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Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound-evoked cochlear compound action potentials, has been proposed to contribute to hearing difficulty in noisy environments in people with normal hearing thresholds and has become a widespread complaint. While most studies on HHL pathogenesis have focused on inner hair cell (IHC) synaptopathy, we recently showed that transient auditory nerve (AN) demyelination also causes HHL in mice. To test the effect of myelinopathy on hearing in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibited the functional hallmarks of HHL together with disorganization of AN heminodes near the IHCs with minor loss of AN fibers. These results support the hypothesis that mild disruptions of AN myelination can cause HHL and that heminodal defects contribute to the alterations in the sound-evoked cochlear compound action potentials seen in this mouse model. Furthermore, these findings suggest that patients with CMT1A or other mild peripheral neuropathies are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in patients with CMT1A might help develop robust clinical tests for HHL, which are currently lacking.

Objective: To assess hearing and speech outcomes in pediatric patients with bilateral cochlear nerve deficiency (CND) who underwent cochlear implantation (CI) and to identify factors associated with improved outcomes., Databases Reviewed: PubMed, Embase, Web of Science, and Cochran databases were searched following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Methods: Studies that reported hearing and speech outcomes of pediatric patients with bilateral CND who underwent CI were included. Demographics, comorbidities, inner ear abnormalities, CND classification (aplasia or hypoplasia), details of diagnostic workup, and outcomes data were extracted. Outcomes were assessed using the four-level auditory performance level (APL) scale. Meta-analysis, using Cochran-Armitage tests, was performed on patients with individual data to assess factors associated with performance., Results: A total of 314 papers were screened, and 40 papers with 378 total patients met inclusion criteria. A total of 339 patients had patient-level data and were included in the meta-analysis. Of the 339 patients, 19% (n = 63) of patients had no measurable stimulation, 28% (n = 95) had improved detection, 22% (n = 76) achieved closed-set speech perception, and 31% (n = 105) achieved open-set speech perception. Patients with cochlear nerve aplasia (p = 0.016) and syndromes (p < 0.001) had significantly worse APL scores relative to patients with cochlear nerve hypoplasia and patients without syndromes, respectively., Conclusions: While most patients with bilateral CND benefit from CI and almost one-third of patients achieved open-set speech perception, outcomes were heterogenous and one-fifth of patients did not experience measurable benefit from CI., (Copyright © 2024, Otology & Neurotology, Inc.)

This study investigated whether selective apical stimulation improves temporal pitch perception in eight MED-EL cochlear implant recipients and whether any such improvement relates to auditory-nerve survival. Three stimulation conditions differing in the place and width of excitation were evaluated: single-electrode stimulation of (i) the most apical, (ii) a mid-array electrode, and (iii) multi-electrode stimulation of the four most apical electrodes. Stimulation-current-induced non-stimulating electrode voltages were recorded to identify extracochlear electrodes and gauge insertion depth. The pitches of the four most apical electrodes were compared using place-pitch ranking. Rate-pitch ranking was assessed between 80 and 981 pulses per second for the three stimulation conditions, to estimate the "upper limit" of temporal pitch. Single-electrode apical stimulation did not increase the upper limit relative to other conditions. The polarity effect (PE), defined as the difference between thresholds obtained for triphasic pulse trains with their central high-amplitude phase either anodic or cathodic, was obtained to evaluate peripheral neural health. The PE did not differ between apical and mid-array stimulation or correlate with the upper limit. In conclusion, we found no improvement of temporal pitch perception with single-electrode apical stimulation, and discuss possible explanations for this observation., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Objectives: Electrocochleography (ECochG) appears to offer the most accurate prediction of post-cochlear implant hearing outcomes. This may be related to its capacity to interrogate the health of underlying cochlear tissue. The four major components of ECochG (cochlear microphonic [CM], summating potential [SP], compound action potential [CAP], and auditory nerve neurophonic [ANN]) are generated by different cochlear tissue components. Analyzing characteristics of these components can reveal the state of hair and neural cell in a cochlea. There is limited evidence on the characteristics of intracochlear (IC) ECochG recordings measured across the array postinsertion but compared with extracochlear recordings has better signal to noise ratio and spatial specificity. The present study aimed to examine the relationship between ECochG components recorded from an IC approach and postoperative speech perception or audiometric thresholds., Design: In 113 human subjects, responses to 500 Hz tone bursts were recorded at 11 IC electrodes across a 22-electrode cochlear implant array immediately following insertion. Responses to condensation and rarefaction stimuli were then subtracted from one another to emphasize the CM and added to one another to emphasize the SP, ANN, and CAP. Maximum amplitudes and extracochlear electrode locations were recorded for each of these ECochG components. These were added stepwise to a multi-factor generalized additive model to develop a best-fit model predictive model for pure-tone audiometric thresholds (PTA) and speech perception scores (speech recognition threshold [SRT] and consonant-vowel-consonant phoneme [CVC-P]) at 3- and 12-month postoperative timepoints. This best-fit model was tested against a generalized additive model using clinical factors alone (preoperative score, age, and gender) as a null model proxy., Results: ECochG-factor models were superior to clinical factor models in predicting postoperative PTA, CVC-P, and SRT outcomes at both timepoints. Clinical factor models explained a moderate amount of PTA variance ( r2 = 45.9% at 3-month, 31.8% at 12-month, both p < 0.001) and smaller variances of CVC-P and SRT ( r2 range = 6 to 13.7%, p = 0.008 to 0.113). Age was not a significant predictive factor. ECochG models explained more variance at the 12-month timepoint ( r2 for PTA = 52.9%, CVC-P = 39.6%, SRT = 36.4%) compared with the 3-month one timepoint ( r2 for PTA = 49.4%, CVC-P = 26.5%, SRT = 22.3%). The ECochG model was based on three factors: maximum SP deflection amplitude, and electrode position of CM and SP peaks. Adding neural (ANN and/or CAP) factors to the model did not improve variance explanation. Large negative SP deflection was associated with poorer outcomes and a large positive SP deflection with better postoperative outcomes. Mid-array peaks of SP and CM were both associated with poorer outcomes., Conclusions: Postinsertion IC-ECochG recordings across the array can explain a moderate amount of postoperative speech perception and audiometric thresholds. Maximum SP deflection and its location across the array appear to have a significant predictive value which may reflect the underlying state of cochlear health., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This paper reports a noninvasive method for quantifying neural synchrony in the cochlear nerve (i.e., peripheral neural synchrony) in cochlear implant (CI) users, which allows for evaluating this physiological phenomenon in human CI users for the first time in the literature. In addition, this study assessed how peripheral neural synchrony was correlated with temporal resolution acuity and speech perception outcomes measured in quiet and in noise in postlingually deafened adult CI users. It tested the hypothesis that peripheral neural synchrony was an important factor for temporal resolution acuity and speech perception outcomes in noise in postlingually deafened adult CI users., Design: Study participants included 24 postlingually deafened adult CI users with a Cochlear™ Nucleus® device. Three study participants were implanted bilaterally, and each ear was tested separately. For each of the 27 implanted ears tested in this study, 400 sweeps of the electrically evoked compound action potential (eCAP) were measured at four electrode locations across the electrode array. Peripheral neural synchrony was quantified at each electrode location using the phase-locking value (PLV), which is a measure of trial-by-trial phase coherence among eCAP sweeps/trials. Temporal resolution acuity was evaluated by measuring the within-channel gap detection threshold (GDT) using a three-alternative, forced-choice procedure in a subgroup of 20 participants (23 implanted ears). For each ear tested in these participants, GDTs were measured at two electrode locations with a large difference in PLVs. For 26 implanted ears tested in 23 participants, speech perception performance was evaluated using consonant-nucleus-consonant (CNC) word lists presented in quiet and in noise at signal to noise ratios (SNRs) of +10 and +5 dB. Linear Mixed effect Models were used to evaluate the effect of electrode location on the PLV and the effect of the PLV on GDT after controlling for the stimulation level effects. Pearson product-moment correlation tests were used to assess the correlations between PLVs, CNC word scores measured in different conditions, and the degree of noise effect on CNC word scores., Results: There was a significant effect of electrode location on the PLV after controlling for the effect of stimulation level. There was a significant effect of the PLV on GDT after controlling for the effects of stimulation level, where higher PLVs (greater synchrony) led to lower GDTs (better temporal resolution acuity). PLVs were not significantly correlated with CNC word scores measured in any listening condition or the effect of competing background noise presented at an SNR of +10 dB on CNC word scores. In contrast, there was a significant negative correlation between the PLV and the degree of noise effect on CNC word scores for a competing background noise presented at an SNR of +5 dB, where higher PLVs (greater synchrony) correlated with smaller noise effects on CNC word scores., Conclusions: This newly developed method can be used to assess peripheral neural synchrony in CI users, a physiological phenomenon that has not been systematically evaluated in electrical hearing. Poorer peripheral neural synchrony leads to lower temporal resolution acuity and is correlated with a larger detrimental effect of competing background noise presented at an SNR of 5 dB on speech perception performance in postlingually deafened adult CI users., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Despite that fact that the cochlear implant (CI) is one of the most successful neuro-prosthetic devices which allows hearing restoration, several aspects still need to be improved. Interactions between stimulating electrodes through current spread occurring within the cochlea drastically limit the number of discriminable frequency channels and thus can ultimately result in poor speech perception. One potential solution relies on the use of new pulse shapes, such as asymmetric pulses, which can potentially reduce the current spread within the cochlea. The present study characterized the impact of changing electrical pulse shapes from the standard biphasic symmetric to the asymmetrical shape by quantifying the evoked firing rate and the spatial activation in the guinea pig primary auditory cortex (A1). At a fixed charge, the firing rate and the spatial activation in A1 decreased by 15 to 25 % when asymmetric pulses were used to activate the auditory nerve fibers, suggesting a potential reduction of the spread of excitation inside the cochlea. A strong "polarity-order" effect was found as the reduction was more pronounced when the first phase of the pulse was cathodic with high amplitude. These results suggest that the use of asymmetrical pulse shapes in clinical settings can potentially reduce the channel interactions in CI users., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The use of cochlear implants (CIs) is on the rise for patients with vestibular schwannoma (VS). Besides CI following tumor resection, new scenarios such as implantation in observed and/or irradiated tumors are becoming increasingly common. A significant emerging trend is the need of intraoperative evaluation of the functionality of the cochlear nerve in order to decide if a CI would be placed. The purpose of this paper is to explore the experience of a tertiary center with the application of the Auditory Nerve Test System (ANTS) in various scenarios regarding VS patients. The results are compared to that of the studies that have previously used the ANTS in this condition. Patients with unilateral or bilateral VS (NF2) who were evaluated with the ANTS prior to considering CI in a tertiary center between 2021 and 2023 were analyzed. The presence of a robust wave V was chosen to define a positive electrical auditory brainstem response (EABR). Two patients underwent promontory stimulation (PromStim) EABR previous to ANTS evaluation. Seven patients, 2 NF-2 and 5 with sporadic VS were included. The initial scenario was simultaneous translabyrinthine (TL) tumor resection and CI in 3 cases while a CI placement without tumor resection was planned in 4 cases. The ANTS was positive in 4 cases, negative in 2 cases, and uncertain in one case. Two patients underwent simultaneous TL and CI, 1 patient simultaneous TL and auditory brainstem implant, 3 patients posterior tympanotomy with CI, and 1 patient had no implant placement. In the 5 patients undergoing CI, sound detection was present. There was a good correlation between the PromStim and ANTS EABR. The literature research yielded 35 patients with complete information about EABR response. There was one false negative and one false positive case; that is, the 28 implanted cases with a present wave V following tumor resection had some degree of auditory perception in all but one case. The ANTS is a useful intraoperative tool to asses CI candidacy in VS patients undergoing observation, irradiation or surgery. A positive strongly predicts at least sound detection with the CI., Competing Interests: Declaration of competing interest Miguel Díaz is employed at MED-EL as a clinical engineer; this function entails support during surgery. MED-EL was not involved in the study design, collection and analysis of data or the decision to submit it for publication., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Deaf children with cochlear nerve canal stenosis (CNCs) are always considered poor candidates for cochlear implantation., Objectives: To investigate the function of the peripheral auditory pathway in deaf children with CNCs, as revealed by the electrically evoked auditory brainstem response (EABR), and postoperative cochlear implants (CIs) outcomes., Materials and Methods: Thirteen children with CNCs and 13 children with no inner ear malformations (IEMs) who received CIs were recruited. The EABR evoked by electrical stimulation from the CI electrode was recorded. Postoperative CI outcomes were assessed using Categories of Auditory Performance (CAP) and Speech Intelligibility Rate (SIR)., Results: Compared with children with no IEMs, children with CNCs showed lower EABR extraction rates, higher thresholds, a longer wave V (eV) latency and lower CAP and SIR scores. The auditory and speech performance was positively correlated with the diameter of the cochlear nerve canal and the number of channels showing wave III (eIII) and eV in children with CNCs., Conclusions and Significance: The physiological function of the peripheral auditory pathway in children with CNCs is poorer than that in children with no IEMs. Postoperative auditory and speech abilities may depend on the severity of cochlear nerve malformation and auditory conduction function.

