Auditory brainstem response to paired clicks as a candidate marker of cochlear synaptopathy in humans.

OBJECTIVE: This study aimed to evaluate whether auditory brainstem response (ABR) using a paired-click stimulation paradigm could serve as a tool for detecting cochlear synaptopathy (CS). METHODS: The ABRs to single-clicks and paired-clicks with various inter-click intervals (ICIs) and scores for word intelligibility in degraded listening conditions were obtained from 57 adults with normal hearing. The wave I peak amplitude and root mean square values for the post-wave I response within a range delayed from the wave I peak (referred to as the RMSpost-w1) were calculated for the single- and second-click responses. RESULTS: The wave I peak amplitudes did not correlate with age except for the second-click responses at an ICI of 7 ms, and the word intelligibility scores. However, we found that the RMSpost-w1 values for the second-click responses significantly decreased with increasing age. Moreover, the RMSpost-w1 values for the second-click responses at an ICI of 5 ms correlated significantly with the scores for word intelligibility in degraded listening conditions. CONCLUSIONS: The magnitude of the post-wave I response for the second-click response could serve as a tool for detecting CS in humans. SIGNIFICANCE: Our findings shed new light on the analytical methods of ABR for quantifying CS.

Age-related alterations in efferent medial olivocochlear-outer hair cell and primary auditory ribbon synapses in CBA/J mice.

Introduction: Hearing decline stands as the most prevalent single sensory deficit associated with the aging process. Giving compelling evidence suggesting a protective effect associated with the efferent auditory system, the goal of our study was to characterize the age-related changes in the number of efferent medial olivocochlear (MOC) synapses regulating outer hair cell (OHC) activity compared with the number of afferent inner hair cell ribbon synapses in CBA/J mice over their lifespan. Methods: Organs of Corti of 3-month-old CBA/J mice were compared with mice aged between 10 and 20 months, grouped at 2-month intervals. For each animal, one ear was used to characterize the synapses between the efferent MOC fibers and the outer hair cells (OHCs), while the contralateral ear was used to analyze the ribbon synapses between inner hair cells (IHCs) and type I afferent nerve fibers of spiral ganglion neurons (SGNs). Each cochlea was separated in apical, middle, and basal turns, respectively. Results: The first significant age-related decline in afferent IHC-SGN ribbon synapses was observed in the basal cochlear turn at 14 months, the middle turn at 16 months, and the apical turn at 18 months of age. In contrast, efferent MOC-OHC synapses in CBA/J mice exhibited a less pronounced loss due to aging which only became significant in the basal and middle turns of the cochlea by 20 months of age. Discussion: This study illustrates an age-related reduction on efferent MOC innervation of OHCs in CBA/J mice starting at 20 months of age. Our findings indicate that the morphological decline of efferent MOC-OHC synapses due to aging occurs notably later than the decline observed in afferent IHC-SGN ribbon synapses.

The role of hidden hearing loss in tinnitus: Insights from early markers of peripheral hearing damage.

Since the presence of tinnitus is not always associated with audiometric hearing loss, it has been hypothesized that hidden hearing loss may act as a potential trigger for increased central gain along the neural pathway leading to tinnitus perception. In recent years, the study of hidden hearing loss has improved with the discovery of cochlear synaptopathy and several objective diagnostic markers. This study investigated three potential markers of peripheral hidden hearing loss in subjects with tinnitus: extended high-frequency audiometric thresholds, the auditory brainstem response, and the envelope following response. In addition, speech intelligibility was measured as a functional outcome measurement of hidden hearing loss. To account for age-related hidden hearing loss, participants were grouped according to age, presence of tinnitus, and audiometric thresholds. Group comparisons were conducted to differentiate between age- and tinnitus-related effects of hidden hearing loss. All three markers revealed age-related differences, whereas no differences were observed between the tinnitus and non-tinnitus groups. However, the older tinnitus group showed improved performance on low-pass filtered speech in noise tests compared to the older non-tinnitus group. These low-pass speech in noise scores were significantly correlated with tinnitus distress, as indicated using questionnaires, and could be related to the presence of hyperacusis. Based on our observations, cochlear synaptopathy does not appear to be the underlying cause of tinnitus. The improvement in low-pass speech-in-noise could be explained by enhanced temporal fine structure encoding or hyperacusis. Therefore, we recommend that future tinnitus research takes into account age-related factors, explores low-frequency encoding, and thoroughly assesses hyperacusis.

