Hearing Research

Damage to the auditory periphery is more widespread than predicted by the gold-standard clinical audiogram. Noise exposure, ototoxicity and aging can destroy cochlear inner-hair-cell afferent synapses and result in a degraded subcortical representation of sound while leaving hearing thresholds unaffected. Damaged afferent synapses, i.e. cochlear synaptopathy, can be quantified using histology, but a differential diagnosis in living humans is difficult: histology cannot be applied and existing auditory evoked potential (AEP) metrics for synaptopathy become insensitive when other sensorineural hearing impairments co-exist (e.g., outer-hair-cell damage associated with elevated hearing thresholds). To develop a non-invasive diagnostic method which quantifies synaptopathy in humans and animals with normal or elevated hearing thresholds, we employ a computational model approach in combination with human AEP and psychoacoustics. We propose the use of a sensorineural hearing loss (SNHL) map which comprises two relative AEP-based metrics to quantify the respective degrees of synaptopathy and OHC damage and evaluate to which degree our predictions of AEP alterations can explain individual data-points in recorded SNHL maps from male and female listeners with normal or elevated audiometric thresholds. We conclude that SNHL maps can offer a more precise diagnostic tool than existing AEP methods for individual assessment of the synaptopathy and OHC-damage aspect of sensorineural hearing loss. Significance StatementHearing loss ranks fourth in global causes for disability and risk factors include noise exposure, ototoxicity and aging. The most vulnerable parts of the cochlea are the inner-hair-cell afferent synapses and their damage (cochlear synaptopathy) results in a degraded subcortical representation of sound. While synaptopathy can be estimated reliably using histology, it cannot be quantified this way in living humans. Secondly, other co-existing sensorineural hearing deficits (e.g., outer-hair-cell damage) can complicate a differential diagnosis. To quantify synaptopathy in humans and animals with normal or elevated hearing thresholds, we adopt a theoretical and interdisciplinary approach. Sensitive diagnostic metrics for synaptopathy are crucial to assess its prevalence in humans, study its impact on sound perception and yield effective hearing restoration strategies.

The aim of this work was to investigate the perceptual relevance of the frequency following response to the syllable /da/ for speech intelligibility in noise based on age and hearing deficits. Recordings of the auditory evoked potential from young normal hearing (NH) and older individuals with both normal hearing and high-frequency (HF) hearing loss were analyzed. EFR metrics obtained in quiet and noise condition were calculated and correlated with speech reception. The envelope following responses were analyzed in terms of amplitude, latency and noise robustness. The response was first simulated to form predictions on the effect of cochlear synaptopathy and outer hair cell loss on the EFR. The experimental findings were in line with the computational predictions in the found observation that the EFR was reduced as a consequence of ageing and HF hearing loss. Both the audiogram and the speech EFR magnitude fell short in the individual prediction of SRT in stationary noise, but they accounted well for group performance. We also obtained within-group EFR latency with a cross covariance matrix. Validation of the method confirmed that speech EFR latency was predictive of click ABR Wave V peak latency. Moreover, statistical analysis not only showed that the robustness of the EFR obtained in the noise condition was dependent on the degree of high-frequency hearing loss in the older NH adults, but also dependent on the EFR magnitude in the NH younger adults. These findings provide evidence towards the important role of the EFR in speech-in-noise perception.

