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

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

Amplitude Parameters Are Predictive of Hearing Preservation in a Randomized Controlled Trial of Intracochlear Electrocochleography During Cochlear Implant Surgery.

OBJECTIVE: To prospectively evaluate the association between hearing preservation after cochlear implantation (CI) and intracochlear electrocochleography (ECochG) amplitude parameters. STUDY DESIGN: Multi-institutional, prospective randomized clinical trial. SETTING: Ten high-volume, tertiary care CI centers. PATIENTS: Adults (n = 87) with sensorineural hearing loss meeting CI criteria (2018-2021) with audiometric thresholds of ≤80 dB HL at 500 Hz. METHODS: Participants were randomized to CI surgery with or without audible ECochG monitoring. Electrode arrays were inserted to the full-depth marker. Hearing preservation was determined by comparing pre-CI, unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to LF-PTA at CI activation. Three ECochG amplitude parameters were analyzed: 1) insertion track patterns, 2) magnitude of ECochG amplitude change, and 3) total number of ECochG amplitude drops. RESULTS: The Type CC insertion track pattern, representing corrected drops in ECochG amplitude, was seen in 76% of cases with ECochG "on," compared with 24% of cases with ECochG "off" ( p = 0.003). The magnitude of ECochG signal drop was significantly correlated with the amount of LF-PTA change pre-CI and post-CI ( p < 0.05). The mean number of amplitude drops during electrode insertion was significantly correlated with change in LF-PTA at activation and 3 months post-CI ( p ≤ 0.01). CONCLUSIONS: ECochG amplitude parameters during CI surgery have important prognostic utility. Higher incidence of Type CC in ECochG "on" suggests that monitoring may be useful for surgeons in order to recover the ECochG signal and preventing potentially traumatic electrode-cochlear interactions.

A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential.

Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20 % of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80 mV compared with around 120 mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.

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

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

Self-Assessment of Cochlear Health by New Cochlear Implant Recipients: Daily Impedance, Electrically Evoked Compound Action Potential and Electrocochleography Measurements Over the First Three Postoperative Months.

HYPOTHESES: In newly implanted cochlear implant (CI) users, electrically evoked compound action (eCAPs) and electrocochleography (ECochGs) will remain stable over time. Electrode impedances will increase immediately postimplantation due to the initial inflammatory response, before decreasing after CI switch-on and stabilizing thereafter. BACKGROUND: The study of cochlear health (CH) has several applications, including explaining variation in CI outcomes, informing CI programming strategies, and evaluating the safety and efficacy of novel biological treatments for hearing loss. Very early postoperative CH patterns have not previously been intensively explored through longitudinal daily testing. Thanks to technological advances, electrode impedances, eCAPs, and ECochGs can be independently performed by CI users at home to monitor CH over time. METHODS: A group of newly implanted CI users performed daily impedances, eCAPs, and ECochGs for 3 months at home, starting from the first day postsurgery (N = 7) using the Active Insertion Monitoring system by Advanced Bionics. RESULTS: Measurement validity of 93.5, 93.0, and 81.6% for impedances, eCAPs, and ECochGs, respectively, revealed high participant compliance. Impedances increased postsurgery before dropping and stabilizing after switch-on. eCAPs showed good stability, though statistical analyses revealed a very small but significant increase in thresholds over time. Most ECochG thresholds did not reach the liberal signal-to-noise criterion of 2:1, with low threshold stability over time. CONCLUSION: Newly implanted CI recipients can confidently and successfully perform CH recordings at home, highlighting the valuable role of patients in longitudinal data collection. Electrode impedances and eCAPs are promising objective measurements for evaluating CH in newly implanted CI users.

Alpha9alpha10 knockout mice show altered physiological and behavioral responses to signals in masking noise.

Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (α9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (α9α10KOs) may exhibit more severe MOC-related phenotypes. Like α9KOs, α9α10KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in α9α10KO mice. Wild-type (WT) and α9α10KO mice had similar ABR thresholds and acoustic startle response amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. α9α10KO mice had larger ABR Wave I amplitudes than WTs in quiet and noise. Other ABR metrics of hearing-in-noise function yielded conflicting findings regarding α9α10KO susceptibility to masking effects. α9α10KO mice also had larger startle amplitudes in tone backgrounds than WTs. Overall, α9α10KO mice had grossly normal auditory function in quiet and noise, although their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.