It is critical for hearing that the descending cochlear efferent system provides a negative feedback to hair cells to regulate hearing sensitivity and protect hearing from noise. The medial olivocochlear (MOC) efferent nerves project to outer hair cells (OHCs) to regulate OHC electromotility, which is an active cochlear amplifier and can increase hearing sensitivity. Here, we report that the MOC efferent nerves also could innervate supporting cells (SCs) in the vicinity of OHCs to regulate hearing sensitivity. MOC nerve fibers are cholinergic, and acetylcholine (ACh) is a primary neurotransmitter. Immunofluorescent staining showed that MOC nerve endings, presynaptic vesicular acetylcholine transporters (VAChTs), and postsynaptic ACh receptors were visible at SCs and in the SC area. Application of ACh in SCs could evoke a typical inward current and reduce gap junctions (GJs) between them, which consequently enhanced the direct effect of ACh on OHCs to shift but not eliminate OHC electromotility. This indirect, GJ-mediated inhibition had a long-lasting influence. In vivo experiments further demonstrated that deficiency of this GJ-mediated efferent pathway decreased the regulation of active cochlear amplification and compromised the protection against noise. In particular, distortion product otoacoustic emission (DPOAE) showed a delayed reduction after noise exposure. Our findings reveal a new pathway for the MOC efferent system via innervating SCs to control active cochlear amplification and hearing sensitivity. These data also suggest that this SC GJ-mediated efferent pathway may play a critical role in long-term efferent inhibition and is required for protection of hearing from noise trauma. NEW & NOTEWORTHY The cochlear efferent system provides a negative feedback to control hair cell activity and hearing sensitivity and plays a critical role in noise protection. We reveal a new efferent control pathway in which medial olivocochlear efferent fibers have innervations with cochlear supporting cells to control their gap junctions, therefore regulating outer hair cell electromotility and hearing sensitivity. This supporting cell gap junction-mediated efferent control pathway is required for the protection of hearing from noise.

A common complaint of older adults is difficulty understanding speech, particularly in challenging listening conditions. Accumulating evidence suggests that these difficulties may reflect a loss and/or dysfunction of auditory nerve (AN) fibers. We used a novel approach to study age-related changes in AN structure and several measures of AN function, including neural synchrony, in 58 older adults and 42 younger adults. AN activity was measured in response to an auditory click (compound action potential; CAP), presented at stimulus levels ranging from 70 to 110 dB pSPL. Poorer AN function was observed for older than younger adults across CAP measures at higher but not lower stimulus levels. Associations across metrics and stimulus levels were consistent with age-related AN disengagement and AN dyssynchrony. High-resolution T2-weighted structural imaging revealed age-related differences in the density of cranial nerve VIII, with lower density in older adults with poorer neural synchrony. Individual differences in neural synchrony were the strongest predictor of speech recognition, such that poorer synchrony predicted poorer recognition of time-compressed speech and poorer speech recognition in noise for both younger and older adults. These results have broad clinical implications and are consistent with an interpretation that age-related atrophy at the level of the AN contributes to poorer neural synchrony and may explain some of the perceptual difficulties of older adults. SIGNIFICANCE STATEMENT Differences in auditory nerve (AN) pathophysiology may contribute to the large variations in hearing and communication abilities of older adults. However, current diagnostics focus largely on the increase in detection thresholds, which is likely because of the absence of indirect measures of AN function in standard clinical test batteries. Using novel metrics of AN function, combined with estimates of AN structure and auditory function, we identified age-related differences across measures that we interpret to represent age-related reductions in AN engagement and poorer neural synchrony. Structure-function associations are consistent with an explanation of AN deficits that arise from age-related atrophy of the AN. Associations between neural synchrony and speech recognition suggest that individual and age-related deficits in neural synchrony contribute to speech recognition deficits., (Copyright © 2021 the authors.)