Cochlear implants (CIs) enable hearing with the deafened ear, via direct, electrical stimulation of the spiral ganglion neurons (SGN). Thus, the outcome depends on the number and excitability of the SGNs. We recently established the electrically-evoked compound action potential (eCAP)-derived Failure Index (FI) as cochlear-health marker in the animal model. The FI informs about the presence, site, and size of a SGN lesion. Here, we translated the FI to clinical recordings of MED-EL CI users. For the retrospective study, we selected patient data from the database of the German Hearing Center Hannover recorded 2017 to 2024. We included 199 post-lingually and 79 pre-lingually deafened ears. Averaged FIs over all contacts of a CI were stable within the analysis period (3rd month to 1st year postoperatively). The FI increased with age and was elevated for etiologies associated with higher SGN loss. Utilizing 3D information from cone beam-computed tomography scans, we confirmed that the FI was independent of distance (0.1-2.5 mm) to the modiolus. The FI showed individual patterns along the array with maxima usually at basal contacts, corresponding to elevated SGN loss at high frequencies. In a selected group of post-lingually deaf ears, we confirmed the correlation of the FI with speech perception in quiet and in noise (n=28, r2=0.12-0.55). Thus, we propose the FI as promising clinical tool to identify CI-implanted ears with reduced neural health and contacts close to areas of SGN loss. Thereby, it can serve to guide speech-processor fitting to optimize CI outcomes.

Hearing sensitivity changes throughout a persons lifetime. This work aimed to describe changes in pure-tone audiometric (PTA) thresholds that occur in the transition from young adulthood to middle age in 121 adults with normal or nearly normal hearing. Results showed that older people had worse high-frequency (4000-8000 Hz) thresholds and better low-frequency (125-500 Hz) thresholds than younger individuals, suggesting that hearing sensitivity in the low-frequency range may improve with age. The improvement of low-frequency thresholds may be part of a central compensation for age-related deterioration of high-frequency hearing sensitivity. Further investigation of age-related changes in low-frequency hearing sensitivity is needed to confirm our findings.

Noise exposures causing transient hearing loss were previously considered benign. However, recent work has revealed that temporary noise-induced threshold shifts may be associated with long-lasting cochlear histopathology. One such effect is cochlear synaptopathy, i.e. changes to the afferent synapse between inner hair cells and auditory nerve fibers. Noise-induced synaptopathy has been extensively characterized in several rodent models, and temporal bone studies suggest similar age-related changes in humans. However, it remains unclear how noise-induced temporary threshold shifts affect cochlear structures in humans and nonhuman primates, which show greater resistance to noise exposure than other animals. Additionally, the long-term sequelae of temporary threshold shifts are largely unknown. Here, we characterized the effects of a noise exposure causing temporary hearing loss on cochlear histopathology in macaque monkeys at long post-exposure survival times. Overall, cochlear histopathology was variable across subjects, similar to the variable susceptibility observed in humans. At 2 and 10 months post-exposure, macaques had no significant loss of hair cells, inner hair cell synapses, or cholinergic efferent innervation. However, enlargement of ribbons in both inner and outer hair cells was observed. Together, these findings provide insight into the cochlear effects of single-exposure temporary threshold shifts in nonhuman primates. HIGHLIGHTS- Macaques exposed to 120 dB SPL noise for 4h showed temporary threshold shifts - Cochlear histopathology was evaluated at 2 and 10 months post-exposure - Macaques had no significant loss of hair cells or inner hair cell synapses - Chronic enlargement of inner and outer hair cell ribbons was observed - Transient loss of outer hair cell ribbons was also observed

Age-related hearing loss is a complex phenomenon. The earliest-onset degenerative event is the gradual loss of neural connections between cochlea and auditory brainstem. To probe for perceptual deficits that might arise from this loss, cochlear synaptopathy was induced pharmacologically in young-adult gerbils, which were then tested in a challenging listening task for the perception of temporal fine structure. Treated gerbils behaved no differently than normal-hearing, young-adult animals. In contrast, old gerbils, which typically express many cochlear and central-neural pathologies, showed impaired perception. To probe for the underlying mechanisms, single-unit responses were obtained from the auditory nerve to the same test stimuli. Responses from old gerbils showed no impairment in temporal locking to the stimulus fine structure. However, responses were significantly more driven by slower temporal fluctuations of the stimulus envelope, suggesting that the central auditory system may be unable to extract the relevant information for discrimination from such altered inputs.

