Hearing Research

Age-related hearing loss (ARHL) is the most common cause of sensorineural hearing loss. The cochlear nucleus, the first central auditory structure to receive input from the cochlea, has been shown to be disrupted by ARHL. Fusiform cells (FC), the principal output cell of the dorsal part of the cochlear nucleus (DCN), mature physiologically during hearing onset. Specifically, FCs increase in rate of action potential (AP) rise and decay, stabilizing by postnatal day 14 (P14) in mice. However, whether FC intrinsic electrophysiological properties and morphological characteristics continue to change throughout the life of mice, and how they change due to ARHL, is unknown. We characterized electrophysiological and morphological properties of FCs from CBA/CaJ mice at five stages of age: preweaning (P15-20), pubescent (P21-49), young adult (P50-179), mature adult (P180-364), and old adult (P550-578). Our old adult mice had smaller auditory brainstem evoked response amplitudes and loss of some hair cells, indicative of ARHL onset. We observed no change in FC membrane properties with age. FCs from the old adult group had elevated firing rates, faster repolarization rates, and shorter AP half-widths. Morphologically, there was no change in FC soma shape or size. However, a significant decrease in basal dendritic arborization occurred between preweaning and pubescent ages, followed by an increase in our old adult group, suggesting age-dependent remodeling of the basal dendritic tree at the onset of ARHL. Together, these results suggest that FC physiology and morphology are relatively stable post weaning and become altered during the onset of ARHL. NEW & NOTEWORTHYEx vivo patch-clamp recordings within the DCN are traditionally performed using young mice, rarely exceeding weaning age. Here, we were able to successfully record FCs from mice that were 15 days old up to 578 days old. We observed changes in FC firing properties, AP half-width, repolarization rate, and basal dendritic complexity in our old adult group, suggesting possible compensation for the development of age-related hearing loss.

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.

Little is known about the effects of childhood mild-to-moderate sensorineural hearing loss (MM HL) on the function of the auditory pathway. We aimed to examine the effect of childhood MM HL and the benefit of frequency-specific amplification on both subcortical and cortical auditory processing, and to relate it to speech-perceptual abilities. We recorded subcortical and cortical responses to speech syllables in nineteen children with congenital MM HL (unamplified and amplified), and sixteen children with typical hearing (unamplified sounds only). Speech perception was measured behaviourally. Congenital HL led to smaller subcortical and cortical responses to unamplified speech sounds. There was a significant benefit of amplification on subcortical and early, but not late, cortical responses, with some effects differing across age. No relationship was found between the neural and behavioural measures. Childhood MM HL affects both subcortical and cortical processing of speech. Amplification mostly benefits subcortical processing of speech in younger children. Childhood HL leads to functional changes in the processing of sounds, with amplification differentially affecting subcortical and cortical levels of the auditory pathway.

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.

Optimal speech perception in noise requires successful separation of the target speech stream from multiple competing background speech streams. The ability to segregate these competing speech streams depends on the fidelity of bottom-up neural representations of sensory information in the auditory system and top-down influences of effortful listening. Here, we use objective neurophysiological measures of bottom-up temporal processing using envelope-following responses (EFRs) to amplitude modulated tones and investigate their interactions with pupil-indexed listening effort, as it relates to performance on the Quick speech in noise (QuickSIN) test in young adult listeners with clinically normal hearing thresholds. We developed an approach using ear-canal electrodes and adjusting electrode montages for modulation rate ranges, which extended the rage of reliable EFR measurements as high as 1024Hz. Pupillary responses revealed changes in listening effort at the two most difficult signal-to-noise ratios (SNR), but behavioral deficits at the hardest SNR only. Neither pupil-indexed listening effort nor the slope of the EFR decay function independently related to QuickSIN performance. However, a linear model using the combination of EFRs and pupil metrics significantly explained variance in QuickSIN performance. These results suggest a synergistic interaction between bottom-up sensory coding and top-down measures of listening effort as it relates to speech perception in noise. These findings can inform the development of next-generation tests for hearing deficits in listeners with normal-hearing thresholds that incorporates a multi-dimensional approach to understanding speech intelligibility deficits.