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

Neurons and sensory cells are particularly vulnerable to oxidative stress due to their high oxygen demand during stimulus perception and transmission. The mechanisms that protect them from stress-induced death and degeneration remain elusive. Here we show that embryonic deletion of the chromodomain helicase DNA-binding protein 7 (CHD7) in auditory neurons or hair cells leads to sensorineural hearing loss due to postnatal degeneration of both cell types. Mechanistically, we demonstrate that CHD7 controls the expression of major stress pathway components. In its absence, hair cells are hypersensitive, dying rapidly after brief exposure to stress inducers, suggesting that sound at the onset of hearing triggers their degeneration. In humans, CHD7 haploinsufficiency causes CHARGE syndrome, a disorder affecting multiple organs including the ear. Our findings suggest that CHD7 mutations cause developmentally silent phenotypes that predispose cells to postnatal degeneration due to a failure of protective mechanisms., (© 2021. The Author(s).)

Background: High-resolution MR imaging enables the visualization of individual nerves in the internal auditory canal (IAC). Cochlear nerve deficiency (CND) is recognized as one of the major causes of sensory neural hearing loss (SNHL), especially in cases of unilateral hearing loss in childhood. Some patients with CND are thought to have accompanying vestibular nerve deficiency (VND). However, there have been few reports focusing on VND and vestibular function in these children., Aims: The aim of this study was to evaluate the frequency of VND and vestibular dysfunction in children with unilateral SNHL caused by CND., Material and Methods: Thirty-eight children with unilateral SNHL, who were diagnosed with CND by 3 T-MRI, were evaluated for VND and underwent caloric testing and cervical vestibular evoked potential (cVEMP)., Results: Fourteen of 38 patients (37%) had VND, and eleven (29%) of the patients [ten of the patients (71%) with VND] had at least one vestibular dysfunction. The patients with VND had significantly worse hearing and an IAC of smaller diameter than did patients without VND., Conclusions and Significance: We should pay attention to VND as well as vestibular dysfunction in hearing loss patients with CND.

Objective: To evaluate the utility of pre-operative transtympanic electrically evoked auditory brainstem responses and post-operative neural response telemetry in auditory neuropathy spectrum disorder patients., Methods: Four auditory neuropathy spectrum disorder patients who had undergone cochlear implantation and used it for more than one year were studied. All four patients underwent pre-operative transtympanic electrically evoked auditory brainstem response testing, intra-operative and post-operative (at 3, 6 and 12 months after switch-on) neural response telemetry, and out-patient cochlear implant electrically evoked auditory brainstem response testing (at 12 months)., Results: Patients with better waveforms on transtympanic electrically evoked auditory brainstem response testing showed superior performance after one year of implant use. Neural response telemetry and electrically evoked auditory brainstem response measures improved in all patients., Conclusion: Inferences related to cochlear implantation outcomes can be based on the waveform of transtympanic electrically evoked auditory brainstem responses. Robust transtympanic electrically evoked auditory brainstem responses suggest better performance. Improvements in electrically evoked auditory brainstem responses and neural response telemetry over time indicate that electrical stimulation is favourable in auditory neuropathy spectrum disorder patients. These measures provide an objective way to monitor changes and progress in auditory pathways following cochlear implantation.

Objective: The object of this study was to ascertain outcomes of cochlear implantation (CI) following stereotactic radiosurgery (SRS) for vestibular schwannoma (VS)., Methods: The authors conducted a retrospective chart review of adult patients with VS treated with SRS who underwent CI between 1990 and 2019 at a single tertiary care referral center. Patient demographics, tumor features, treatment parameters, and pre- and postimplantation audiometric and clinical outcomes are presented., Results: Seventeen patients (18 ears) underwent SRS and ipsilateral CI during the study period. Thirteen patients (76%) had neurofibromatosis type 2 (NF2). Median age at SRS and CI were 44 and 48 years, respectively. Median time from SRS to CI was 60 days, but notably, 4 patients underwent SRS and CI within 1 day and 5 patients underwent CI more than 7 years after SRS. Median marginal dose was 13 Gy. Median treatment volume at the time of SRS was 1400 mm3 (range 84-6080 mm3, n = 15 patients). Median post-CI PTA was 28 dB HL, improved from 101 dB HL preoperatively (p < 0.001). Overall, 11 patients (12 ears) exhibited open-set speech understanding. Sentence testing was performed at a median of 10 months (range 1-143 months) post-CI. The median AzBio sentence score for patients with open-set speech understanding was 76% (range 19%-95%, n = 10 ears). Two ears exhibited Hearing in Noise Test (HINT) sentence scores of 49% and 95%, respectively. Four patients achieved environmental sound awareness without open-set speech recognition. Two had no detectable auditory percepts., Conclusions: Most patients who underwent CI following SRS for VS enjoyed access to sound at near-normal levels, with the majority achieving good open-set speech understanding. Implantation can be performed immediately following SRS or in a delayed fashion, depending on hearing status as well as other factors. This strategy may be applied to cases of sporadic or NF2-associated VS., Abbreviations: AAO-HNS = American Academy of Otolaryngology-Head and Neck Surgery; ABI = auditory brainstem implant; CI = cochlear implantation; CN = cranial nerve; CNC = consonant-nucleus-consonant; CPA = cerebellopontine angle; EPS = electrical promontory stimulation; ESA = environmental sound awareness; HINT = Hearing in Noise Test; IAC = internal auditory canal; NF2 = neurofibromatosis type 2; OSP = open-set speech perception; PTA = pure tone average; SRS = stereotactic radiosurgery; VS = vestibular schwannoma; WRS = word recognition score., Competing Interests: Dr. Carlson is a consultant for Advanced Bionics, Cochlear Corp., and MED-EL GmbH. Dr. Driscoll is a consultant for Advanced Bionics, Cochlear Corp., and Envoy Medical.

Cochlear implants are considered the gold standard therapy for subjects with severe hearing loss and deafness. Cochlear implants bypass the damaged hair cells and directly stimulate spiral ganglion neurons (SGNs) of the auditory nerve. Hence, the presence of functional SGNs is crucial for speech perception in electric hearing with a cochlear implant. In deaf individuals, SGNs progressively degenerate due to the lack of neurotrophic support, normally provided by sensory cells of the inner ear. Adipose-derived stromal cells (ASCs) are known to produce neurotrophic factors. In a guinea pig model of sensory hearing loss and cochlear implantation, ASCs were autologously transplanted into the scala tympani prior to insertion of a cochlear implant on one side. Electrically evoked auditory brain stem responses (eABR) were recorded 8 weeks after cochlear implantation. At conclusion of the experiment, the cochleae were histologically evaluated. Compared to untreated control animals, transplantation of ASCs resulted in an increased number of SGNs and their peripheral neurites. In ASC-transplanted animals, mean eABR thresholds were lower and suprathreshold amplitudes larger, suggesting a larger population of intact auditory nerve fibers. Moreover, when compared to controls, amplitude-level functions of eABRs in ASC transplanted animals demonstrated steeper slopes in response to increasing interphase gaps (IPGs), indicative of better functionality of the auditory nerve. In summary, results suggest that transplantation of autologous ASCs into the deaf inner ear may have protective effects on the survival of SGNs and their peripheral processes and may thus contribute to long-term benefits in speech discrimination performance in cochlear implant subjects., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The study aimed at the analysis of the parameters of acoustic cervical and ocular vestibular evoked myogenic potentials (AC-cVEMP and AC-oVEMP) response in patients with a confirmed tumor located in the internal auditory canal. It also aimed to assess to what degree a combination of these tests may be of benefit in the preoperative indication of the affected nerve division via preoperative determination whether the tumor originated from the superior or inferior division of the vestibular nerve, both divisions, or if it originated from a different nerve in the internal auditory canal., Methods: The study group included 50 patients. Preoperative MRI scans were used to measure tumor diameter. AC-cVEMP and AC-oVEMP testing were performed before tumor resection. The surgeon was asked for a detailed description of the tumor origin., Results: The corrected amplitude of cVEMP was significantly lower on the tumor side than on the non-affected side and in the control group. The corrected Asymmetry Ratio (AR) of cVEMPs in patients with the tumor was significantly elevated above the reference values with the mean being 58.29% and the mean AR of oVEMPs in patients the tumor was 71.78% which made both results significantly higher than in the control group. Neither cVEMP nor oVEMP latency was significantly correlated with tumor size. Data obtained from cVEMP and oVEMP tests was an effective indicator of tumor origin in 74% of patients showing which division (or both divisions) of the VIII th nerve was affected in comparison with information obtained from the surgeon., Conclusions: The combined use of AC-cVEMP and AC-oVEMP tests may be useful in surgical planning in patients the tumor located in the internal auditory canal, providing a highly probable determination of the division of the affected nerve. Such information is valuable for the surgeon as it offers additional knowledge about the tumor before the procedure. cVEMP and oVEMP results may not be used as the basis for the calculation of tumor size in patients., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interest including any financial interest or financial support related to this manuscript to be disclosed. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2020. Published by Elsevier B.V.)