The middle ear muscle reflex (MEMR) and medial olivocochlear reflex (MOCR) are increasingly studied for their role in suprathreshold auditory processing. However, recording these reflexes in humans is potentially complicated by age-related (sub)clinical hearing loss and co-activation. This study investigates (1) the influence of age-related (sub)clinical hearing loss, (2) methodological differences between conventional and wideband MEMR techniques, and (3) how MEMR activation contaminates MOCR recordings. Three test groups were included: young normal-hearing adults, middle-aged normal-hearing adults, and middle-aged adults with audiometric hearing loss. Cochlear status and neural encoding was assessed using distortion-product otoacoustic emissions (DPOAEs) and envelope following responses (EFRs). MEMR recordings were compared using conventional tonal stimuli and wideband stimuli. MOCR was recorded at elicitor levels of 60 and 75 dB to evaluate MEMR co-activation. MEMR was related to age, suggesting sensitivity to subclinical cochlear damage. Wideband stimuli were beneficial as elicitor (noise vs. tone), while changing the probe stimuli added no significant benefit (click vs. tone). MOCR strength did not correlate with age-related subclinical hearing, suggesting that MOCR measurements may reflect efferent function relatively independently of afferent sensorineural status in audiometric normal hearing subjects. However, reliable recordings were challenging in participants with audiometric hearing loss due to poor OAE baselines. MEMR co-activation was detectable in the click response and could alter MOCR-induced suppression. These findings suggest that, in cases of normal hearing thresholds, MEMR amplitude may be a marker of subclinical cochlear damage and MOCR measurements may more specifically reflect efferent function. Clinical measurements can be improved using broadband stimuli, accounting for outer-hair-cell damage, and defining criteria for reflex co-activation.

The human auditory system decomposes complex sounds into distinct components via a collection of processing steps. Knowing whether Spiral Ganglion Cells (SGCs) play an active role in the decoding of complex sounds can facilitate the development of Cochlear Implant (Cl) coding strategies and clinical assessment tools. Early animal studies reported SGCs being similar across different characteristic frequencies (CFs). In this study, human electrically evoked compound action potentials (eCAPs) were analysed to probe the relationship between the reciprocal of CF and the duration of the eCAP. A significant relationship could indicate that SGCs may not simply be passive cables. eCAP datasets from 6 published studies (175 Cl users, 1243 recordings) were analysed and their peaks were automatically labelled. The nlp2 latency was derived for each recording as a proxy of the action potential duration. The CF of each recording was estimated by mapping the average insertion angle of the electrode to the human SGC map. A weak but statistically significant relationship was observed between the n1p2 latency and the reciprocal of CF (random-effects model with random intercepts for subject, r = 0.09, p = 0.024, n= 450) supporting the hypothesis that lower CF is associated with slower repolarisation (longer n1p2 latency) in human spiral ganglion cells.

ObjectivesCochlear synaptopathy, a type of cochlear deafferentation that occurs with aging and following loud noise exposure, is expected to be common in humans and to have negative impacts on auditory perception. However, there is currently no means for diagnosing cochlear deafferentation in living humans. Auditory brainstem response (ABR) wave I amplitude and the envelope following response (EFR) are auditory evoked potentials that have been proposed as potential non-invasive indicators of cochlear deafferentation. However, these measures may be impacted by outer hair cell (OHC) dysfunction, making them difficult to interpret. One potential method for estimating the degree of deafferentation in individual patients is to combine evoked potential and distortion product otoacoustic emission (DPOAE) measurements with a computational model of the auditory periphery (CMAP). The goal of this study was to evaluate the ability of auditory evoked potentials, with and without the CMAP, to predict risk factors for cochlear synaptopathy (age and history of military noise exposure). DesignIn a population of military Veterans and non-Veterans with up to a mild sensorineural hearing loss, a CMAP was used with Bayesian regression to predict synapse numbers across cochlear frequency (synaptograms) for individual human participants based on their ABR, EFR, and/or DPOAE measurements. Linear regression models were then used to evaluate the ability of the synaptograms and various ABR wave I amplitude, EFR magnitude, and DPOAE measurements to predict age and Veteran status. All Veterans were assumed to have at least some history of military noise exposure. ResultsHigh frequency (4 and 5.6 kHz) ABR wave I amplitude measurements and synaptograms generated from high frequency ABR wave I amplitudes performed the best at predicting participant age. Accounting for OHC function (as indicated by DPOAEs) in the generation of the synaptograms or by including DPOAEs in the linear regression models had limited impact on the ability of ABR wave I amplitudes to predict age. DPOAEs were highly predictive of Veteran status, making it difficult to isolate the ability of the auditory evoked potentials to predict Veteran status. ConclusionsHigh frequency ABR wave I amplitudes and synaptograms generated from high frequency ABR wave I amplitudes were able to predict participant age within approximately 6 years, with or without incorporating DPOAE measurements. This suggests that high frequency ABR wave I amplitude measurements are good candidates for non-invasive diagnosis of age-related cochlear deafferentation and it may not be necessary to use the CMAP or measure DPOAEs to predict deafferentation in individual patients. Unfortunately, specific recommendations for predicting noise-induced cochlear deafferentation could not be ascertained from this study due to confounding related to OHC dysfunction.