Effects of Temporal Processing on Speech-in-Noise Perception in Middle-Aged Adults.

Auditory temporal processing is a vital component of auditory stream segregation, or the process in which complex sounds are separated and organized into perceptually meaningful objects. Temporal processing can degrade prior to hearing loss, and is suggested to be a contributing factor to difficulties with speech-in-noise perception in normal-hearing listeners. The current study tested this hypothesis in middle-aged adults-an under-investigated cohort, despite being the age group where speech-in-noise difficulties are first reported. In 76 participants, three mechanisms of temporal processing were measured: peripheral auditory nerve function using electrocochleography, subcortical encoding of periodic speech cues (i.e., fundamental frequency; F0) using the frequency following response, and binaural sensitivity to temporal fine structure (TFS) using a dichotic frequency modulation detection task. Two measures of speech-in-noise perception were administered to explore how contributions of temporal processing may be mediated by different sensory demands present in the speech perception task. This study supported the hypothesis that temporal coding deficits contribute to speech-in-noise difficulties in middle-aged listeners. Poorer speech-in-noise perception was associated with weaker subcortical F0 encoding and binaural TFS sensitivity, but in different contexts, highlighting that diverse aspects of temporal processing are differentially utilized based on speech-in-noise task characteristics.

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.

Neural Adaptation at Stimulus Onset and Speed of Neural Processing as Critical Contributors to Speech Comprehension Independent of Hearing Threshold or Age.

Background: It is assumed that speech comprehension deficits in background noise are caused by age-related or acquired hearing loss. Methods: We examined young, middle-aged, and older individuals with and without hearing threshold loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (pDPOAEs), auditory brainstem responses (ABRs), auditory steady-state responses (ASSRs), speech comprehension (OLSA), and syllable discrimination in quiet and noise. Results: A noticeable decline of hearing sensitivity in extended high-frequency regions and its influence on low-frequency-induced ABRs was striking. When testing for differences in OLSA thresholds normalized for PT thresholds (PTTs), marked differences in speech comprehension ability exist not only in noise, but also in quiet, and they exist throughout the whole age range investigated. Listeners with poor speech comprehension in quiet exhibited a relatively lower pDPOAE and, thus, cochlear amplifier performance independent of PTT, smaller and delayed ABRs, and lower performance in vowel-phoneme discrimination below phase-locking limits (/o/-/u/). When OLSA was tested in noise, listeners with poor speech comprehension independent of PTT had larger pDPOAEs and, thus, cochlear amplifier performance, larger ASSR amplitudes, and higher uncomfortable loudness levels, all linked with lower performance of vowel-phoneme discrimination above the phase-locking limit (/i/-/y/). Conslusions: This study indicates that listening in noise in humans has a sizable disadvantage in envelope coding when basilar-membrane compression is compromised. Clearly, and in contrast to previous assumptions, both good and poor speech comprehension can exist independently of differences in PTTs and age, a phenomenon that urgently requires improved techniques to diagnose sound processing at stimulus onset in the clinical routine.

Perceptual Consequences of Cochlear Deafferentation in Humans.