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation and intellectual disability syndrome resulting from variants in DHCR7. Auditory characteristics of persons with SLOS have been described in limited case reports but have not been systematically evaluated. The objective of this study is to describe the auditory phenotype in SLOS. Age- and ability-appropriate hearing evaluations were conducted on 32 patients with SLOS. A subset of 21 had auditory brainstem response testing, from which an auditory neural phenotype is described. Peripheral or retrocochlear auditory dysfunction was observed in at least one ear of 65.6% (21) of the patients in our SLOS cohort. The audiometric phenotype was heterogeneous and included conductive, mixed, and sensorineural hearing loss. The most common presentation was a slight to mild conductive hearing loss, although profound sensorineural hearing loss was also observed. Abnormal auditory brainstem responses indicative of retrocochlear dysfunction were identified in 21.9% of the patients. Many were difficult to test behaviorally and required objective assessment methods to estimate hearing sensitivity. Individuals with SLOS are likely to have hearing loss that may impact communication, including speech and language development. Routine audiologic surveillance should be conducted to ensure prompt management of hearing loss., (© 2021 Wiley Periodicals LLC.)

The use of neonatal hearing screening has enabled the identification of congenital unilateral sensorineural hearing loss (USNHL) immediately after birth, and today there are several intervention options available to minimize potential adverse effects of this disease, including cochlear implantation. This study aims to analyze the characteristics of the inner ear of a homogeneous group of congenital non-syndromic USNHL to highlight the features of the inner ear, which can help in clinical, surgical, and rehabilitative decision-making. A retrospective chart review was carried out at a tertiary referral center. Systematic diagnostic work-up and rigorous inclusion-exclusion criteria were applied to 126 children with unilateral hearing impairment, leading to a selection of 39 strictly congenital and non-syndromic USNHL cases, undergoing computed tomography (CT) and magnetic resonance (MR) imaging studies. The frequency and type of malformations of the inner ear in USNHL and unaffected contralateral ears were assessed, with an in-depth analysis of the deficiency of the cochlear nerve (CND), the internal auditory canal (IAC) and the cochlear aperture (CA). Inner ear anomalies were found in 18 out of 39 (46%) of the USNHL patients. In 1 subject, the anomalies were bilateral, and the CND resulted in the predominant identified defect (78% of our abnormal case series), frequently associated with CA stenosis. Only 3 out of 14 children with CND presented stenosis of the IAC. CND and CA stenosis (and to a much lesser extent IAC stenosis) are a frequent association within congenital and non-syndromic USNHL that could represent a distinct pathological entity affecting otherwise healthy infants. In the context of a diagnostic work-up, the evaluation with CT and MRI measurements should take place in a shared decision-making setting with thorough counseling. Both imaging techniques have proven useful in differentiating the cases that will most likely benefit from the cochlear implant, from those with potentially poor implant performance.

TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid-induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline, and 7,8-dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 hours after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the auditory brainstem response (ABR) were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact 1 year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of postexposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposures.

Hidden hearing loss (HHL) is an auditory neuropathy characterized by normal hearing thresholds but reduced amplitudes of the sound-evoked auditory nerve compound action potential (CAP). In animal models, HHL can be caused by moderate noise exposure or aging, which induces loss of inner hair cell (IHC) synapses. In contrast, recent evidence has shown that transient loss of cochlear Schwann cells also causes permanent auditory deficits in mice with similarities to HHL. Histological analysis of the cochlea after auditory nerve remyelination showed a permanent disruption of the myelination patterns at the heminode of type I spiral ganglion neuron (SGN) peripheral terminals, suggesting that this defect could be contributing to HHL. To shed light on the mechanisms of different HHL scenarios observed in animals and to test their impact on type I SGN activity, we constructed a reduced biophysical model for a population of SGN peripheral axons whose activity is driven by a well-accepted model of cochlear sound processing. We found that the amplitudes of simulated sound-evoked SGN CAPs are lower and have greater latencies when heminodes are disorganized, i.e. they occur at different distances from the hair cell rather than at the same distance as in the normal cochlea. These results confirm that disruption of heminode positions causes desynchronization of SGN spikes leading to a loss of temporal resolution and reduction of the sound-evoked SGN CAP. Another mechanism resulting in HHL is loss of IHC synapses, i.e., synaptopathy. For comparison, we simulated synaptopathy by removing high threshold IHC-SGN synapses and found that the amplitude of simulated sound-evoked SGN CAPs decreases while latencies remain unchanged, as has been observed in noise exposed animals. Thus, model results illuminate diverse disruptions caused by synaptopathy and demyelination on neural activity in auditory processing that contribute to HHL as observed in animal models and that can contribute to perceptual deficits induced by nerve damage in humans., Competing Interests: The authors have declared that no competing interests exist.

Background: The spread of excitation (SOE) and auditory nerve recovery function (REC) are objective measures recorded by neural response telemetry and may interfere in cochlear implant (CI) stimulation., Objective: To analyze and correlate SOE with the refractory periods in subjects with pre- and postlingual deafness implanted with different electrode arrays., Methods: This was a retrospective study of 323 ears separated by perimodiolar or straight arrays and by pre- or postlingually deaf recipients. Measures were collected intraoperatively on electrode 11. The SOE width was measured in millimeters at the 0.75 point of the curve, and the relative (tau) and absolute (t0) refractory periods were measured in microseconds., Results: There was a statistical correlation between the SOE and the t0 in the patients with postlingual deafness implanted with the perimodiolar array. The SOE width was statistically different between the straight and perimodiolar arrays and between the pre- and postlingual groups in the perimodiolar array. Tau was statistically different between the pre- and postlingual groups with the straight array and the t0, between the pre- and postlingual groups with the perimodiolar array. Neural response threshold and amplitude of the neural response were not statistically different among groups., Conclusion: There was a correlation between SOE width and t0 only in patients with acquired deafness. The findings suggest that different factors influence SOE and REC, considering SOE is different according to the electrode array and REC being different according the onset of deafness., (© 2020 S. Karger AG, Basel.)

Background: Clinical application of electrically-evoked intracochlear auditory brainstem responses (eABRs) for evaluation of brainstem maturity or aging changes has not been well investigated., Aim/objective: We compare the eV latencies of intraoperative eABR measurements in one-year-olds, infants, children, adults, and the elderly, with the goal of investigating the changes in the brainstem auditory pathway due to development and aging., Materials and Methods: We studied 58 ears of 51 patients who underwent cochlear implantation between 2013 and 2019 using MED-EL's Concerto or Synchrony implants with Flex28 or Flex soft electrodes. EABRs were recorded during cochlear implantation. The stimuli were delivered by the MED-EL Maestro to the apical, middle, and basal turn electrodes at stimulus levels 1000, 800, and 600 cu, with a pulse width of 30 µs., Results: In eABRs recorded from electrodes installed at both the mastoid and nape, there was no difference in latency between age groups within each stimulus level., Conclusion and Significance: ABR latency was not affected by development after age one and aging of the brainstem auditory pathway. Our study will be useful as a control in identifying abnormal eABR wave configurations in patients with cochlear malformations, cochlear nerve deficiencies, or auditory neuropathy, regardless of age.