Does Intraoperative Extracochlear Electrocochleography Correlate With Postoperative Audiometric Hearing Thresholds in Cochlear Implant Surgery? A Retrospective Analysis of Cochlear Monitoring.

In recent years, tools for early detection of irreversible trauma to the basilar membrane during hearing preservation cochlear implant (CI) surgery were established in several clinics. A link with the degree of postoperative hearing preservation in patients was investigated, but patient populations were usually small. Therefore, this study's aim was to analyze data from intraoperative extracochlear electrocochleography (ECochG) recordings for a larger group.During hearing preservation CI surgery, extracochlear recordings were made before, during, and after CI electrode insertion using a cotton wick electrode placed at the promontory. Before and after insertion, amplitudes and stimulus response thresholds were recorded at 250, 500, and 1000 Hz. During insertion, response amplitudes were recorded at one frequency and one stimulus level. Data from 121 patient ears were analyzed.The key benefit of extracochlear recordings is that they can be performed before, during, and after CI electrode insertion. However, extracochlear ECochG threshold changes before and after CI insertion were relatively small and did not independently correlate well with hearing preservation, although at 250 Hz they added some significant information. Some tendencies-although no significant relationships-were detected between amplitude behavior and hearing preservation. Rising amplitudes seem favorable and falling amplitudes disadvantageous, but constant amplitudes do not appear to allow stringent predictions.Extracochlear ECochG measurements seem to only partially realize expected benefits. The questions now are: do gains justify the effort, and do other procedures or possible combinations lead to greater benefits for patients?

Intracochlear Recording of Electrocochleography During and After Cochlear Implant Insertion Dependent on the Location in the Cochlea.

To preserve residual hearing during cochlear implant (CI) surgery it is desirable to use intraoperative monitoring of inner ear function (cochlear monitoring). A promising method is electrocochleography (ECochG). Within this project the relations between intracochlear ECochG recordings, position of the recording contact in the cochlea with respect to anatomy and frequency and preservation of residual hearing were investigated. The aim was to better understand the changes in ECochG signals and whether these are due to the electrode position in the cochlea or to trauma generated during insertion. During and after insertion of hearing preservation electrodes, intraoperative ECochG recordings were performed using the CI electrode (MED-EL). During insertion, the recordings were performed at discrete insertion steps on electrode contact 1. After insertion as well as postoperatively the recordings were performed at different electrode contacts. The electrode location in the cochlea during insertion was estimated by mathematical models using preoperative clinical imaging, the postoperative location was measured using postoperative clinical imaging. The recordings were analyzed from six adult CI recipients. In the four patients with good residual hearing in the low frequencies the signal amplitude rose with largest amplitudes being recorded closest to the generators of the stimulation frequency, while in both cases with severe pantonal hearing losses the amplitude initially rose and then dropped. This might be due to various reasons as discussed in the following. Our results indicate that this approach can provide valuable information for the interpretation of intracochlearly recorded ECochG signals.

Perceptual Consequences of Cochlear Deafferentation in Humans.

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

Murine cochlear damage models in the context of hair cell regeneration research.

Understanding the complex pathologies associated with hearing loss is a significant motivation for conducting inner ear research. Lifelong exposure to loud noise, ototoxic drugs, genetic diversity, sex, and aging collectively contribute to human hearing loss. Replicating this pathology in research animals is challenging because hearing impairment has varied causes and different manifestations. A central aspect, however, is the loss of sensory hair cells and the inability of the mammalian cochlea to replace them. Researching therapeutic strategies to rekindle regenerative cochlear capacity, therefore, requires the generation of animal models in which cochlear hair cells are eliminated. This review discusses different approaches to ablate cochlear hair cells in adult mice. We inventoried the cochlear cyto- and histo-pathology caused by acoustic overstimulation, systemic and locally applied drugs, and various genetic tools. The focus is not to prescribe a perfect damage model but to highlight the limitations and advantages of existing approaches and identify areas for further refinement of damage models for use in regenerative studies.

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

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

L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice.

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25-26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing - Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Surface electrical stimulation of the auditory cortex preserves efferent medial olivocochlear neurons and reduces cochlear traits of age-related hearing loss.