Speech perception difficulties in noise are common among older adults and individuals with hearing impairment, even when audiometric thresholds appear normal. We examined how aging, cochlear synaptopathy (CS), and outer hair cell (OHC) damage affect speech encoding and phoneme discrimination. Envelope-following responses (EFRs) to rectangular amplitude-modulated (RAM) tones and speech-like phoneme pairs were recorded in quiet using EEG, and behavioral discrimination was assessed in quiet, ipsilateral, and contralateral noise. Stimuli were designed to target temporal envelope (TENV) or temporal fine structure (TFS) encoding. Results showed that RAM-EFR amplitudes decreased gradually with age, consistent with emerging CS, while magnitudes of high-frequency TENV-based EFRs in quiet were most reduced in older hearing-impaired listeners with combined CS and OHC damage. In contrast, EFRs targeting low-frequency TENV encoding in quiet remained preserved. Behaviorally, phoneme discrimination of TFS contrasts worsened with OHC loss and age in quiet and contralateral noise, respectively, while there was no significant effect of age on the discrimination of TENV contrasts. Considering that high-frequency contrasts are discriminated via place-based spectral cues, low-frequency contrasts rely on TFS, and the EFR reflects primarily TENV, this framework explains why EFRs decline for high-frequency cues without perceptual loss, while EFRs remain stable for low-frequency cues even as TFS-based discrimination deteriorates. These findings highlight the need for further investigation into how neural coding deficits relate to perceptual outcomes. Combining electro-physiological and behavioral measures might provide a sensitive framework for detecting subclinical auditory deficits to earlier diagnose age-related and hidden hearing loss. HighlightsO_LISpeech-evoked EEG shows OHC loss-related decline of high-CF enve- lope encoding. C_LIO_LISpeech-evoked EEG shows low-CF envelope encoding stays intact with age. C_LIO_LIFine-structure contrast discrimination worsens with OHC loss in quiet. C_LIO_LIFine-structure contrast discrimination worsens with age in contralateral noise. C_LIO_LIHigh-frequency place-based spectral cues discrimination remains robust with age. C_LIO_LIPeripheral coding strength is not directly reflected at behavioral level. C_LI

ObjectiveThis binational cross-centre study analyses a consented audiological-vestibular test battery for characterising age-related hearing loss, enabling precise phenotyping of suprathreshold functional, physiological, and vestibular factors beyond audibility. DesignStatistical analysis of centre effects to assess comparability of the test battery measured at two centres (Germany and France); statistical analysis of age and pure-tone average (PTA) effects per test to identify potential covariates. Samplen = 55 (39 German and 16 French) participants with hearing thresholds better than the age-dependent median of the PTA, aged 40 years or older. ResultsAge- and PTA-dependent reference data were derived. Due to negligible centre effects, all data were pooled across centres. Age and PTA effects were identified for some tests, especially for audiological-functional tests. No age effects were found for vestibular tests. ConclusionsNormative values for a clinically feasible, multidimensional audiological-vestibular test battery were provided, including several measures whose age and PTA dependencies were previously unclear. Age and PTA should be considered as covariates for interpretation of these tests in future applications such as, e.g., phenotype-genotype relations in specified cohorts.