Although estrogen affects the structure and function of the nervous system and brain and has a number of effects on cognition, its roles in the auditory and vestibular systems remain unclear. The actions of estrogen are mediated predominately through two classical nuclear estrogen receptors, estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2). In the current study, we investigated the roles of ESR1 in normal auditory function and balance performance using 3-month-old wild-type (WT) and Esr1 knockout (KO) mice on a CBA/CaJ background, a normal-hearing strain. As expected, body weight of Esr1 KO females was lower than that of Esr1 KO males. Body weight of Esr1 KO females was higher than that of WT females, while there was no difference in body weight between WT and Esr1 KO males. Similarly, head diameter was higher in Esr1 KO vs. WT females. Contrary to our expectations, there were no differences in auditory brainstem response (ABR) thresholds, ABR waves I-V amplitudes and ABR waves I-V latencies at 8, 16, 32, and 48 kHz, distortion product otoacoustic emission (DPOAE) thresholds and amplitudes at 8, 16, and 32 kHz, and rotarod balance performance (latency to fall) between WT and Esr1 KO mice. Furthermore, there were no sex differences in ABRs, DPOAEs, and rotarod balance performance in Esr1 KO mice. Taken together, our findings show that Esr1 deficiency does not affect auditory function or balance performance in normal hearing mice, and suggest that loss of Esr1 is likely compensated by ESR2 or other estrogen receptors to maintain the structure and function of the auditory and vestibular systems under normal physiological conditions. HighlightsO_LIHead diameter of female Esr1 KO mice was higher than that of female WT mice. C_LIO_LIABRs and DPOAEs were not different in WT and Esr1 KO mice. C_LIO_LIThere were no sex differences in ABRs and DPOAEs in Esr1 KO mice. C_LIO_LIRotarod balance performance was not different in WT and Esr1 KO mice. C_LIO_LIThere were no sex differences in rotarod balance performance in Esr1 KO mice. C_LIO_LILoss of Esr1 does not affect auditory function or balance performance under normal physiological conditions. C_LI

One of the fundamental features of age-related hearing loss (ARHL) is difficulty discriminating speech signals from background noise. In addition to protecting the ear from acoustic trauma, olivocochlear (OC) efferent neurons participate in signal discrimination by virtue of their inhibitory actions on auditory nerve firing. Given the time course of peripheral degeneration in ARHL, we sought to investigate the central degeneration of medial (MOC) and lateral (LOC) efferent neurons in mutant mice that exhibit genetic hearing loss or deafness at different ages. Tests of cochlear function were combined with anatomical and morphological quantification of changes to somatic number, morphology, and location of OC neurons. Neuronal tract tracing methods were employed to label OC neurons in 1-, 3-, and 6-month-old CBA/CaH mice with normal hearing; DBA/2J mice with progressive, high frequency hearing loss; and homozygous Shaker2 mice with congenital deafness. Deaf Shaker2-/- animals exhibited age-related atrophy and loss of MOCs, with contralateral MOCs more affected than ipsilateral MOCs, while LOCs were largely unaffected. No such OC degeneration was observed in DBA/2J mice, even after progressive elevation of low frequency auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAE) thresholds. Thus, OC efferent neurons can appear morphologically normal in the complete absence of acoustic input in early life (as in deaf Shaker2-/- animals) and that the retention of these neurons is not affected by late onset high-frequency hearing loss observed in DBA/2J animals. Differential patterns of MOC neuron degeneration may affect functional plasticity of auditory brainstem feedback circuitry in ARHL.

GABAergic neurons in the inferior colliculus (IC) play a crucial role in auditory processing by extracting specific features of sounds (Ono et al., 2005). The Gad67-GFP mouse model developed by Tamamaki et al. in 2003 on a Swiss background facilitates studying these neurons by using a green fluorescent protein that is expressed endogenously via the GAD67 promoter. Unfortunately, this mouse suffers from accelerated aging-related hearing loss, limiting its utility in studying the auditory system. Here, we report the results of an 8-generation backcross of this line onto CBA/CaJ mice, which produces mice with stable low-threshold hearing while retaining GFP expression in GAD+ neurons. Additionally, this study investigates mechanisms that underlie hearing loss in the Gad67-GFP mouse model by focusing specifically on cochlear hair cells (HCs) and ribbon synapses, which may contribute to both model-specific hearing loss and clinical disorders like presbycusis. Findings revealed the newly generated F1 mouse model that resulted from the Gad67-GFP x CBA/CaJ backcross maintained better hearing thresholds when compared to ABR data for Gad67 and Swiss mice and very closely resembled those of the CBA/CaJ mice, mirroring progression of presbycusis in humans. Additionally, all morphological changes observed in cochlear structure correlated to ABR thresholds. F1 mice continued maintained expression of the GAD67 promoter in the IC via immunostaining.