Cochlear synaptopathy, a form of cochlear deafferentation, has been demonstrated in a number of animal species, including non-human primates. Both age and noise exposure contribute to synaptopathy in animal models, indicating that it may be a common type of auditory dysfunction in humans. Temporal bone and auditory physiological data suggest that age and occupational/military noise exposure also lead to synaptopathy in humans. The predicted perceptual consequences of synaptopathy include tinnitus, hyperacusis, and difficulty with speech-in-noise perception. However, confirming the perceptual impacts of this form of cochlear deafferentation presents a particular challenge because synaptopathy can only be confirmed through post-mortem temporal bone analysis and auditory perception is difficult to evaluate in animals. Animal data suggest that deafferentation leads to increased central gain, signs of tinnitus and abnormal loudness perception, and deficits in temporal processing and signal-in-noise detection. If equivalent changes occur in humans following deafferentation, this would be expected to increase the likelihood of developing tinnitus, hyperacusis, and difficulty with speech-in-noise perception. Physiological data from humans is consistent with the hypothesis that deafferentation is associated with increased central gain and a greater likelihood of tinnitus perception, while human data on the relationship between deafferentation and hyperacusis is extremely limited. Many human studies have investigated the relationship between physiological correlates of deafferentation and difficulty with speech-in-noise perception, with mixed findings. A non-linear relationship between deafferentation and speech perception may have contributed to the mixed results. When differences in sample characteristics and study measurements are considered, the findings may be more consistent.

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.

Effects of age and noise exposure history on auditory nerve response amplitudes: A systematic review, study, and meta-analysis.

Auditory nerve (AN) function has been hypothesized to deteriorate with age and noise exposure. Here, we perform a systematic review of published studies and find that the evidence for age-related deficits in AN function is largely consistent across the literature, but there are inconsistent findings among studies of noise exposure history. Further, evidence from animal studies suggests that the greatest deficits in AN response amplitudes are found in noise-exposed aged mice, but a test of the interaction between effects of age and noise exposure on AN function has not been conducted in humans. We report a study of our own examining differences in the response amplitude of the compound action potential N1 (CAP N1) between younger and older adults with and without a self-reported history of noise exposure in a large sample of human participants (63 younger adults 18-30 years of age, 103 older adults 50-86 years of age). CAP N1 response amplitudes were smaller in older than younger adults. Noise exposure history did not appear to predict CAP N1 response amplitudes, nor did the effect of noise exposure history interact with age. We then incorporated our results into two meta-analyses of published studies of age and noise exposure history effects on AN response amplitudes in neurotypical human samples. The meta-analyses found that age effects across studies are robust (r = -0.407), but noise exposure effects are weak (r = -0.152). We conclude that noise exposure effects may be highly variable depending on sample characteristics, study design, and statistical approach, and researchers should be cautious when interpreting results. The underlying pathology of age-related and noise-induced changes in AN function are difficult to determine in living humans, creating a need for longitudinal studies of changes in AN function across the lifespan and histological examination of the AN from temporal bones collected post-mortem.

Effects of Age and Noise Exposure History on Auditory Nerve Response Amplitudes: A Systematic Review, Study, and Meta-Analysis.

Auditory nerve (AN) function has been hypothesized to deteriorate with age and noise exposure. Here, we perform a systematic review of published studies and find that the evidence for age-related deficits in AN function is largely consistent across the literature, but there are inconsistent findings among studies of noise exposure history. Further, evidence from animal studies suggests that the greatest deficits in AN response amplitudes are found in noise-exposed aged mice, but a test of the interaction between effects of age and noise exposure on AN function has not been conducted in humans. We report a study of our own examining differences in the response amplitude of the compound action potential N1 (CAP N1) between younger and older adults with and without a self-reported history of noise exposure in a large sample of human participants (63 younger adults 18-30 years of age, 103 older adults 50-86 years of age). CAP N1 response amplitudes were smaller in older than younger adults. Noise exposure history did not appear to predict CAP N1 response amplitudes, nor did the effect of noise exposure history interact with age. We then incorporated our results into two meta-analyses of published studies of age and noise exposure history effects on AN response amplitudes in neurotypical human samples. The meta-analyses found that age effects across studies are robust (r=-0.407), but noise-exposure effects are weak (r=-0.152). We conclude that noise-exposure effects may be highly variable depending on sample characteristics, study design, and statistical approach, and researchers should be cautious when interpreting results. The underlying pathology of age-related and noise-induced changes in AN function are difficult to determine in living humans, creating a need for longitudinal studies of changes in AN function across the lifespan and histological examination of the AN from temporal bones collected post-mortem.