Many individuals with seemingly normal hearing abilities struggle to understand speech in noisy backgrounds. To understand why this might be the case, we investigated the neural representation of speech in the auditory midbrain of gerbils with "hidden hearing loss" through noise exposure that increased hearing thresholds only temporarily. In noise-exposed animals, we observed significantly increased neural responses to speech stimuli, with a more pronounced increase at moderate than at high sound intensities. Noise exposure reduced discriminability of neural responses to speech in background noise at high sound intensities, with impairment most severe for tokens with relatively greater spectral energy in the noise-exposure frequency range (2-4 kHz). At moderate sound intensities, discriminability was surprisingly improved, which was unrelated to spectral content. A model combining damage to high-threshold auditory nerve fibers with increased response gain of central auditory neurons reproduced these effects, demonstrating that a specific combination of peripheral damage and central compensation could explain listening difficulties despite normal hearing thresholds., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sensorineural deafness is caused by the loss of peripheral neural input to the auditory nerve, which may result from peripheral neural degeneration and/or a loss of inner hair cells. Provided spiral ganglion cells and their central processes are patent, cochlear implants can be used to electrically stimulate the auditory nerve to facilitate hearing in the deaf or severely hard-of-hearing. Neural degeneration is a crucial impediment to the functional success of a cochlear implant. The present, first-of-its-kind two-dimensional finite-element model investigates how the depletion of neural tissues might alter the electrically induced transmembrane potential of spiral ganglion neurons. The study suggests that even as little as 10% of neural tissue degeneration could lead to a disproportionate change in the stimulation profile of the auditory nerve. This result implies that apart from encapsulation layer formation around the cochlear implant electrode, tissue degeneration could also be an essential reason for the apparent inconsistencies in the functionality of cochlear implants.

&lt;b&gt;Background:&lt;/b&gt; The aim was to present the methodology and interpretation of intraoperative hearing monitoring with simultaneous Transtympanic Electrocochleography (TT-ECochG) and direct Cochlear Nerve Action Potential (CNAP) measurements during vestibular schwannoma removal. &lt;br&gt;&lt;b&gt;Materials and Methods:&lt;/b&gt; Detailed methodology of measurements and interpretation of results are presented in three exemplary patients who underwent tumor removal via middle fossa approach (MFA) with the use of intraoperative monitoring of hearing with TT-ECochG and direct CNAP performed in real time. In addition, all responses were automatically recorded and stored along with surgical information and subjected to detailed analyses and calculation after surgery. &lt;br&gt;&lt;b&gt;Results:&lt;/b&gt; The following changes in TT-ECochG and direct CNAP responses were observed: Patient #1 - TT-ECochG and CNAP responses with minor, but transient, morphology changes (hearing was preserved); Patient #2 - CNAP responses changed significantly but, temporarily, from triphasic into biphasic responses later, with marked but partially reversible desynchronization of CNAP; changes in TT-ECochG responses were also observed but, at the end, returned to baseline (surgery-related deterioration of hearing); Patient #3 - irreversible changes of TT-ECochG and direct CNAP (complete loss of hearing). &lt;br&gt;&lt;b&gt;Conclusions:&lt;/b&gt; A combination of TT-ECochG and direct CNAP allows for real-time monitoring of auditory function during vestibular schwannoma resection and surgical manipulation which contribute to the risk of hearing loss. Therefore, the surgeon can be instantly informed about changes which could increase the possibility of preserving the patient's hearing.

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

The envelope following response (EFR) has been proposed as a non-invasive marker of synaptopathy in animal models. However, its amplitude is affected by the spread of basilar-membrane excitation and other coexisting sensorineural hearing deficits. This study aims to (i) improve frequency specificity of the EFR by introducing a derived-band EFR (DBEFR) technique and (ii) investigate the effect of lifetime noise exposure, age and outer-hair-cell (OHC) damage on DBEFR magnitudes. Additionally, we adopt a modelling approach to validate the frequency-specificity of the DBEFR and test how different aspects of sensorineural hearing loss affect peripheral generators. The combined analysis of simulations and experimental data proposes that the DBEFRs extracted from the [2-6]-kHz frequency band is a sensitive and frequency-specific measure of synaptopathy in humans. Individual variability in DBEFR magnitudes among listeners with normal audiograms was explained by their self-reported amount of experienced lifetime noise-exposure and corresponded to amplitude variability predicted by synaptopathy. Older listeners consistently had reduced DBEFR magnitudes in comparison to young normal-hearing listeners, in correspondence to how age-induced synaptopathy affects EFRs and compromises temporal envelope encoding. To a lesser degree, OHC damage was also seen to affect the DBEFR magnitude, hence the DBEFR metric should ideally be combined with a sensitive marker of OHC damage to offer a differential diagnosis of synaptopathy in listeners with impaired audiograms., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To determine the prevalence and distribution of inner-ear malformations in congenital single-sided deafness cases, as details of malformation type are crucial for disease prognosis and management., Methods: A retrospective study was conducted of 90 patients aged under 16 years with congenital single-sided deafness. Radiological findings were evaluated using computed tomography and magnetic resonance imaging. Inner-ear malformations were identified and cochlear nerve status was determined in affected ears., Results: Out of 90 ears, 42 (46.7 per cent) were found to have inner-ear malformation. Isolated cochlear aperture stenosis was the most common anomaly (n = 18, 20 per cent), followed by isolated cochlear aperture atresia (n = 11, 12.2 per cent) and cochlear hypoplasia (n = 7, 7.8 per cent). Cochlear nerve deficiency was encountered in 41 ears (45.6 per cent). The internal auditory canal was also stenotic in 49 ears (54.4 per cent)., Conclusion: Inner-ear malformations, especially cochlear aperture anomalies, are involved in the aetiology of single-sided deafness more than expected. The cause of single-sided deafness differs greatly between congenital and adult-onset cases. All children with single-sided deafness should undergo radiological evaluation, as the prognosis and management, as well as the aetiology, may be significantly influenced by inner-ear malformation type.

Acoustic overexposure, such as listening to loud music too often, results in noise-induced hearing loss. The pathologies of this prevalent sensory disorder begin within the ear at synapses of the primary auditory receptors, their postsynaptic partners and their supporting cells. The extent of noise-induced damage, however, is determined by overstimulation of primary auditory receptors, upstream of where the pathologies manifest. A systematic characterization of the electrophysiological function of the upstream primary auditory receptors is warranted to understand how noise exposure impacts on downstream targets, where the pathologies of hearing loss begin. Here, we used the experimentally-accessible locust ear (male, Schistocerca gregaria) to characterize a decrease in the auditory receptor's ability to respond to sound after noise exposure. Surprisingly, after noise exposure, the electrophysiological properties of the auditory receptors remain unchanged, despite a decrease in the ability to transduce sound. This auditory deficit stems from changes in a specialized receptor lymph that bathes the auditory receptors, revealing striking parallels with the mammalian auditory system. SIGNIFICANCE STATEMENT Noise exposure is the largest preventable cause of hearing loss. It is the auditory receptors that bear the initial brunt of excessive acoustic stimulation, because they must convert excessive sound-induced movements into electrical signals, but remain functional afterward. Here we use the accessible ear of an invertebrate to, for the first time in any animal, characterize changes in auditory receptors after noise overexposure. We find that their decreased ability to transduce sound into electrical signals is, most probably, due to changes in supporting (scolopale) cells that maintain the ionic composition of the ear. An emerging doctrine in hearing research is that vertebrate primary auditory receptors are surprisingly robust, something that we show rings true for invertebrate ears too., (Copyright © 2020 Warren et al.)