The auditory cortex is the source of descending connections providing contextual feedback for auditory signal processing at almost all levels of the lemniscal auditory pathway. Such feedback is essential for cognitive processing. It is likely that corticofugal pathways are degraded with aging, becoming important players in age-related hearing loss and, by extension, in cognitive decline. We are testing the hypothesis that surface, epidural stimulation of the auditory cortex during aging may regulate the activity of corticofugal pathways, resulting in modulation of central and peripheral traits of auditory aging. Increased auditory thresholds during ongoing age-related hearing loss in the rat are attenuated after two weeks of epidural stimulation with direct current applied to the surface of the auditory cortex for two weeks in alternate days (Fernández del Campo et al., 2024). Here we report that the same cortical electrical stimulation protocol induces structural and cytochemical changes in the aging cochlea and auditory brainstem, which may underlie recovery of age-degraded auditory sensitivity. Specifically, we found that in 18 month-old rats after two weeks of cortical electrical stimulation there is, relative to age-matched non-stimulated rats: a) a larger number of choline acetyltransferase immunoreactive neuronal cell body profiles in the ventral nucleus of the trapezoid body, originating the medial olivocochlear system.; b) a reduction of age-related dystrophic changes in the stria vascularis; c) diminished immunoreactivity for the pro-inflammatory cytokine TNFα in the stria vascularis and spiral ligament. d) diminished immunoreactivity for Iba1 and changes in the morphology of Iba1 immunoreactive cells in the lateral wall, suggesting reduced activation of macrophage/microglia; d) Increased immunoreactivity levels for calretinin in spiral ganglion neurons, suggesting excitability modulation by corticofugal stimulation. Altogether, these findings support that non-invasive neuromodulation of the auditory cortex during aging preserves the cochlear efferent system and ameliorates cochlear aging traits, including stria vascularis dystrophy, dysregulated inflammation and altered excitability in primary auditory neurons.

Is the spread of excitation different between adults and children cochlear implants users?

PURPOSE: While cochlea is adult size at birth, etiologies and bone density may differ between children and adults. Differences in neural response thresholds (tNRT) and the spread of excitation (SOE) width may impact the use of artificial intelligence algorithms in speech processor fitting. AIM: To identify whether neural response telemetry threshold and spread of excitation width are similar in adults and children. METHODS: Retrospective cross-sectional study approved by the Ethical Board. Intraoperative tNRT and SOE recordings of consecutive cochlear implant surgeries in adults and children implanted with Cochlear devices (Cochlear™, Australia) were selected. SOE was recorded on electrode 11 (or adjacent, corresponding to the medial region of the cochlea) through the standard forward-masking technique in Custom Sound EP software, which provides SOE width in millimeters. Statistical comparison between adults and children was performed using the Mann-Whitney test (p ≤ 0.05). RESULTS: Of 1282 recordings of intraoperative evaluations, 414 measurements were selected from children and adults. Despite the tNRT being similar between adults and children, SOE width was significantly different, with lower values in children with perimodiolar arrays. Besides, it was observed that there is a difference in the electrode where the SOE function peak occurred, more frequently shifted to electrode 12 in adults implanted. In straight arrays, there was no difference in any of the parameters analyzed on electrode 11. CONCLUSION: Although eCAP thresholds are similar, SOE measurements differ between adults and children in perimodiolar electrodes.

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

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

3D printed biomimetic cochleae and machine learning co-modelling provides clinical informatics for cochlear implant patients.

Cochlear implants restore hearing in patients with severe to profound deafness by delivering electrical stimuli inside the cochlea. Understanding stimulus current spread, and how it correlates to patient-dependent factors, is hampered by the poor accessibility of the inner ear and by the lack of clinically-relevant in vitro, in vivo or in silico models. Here, we present 3D printing-neural network co-modelling for interpreting electric field imaging profiles of cochlear implant patients. With tuneable electro-anatomy, the 3D printed cochleae can replicate clinical scenarios of electric field imaging profiles at the off-stimuli positions. The co-modelling framework demonstrated autonomous and robust predictions of patient profiles or cochlear geometry, unfolded the electro-anatomical factors causing current spread, assisted on-demand printing for implant testing, and inferred patients' in vivo cochlear tissue resistivity (estimated mean = 6.6 kΩcm). We anticipate our framework will facilitate physical modelling and digital twin innovations for neuromodulation implants.