Tinnitus is commonly associated with hearing loss, yet it can also occur in individuals with clinically normal audiometric thresholds. This dissociation has led to the hypothesis that hidden sensorineural hearing loss underlies tinnitus in audiometrically normal-hearing individuals. However, identifying such subclinical deficits non-invasively is challenging because audiometric measures are influenced by age-related changes and interactions among sensorineural processes. In this study, we disentangled the contributions of tinnitus, age, and hearing status to sensorineural encoding and speech perception. We included 113 participants, divided into age- and hearing-status-matched groups with and without tinnitus, and assessed them using otoacoustic emissions, auditory evoked potentials, auditory reflex measurements, and behavioral tasks of speech perception. This design enabled a rigorous evaluation of whether hidden sensorineural deficits underlie tinnitus. Age and hearing status had substantial effects on objective measures of sensorineural function, whereas tinnitus-related effects were subtle and age specific. Young adults with tinnitus and normal audiometric thresholds exhibited enhanced auditory brainstem responses, elevated envelope following responses, and better vowel discrimination. In contrast, middle-aged adults with tinnitus showed no such enhancements and demonstrated poorer speech-in-noise performance. Correlation analyses revealed a tinnitus-related shift toward greater reliance on central auditory processing, compared with the predominantly peripheral associations observed in controls. The middle ear muscle reflex was unaffected by tinnitus but was correlated with hyperacusis-related parameters. Together, these findings suggest distinct tinnitus-related auditory profiles across the lifespan: neural enhancement and improved vowel discrimination in young adults, versus degraded sensorineural encoding and reduced speech intelligibility in middle-aged adults. Significance StatementTinnitus affects a significant portion of the population, yet its underlying origins are still unclear. While hearing loss is a common cause, individuals with tinnitus may also have normal hearing thresholds. This suggests that subtle sensorineural damage may also play a role. This study critically investigates tinnitus-, age-, and hearing-related sensorineural encoding using non-invasive electrophysiological measures, auditory reflexes, and speech perception tasks in carefully matched participant groups. The study reveals distinct tinnitus-related auditory profiles throughout the lifespan; including enhanced sensorineural processing in young adults and degraded encoding with impaired speech perception in middle-aged adults. These findings provide critical insight into the mechanisms underlying tinnitus and offer objective markers for future research on tinnitus diagnosis and treatment