Objectives: To evaluate the functions of cochlear structures and the distal part of auditory nerve as well as dead regions within the cochlea in individuals with normal hearing with or without tinnitus by using electrophysiological tests., Materials and Methods: Nine individuals (ages: 21-59 years) with normal hearing with tinnitus were included in the study group. Thirteen individuals (ages: 25-60 years) with normal hearing without tinnitus were included in the control group. Immitancemetric examination, pure-tone audiometry (125Hz-16kHz), speech audiometry in quiet and noise environments, transient evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAEs), threshold equalizing noise (TEN test (500Hz-4kHz), and ECochG tests, Beck Depression Questionnaire, Tinnitus Handicap Questionnaire, and Visual Analog Scale were performed., Results: In the study group, three patients were found to have a minimal depression and six were found to have a mild depression. In pure-tone audiometry, the threshold (6-16 kHz) in the study group was significantly higher than that of the control group at all frequencies. In the study group, lower performance scores were obtained in speech discrimination in noise in both ears. In the control group, no dead region was detected in the TEN test whereas 75% of subjects in the study group had dead regions. DPOAE and TEOAE responses between study and control group subjects were not different. In the ECochG test, subjects in the study group showed an increase in the summating potential/action potential (SP/AP) ratio in both ears., Conclusion: Determination of the SP/AP ratio in patients with tinnitus may be useful in diagnosing hidden hearing loss. Detection of dead regions in 75% of patients in the TEN test may indicate that inner hair cells may be responsible for tinnitus.

Objective: Auditory neuropathy spectrum disorder (ANSD) is a condition wherein the pre-neural or cochlear outer hair cell activity is intact, but the neural activity in the auditory nerve is disrupted. Cochlear implant (CI) can be beneficial for subjects with ANSD; however, little is known about the music perception and psychoacoustic abilities of CI users with ANSD. Music perception in CI users is a multidimensional and complex ability requiring the contribution of both auditory and nonauditory abilities. Even though auditory abilities lay the foundation, the contribution of patient-related variables such as ANSD may affect the music perception. This study aimed to evaluate the psychoacoustic and music perception abilities of CI recipients with ANSD., Study Design: Twelve CI users with ANSD and twelve age- and gendermatched CI users with sensorineural hearing loss (SNHL) were evaluated. Music perception abilities were measured using the Turkish version of the Clinical Assessment of Music Perception (T-CAMP) test. Psychoacoustic abilities were measured using the spectral ripple discrimination (SRD) and temporal modulation transfer function (TMTF) tests. In addition, the age of diagnosis and implantation was recorded., Results: Pitch direction discrimination (PDD), timbre recognition, SRD, and TMTF performance of CI users with ANSD were concordant with those reported in previous studies, and differences between ANSD and SNHL groups were not statistically significant. However, the ANSD group performed poorly compared with SNHL group in melody recognition subtest of T-CAMP, and the difference was statistically significant., Conclusion: CI can prove beneficial for patients with ANSD with respect to their music and psychoacoustic abilities, similar to patients with SNHL, except for melody recognition. Recognition of melodies requires both auditory and non-auditory abilities, and ANSD may have an extensive but subtle effect in the life of CI users., Competing Interests: Declaration of competing interest All authors declare there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: The electrically evoked compound action potential (ECAP) is widely used in clinical to reflect the functional states of the auditory nerve in cochlear implant (CI) recipients, especially in pediatric CI users. Currently, the software can automatically provide the ECAP threshold, which is convenient and not affected by the subjective judgement of the clinicians. However, it remains unclear whether the correlations between human and computer decisions for ECAP threshold can be affected by auditory nerve functional states, which is also the main purpose of our present study., Methods: Intracochlear electrical stimulation, which can decrease the excitability of the auditory nerve, was used to change the auditory nerve functional states of guinea pigs. Ten normal-hearing guinea pigs were implanted with CIs unilaterally. ECAPs were recorded both before and after the electrical stimulation, representing different functional states of the auditory nerve. Forward masking (FwdMsk) and alternating polarity (AltPol), two most commonly-used artifact-reduction methods, were applied to the measurements. All measurements recorded by the software were saved for computer and human analysis with linear regression and visual detection methods., Results: The correlations between human and computer performance in the peak-picking process were not affected by auditory nerve states and artifact-reduction methods. However, complicated findings were observed for ECAP threshold. With FwdMsk utilized, weaker correlations between human and computer performance were observed in abnormal state compared to those in normal state. Regardless of the functional states of the auditory nerve, the results revealed stronger correlations in AltPol than those in FwdMsk. Furthermore, when compared with human decision, computer linear-regression threshold (C-LRT) was always less accurate than computer visual-detection threshold (C-VDT), which was not affected by auditory nerve states., Conclusions: (1) the functional states of the auditory nerve can definitely affect the correlations between human and computer decisions for ECAP threshold, but the impact is limited to the FwdMsk method; (2) AltPol can produce stronger correlations compared with FwdMsk, which is not affected by auditory nerve states; and (3) regardless of the auditory nerve states, C-VDT can always show higher consistency with human decision, while C-LRT reveals more variability., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Cochlear implants (CIs) have become important for the treatment of severe-to-profound sensorineural hearing loss (SNHL). Meanwhile, electrically evoked compound action potentials (ECAPs) and electrically evoked auditory brainstem responses (EABRs), which can be examined and evaluated with minimal patient cooperation, have become more reliable for tone measurement and speech recognition postoperatively. However, few studies have compared the electrophysiological characteristics of the auditory nerve using ECAPs and EABRs under different functional states of the auditory nerve (FSANs). We used guinea pig models in which six electrodes were implanted unilaterally with continuous electrical stimulation (ES) for 4 h. The amplitude growth functions (AGFs) of the alternating polarity ECAP (AP-ECAP) and forward-masking subtraction ECAP (FM-ECAP), as well as the EABR waves under "normal" and "abnormal" FSANs, were obtained., Results: Both the AP-ECAP and FM-ECAP thresholds were significantly higher than those measured by EABR under both "normal" FSAN and "abnormal" FSANs (p < 0.05). There was a significant difference in the slope values between electrodes 1 and 2 and electrodes 3 and 4 in terms of the AP-ECAP under the "abnormal" FSAN (p < 0.05). The threshold gaps between the AP-ECAP and FM-ECAP were significantly larger under the "abnormal" FSAN than under the "normal" FSAN (p < 0.05)., Conclusions: Both of the ECAP thresholds were higher than the EABR thresholds. The AP-ECAP was more sensitive than the FM-ECAP under the "abnormal" FSAN.

Hidden hearing loss (HHL), a recently described auditory disorder, has been proposed to affect auditory neural processing and hearing acuity in subjects with normal audiometric thresholds, particularly in noisy environments. In contrast to central auditory processing disorders, HHL is caused by defects in the cochlea, the peripheral auditory organ. Noise exposure, aging, ototoxic drugs, and peripheral neuropathies are some of the known risk factors for HHL. Our knowledge of the causes and mechanisms of HHL are based primarily on animal models. However, recent clinical studies have also shed light on the etiology and prevalence of this cochlear disorder and how it may affect auditory perception in humans. Here, we review the current knowledge regarding the causes and cellular mechanisms of HHL, summarize information on available noninvasive tests for differential diagnosis, and discuss potential therapeutic approaches for treatment of HHL., (Copyright © 2020 Cold Spring Harbor Laboratory Press; all rights reserved.)

Objective: This article reviews: (1) the evidence related to enhanced central gain as a potential mechanism for the generation of tinnitus and hyperacusis, (2) the neuroplastic changes induced by prolonged, low-level sound stimulation and (3) the clinical effectiveness of various sound therapies and amplification for the treatment of tinnitus and hyperacusis. Design: General literature review. Study sample: Peer-reviewed articles related to auditory neural gain, prolonged low-level noise exposure and effectiveness of sound therapy. Results: A large body of literature exists supporting the enhanced neural gain model of tinnitus and hyperacusis. Neuroplastic changes associated with prolonged low-level noise show evidence of reversing enhanced neural gain, which should theoretically reduce percepts of tinnitus and/or hyperacusis. However, the available clinical evidence assessing the efficacy of sound therapy to reduce tinnitus or hyperacusis lacks controlled clinical trials to accurately assess the effectiveness of sound therapy. Conclusions: The available literature from basic science studies supports the neural gain model of tinnitus and hyperacusis, which conceivably should be effectively managed with sound therapy. However, well-controlled clinical trials are needed before conclusions can be made on the effectiveness of sound therapy for tinnitus and hyperacusis.