Electrocochleographic frequency-following responses as a potential marker of age-related cochlear neural degeneration.

Auditory nerve (AN) fibers that innervate inner hair cells in the cochlea degenerate with advancing age. It has been proposed that age-related reductions in brainstem frequency-following responses (FFR) to the carrier of low-frequency, high-intensity pure tones may partially reflect this neural loss in the cochlea (Märcher-Rørsted et al., 2022). If the loss of AN fibers is the primary factor contributing to age-related changes in the brainstem FFR, then the FFR could serve as an indicator of cochlear neural degeneration. In this study, we employed electrocochleography (ECochG) to investigate the effects of age on frequency-following neurophonic potentials, i.e., neural responses phase-locked to the carrier frequency of the tone stimulus. We compared these findings to the brainstem-generated FFRs obtained simultaneously using the same stimulation. We conducted recordings in young and older individuals with normal hearing. Responses to pure tones (250 ms, 516 and 1086 Hz, 85 dB SPL) and clicks were recorded using both ECochG at the tympanic membrane and traditional scalp electroencephalographic (EEG) recordings of the FFR. Distortion product otoacoustic emissions (DPOAE) were also collected. In the ECochG recordings, sustained AN neurophonic (ANN) responses to tonal stimulation, as well as the click-evoked compound action potential (CAP) of the AN, were significantly reduced in the older listeners compared to young controls, despite normal audiometric thresholds. In the EEG recordings, brainstem FFRs to the same tone stimulation were also diminished in the older participants. Unlike the reduced AN CAP response, the transient-evoked wave-V remained unaffected. These findings could indicate that a decreased number of AN fibers contributes to the response in the older participants. The results suggest that the scalp-recorded FFR, as opposed to the clinical standard wave-V of the auditory brainstem response, may serve as a more reliable indicator of age-related cochlear neural degeneration.

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.

How 'hidden hearing loss' noise exposure affects neural coding in the inferior colliculus of rats.

Exposure to brief, intense sound can produce profound changes in the auditory system, from the internal structure of inner hair cells to reduced synaptic connections between the auditory nerves and the inner hair cells. Moreover, noisy environments can also lead to alterations in the auditory nerve or to processing changes in the auditory midbrain, all without affecting hearing thresholds. This so-called hidden hearing loss (HHL) has been shown in tinnitus patients and has been posited to account for hearing difficulties in noisy environments. However, much of the neuronal research thus far has investigated how HHL affects the response characteristics of individual fibres in the auditory nerve, as opposed to higher stations in the auditory pathway. Human models show that the auditory nerve encodes sound stochastically. Therefore, a sufficient reduction in nerve fibres could result in lowering the sampling of the acoustic scene below the minimum rate necessary to fully encode the scene, thus reducing the efficacy of sound encoding. Here, we examine how HHL affects the responses to frequency and intensity of neurons in the inferior colliculus of rats, and the duration and firing rate of those responses. Finally, we examined how shorter stimuli are encoded less effectively by the auditory midbrain than longer stimuli, and how this could lead to a clinical test for HHL.

Complete Restoration of Hearing Loss and Cochlear Synaptopathy via Minimally Invasive, Single-Dose, and Controllable Middle Ear Delivery of Brain-Derived Neurotrophic Factor-Poly(dl-lactic acid-co-glycolic acid)-Loaded Hydrogel.

