure for 3 h at a sound pressure of 118 dB, the guinea pigs intratympanically administered 5 µg/mL C-PC exhibited greater wave I amplitudes in the auditory brainstem response, more IHC synaptic ribbons and more IHC-SGN synapses according to microscopic analysis than the saline-treated guinea pigs. Furthermore, the group treated with C-PC had less intense 4-hydroxynonenal and intercellular adhesion molecule-1 staining in the cochlea compared with the saline group. Our results suggest that C-PC improves cochlear synaptopathy by inhibiting noise-induced oxidative stress and the inflammatory response in the cochlea.

Cochlear Synaptopathy Evaluation With Electrocochleography in Patients With Hearing Difficulty in Noise Despite Normal Hearing Levels.

OBJECTIVE: This study examined patients with normal hearing thresholds who had trouble understanding speech in noise. We used electrocochleography (ECochG) to detect and compare SP/AP amplitude area ratios, a potential indicator of cochlear synaptopathy, and investigate speech perception disorder in noise. METHODS: The study included 68 people aged between 18 and 65 years, 35 patients and 33 healthy volunteers, who applied to the otorhinolaryngology clinic between November 2023 and March 2024 with a 2-month history of difficulty understanding speech in noisy environments. Everyone was given a tiptrode electrode ECochG test, and the results were compared between groups. An ECochG test was recorded with tiptrode electrodes and was performed on all participants, and the results were compared between groups. RESULTS: In the ECochG test, the summation potential/action potential (SP/AP) amplitude and area ratios of patients who had difficulty understanding speech in a noisy environment were statistically higher than those of the control group. CONCLUSION: ECochG testing may provide additional evidence to evaluate auditory nerve pathways.

Loss of synaptic ribbons is an early cause in ROS-induced acquired sensorineural hearing loss.

Considerable evidence of reactive oxygen species (ROS) involvement in cochlear hair cell (HC) loss, leading to acquired sensorineural hearing loss (SNHL), were reported. Cochlear synaptopathy between HCs and spiral ganglion neurons has been gathering attention as a cochlear HC loss precursor not detectable by normal auditory evaluation. However, the molecular mechanisms linking ROS with HC loss, as well as the relationship between ROS and cochlear synaptopathy have not been elucidated. Here, we examined these linkages using NOX4-TG mice, which constitutively produce ROS without stimulation. mRNA levels of Piccolo 1, a major component of the synaptic ribbon (a specialized structure surrounded by synaptic vesicles in HCs), were decreased in postnatal day 6 NOX4-TG mice cochleae compared to those in WT mice; they were also decreased by noise exposure in 2-week-old WT cochleae. As noise exposure induces ROS production, this suggests that the synaptic ribbon is a target of ROS. The level of CtBP2, another synaptic ribbon component, was significantly lower in NOX4-TG cochleae of 1-month-old and 4-month-old mice compared to that in WT mice, although no significant differences were noted at 1.5- and 2-months. The decrease in CtBP2 plateaued in 4-month-old NOX4-TG, while it gradually decreased from 1 to 6 months in WT mice. Furthermore, CtBP2 level in 2-month-old NOX4-TG mice decreased significantly after exposure to cisplatin and noise compared to that in WT mice. These findings suggest that ROS lead to developmental delays and early degeneration of synaptic ribbons, which could be potential targets for novel therapeutics for ROS-induced SNHL.

Animal models of hidden hearing loss: Does auditory-nerve-fiber loss cause real-world listening difficulties?