Cochlear implantation has become the most effective hearing restoration method and is one of the great advances in modern medicine. Early implants have been continuously developed into more efficient devices, and electro-acoustic stimulation is increasingly expanding the indication criteria for cochlear implants to patients with more residual hearing. Therefore, protecting the cochlear structures and maintaining its intrinsic capacities like residual hearing has become more important than ever before. In the present study, we aimed to assess the long-term protective effects of a dexamethasone-eluting electrode combined with the preoperative intratympanic application of a dexamethasone-loaded thermoreversible hydrogel in a cochlear implant guinea pig model. 40 normal-hearing animals were equally randomized into a control group receiving an unloaded hydrogel and a non-eluting electrode, a group receiving a dexamethasone-loaded hydrogel and a non-eluting electrode, a group receiving an unloaded hydrogel and a dexamethasone-eluting electrode and a group receiving both a dexamethasone-loaded hydrogel and a dexamethasone-eluting electrode. Residual hearing and impedances were investigated during a period of 120 days. Tissue response and histological changes of cochlear structures were analyzed at the end of the experiments. Treatment with dexamethasone did not show a significant protective effect on residual hearing independent of treatment group. Although the majority of the cochleae didn't exhibit any signs of electrode insertion trauma, a small degree of tissue response could be observed in all animals without a significant difference between the groups. Foreign body giant cells and osteogenesis were significantly associated with tissue response. Hair cells, synapsin-1-positive cells and spiral ganglion cells were preserved in all study groups. Cochlear implantation using a dexamethasone-eluting electrode alone and in combination with a dexamethasone-loaded hydrogel significantly protected auditory nerve fibers on day 120. Post-implantation impedances were equal across study groups and remained stable over the duration of the experiment. In this study we were able to show that use of a dexamethasone-eluting electrode alone and in combination with preoperative application of dexamethasone-loaded hydrogel significantly protects auditory nerve fibers. Furthermore, we have shown that a cochlear implantation-associated hearing threshold shift and tissue response may not be completely prevented by the sole application of dexamethasone., (Copyright © 2019 Elsevier B.V. All rights reserved.)

It is well-established that excessive noise exposure can systematically shift audiometric thresholds (i.e., noise-induced hearing loss, NIHL) making sounds at the lower end of the dynamic range difficult to detect. An often overlooked symptom of NIHL is the degraded ability to resolve temporal fluctuations in supra-threshold signals. Given that the temporal properties of speech are highly dynamic, it is not surprising that NIHL greatly reduces one's ability to clearly decipher spoken language. However, systematic characterization of noise-induced impairments on supra-threshold signals in humans is difficult given the variability in noise exposure among individuals. Fortunately, the chinchilla is audiometrically similar to humans, making it an ideal animal model to investigate noise-induced supra-threshold deficits. Through a series of studies using the chinchilla, the authors have elucidated several noise-induced deficits in temporal processing that occur at supra-threshold levels. These experiments highlight the importance of the chinchilla model in developing an understanding of noise-induced deficits in temporal processing.

Tinnitus is one of the predicted perceptual consequences of cochlear synaptopathy, a type of age-, noise-, or drug-induced auditory damage that has been demonstrated in animal models to cause homeostatic changes in central auditory gain. Although synaptopathy has been observed in human temporal bones, assessment of this condition in living humans is limited to indirect non-invasive measures such as the auditory brainstem response (ABR). In animal models, synaptopathy is associated with a reduction in ABR wave I amplitude at suprathreshold stimulus levels. Several human studies have explored the relationship between wave I amplitude and tinnitus, with conflicting results. This study investigates the hypothesis that reduced peripheral auditory input due to synaptic/neuronal loss is associated with tinnitus. Wave I amplitude data from 193 individuals [43 with tinnitus (22%), 150 without tinnitus (78%)], who participated in up to 3 out of 4 different studies, were included in a logistic regression analysis to estimate the relationship between wave I amplitude and tinnitus at a variety of stimulus levels and frequencies. Statistical adjustment for sex and distortion product otoacoustic emissions (DPOAEs) was included. The results suggest that smaller wave I amplitudes and/or lower DPOAE levels are associated with an increased probability of tinnitus.

Objectives: To compare the Neural Response Telemetry (NRT) results of the cochlear implanted children who showed wave 5 and who could not, in preimplantation ABR., Material and Method: 24 children (11 boys, 13 girls) with bilateral profound sensorineural hearing loss participated in this study. Age of children ranged between 13 and 60 months (mean 30 months). All participated children were implanted with Cochlear® Nucleus brand devices. In preoperative ABR evaluation with click stimulus in 100 dBnHL intensity level, 9 children showed wave V and 15 children did not. We compared intraoperative NRT results of 1st, 6th, 11th, 16th and 22nd electrodes, those were selected from 22 electrodes, of the two groups., Results: There was no statistically significant difference between the children who showed wave V and who did not in preoperative ABR, when compared the intraoperative NRT results of 1st, 6th, 11th, 16th and 22nd electrodes (p>0,05)., Conclusion: intraoperative NRT was obtained in all the implanted children with bilateral profound sensorineural hearing loss, even if they received wave V or not in preoperative ABR. There was no difference between any of the parameters of the test results of the two groups. Normal NRT results can be achievable when there is no wave V in preoperative ABR.

Auditory nerve fibers' (ANFs) refractoriness and facilitation can be quantified in electrically evoked compound action potentials (ECAPs) recorded via neural response telemetry (NRT). Although facilitation has been observed in animals and human cochlear implant (CI) recipients, no study has modeled this in human CI users until now. In this study, recovery and facilitation effects at different masker and probe levels for three test electrodes (E6, E12 and E18) in 11 CI subjects were recorded. The ECAP recovery and facilitation were modeled by exponential functions and the same function used for +10 CL masker offset condition can be applied to all other masker offsets measurements. Goodness of fit was evaluated for the exponential functions. A significant effect of probe level was observed on a recovery time constant which highlights the importance of recording the recovery function at the maximum acceptable stimulus level. Facilitation time constant and amplitude showed no dependency on the probe level. However, facilitation was stronger for masker level at or around the threshold of the ECAP (T-ECAP). There was a positive correlation between facilitation magnitude and amplitude growth function (AGF) slope, which indicates that CI subjects with better peripheral neural survival have stronger facilitation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Speech intelligibility can vary dramatically between individuals with similar clinically defined severity of hearing loss based on the audiogram. These perceptual differences, despite equal audiometric-threshold elevation, are often assumed to reflect central-processing variations. Here, we compared peripheral-processing in auditory nerve (AN) fibers of male chinchillas between two prevalent hearing loss etiologies: metabolic hearing loss (MHL) and noise-induced hearing loss (NIHL). MHL results from age-related reduction of the endocochlear potential due to atrophy of the stria vascularis. MHL in the present study was induced using furosemide, which provides a validated model of age-related MHL in young animals by reversibly inhibiting the endocochlear potential. Effects of MHL on peripheral processing were assessed using Wiener-kernel (system identification) analyses of single AN fiber responses to broadband noise, for direct comparison to previously published AN responses from animals with NIHL. Wiener-kernel analyses show that even mild NIHL causes grossly abnormal coding of low-frequency stimulus components. In contrast, for MHL the same abnormal coding was only observed with moderate to severe loss. For equal sensitivity loss, coding impairment was substantially less severe with MHL than with NIHL, probably due to greater preservation of the tip-to-tail ratio of cochlear frequency tuning with MHL compared with NIHL rather than different intrinsic AN properties. Differences in peripheral neural coding between these two pathologies-the more severe of which, NIHL, is preventable-likely contribute to individual speech perception differences. Our results underscore the need to minimize noise overexposure and for strategies to personalize diagnosis and treatment for individuals with sensorineural hearing loss. SIGNIFICANCE STATEMENT Differences in speech perception ability between individuals with similar clinically defined severity of hearing loss are often assumed to reflect central neural-processing differences. Here, we demonstrate for the first time that peripheral neural processing of complex sounds differs dramatically between the two most common etiologies of hearing loss. Greater processing impairment with noise-induced compared with an age-related (metabolic) hearing loss etiology may explain heightened speech perception difficulties in people overexposed to loud environments. These results highlight the need for public policies to prevent noise-induced hearing loss, an entirely avoidable hearing loss etiology, and for personalized strategies to diagnose and treat sensorineural hearing loss., (Copyright © 2019 the authors.)