Noise-induced hearing loss (NIHL) often accompanies cochlear synaptopathy, which can be potentially reversed to restore hearing. However, there has been little success in achieving complete recovery of sensorineural deafness using nearly noninvasive middle ear drug delivery before. Here, we present a study demonstrating the efficacy of a middle ear delivery system employing brain-derived neurotrophic factor (BDNF)-poly-(dl-lactic acid-co-glycolic acid) (PLGA)-loaded hydrogel in reversing synaptopathy and restoring hearing function in a mouse model with NIHL. The mouse model achieved using the single noise exposure (NE, 115 dBL, 4 h) exhibited an average 20 dBL elevation of hearing thresholds with intact cochlear hair cells but a loss of ribbon synapses as the primary cause of hearing impairment. We developed a BDNF-PLGA-loaded thermosensitive hydrogel, which was administered via a single controllable injection into the tympanic cavity of noise-exposed mice, allowing its presence in the middle ear for a duration of 2 weeks. This intervention resulted in complete restoration of NIHL at frequencies of click, 4, 8, 16, and 32 kHz. Moreover, the cochlear ribbon synapses exhibited significant recovery, whereas other cochlear components (hair cells and auditory nerves) remained unchanged. Additionally, the cochlea of NE treated mice revealed activation of tropomyosin receptor kinase B (TRKB) signaling upon exposure to BDNF. These findings demonstrate a controllable and minimally invasive therapeutic approach that utilizes a BDNF-PLGA-loaded hydrogel to restore NIHL by specifically repairing cochlear synaptopathy. This tailored middle ear delivery system holds great promise for achieving ideal clinical outcomes in the treatment of NIHL and cochlear synaptopathy.

Quantifying the Impact of Auditory Deafferentation on Speech Perception.

The past decade has seen a wealth of research dedicated to determining which and how morphological changes in the auditory periphery contribute to people experiencing hearing difficulties in noise despite having clinically normal audiometric thresholds in quiet. Evidence from animal studies suggests that cochlear synaptopathy in the inner ear might lead to auditory nerve deafferentation, resulting in impoverished signal transmission to the brain. Here, we quantify the likely perceptual consequences of auditory deafferentation in humans via a physiologically inspired encoding-decoding model. The encoding stage simulates the processing of an acoustic input stimulus (e.g., speech) at the auditory periphery, while the decoding stage is trained to optimally regenerate the input stimulus from the simulated auditory nerve firing data. This allowed us to quantify the effect of different degrees of auditory deafferentation by measuring the extent to which the decoded signal supported the identification of speech in quiet and in noise. In a series of experiments, speech perception thresholds in quiet and in noise increased (worsened) significantly as a function of the degree of auditory deafferentation for modeled deafferentation greater than 90%. Importantly, this effect was significantly stronger in a noisy than in a quiet background. The encoding-decoding model thus captured the hallmark symptom of degraded speech perception in noise together with normal speech perception in quiet. As such, the model might function as a quantitative guide to evaluating the degree of auditory deafferentation in human listeners.

Sinaptopatia coclear e perda auditiva oculta: uma revisão de escopo / Cochlear synaptopathy and hidden hearing loss: a scoping review

RESUMO Objetivo Identificar as definições fisiopatológicas adotadas pelos estudos que investigaram a "sinaptopatia coclear" (SC) e "perda auditiva oculta" (PAO). Estratégia de pesquisa Utilizou-se a combinação de unitermos "Auditory Synaptopathy" or "Neuronal Synaptopathy" or "Hidden Hearing Loss" com "etiology" or "causality" or "diagnosis" nas bases de dados EMBASE, Pubmed (MEDLINE), CINAHL (EBSCO) e Web of Science. Critérios de seleção Incluiu-se estudos que investigaram a SC ou PAO em humanos com procedimentos comportamentais e/ou eletrofisiológicos. Análise dos dados Realizou-se a análise e extração de dados quanto a terminologia, definição e população estudada. Resultados Foram incluídos 49 artigos. Destes, 61,2% utilizaram a terminologia SC, 34,7% ambos os termos e 4,1% utilizaram PAO. As condições mais estudadas foram exposição ao ruído e zumbido. Conclusão A terminologia SC foi empregada na maioria dos estudos, com referência ao processo fisiopatológico de desaferenciação entre as fibras do nervo coclear e as células ciliadas internas