The auditory system is extremely efficient to extract audio information in the presence of background noise. However, the neural mechanisms related to this efficiency is still greatly misunderstood, especially in the inferior colliculus (IC). In fact, while noise processing under different conditions has been investigated at the auditory cortex level, studies in the IC have been much limited. One interesting observation has been that there seems to be some degree of noise invariance in the IC in the presence of white noise. We wish to broaden this knowledge by investigating if there is a difference in the activity of neurons in the IC, when presenting noisy vocalisations with different types of noises, input signal-to-noise ratios (SNR) and signal levels. We do so using a generalized linear model (GLM), which gives us the ability to study the neural activity under these different conditions at a per neuron level. We found that non-stationary noise is the only noise type that clearly contributes to the neural activity in the IC, regardless of the SNR, input level or vocalisation type. However, when presenting white or natural stationary noises, a great diversity of responses was observed for the different conditions, where the activity of some neurons was affected by the presence of noise and the activity of others was not. Therefore, there seems to be some level of background noise invariance as early as the IC level, as reported before, however, this invariance seems to be highly dependent on the noisy conditions. New & NoteworthyThe neural mechanisms of auditory perception in the presence of background noise are still not well understood, especially in the IC. We studied neural activity in the IC when presenting noisy vocalisations using different background noise types, SNRs and input sound levels. We observed that only the non-stationary noise type clearly contributes to the neural activity in the IC. The noise invariance previously observed in the IC thus seems dependent on the noisy conditions.

Information about eye movements is necessary for linking auditory and visual information across space. Recent work has suggested that such signals are incorporated into processing at the level of the ear itself (Gruters, Murphy et al. 2018). Here we report confirmation that the eye movement signals that reach the ear can produce perceptual consequences, via a case report of an unusual participant with tensor tympani myoclonus who hears sounds when she moves her eyes. The sounds she hears could be recorded with a microphone in the ear in which she hears them (left), and occurred for large leftward eye movements to extreme orbital positions of the eyes. The sounds elicited by this participants eye movements were reminiscent of eye movement-related eardrum oscillations (EMREOs, (Gruters, Murphy et al. 2018, Brohl and Kayser 2023, King, Lovich et al. 2023, Lovich, King et al. 2023, Lovich, King et al. 2023, Abbasi, King et al. 2025, Sotero Silva, Kayser et al. 2025, King and Groh 2026, Leon, Ramos et al. 2026, Sotero Silva, Brohl et al. 2026)), but were larger and longer lasting than classical EMREOs, helping to explain why they were audible to her. Overall, the observations from this patient help establish that (a) eye movement-related signals specifically reach the tensor tympani muscle and that (b) when there is an abnormality involving that muscle, such signals can lead to actual audible percepts. Given that the tensor tympani contributes to the regulation of sound transmission in the middle ear, these findings support that eye movement signals reaching the ear have functional consequences for auditory perception. The findings also expand the types of medical conditions that produce gaze-evoked tinnitus, to date most commonly observed in connection with acoustic neuromas.