Objectives: Patients with Cystic fibrosis (CF) often receive aminoglycosides (AGs) to manage recurrent pulmonary infections, placing them at risk for ototoxicity. Chronic AG use can lead to complex cochlear damage affecting inner and outer hair cells, the stria vascularis, and spiral ganglion neurons. The greatest damage is typically in the basal cochlear region, which encodes high-frequency hearing, with additional involvement of more apical regions. While extended-high-frequency (EHF) hearing loss (EHFHL; 9-16 kHz) is often the earliest sign of AG ototoxicity, speech in noise (SiN) effects are rarely studied. Our overall hypothesis is that SiN perception difficulties in individuals with CF, treated with AGs, are related to combined cochlear and neural damage, primarily in the EHF range but also in the standard frequency (SF; 0.25-8 kHz) range. Three mechanisms that contribute to SiN perception were evaluated in children and young adults: 1) a primary effect of reduced EHF sensitivity, measured by pure-tone audiometry (PTA) and transient-evoked otoacoustic emissions (TEOAEs); 2) a secondary effect of subclinical damage in the SF range, measured by PTA and TEOAEs; and 3) additional neural effects, measured by middle ear muscle reflex (MEMR) threshold (afferent) and growth functions (efferent).Design:A total of 185 participants were enrolled; 101 individuals with CF treated with intravenous AGs and 84 age and sex-matched Controls without hearing concerns or CF. Assessments included EHF and SF PTA; the Bamford-Kowal-Bench (BKB)-SIN test for SiN perception; double-evoked TEOAEs with chirp stimuli from 0.71 to 14.7 kHz; and ipsilateral and contralateral wideband MEMR thresholds and growth functions using broadband stimuli. Results: Reduced sensitivity at EHFs (PTA, TEOAEs) was not associated with impaired SiN perception in the CF group. SF hearing, regardless of EHF status, was the primary predictor of SiN performance in the CF group. Increased MEMR growth was also significantly associated with poorer SiN in the CF group. Conclusions: In CF, impaired SiN perception was primarily predicted by SF hearing impairment, with additional involvement of the efferent auditory pathway through increased MEMR growth. These results build on prior evidence for efferent neural effects due to ototoxic exposures, supporting both sensory (afferent) and neural (efferent) mechanisms that contribute to listening difficulties in CF. Thus, preventive and intervention strategies should consider these combined mechanisms in people with AG ototoxicity to address their SiN problems.

It is well known that the medial olivocochlear reflex (MOCR) in the brainstem, part of the efferent network, inhibits the cochlear active gain mechanism. The upstream neural influence of this peripheral inhibition is less understood. When the MOCR is activated, responses generated in the cochlea and cortex undergo putative attenuation, yet the amplitude of responses generated in the brainstem are perplexingly unaffected despite decreased input from the periphery. Based on known neural circuitry, we hypothesized that the inhibition of peripheral input is compensated for by equivalent positive feedback in the brainstem over time. We predicted that the inhibition can be captured at the brainstem with stimuli shorter (1.5 s) than previously employed long durations (4 min) where this inhibition is diminished due to compensation. Results from 18 normal hearing human listeners support our hypothesis in that when the MOCR is activated, there is a robust reduction of responses generated at the periphery, brainstem, and cortex for short stimuli and that brainstem inhibition diminishes for longer stimuli. Our methodology and findings have implications for auditory disorders such as tinnitus, evaluation of efferent function, and provides a novel non-invasive window into potential gain compensation mechanisms in the brainstem.

Sensorineural hearing loss can result from different pathologies, but the primary diagnostic method is a threshold-based audiogram, which is insensitive to some forms of cochlear dysfunction. Individuals may experience difficulty understanding speech in noise despite normal audiometric thresholds. Because most cochlear insults damage both inner (IHCs) and outer hair cells (OHCs), the contribution of IHC dysfunction to auditory-nerve coding has been difficult to isolate. We used the IHC-selective ototoxicity of carboplatin in chinchillas to examine how IHC dysfunction, with preserved OHC function, affects temporal-envelope coding in auditory-nerve fibers (ANFs). Carboplatin produced 10 to 20% IHC loss with stereocilia damage in surviving IHCs, while OHC-dependent measures such as DPOAEs and ANF thresholds were unchanged. Suprathreshold ABR wave 1 was reduced, whereas wave 5 was preserved, suggesting central compensation. Both spontaneous and driven firing rates decreased following exposure. Mean vector strength to amplitude-modulated tones was unchanged, but response variability increased. Neurometric analysis and mutual information showed degraded AM detection in carboplatin-exposed fibers, an effect accounted for by reduced driven rate (i.e., normalizing spike counts across groups removed the group difference). Background noise degraded AM coding similarly in both groups. Pooled-neurometric modeling showed that population redundancy compensated for impaired fibers in quiet, but not in noise, where carboplatin-exposed pools remained worse. These findings indicate that IHC dysfunction degrades envelope coding by reducing neural output rather than by altering temporal synchrony. This study suggests IHC dysfunction is a phenotype consistent with "hidden hearing loss" (but distinct from cochlear synaptopathy), and motivates suprathreshold clinical assays.