ABSTRACT Purpose To identify the pathophysiological definitions adopted by studies investigating "cochlear synaptopathy" (CS) and "hidden hearing loss" (HHL). Research strategies The combination of keywords "Auditory Synaptopathy" or "Neuronal Synaptopathy" or "Hidden Hearing Loss" with "etiology" or "causality" or "diagnosis" was used in the databases EMBASE, Pubmed (MEDLINE), CINAHL (EBSCO), and Web of Science. Selection criteria Studies that investigated CS or HHL in humans using behavioral and/or electrophysiological procedures were included. Data analysis Data analysis and extraction were performed with regard to terminology, definitions, and population. Results 49 articles were included. Of these, 61.2% used the CS terminology, 34.7% used both terms, and 4.1% used HHL. The most-studied conditions were exposure to noise and tinnitus. Conclusion CS terminology was used in most studies, referring to the pathophysiological process of deafferentiation between the cochlear nerve fibers and inner hair cells.

Gentamicin administration leads to synaptic dysfunction in inner hair cells.

Ototoxicity is a major side effect of aminoglycosides, which can cause irreversible hearing loss. Previous studies on aminoglycoside-induced ototoxicity have primarily focused on the loss of sensory hair cells. Recent investigations have revealed that aminoglycosides can also lead to the loss of ribbon synapses in inner hair cells (IHCs). However, the functional implications of ribbon synapse loss and the underlying mechanisms remain unclear. In this study, we intraperitoneally injected C57BL/6 J mice with 300 mg/kg gentamicin once daily for 3, 10, and 20 days. Then, we performed immunofluorescence staining, patch-clamp recording, proteomics analysis and western blotting to characterize the changes in ribbon synapses in IHCs and the associated mechanisms. After gentamicin treatment, the auditory brainstem response (ABR) threshold was elevated, and the ABR wave I amplitude was decreased. We also observed loss of ribbon synapses in IHCs. Interestingly, ribbon synapse loss occurred on both the modiolar and pillar sides of IHCs. Whole-cell patch-clamp recordings in IHCs revealed a reduction in the calcium current amplitude, along with a shifted half-activation voltage and altered calcium voltage dependency. Moreover, exocytosis of IHCs was reduced, consistent with the reduction in the ABR wave I amplitude. Through proteomic analysis, western blotting, and immunofluorescence staining, we found that gentamicin treatment resulted in downregulation of myosin VI, a protein crucial for synaptic vesicle recycling and replenishment in IHCs. Furthermore, we evaluated the kinetics of endocytosis and found a significant reduction in IHC exocytosis, possibly reflecting the impact of myosin VI downregulation on synaptic vesicle recycling. In summary, our findings demonstrate that gentamicin treatment leads to synaptic dysfunction in IHCs, highlighting the important role of myosin VI downregulation in gentamicin-induced synaptic damage.

Normal behavioral discrimination of envelope statistics in budgerigars with kainate-induced cochlear synaptopathy.