Many elderly listeners have difficulties with speech-in-noise perception, even if auditory thresholds in quiet are normal. The mechanisms underlying this compromised speech perception with age are still not understood. For identifying the physiological causes of these age-related speech perception difficulties, an appropriate animal model is needed enabling the use of invasive methods. In a comparative behavioral study, we used young-adult and quiet-aged Mongolian gerbils as well as young and elderly human subjects to investigate the age-related changes in speech-in-noise perception evaluating whether gerbils are an appropriate animal model for the age-related decline in speech-in-noise processing of human listeners. Gerbils and human subjects had to report a deviant consonant-vowel-consonant combination (CVC) or vowel-consonant-vowel combination (VCV) in a sequence of CVC or VCV standards, respectively. The logatomes were spoken by different speakers and masked by a steady-state speech-shaped noise. Response latencies were measured to generate perceptual maps employing multidimensional scaling, visualizing the subjects internal representation of the sounds. By analyzing response latencies for different types of vowels and consonants, we investigated whether aging had similar effects on speech-in-noise perception in gerbils compared to humans. For evaluating peripheral auditory function, auditory brainstem responses and audiograms were measured in gerbils and human subjects, respectively. We found that the overall phoneme discriminability in gerbils was independent of age, whereas consonant discriminability was declined in humans with age. Response latencies were generally longer in aged than in young gerbils and humans, respectively. Response latency patterns for the discrimination of different vowel or consonant types were different between species, but both gerbils and humans made use of the same articulatory features for phoneme discrimination. The species-specific response latency patterns were mostly unaffected by age across vowel types, while there were differential aging effects on the species-specific response latency patterns of different consonant types.

ObjectivesSensorineural hearing loss is common with advancing age, but even with normal or near-normal hearing in older persons, performance deficits are often seen for suprathreshold listening tasks such as understanding speech in background noise or localizing sound direction. This suggests there is also a more central source of the problem. Objectives of this study were to examine as a function of age (young adult to septuagenarian) performance on: 1) a spatial acuity task examining localization ability, and a spatial speech-in-noise (SSIN) recognition task, both measured in a hemi-anechoic sound field using a circular horizontal-plane loudspeaker array, and 2) a suprathreshold auditory temporal processing task and a spectro-temporal processing task, both measured under headphones. Further, we examined any correlations between age, hearing thresholds including extended high frequency (EHF: >8000 Hz), and these measures. DesignSubjects were 48 adults, aged 21 to 78, with either normal hearing or only a mild sensorineural hearing loss through 4000 Hz. The localization task measured minimum audible angle (MAA) for 500 and 4000 Hz 1/3rd octave narrowband noise (NBN) in diffuse background noise for both an on-axis (reference source 0{degrees}) and off-axis (reference source 45{degrees}) listening condition at signal-to-noise ratios (SNRs) of -3, -6, -9, and -12 dB. SSIN testing was also completed for key word recognition in sentences in multi-talker babble noise; specifically, the separation between speech and noise loudspeakers was adaptively varied to determine the difference needed for 40% and 80% correct performance levels. Finally, auditory temporal processing ability was examined using the Temporal Fine Structure (TFS) test, and the Spectro-Temporal Modulation (STM) test. ResultsSpatial acuity was poorer (larger MAAs) in older compared to younger subjects, particularly in the more adverse listening conditions (off-axis, and poorer SNRs). The SSIN data also showed declining mean performance with age at both criterion levels, emerging in the middle age group (> 40 years), but was not correlated with standard audiometric hearing thresholds. Decreased performance on the TFS and STM tasks was dependent on age, emerging only in the older (> 60 years) and middle (>40 years) age groups, respectively; neither was dependent on hearing thresholds. Results of multiple regression analyses suggest that SSIN recognition scales with the ability of the subjects to use both low-frequency binaural temporal fine structure as well as higher-frequency binaural envelope cues, both of which are impacted by aging but not necessarily audiometric hearing thresholds. Finally, EHF range hearing thresholds significantly decreased with age, but performance on tasks remained significantly correlated with age when controlled for EHF hearing. ConclusionsParticularly for more adverse listening conditions, age-related deficits, but not hearing-threshold-related deficits, were found on both of the spatial hearing tasks and in temporal and spectro-temporal processing abilities. It may be that deficits in temporal processing ability contribute to poorer spatial hearing performance in older subjects due to inaccurate coding of binaural/interaural timing information sent from the periphery to the binaural brainstem. In addition, EHF hearing loss may be a coexisting factor in the reduced performance seen in older subjects.