Recently, it was proposed that a processing principle called adaptive stochastic resonance plays a major role in the auditory system, and serves to maintain optimal sensitivity even to highly variable sound pressure levels. As a side effect, in case of reduced auditory input, such as permanent hearing loss, this mechanism may eventually lead to the perception of phantom sounds like tinnitus or the Zwicker tone illusion. Using computational modeling, the biological plausibility of this processing principle was already demonstrated. Here, we provide empirical results that further support the stochastic resonance model of auditory perception. In particular, Mongolian gerbils were exposed to long-term notched noise, which mimics hearing loss for frequencies within the notch. Remarkably, the animals developed increased sensitivity, i.e. improved hearing thresholds, for the frequency centered within the notch, but nut for frequencies outside the notch. In addition, most animals treated with the new paradigm showed identical behavioral signs of phantom sound perception as animals with acoustic trauma induced tinnitus. In contrast, animals treated with broadband noise as a control condition did not show any significant threshold change, nor behavioral signs of phantom sound perception.

The relation between speech recognition and hereditary hearing loss is not straightforward. Impaired cochlear processing of sound might be determined by underlying genetic defects. Data obtained in nine groups of patients with a specific type of genetic hearing loss were evaluated. For each group, the affected cochlear structure, or site-of-lesion, was determined based on previously published animal studies. Retrospectively obtained speech recognition scores in noise were related to several aspects of supra-threshold cochlear processing, as assessed by psychophysical measurements. The differences in speech perception in noise between these patient groups could be explained by these factors, and partially by the hypothesized affected structure of the cochlea, suggesting that speech recognition in noise was associated with genetics-related malfunctioning of the cochlea.

Human temporal bones suggest a steady decline of cochlear synapses with age and greater synapse loss in adults with a history of military or occupational noise exposure. However, there is currently no validated method of diagnosing this type of cochlear deafferentation in living humans. Animal models indicate that cochlear synaptopathy is associated with reduced auditory brainstem response (ABR) wave 1 amplitude and envelope following response (EFR) magnitude for a sinusoidally amplitude modulated (SAM) tone. However, translating the SAM EFR to humans is complicated because it is difficult to obtain this measurement in humans using the same modulation frequency that showed the strongest relationship with synaptopathy in mice (1000 Hz). Computational modeling suggests that EFR magnitude measured with a rectangular amplitude modulated (RAM) tone may be a more sensitive measure of synaptopathy than the SAM EFR. In addition, because synaptopathy likely co-occurs with outer hair cell dysfunction, a diagnostic assay for synaptopathy needs to be robust even when auditory thresholds are abnormal. This study compared the relative ability of the ABR, SAM EFR, and RAM EFR to predict synapse numbers in mice with a large range of auditory thresholds and degrees of synaptopathy. The results indicate that the RAM EFR modulated at 1000 Hz is the single best predictor of synapse number when there is a broad loss of synapses across frequency, while combining RAM EFR and ABR further improves synapse prediction. In contrast, focal synaptopathy is best predicted by ABR wave 1 amplitude. Significance StatementThis study assessed the relative ability of two auditory evoked potentials to identify cochlear synaptopathy, a type of cochlear deafferentation that occurs with age and noise exposure, in mice. Performance of these measures in the presence of outer hair cell (OHC) damage was also evaluated because synaptopathy is expected to often co-occur with OHC dysfunction. Concrete recommendations of measurements to use for non-invasive diagnosis of synaptopathy in humans are provided. This represents a significant advance toward diagnosis of a condition that is thought to have a high prevalence in humans. The ability to identify individuals with cochlear synaptopathy is vital for furthering our understanding of how this auditory deficit impairs auditory perception and the future development of treatment options.