Afferent innervation of the cochlea by the auditory nerve declines during aging and potentially after sound overexposure, producing the common pathology known as cochlear synaptopathy. Auditory-nerve-fiber loss is difficult to detect with the clinical audiogram and has been proposed to cause 'hidden hearing loss' including impaired speech-in-noise perception. While evidence that auditory-nerve-fiber loss causes hidden hearing loss in humans is controversial, behavioral animal models hold promise to rigorously test this hypothesis because neural lesions can be induced and histologically validated. Here, we review recent animal behavioral studies on the impact of auditory-nerve-fiber loss on perception in a range of species. We first consider studies of tinnitus and hyperacusis inferred from acoustic startle reflexes, followed by a review of operant-conditioning studies of the audiogram, temporal integration for tones of varying duration, temporal resolution of gaps in noise, and tone-in-noise detection. Studies quantifying the audiogram show that tone-in-quiet sensitivity is unaffected by auditory-nerve-fiber loss unless neural lesions exceed 80%, at which point large deficits are possible. Changes in other aspects of perception, which were typically investigated for moderate-to-severe auditory-nerve-fiber loss of 50-70%, appear heterogeneous across studies and might be small compared to impairment caused by hair-cell pathologies. Future studies should pursue recent findings that behavioral sensitivity to brief tones and silent gaps in noise may be particularly vulnerable to auditory-nerve-fiber loss. Furthermore, aspects of auditory perception linked to central inhibition and fine neural response timing, such as modulation masking release and spatial hearing, may be productive directions for further animal behavioral research.

Preventing presbycusis in mice with enhanced medial olivocochlear feedback.

"Growing old" is the most common cause of hearing loss. Age-related hearing loss (ARHL) (presbycusis) first affects the ability to understand speech in background noise, even when auditory thresholds in quiet are normal. It has been suggested that cochlear denervation ("synaptopathy") is an early contributor to age-related auditory decline. In the present work, we characterized age-related cochlear synaptic degeneration and hair cell loss in mice with enhanced α9α10 cholinergic nicotinic receptors gating kinetics ("gain of function" nAChRs). These mediate inhibitory olivocochlear feedback through the activation of associated calcium-gated potassium channels. Cochlear function was assessed via distortion product otoacoustic emissions and auditory brainstem responses. Cochlear structure was characterized in immunolabeled organ of Corti whole mounts using confocal microscopy to quantify hair cells, auditory neurons, presynaptic ribbons, and postsynaptic glutamate receptors. Aged wild-type mice had elevated acoustic thresholds and synaptic loss. Afferent synapses were lost from inner hair cells throughout the aged cochlea, together with some loss of outer hair cells. In contrast, cochlear structure and function were preserved in aged mice with gain-of-function nAChRs that provide enhanced olivocochlear inhibition, suggesting that efferent feedback is important for long-term maintenance of inner ear function. Our work provides evidence that olivocochlear-mediated resistance to presbycusis-ARHL occurs via the α9α10 nAChR complexes on outer hair cells. Thus, enhancement of the medial olivocochlear system could be a viable strategy to prevent age-related hearing loss.

Normal Tone-In-Noise Sensitivity in Trained Budgerigars despite Substantial Auditory-Nerve Injury: No Evidence of Hidden Hearing Loss.

Loss of auditory-nerve (AN) afferent cochlear innervation is a prevalent human condition that does not affect audiometric thresholds and therefore remains largely undetectable with standard clinical tests. AN loss is widely expected to cause hearing difficulties in noise, known as "hidden hearing loss," but support for this hypothesis is controversial. Here, we used operant conditioning procedures to examine the perceptual impact of AN loss on behavioral tone-in-noise (TIN) sensitivity in the budgerigar (Melopsittacus undulatus; of either sex), an avian animal model with complex hearing abilities similar to humans. Bilateral kainic acid (KA) infusions depressed compound AN responses by 40-70% without impacting otoacoustic emissions or behavioral tone sensitivity in quiet. Surprisingly, animals with AN damage showed normal thresholds for tone detection in noise (0.1 ± 1.0 dB compared to control animals; mean difference ± SE), even under a challenging roving-level condition with random stimulus variation across trials. Furthermore, decision-variable correlations (DVCs) showed no difference for AN-damaged animals in their use of energy and envelope cues to perform the task. These results show that AN damage has less impact on TIN detection than generally expected, even under a difficult roving-level condition known to impact TIN detection in individuals with sensorineural hearing loss (SNHL). Perceptual deficits could emerge for different perceptual tasks or with greater AN loss but are potentially minor compared with those caused by SNHL.SIGNIFICANCE STATEMENT Loss of auditory-nerve (AN) cochlear innervation is a common problem in humans that does not affect audiometric thresholds on a clinical hearing test. AN loss is widely expected to cause hearing problems in noise, known as "hidden hearing loss," but existing studies are controversial. Here, using an avian animal model with complex hearing abilities similar to humans, we examined for the first time the impact of an experimentally induced AN lesion on behavioral tone sensitivity in noise. Surprisingly, AN-lesioned animals showed no difference in hearing performance in noise or detection strategy compared with controls. These results show that perceptual deficits from AN damage are smaller than generally expected, and potentially minor compared with those caused by sensorineural hearing loss (SNHL).