ObjectiveIn recent years, many researchers have recommended using narrowband chirp (NBchirp) stimuli for Auditory Brainstem Response (ABR) audiometry instead of more-standard 2-1-2 cycles linear-gated tones, primarily because NBchirps often result in larger ABR wave V amplitudes. However, the acoustic frequency spectra of currently recommended NBchirps are wider than those for 2-1-2 tones, and it is currently not known whether ABRs to these NBchirps have similar (or poorer) cochlear place specificity compared to 2-1-2 tones. The current study used the high-pass noise/derived response technique to assess the cochlear regions contributing to ABRs evoked by NBchirp versus 2-1-2 stimuli. DesignA total of 24 adults with normal hearing participated (N=12 for each stimulus frequency). Stimuli were 60-dB peSPL 500- and 2000-Hz NBchirps and 2-1-2 tones mixed with high-pass (HP) filtered masking noise. The level of broadband (pink) noise required to mask the ABR was determined individually, then the broadband noise at this level was HP filtered at [1/2]-octave intervals. Three ABR replications were obtained for each condition, with recordings stopped when the residual noise level of each replication was reduced to 40 nanovolts. Derived responses (DRs) representing 1-octave-wide or [1/2]-octave-wide cochlear regions were calculated by subtracting ABRs recorded in HP noise. ResultsNon-masked ABR amplitudes in response to NBchirps were significantly larger than those to 2-1-2 stimuli, averaging 55% larger for 500 Hz and 81% larger for 2000 Hz. For both 500- and 2000-Hz stimuli, HP noise masking produced significant amplitude decreases, occurring 1 to [1/2] octave higher for ABRs to NBchirps versus 2-1-2 tones. One-octave-wide and [1/2]-octave-wide DR amplitude profiles for the ABRs to 2-1-2 tones showed good cochlear place specificity, as described in previous studies. DR results for the NBchirps were similar but showed important differences. The profiles for the 2000-Hz NBchirps showed significantly larger amplitudes in the 4- and 1-kHz DRs compared to the 2-1-2 stimuli. Many more responses were seen 1-octave away for the 2000-Hz NBchirp compared to 2-1-2 tone. DR results for 500-Hz tones showed similar patterns but differences did not quite reach statistical significance, except amplitudes to NBchirps were larger at DR354, DR500 and DR707. A measure of the width of the 1-octave-wide and [1/2]-octave-wide DR amplitude profiles (BW0.075, in Hz) showed the 500- and 2000-Hz NBchirp profiles were significantly wider (32% to 77%) compared to those for 2-1-2 stimuli. As the cochlear area able to respond decreased, wave V amplitudes to NBchirp stimuli decreased more than those for 2-1-2 stimuli, with no difference between stimuli for [1/2]-octave-wide responses. ConclusionABRs to narrowband chirps reflect wider cochlear contributions than those to 2-1-2 tones. Responses to NBchirps arise from cochlear regions as far as one octave away from the stimulus frequency. In contrast, responses to 2-1-2 tones arise from cochlear regions primarily within approximately {+/-}0.5 octaves of the stimulus frequency. Further research in individuals with hearing loss is required to determine whether the wider bandwidths for NBchirps result in threshold mis-estimations, and whether NBchirp amplitude advantages over more-standard stimuli remain with hearing loss.

Developmental plasticity of hearing sensitivity (DPHS) has been verified in some groups of vertebrates. Turtles face a trade-off between terrestrial and aquatic hearing in different acoustic environments throughout ontogeny. However, how chelonian hearing sensitivity changes throughout ontogeny is still unclear. To verify DPHS in turtles, auditory brainstem responses (ABR) were compared using hearing thresholds and latencies in female red-eared slider (Trachemys scripta elegans) aged 1 week, 1 month, 1 year, and 5 years, and the results showed hearing sensitivity bandwidths of approximately 200-1100, 200-1100, 200-1300, and 200-1400 Hz, respectively. The lowest threshold sensitivity was approximately 600{square}Hz. Below 600 Hz, ABR threshold decreased rapidly with increasing age (1 week to 1 year), with significant differences between age groups, but no significant difference between the 1- and 5-year age groups (stimulus frequency, 200-600 Hz). Above 600 Hz, ABR threshold was the lowest in the 5-year age group. These findings show that aging was accompanied by hearing sensitivity changes, suggesting rapid, frequency-segmented development during ontogeny. This variability in hearing sensitivity differs from that reported in other vertebrates, and allows adaptation to acoustically distinct environments throughout ontogeny. Our findings further elucidate the developmental patterns of the vertebrate auditory system.