The healthy auditory system enables communication in challenging situations with high levels of background noise. Yet, despite normal sensitivity to pure tones, many listeners complain about having difficulties in such situations. Recent animal studies demonstrated that noise overexposure that produces temporary threshold shifts can cause the loss of auditory nerve (AN) fiber synapses (i.e., cochlear synaptopathy, CS), which appears to predominantly affect medium- and low-spontaneous rate (SR) fibers. In the present study, envelope following response (EFR) magnitude-level functions were recorded in normal hearing (NH) threshold and mildly hearing-impaired (HI) listeners with thresholds elevated above 2 kHz. EFRs were elicited by sinusoidally amplitude modulated (SAM) tones presented in quiet with a carrier frequency of 2 kHz, modulated at 93 Hz, and modulation depths of 0.85 (deep) and 0.25 (shallow). While EFR magnitude-level functions for deeply modulated tones were similar for all listeners, EFR magnitudes for shallowly modulated tones were reduced at medium stimulation levels in some NH threshold listeners and saturated in all HI listeners for the whole level range. A phenomenological model of the AN was used to investigate the extent to which hair-cell dysfunction and/or CS could explain the trends observed in the EFR data. Hair-cell dysfunction alone, including postulated elevated hearing thresholds at extended high frequencies (EHF) beyond 8 kHz, could not account for the recorded EFR data. Postulated CS led to simulations generally consistent with the recorded data, but a loss of all types of AN fibers was required within the model framework. The effects of off-frequency contributions (i.e., away from the characteristic place of the stimulus) and the differential loss of different AN fiber types on EFR magnitude-level functions were analyzed. When using SAM tones in quiet as the stimulus, model simulations suggested that (1) EFRs are dominated by the activity of high-SR fibers at all stimulus intensities, and (2) EFRs at medium-to-high stimulus levels are dominated by off-frequency contributions.

Objective: The aim of this study is to investigate the use of CT, magnetic resonance imaging （MRI）, functional magnetic resonance （fMRI） and electrical evoked auditory brainstem response in children with cochlear nerve deficiency （CND） before cochlear implantation （CI） （electrically evoked auditory brain stem response, EABR） evaluated auditory pathway, auditory cortex function, and cochlear nerve function. Method: Of 6 children with bilateral profound sensorineural hearing loss, bilateral internal auditory meatus stenosis was diagnosed by CT as in 4 cases and unilateral internal auditory meatus stenosis in 1 case. In 3 cases, oblique sagittal MRI reconstruction of the internal auditory meatus showed only facial nerve and vestibular nerve existence. 6 cases were diagnosed as CND by imaging, among which underwent fMRI and EABR in 3 cases, respectively. All the children received unilateral CI and were followed up for at least 1 year after hearing and speech rehabilitation. Result: fMRI was examed in 3 cases with CND. It showed that the right auditory cortex was activated in 1 case after sound given to the left ear but no activation was found in the left cortex when sound given to the right ear. 1 case showed activation in bilateral transverse temporal gyrus while sound was given to the left, right and both ears at 2000Hz. Another case had no activation in both auditory cortex. EABR detection elicited V wave in 2 of 3 cases. 6 children received audiological and speech evaluation 1 month, 6 and 12 months after CI. Among them, the hearing level was improved within 6 months after surgery in 4 cases, and the threshold of sound field was （48.15±6.60） dB HL, MAIS and CAP scores were improved. However, SIR score improvement is limited in 3 cases. The hearing level was improved in 1 case, but speech rehabilitation was poor mainly due to the older age. Conclusion: Preoperative comprehensive application of imaging and electrophysiological evaluation of children with CND can more accurately assess the integrity of the auditory pathway and understand the function of the cochlear nerve. It has important reference significance for whether or not to perform surgery. There was a significant difference in auditory speech rehabilitation after CND in children with CND., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Electrically evoked compound action potentials (eCAPs) are measurements of the auditory nerve's response to electrical stimulation. ECAP amplitudes during pulse trains can exhibit temporal alternations. The magnitude of this alternation tends to diminish over time during the stimulus. How this pattern relates to the temporal behavior of nerve fibers is not known. We hypothesized that the stochasticity, refractoriness, adaptation of the threshold and spike-times influence pulse-train eCAP responses. Thirty thousand auditory nerve fibers were modeled in a three-dimensional cochlear model incorporating pulse-shape effects, pulse-history effects, and stochasticity in the individual neural responses. ECAPs in response to pulse trains of different rates and amplitudes were modeled for fibers with different stochastic properties (by variation of the relative spread) and different temporal properties (by variation of the refractory periods, adaptation and latency). The model predicts alternation of peak amplitudes similar to available human data. In addition, the peak alternation was affected by changing the refractoriness, adaptation, and relative spread of auditory nerve fibers. As these parameters are related to factors such as the duration of deafness and neural survival, this study suggests that the eCAP pattern in response to pulse trains could be used to assess the underlying temporal and stochastic behavior of the auditory nerve. As these properties affect the nerve's response to pulse trains, they are of uttermost importance to sound perception with cochlear implants., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Strial dysfunction is commonly observed as a key consequence of aging in the cochlea. A large body of animal research, especially in the quiet-aged Mongolian gerbil, shows specific histopathological changes in the cochlear stria vascularis and the putatively corresponding effects on endocochlear potential and auditory nerve responses. However, recent work suggests that synaptopathy, or the loss of inner hair cell-auditory nerve fiber synapses, also presents as a consequence of aging. It is now believed that the loss of synapses is the earliest age-related degenerative event. The present review aims to integrate classic and novel research on age-related pathologies of the inner ear. First, we summarize current knowledge on age-related strial dysfunction and synaptopathy. We describe how these cochlear pathologies fit into the categories for presbyacusis, as first defined by Schuknecht in the '70s. Further, we discuss how strial dysfunction and synaptopathy affect sound coding by the auditory nerve and how they can be experimentally induced to study their specific contributions to age-related hearing deficits. As such, we aim to give an overview of the current literature on age-related cochlear pathologies and hope to inspire further research on the role of cochlear aging in age-related hearing deficits., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Cochlear implant (CI) outcomes can be assessed using objective measures that reflect the integrity of the auditory pathway. One such measure is the middle latency response (MLR), which can provide valuable information for clinicians., Purpose: Traditional stimuli for evoking MLRs, that is, clicks or tone bursts, do not stimulate all parts of the cochlea simultaneously, whereas chirp stimuli compensate for the cochlear neural delay and, therefore, produce more synchronous responses from the different neural elements of the cochlea. The purpose of the present study was to determine whether chirp stimuli can elicit reliable MLRs in CI users and whether those responses correlate with clinical outcomes and with deprivation-related factors., Research Design: We presented 2,000 free-field optimized chirp stimuli to CI and control participants while their electroencephalography (EEG) was being recorded., Study Sample: Twenty-four adult CI users and 24 matched normal-hearing (NH) individuals (age range from 18 to 63 years) participated in this study., Data Collections and Analysis: The EEG was recorded from 64 active electrodes placed on the scalp. EEG signals were processed using EEGLAB and ERPLAB toolboxes. We characterized the latencies and amplitudes of the different MLR components in both groups., Results: Chirp stimuli reliably evoked qualitatively similar MLRs across all NH and CI participants with a couple of differences observed between the NH and CI group. Among the different MLR components, the Na latency was significantly shorter for the CI group. A significant amplitude difference was also found between groups for the Pa-Nb complex, with higher amplitudes observed in the NH group. Finally, there were no significant correlations between MLR latencies (or amplitudes) and clinical outcomes or deprivation-related measures., Conclusions: Free-field-presented optimized chirp stimuli were shown to evoke measurable and reliable MLRs in CI users. In this experiment, the MLR morphology in CI users was similar to those observed in NH participants. Even though we did not replicate here a significant relationship between MLR and speech perception measures, we were able to successfully collect acoustically evoked MLRs, which could constitute an important supplemental measure to the standard behavioral tests presently being used in postoperative clinical evaluation settings., (American Academy of Audiology.)