Noise Masking in Cochlear Synaptopathy: Auditory Brainstem Response vs. Auditory Nerve Response in Mouse.

After acoustic overexposure, many auditory-nerve fiber (ANF) synapses permanently retract from surviving cochlear hair cells. This synaptopathy is hard to diagnose, since it does not elevate audiometric thresholds until almost no synapses remain, nevertheless it may degrade discrimination of complex stimuli especially in noisy environments. Here, we study an assay based on masking the auditory brainstem responses (ABRs) to a moderate-level probe tone with continuous noise of varied sound levels, and we investigate the underlying ANF responses at the single-fiber level. Synaptopathy was induced by overexposure to octave-band noise, resulting in a permanent synaptic loss of ~50%, without permanent threshold elevation except at the highest frequencies. The normal progressive delay of ABR peaks with increasing masker level is diminished in synaptopathic ears; however, the single-fiber analysis suggests that this normal latency shift does not arise because contributing ANFs shift from low-threshold fibers (with high spontaneous rates) to high-threshold fibers (with low spontaneous rates). Rather, it may arise because of a shift in the cochlear region dominating the response. Surprisingly, the dynamic range of masking, i.e. the difference between the lowest masker level that attenuates the ABR to a fixed-level probe and the lowest masker level that eliminates the ABR, is enhanced in the synaptopathic ears. This ABR behavior mirrors the single-fiber data showing a paradoxical enhancement of onset-response synchrony and resistance to masking in responses of ANFs in the synaptopathic regions. An assay based on the dynamic range of masking could be useful in diagnosing synaptic damage in human populations.

Efficacy of behavioral audiological tests in identifying cochlear synaptopathy: a systematic review.

PURPOSE: Cochlear synaptopathy or hidden hearing loss is difficult to assess due to the lack of sensitivity with standard audiological tests. Poor speech perception, especially in the presence of noise or tinnitus, is the most common complaint of these patients. The purpose of this systematic review is to identify articles in peer-reviewed journals that used behavioral measures in the effective assessment of cochlear synaptopathy or hidden hearing loss. METHODS: The manuscripts were searched in various international databases, and the manuscripts were screened based on titles, abstracts, and full-length content. A total of 14 human studies were selected after the appropriate exclusion of other articles. RESULTS: Results showed that high-frequency audiometry could be used for the early identification of cochlear synaptopathy. The tone in noise detection test can also be added in the test battery along with speech perception in noise. The amplitude modulation detection test, interaural phase difference, and differential sensitivity tests require more research before using them for the assessment of cochlear synaptopathy or hidden hearing loss. CONCLUSIONS: Self-reports and questionnaires also help in determining the extent of noise exposure.

Auditory brainstem response in unilateral tinnitus patients: does symmetrical hearing thresholds and within-subject comparison affect responses?