ObjectivesThis study investigated the relationships between the cochlear nerve (CN) health and sentence-level speech perception outcomes measured in quiet and noise in postlingually deafened adult cochlear implant (CI) users. DesignStudy participants included 28 postlingually deafened adult CI users with a Cochlear(R) Nucleus device. For each participant, only one ear was tested. Neural health of the CN was assessed at three or four electrode locations across the electrode array using two parameters derived from results of the electrically evoked compound action potential (eCAP). One parameter was the phase locking value (PLV) which estimated neural synchrony in the CN. The other parameter was the sensitivity of the eCAP amplitude growth function (AGF) slope to changes in the interphase gap (IPG) of biphasic electrical pulses (i.e., the IPGEslope). Speech perception was tested using AzBio sentences in both quiet and a ten-talker babble background noise with +5 dB and +10 dB signal-to-noise ratios (SNR). IPGEslope and PLV values were averaged across electrodes for each subject, both with and without weighting by the frequency importance function (FIF) of the AzBio sentences. Pearson and Spearman correlations were used to assess the pairwise relationships between the IPGEslope, the PLV, and age. Multiple linear regression models with AzBio score as the outcome and the PLV and the IPGEslope as predictors were used to evaluate the associations between the three variables while controlling for age. ResultsThe IPGEslope and the PLV demonstrated different patterns with regards to their relationships with electrode location, age, and speech perception. The PLV, but not the IPGEslope, differed significantly across electrodes, where the apical electrodes had larger PLVs (better neural synchrony) than the basal electrodes. The IPGEslope, but not the PLV, was significantly correlated with participants age, where smaller IPGEslope values (poorer spiral ganglion neuron density) were associated with more advanced age. The PLV, but not the IPGEslope, was significantly associated with AzBio scores in the +5 dB SNR condition, where larger PLVs predicted better speech perception. Neither the PLV nor the IPGEslope was significantly associated with AzBio score in quiet or in the +10 dB SNR condition. The result patterns remained the same regardless of whether the mean values of the IPGEslope and the PLV were weighted by the AzBio FIF. The result patterns generally did not change with fitting methods or input/output scales of the AGF slopes. ConclusionsThe IPGEslope and the PLV quantify different aspects of CN health. The positive association between the PLV and AzBio scores in the +5 dB SNR condition suggests that neural synchrony is important for speech perception in adult CI users in challenging listening conditions with a relatively high noise level. The lack of association between age and the PLV indicates that reduced neural synchrony in the CN is unlikely the primary factor accounting for the greater deficits in understanding speech in noise observed in older CI users, as compared to middle-aged CI users.

Spiral ganglion neurons (SGNs) are the primary auditory afferents in the inner ear. These neurons degenerate in response to a number of conditions, including auditory neuropathies, concussions, and aging. Research to assess the extent of degeneration and to test the efficacy of protective or rehabilitative strategies requires quantification of SGNs from tissue sections. However, manual counting of SGNs can be arduous and time-consuming due to dense crowding and the lack of reliable nuclear-specific labels. SGNs receive afferent input via GluA2-containing AMPA receptors. As the Gria2 transcripts that code for GluA2 must undergo RNA editing to ensure calcium impermeability, we hypothesized that SGNs would express high levels of the adenosine deaminase acting on RNA (ADAR) enzyme ADARB1. Here we confirm enriched expression of Adarb1 in SGNs via in situ hybridization and show that anti-ADARB1 antibodies robustly label the nuclei of both type I and type II SGNs in cochlear sections from young and aged mice. Neuronal specificity was confirmed using antibodies against neurofilament heavy chain (NFH), human antigen D (HuD), GATA binding protein 3 (GATA3), and SRY-box 2 (SOX2). A blinded investigator manually counted SGNs via NFH staining, and these were compared to automated counts of ADARB1-positive nuclei using the analyze particles function in ImageJ. A concordance correlation coefficient and Bland-Altman analysis demonstrated strong agreement between the manual and automated counts. Additionally, immunolabeling of ADARB1 in macaque and human temporal bone sections confirm robust labeling of SGN nuclei, suggesting broad utility of ADARB1 immunolabeling for automated counts of SGNs across species.