A single dose of AC102 restores hearing in a guinea pig model of noise-induced hearing loss to almost prenoise levels.

Although sudden sensorineural hearing loss (SSNHL) is a serious condition, there are currently no approved drugs for its treatment. Nevertheless, there is a growing understanding that the cochlear pathologies that underlie SSNHL include apoptotic death of sensory outer hair cells (OHCs) as well as loss of ribbon synapses connecting sensory inner hair cells (IHCs) and neurites of the auditory nerve, designated synaptopathy. Noise-induced hearing loss (NIHL) is a common subtype of SSNHL and is widely used to model hearing loss preclinically. Here, we demonstrate that a single interventive application of a small pyridoindole molecule (AC102) into the middle ear restored auditory function almost to prenoise levels in a guinea pig model of NIHL. AC102 prevented noise-triggered loss of OHCs and reduced IHC synaptopathy suggesting a role of AC102 in reconnecting auditory neurons to their sensory target cells. Notably, AC102 exerted its therapeutic properties over a wide frequency range. Such strong improvements in hearing have not previously been demonstrated for other therapeutic agents. In vitro experiments of a neuronal damage model revealed that AC102 protected cells from apoptosis and promoted neurite growth. These effects may be explained by increased production of adenosine triphosphate, indicating improved mitochondrial function, and reduced levels of reactive-oxygen species which prevents the apoptotic processes responsible for OHC death. This action profile of AC102 might be causal for the observed hearing recovery in in vivo models.

Towards ASSR-based hearing assessment using natural sounds.

Objective. The auditory steady-state response (ASSR) allows estimation of hearing thresholds. The ASSR can be estimated from electroencephalography (EEG) recordings from electrodes positioned on both the scalp and within the ear (ear-EEG). Ear-EEG can potentially be integrated into hearing aids, which would enable automatic fitting of the hearing device in daily life. The conventional stimuli for ASSR-based hearing assessment, such as pure tones and chirps, are monotonous and tiresome, making them inconvenient for repeated use in everyday situations. In this study we investigate the use of natural speech sounds for ASSR estimation.Approach.EEG was recorded from 22 normal hearing subjects from both scalp and ear electrodes. Subjects were stimulated monaurally with 180 min of speech stimulus modified by applying a 40 Hz amplitude modulation (AM) to an octave frequency sub-band centered at 1 kHz. Each 50 ms sub-interval in the AM sub-band was scaled to match one of 10 pre-defined levels (0-45 dB sensation level, 5 dB steps). The apparent latency for the ASSR was estimated as the maximum average cross-correlation between the envelope of the AM sub-band and the recorded EEG and was used to align the EEG signal with the audio signal. The EEG was then split up into sub-epochs of 50 ms length and sorted according to the stimulation level. ASSR was estimated for each level for both scalp- and ear-EEG.Main results. Significant ASSRs with increasing amplitude as a function of presentation level were recorded from both scalp and ear electrode configurations.Significance. Utilizing natural sounds in ASSR estimation offers the potential for electrophysiological hearing assessment that are more comfortable and less fatiguing compared to existing ASSR methods. Combined with ear-EEG, this approach may allow convenient hearing threshold estimation in everyday life, utilizing ambient sounds. Additionally, it may facilitate both initial fitting and subsequent adjustments of hearing aids outside of clinical settings.

Assessing the accuracy and reliability of application-based audiometry for hearing evaluation.