OBJECTIVE: In recent studies, cochlear synaptopathy has been suggested as a potential pathophysiology mechanism for tinnitus, which occurs in individuals with normal hearing thresholds. Auditory Brainstem Response (ABR) is a noninvasive method frequently used in the literature to evaluate cochlear synaptopathy in tinnitus patients. However, possible factors such as high-frequency pure-tone hearing thresholds, age, gender, and head characteristics that may affect ABR were not considered sufficiently in previous studies. Therefore, the present study aims to evaluate tinnitus ears and non-tinnitus ears with ABR in unilateral chronic tinnitus patients with symmetrical hearing. METHODS: Twenty unilateral chronic tinnitus patients having normal pure-tone average with symmetrical hearing thresholds was included in the study. Subjects were evaluated with 0.25-16 kHz pure-tone audiometry, Tinnitus Handicap Inventory (THI) and ABR were administered. All ears were evaluated monaurally using click stimuli at 80 dB nHL, alternating polarity (21.1 rate/s, 2000 sweeps). RESULTS: Wave I amplitude of the ABR and the ratio of III/I, V/I, and V/III wave amplitudes from tinnitus ears was higher than non-tinnitus ears. At the same time, there was a positive correlation between THI and V-I and V-III interpeak latency range, and a negative correlation between V/III wave amplitude ratio. CONCLUSION: ABR can be used as an evaluation method to provide evidence that the neural organizations of individuals with chronic tinnitus differ in certain regions in their auditory pathways. The correlation between THI and ABR findings suggests that there may be a connection between tinnitus distress and the neural organization of the auditory system.

Auditory-nerve responses in mice with noise-induced cochlear synaptopathy.

Cochlear synaptopathy is the noise-induced or age-related loss of ribbon synapses between inner hair cells (IHCs) and auditory-nerve fibers (ANFs), first reported in CBA/CaJ mice. Recordings from single ANFs in anesthetized, noise-exposed guinea pigs suggested that neurons with low spontaneous rates (SRs) and high thresholds are more vulnerable than low-threshold, high-SR fibers. However, there is extensive postexposure regeneration of ANFs in guinea pigs but not in mice. Here, we exposed CBA/CaJ mice to octave-band noise and recorded sound-evoked and spontaneous activity from single ANFs at least 2 wk later. Confocal analysis of cochleae immunostained for pre- and postsynaptic markers confirmed the expected loss of 40%-50% of ANF synapses in the basal half of the cochlea; however, our data were not consistent with a selective loss of low-SR fibers. Rather they suggested a loss of both SR groups in synaptopathic regions. Single-fiber thresholds and frequency tuning recovered to pre-exposure levels; however, response to tone bursts showed increased peak and steady-state firing rates, as well as decreased jitter in first-spike latencies. This apparent gain-of-function increased the robustness of tone-burst responses in the presence of continuous masking noise. This study suggests that the nature of noise-induced synaptic damage varies between different species and that, in mouse, the noise-induced hyperexcitability seen in central auditory circuits is also observed at the level of the auditory nerve.NEW & NOTEWORTHY Noise-induced damage to synapses between inner hair cells and auditory-nerve fibers (ANFs) can occur without permanent hair cell damage, resulting in pathophysiology that "hides" behind normal thresholds. Prior single-fiber neurophysiology in guinea pig suggested that noise selectively targets high-threshold ANFs. Here, we show that the lingering pathophysiology differs in mouse, with both ANF groups affected and a paradoxical gain-of-function in surviving low-threshold fibers, including increased onset rate, decreased onset jitter, and reduced maskability.

Envelope following responses predict speech-in-noise performance in normal-hearing listeners.