The medial olivocochlear (MOC) efferent system modulates outer hair cell (OHC) excitability and protects cochlea from overstimulation. Cholinergic activation of 910 nicotinic acetylcholine receptors (nAChRs) triggers Ca{superscript 2} influx, activating BK and SK2 Ca{superscript 2}-dependent K channels, and K extrusion through KCNQ4 to restore membrane potential. KCNQ4-loss causes chronic depolarization, OHC dysfunction, and hearing loss. Here, we investigated how KCNQ4 deficiency affects cochlear efferent synapse development and organization. Using confocal immunofluorescence, we analyzed efferent innervation in the organ of Corti of Kcnq4-/- (KO) and Kcnq4+/+(WT) mice at 2, 3, 4, and 10 postnatal weeks (W). At 2 W, efferent terminals were similarly distributed between basal and lateral OHC membrane domains in both genotypes. During maturation, WT mice exhibited complete relocation of MOC terminals to the basal domain, whereas KO mice showed delayed maturation, with some terminals laterally displaced up to 10 W. KCNQ4 absence was associated with reduced number and volume of efferent boutons on OHCs. Milder morphometric alterations were observed in efferent boutons within the inner hair cell region. At the molecular level, qPCR revealed downregulation of 10 nAChR subunit, BK, and SK2 transcripts in KO at 4 W, with recovery to 10 W. Despite this recovery, BK protein showed reduced expression, mislocalization, and disorganized synaptic plaques in OHCs. KO also displayed age-dependent upregulation of the calcium-binding proteins calbindin and calretinin, suggesting compensatory responses to altered Ca+{superscript 2} homeostasis. Together, these findings demonstrate that KCNQ4 is essential for OHC repolarization, maturation and maintenance of cochlear efferent synapses. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=179 HEIGHT=200 SRC="FIGDIR/small/700803v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@134e2caorg.highwire.dtl.DTLVardef@1155f45org.highwire.dtl.DTLVardef@21b4ccorg.highwire.dtl.DTLVardef@e4ee62_HPS_FORMAT_FIGEXP M_FIG C_FIG

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

The sounds we experience in our everyday communication can vary greatly in terms of level and background noise depending on the environment. Paradoxically, increasing the sound intensity may lead to worsened speech understanding, especially in noise. This is known as the "Rollover" phenomenon. There have been limited studies on rollover and how it is experienced differentially across aging groups, for those with and without hearing loss, as well as cochlear implant (CI) users. There is also mounting evidence that listening effort plays an important role in challenging listening conditions and can be directly quantified with objective measures such as pupil dilation. We found that listening effort was modulated by sound level and that rollover occurred primarily in the presence of background noise. The effect on listening effort was exacerbated by age and hearing loss in acoustic listeners, with greatest effect in older listeners with hearing loss, while there was no effect in CI users. The age- and hearing-dependent effects of rollover highlight the potential negative impact of amplification to high sound levels and therefore has implications for effective treatment of age-related hearing loss.

PurposeThe sensitivity of auditory neurons in response to electric stimulation in cochlear implant (CI) listeners may reflect neuronal health, which is a major contributor to variability in performance outcomes among CI listeners. In the current study, we explore the interplay of three outcome measures of neural sensitivity, perceptual focused thresholds, objective electrically-evoked compound action potentials (ECAP), and the Failure Index (FI). We further explore the influence of CI experience and how the measures may contribute to speech perception performance. MethodsWe examined focused perceptual threshold measures, ECAP stimulation levels and N1P2 peak response amplitudes, and ECAP input-to-output relationships in 29 adult CI recipients (14 females, 11 males, four who were bilaterally implanted). Pearson correlation analysis was performed to investigate subject specific relationships across CI electrodes, and linear mixed-effects models (LMM) were used to identify links between the outcome measures accounting for individual variation. ResultsIndividual outcomes revealed large within and across subject variability for focused thresholds, ECAP peak amplitudes, and FI. The LMMs showed, that low focused threshold measurements correspond to large ECAP peak amplitudes, while high ECAP stimulation levels reflect large ECAP peak amplitudes. Furthermore, clinical speech perception seems to be influenced by the relationship of focused thresholds and FI, with lower performance for stronger associations. ConclusionOur findings suggest that the combination of objective ECAP response measures and perceptual measures could be a robust estimate of neural health and may act as an early estimate of the speech performance abilities in CI listeners.

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.

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