A cell-type-specific atlas of the inner ear transcriptional response to acoustic trauma.

Noise-induced hearing loss (NIHL) results from a complex interplay of damage to the sensory cells of the inner ear, dysfunction of its lateral wall, axonal retraction of type 1C spiral ganglion neurons, and activation of the immune response. We use RiboTag and single-cell RNA sequencing to survey the cell-type-specific molecular landscape of the mouse inner ear before and after noise trauma. We identify induction of the transcription factors STAT3 and IRF7 and immune-related genes across all cell-types. Yet, cell-type-specific transcriptomic changes dominate the response. The ATF3/ATF4 stress-response pathway is robustly induced in the type 1A noise-resilient neurons, potassium transport genes are downregulated in the lateral wall, mRNA metabolism genes are downregulated in outer hair cells, and deafness-associated genes are downregulated in most cell types. This transcriptomic resource is available via the Gene Expression Analysis Resource (gEAR; https://umgear.org/NIHL) and provides a blueprint for the rational development of drugs to prevent and treat NIHL.

Thymoquinone ameliorates age-related hearing loss in C57BL/6J mice by modulating Sirt1 activity and Bak1 expression.

Age-related hearing loss (AHL) is the most common sensory disorder of aged population. Currently, one of the most important sources of experimental medicine for AHL is medicinal plants. This study performed the first investigation of the effect of thymoquinone (TQ), a potent antioxidant, on AHL. Here, we used inbred C57BL/6J mice (B6 mice) as a successful experimental model of the early onset of AHL. The behavioral assessment of hearing revealed that the injection of a high dose of TQ (40 mg/kg; TQ40) significantly improved the auditory sensitivity of B6 mice at all tested frequencies (8, 16 and 22 kHz). Histological sections of cochlea from B6 mice injected with a low dose (20 mg/kg; TQ20) and high dose showed relatively less degenerative signs in the modiolus, hair cells and spiral ligaments, the main constituents of the cochlea. In addition, TQ40 completely restored the normal pattern of hair cells in B6 mice, as shown in scanning electron micrographs. Our data indicated that TQ20 and TQ40 reduced levels of Bak1-mediated apoptosis in the cochlea of B6 mice. Interestingly, the level of Sirt1, a positive regulator of autophagy, was significantly increased in B6 mice administered TQ40. In conclusion, TQ relieves the symptoms of AHL by downregulating Bak1 and activating Sirt1 in the cochlea of B6 mice.

IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss.

Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/- mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency.

Cochlear Synaptopathy: A Primary Factor Affecting Speech Recognition Performance in Presbycusis.

The results of recent animal studies have suggested that cochlear synaptopathy may be an important factor involved in presbycusis. Therefore, here, we aimed to examine whether cochlear synaptopathy frequently exists in patients with presbycusis and to describe the effect of cochlear synaptopathy on speech recognition in noise. Based on the medical history and an audiological examination, 94 elderly patients with bilateral, symmetrical, sensorineural hearing loss were diagnosed as presbycusis. An electrocochleogram, auditory brainstem responses, auditory cortical evoked potentials, and speech audiometry were recorded to access the function of the auditory pathway. First, 65 ears with hearing levels of 41-50 dB HL were grouped based on the summating potential/action potential (SP/AP) ratio, and the amplitudes of AP and SP were compared between the two resulting groups. Second, 188 ears were divided into two groups: the normal SP/AP and abnormal SP/AP groups. The speech recognition abilities in the two groups were compared. Finally, the relationship between abnormal electrocochleogram and poor speech recognition (signal-to-noise ratio loss ≥7 dB) was analyzed in 188 ears. The results of the present study showed: (1) a remarkable reduction in the action potential amplitude was observed in patients with abnormal SP/AP ratios; this suggests that cochlear synaptopathy was involved in presbycusis. (2) There was a large proportion of patients with poor speech recognition in the abnormal SP/AP group. Furthermore, a larger number of cases with abnormal SP/AP ratios were confirmed among patients with presbycusis and poor speech recognition. We concluded that cochlear synaptopathy is not uncommon among elderly individuals who have hearing ability deficits, and it may have a more pronounced effect on ears with declining auditory performance in noisy environments.