Permanent threshold elevation after noise exposure or aging is caused by loss of sensory cells; however, animal studies show that hair cell loss is often preceded by degeneration of the synapses between sensory cells and auditory nerve fibers. Silencing these neurons is likely to degrade auditory processing and may contribute to difficulties understanding speech in noisy backgrounds. Reduction of suprathreshold ABR amplitudes can be used to quantify synaptopathy in inbred mice. However, ABR amplitudes are highly variable in humans, and thus more challenging to use. Since noise-induced neuropathy preferentially targets fibers with high thresholds and low spontaneous rate and because phase locking to temporal envelopes is particularly strong in these fibers, measuring envelope following responses (EFRs) might be a more robust measure of cochlear synaptopathy. A recent auditory model further suggests that modulation of carrier tones with rectangular envelopes should be less sensitive to cochlear amplifier dysfunction and, therefore, a better metric of cochlear neural damage than sinusoidal amplitude modulation. In this study, we measure performance scores on a variety of difficult word-recognition tasks among listeners with normal audiograms and assess correlations with EFR magnitudes to rectangular versus sinusoidal modulation. Higher harmonics of EFR magnitudes evoked by a rectangular-envelope stimulus were significantly correlated with word scores, whereas those evoked by sinusoidally modulated tones did not. These results support previous reports that individual differences in synaptopathy may be a source of speech recognition variability despite the presence of normal thresholds at standard audiometric frequencies.NEW & NOTEWORTHY Recent studies suggest that millions of people may be at risk of permanent impairment from cochlear synaptopathy, the age-related and noise-induced degeneration of neural connections in the inner ear. This study examines electrophysiological responses to stimuli designed to improve detection of neural damage in subjects with normal hearing sensitivity. The resultant correlations with word recognition performance are consistent with a contribution of cochlear neural damage to deficits in hearing in noise abilities.

Assessment of cochlear toxicity in response to chronic 3,3'-iminodipropionitrile in mice reveals early and reversible functional loss that precedes overt histopathology.

The peripheral auditory and vestibular systems rely on sensorineural structures that are vulnerable to ototoxic agents that cause hearing loss and/or equilibrium deficits. Although attention has focused on hair cell loss as the primary pathology underlying ototoxicity, evidence from the peripheral vestibular system indicates that hair cell loss during chronic exposure is preceded by synaptic uncoupling from the neurons and is potentially reversible. To determine if synaptic pathology also occurs in the peripheral auditory system, we examined the extent, time course, and reversibility of functional and morphological alterations in cochleae from mice exposed to 3,3'-iminodipropionitrile (IDPN) in drinking water for 2, 4 or 6 weeks. Functionally, IDPN exposure caused progressive high- to low-frequency hearing loss assessed by measurement of auditory brainstem response wave I absolute thresholds and amplitudes. The extent of hearing loss scaled with the magnitude of vestibular dysfunction assessed behaviorally. Morphologically, IDPN exposure caused progressive loss of outer hair cells (OHCs) and synapses between the inner hair cells (IHCs) and primary auditory neurons. In contrast, IHCs were spared from ototoxic damage. Importantly, hearing loss consistent with cochlear synaptopathy preceded loss of OHCs and synapses and, moreover, recovered if IDPN exposure was stopped before morphological pathology occurred. Our observations suggest that synaptic uncoupling, perhaps as an early phase of cochlear synaptopathy, also occurs in the peripheral auditory system in response to IDPN exposure. These findings identify novel mechanisms that contribute to the earliest stages of hearing loss in response to ototoxic agents and possibly other forms of acquired hearing loss.

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice.

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17ß-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.

[Research progress on non-steady state noise-induced hearing loss].

Non-steady state noise has become the main type of workplace noise. Compared with steady state noise, non-steady state noise may cause more serious hearing loss. This paper reviews the new situation of occupational hearing loss caused by non-steady state noise exposure, the overview of international noise exposure assessment standards and new challenges, and the new evidence of non-steady state noise induced hearing loss, so as to provide the basis for the future research of non-steady state noise induced hearing loss.

Electrophysiological markers of cochlear function correlate with hearing-in-noise performance among audiometrically normal subjects.