Cochlear synaptopathy is a common pathology in humans associated with aging and potentially sound overexposure. Synaptopathy is widely expected to cause "hidden hearing loss," including difficulty perceiving speech in noise, but support for this hypothesis is controversial. Here in budgerigars (Melopsittacus undulatus), we evaluated the impact of long-term cochlear synaptopathy on behavioral discrimination of Gaussian noise (GN) and low-noise noise (LNN) signals processed to have a flatter envelope. Stimuli had center frequencies of 1-3kHz, 100-Hz bandwidth, and were presented at sensation levels (SLs) from 10 to 30dB. We reasoned that narrowband, low-SL stimuli of this type should minimize spread of excitation across auditory-nerve fibers, and hence might reveal synaptopathy-related defects if they exist. Cochlear synaptopathy was induced without hair-cell injury using kainic acid (KA). Behavioral threshold tracking experiments characterized the minimum stimulus duration above which animals could reliably discriminate between LNN and GN. Budgerigar thresholds for LNN-GN discrimination ranged from 40 to 60ms at 30dB SL, were similar across frequencies, and increased for lower SLs. Notably, animals with long-term 39-77% estimated synaptopathy performed similarly to controls, requiring on average a ∼7.5% shorter stimulus duration (-0.7±1.0dB; mean difference ±SE) for LNN-GN discrimination. Decision-variable correlation analyses of detailed behavioral response patterns showed that individual animals relied on envelope cues to discriminate LNN and GN, with lesser roles of FM and energy cues; no difference was found between KA-exposed and control groups. These results suggest that long-term cochlear synaptopathy does not impair discrimination of low-level signals with different envelope statistics.

Exploring Electrode Placements to Optimize the Identification and Measurement of Early Auditory Evoked Potentials.

Cochlear synaptic loss (termed cochlear synaptopathy) has been suggested to contribute to suprathreshold hearing difficulties. However, its existence and putative effects in humans remain inconclusive, largely due to the heterogeneous methods used across studies to indirectly evaluate the health of cochlear synapses. There is a need to standardize proxies of cochlear synaptopathy to appropriately compare and interpret findings across studies. Early auditory evoked potentials (AEPs), including the compound action potential (AP)/Wave I of the auditory brainstem response are a popular proxy, yet remain variable based on technical considerations. This study evaluated one such consideration-electrode array (i.e., montage)-to optimize the use of early AEP waveforms. In 35 young adults, electrocochleography (ECochG) responses were collected using vertical and horizontal montages. Standard ECochG measures and AP/Wave I and Wave II peak-to-trough amplitudes and latencies were compared between montages. Vertical montage recordings consistently produced significantly larger AP/Wave I peak-to-trough amplitudes compared to horizontal recordings. These findings support the use of a vertical electrode montage for optimal recordings of peripheral cochlear nerve activity. As cochlear synaptopathy continues to be explored in humans, the methods highlighted here should be considered in the development of a standardized assessment.

Histological Correlates of Auditory Nerve Injury from Kainic Acid in the Budgerigar (Melopsittacus undulatus).

PURPOSE: Loss of auditory nerve afferent synapses with cochlear hair cells, called cochlear synaptopathy, is a common pathology in humans caused by aging and noise overexposure. The perceptual consequences of synaptopathy in isolation from other cochlear pathologies are still unclear. Animal models provide an effective approach to resolve uncertainty regarding the physiological and perceptual consequences of auditory nerve loss, because neural lesions can be induced and readily quantified. The budgerigar, a parakeet species, has recently emerged as an animal model for synaptopathy studies based on its capacity for vocal learning and ability to behaviorally discriminate simple and complex sounds with acuity similar to humans. Kainic acid infusions in the budgerigar produce a profound reduction of compound auditory nerve responses, including wave I of the auditory brainstem response, without impacting physiological hair cell measures. These results suggest selective auditory nerve damage. However, histological correlates of neural injury from kainic acid are still lacking. METHODS: We quantified the histological effects caused by intracochlear infusion of kainic acid (1 mM; 2.5 µL), and evaluated correlations between the histological and physiological assessments of auditory nerve status. RESULTS: Kainic acid infusion in budgerigars produced pronounced loss of neural auditory nerve soma (60% on average) in the cochlear ganglion, and of peripheral axons, at time points 2 or more months following injury. The hair cell epithelium was unaffected by kainic acid. Neural loss was significantly correlated with reduction of compound auditory nerve responses and auditory brainstem response wave I. CONCLUSION: Compound auditory nerve responses and wave I provide a useful index of cochlear synaptopathy in this animal model.