Hearing loss caused by noise exposure, ototoxic drugs, or aging results from the loss of sensory cells, as reflected in audiometric threshold elevation. Animal studies show that loss of hair cells can be preceded by loss of auditory-nerve peripheral synapses, which likely degrades auditory processing. While this condition, known as cochlear synaptopathy, can be diagnosed in mice by a reduction of suprathreshold cochlear neural responses, its diagnosis in humans remains challenging. To look for evidence of cochlear nerve damage in normal hearing subjects, we measured their word recognition performance in difficult listening environments and compared it to cochlear function as assessed by otoacoustic emissions and click-evoked electrocochleography. Several electrocochleographic markers were correlated with word scores, whereas distortion product otoacoustic emissions were not. Specifically, the summating potential (SP) was larger and the cochlear nerve action potential (AP) was smaller in those with the worst word scores. Adding a forward masker or increasing stimulus rate reduced SP in the worst performers, suggesting that this potential includes postsynaptic components as well as hair cell receptor potentials. Results suggests that some of the variance in word scores among listeners with normal audiometric threshold arises from cochlear neural damage.NEW & NOTEWORTHY Recent animal studies suggest that millions of people may be at risk of permanent impairment from cochlear synaptopathy, the age-related and noise-induced degeneration of neural connections in the inner ear that "hides" behind a normal audiogram. This study examines electrophysiological responses to clicks in a large cohort of subjects with normal hearing sensitivity. The resultant correlations with word recognition performance are consistent with an important contribution cochlear neural damage to deficits in hearing in noise abilities.

Association between speech perception in noise and electrophysiological measures: an exploratory study of possible techniques to evaluate cochlear synaptopathy in humans.

Objective: The primary aim of this study was to investigate whether scores for a speech-in-noise test were associated with the results of two electrophysiological techniques mainly targeting low spontaneous rate, high-threshold auditory fibres.Design: Cross-sectional study. Participants were evaluated with the hearing-in-noise test (HINT), along with the Auditory Brainstem Response (ABR) with and without ipsilateral noise. The wave V/I amplitude ratio for the ABR without ipsilateral noise and ABR wave V latency shift in the presence of ipsilateral noise were obtained.Study sample: Twenty adults aged between 20 and 34 years (10 females) who did not report occupational exposure to noise were selected. All participants presented with normal hearing thresholds (0.250-8 kHz) and the presence of distortion product otoacoustic emissions, bilaterally.Results: A significant association between the wave V/I amplitude ratio for the left ear and the HINT scores for the left ear was found.Conclusions: Based on the results of this study, in normal-hearing listeners, the wave V/I ratio is associated with speech-in-noise performance, specifically in the left ear. This non-invasive procedure has the potential to be used in clinical populations who present with speech-in-noise difficulties despite having normal audiograms.

Effects of noise exposure on auditory brainstem response and speech-in-noise tasks: a review of the literature.

OBJECTIVE: Short-term noise exposure that induces transient changes in thresholds has induced permanent cochlear synaptopathy in multiple species. Here, the literature was reviewed to gain translational insight into the relationships between noise exposure, ABR metrics, speech-in-noise performance and TTS in humans. DESIGN: PubMed-based literature search, retrieval and review of full-text articles. STUDY SAMPLE: Peer-reviewed literature identified using PubMed search. RESULTS: Permanent occupational noise-induced hearing loss (NIHL) is frequently accompanied by abnormal ABR amplitude and latency. In the absence of NIHL, there are mixed results for relationships between noise exposure and ABR metrics. Interpretation of speech-in-noise deficits is difficult as both cochlear synaptopathy and outer hair cell (OHC) loss can drive deficits. Reductions in Wave I amplitude during TTS may reflect temporary OHC pathology rather than cochlear synaptopathy. Use of diverse protocols across studies reduces the ability to compare outcomes across studies. CONCLUSIONS: Longitudinal ABR and speech-in-noise data collected using consistent protocols are needed. Although speech-in-noise testing may not reflect cochlear synaptopathy, speech-in-noise testing should be completed as part of a comprehensive test battery to provide the objective measurement of patient difficulty.