Pure-tone audiometry (PTA) is the gold standard for assessing hearing loss. However, traditional PTA tests require specialized equipment, trained personnel, and a soundproof environment. Recently, smartphone-based PTA tests have been developed as an alternative method for hearing assessment. The aim of this study was to validate the accuracy and reliability of a smartphone application-based audiometry test. This study was conducted to assess the performance of application-based audiometry from November 2021 to January 2022. Pure-tone thresholds were measured using a smartphone application-based PTA test and compared with results obtained using a traditional audiometer in a sound-treated booth. The smartphone application used in this study was the "Care4Ear (Care4ear, version 1.0.6, MIJ Co., Ltd.)". Hearing thresholds less than 35 dB HL were classified as group A, 35-64 dB HL as group B, and 65 dB HL or greater as group C for the classification of hearing levels. We evaluated the accuracy of smartphone audiometry for each group and compared the results of frequency-specific hearing tests. Additionally, we examined the results of smartphone audiometry in individuals (n = 27) with asymmetric hearing loss. Seventy subjects completed both conventional audiometry and smartphone application-based hearing tests. Among the ears assessed, 55.7% were classified as group A, while 25.7% and 18.6% were classified as group B and group C, respectively. The average hearing threshold obtained from conventional pure-tone audiometry was 37.7 ± 25.2 dB HL, whereas the application-based hearing test yielded thresholds of 21.0 ± 23.0 dB HL. A significant correlation (r = 0.69, p < 0.01) was found between the average hearing thresholds obtained from the application-based and conventional pure-tone audiometry tests. The application-based test achieved a 97.4% hit rate for classifying hearing thresholds as class A, but lower rates of 22.2% for class B and 38.5% for class C. Notably, a discrepancy was observed between the hearing threshold measured by the application and the conventional audiometry for the worse ear with asymmetric hearing. The smartphone-based audiometry is a feasible method for hearing evaluation especially in persons with normal hearing. In cases of hearing loss or asymmetric hearing loss, the results of the application-based audiometry may be inaccurate, limiting its diagnostic utility.

A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss.

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change -0.87 dB; 95% CI -2.37 to 0.63; P = 0.252 and -0.46 dB; 95% CI -1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial's primary endpoint was not met.

Correlation Analysis and Comparison of Adult CE-Chirp ABR Response Threshold and Pure Tone Hearing Threshold.

OBJECTIVES: To study the application of CE-Chirp in the evaluation of hearing impairment in forensic medicine by testing the auditory brainstem response (ABR) in adults using CE-Chirp to analyze the relationship between the V-wave response threshold of CE-Chirp ABR test and the pure tone hearing threshold. METHODS: Subjects (aged 20-77 with a total of 100 ears) who underwent CE-Chirp ABR test in Changzhou De'an Hospital from January 2018 to June 2019 were selected to obtain the V-wave response threshold, and pure tone air conduction hearing threshold tests were conducted at 0.5, 1.0, 2.0 and 4.0 kHz, respectively, to obtain pure tone listening threshold. The differences and statistical differences between the average pure tone hearing threshold and V-wave response threshold were compared in different hearing levels and different age groups. The correlation, differences and statistical differences between the two tests at each frequency were analyzed for all subjects. The linear regression equation for estimating pure tone hearing threshold for all subjects CE-Chirp ABR V-wave response threshold was established, and the feasibility of the equation was tested. RESULTS: There was no statistical significance in the CE-Chirp ABR response threshold and pure tone hearing threshold difference between different hearing level groups and different age groups (P>0.05). There was a good correlation between adult CE-Chirp ABR V-wave response threshold and pure tone hearing threshold with statistical significance (P<0.05), and linear regression analysis showed a significant linear correlation between the two (P<0.05). CONCLUSIONS: The use of CE-Chirp ABR V-wave response threshold can be used to evaluate subjects' pure tone hearing threshold under certain conditions, and can be used as an audiological test method for forensic hearing impairment assessment.

Noise-induced synaptic loss and its post-exposure recovery in CBA/CaJ vs. C57BL/6J mice.

Acute noise-induced loss of synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) has been documented in several strains of mice, but the extent of post-exposure recovery reportedly varies dramatically. If such inter-strain heterogeneity is real, it could be exploited to probe molecular pathways mediating neural remodeling in the adult cochlea. Here, we compared synaptopathy repair in CBA/CaJ vs. C57BL/6J, which are at opposite ends of the reported recovery spectrum. We evaluated C57BL/6J mice 0 h, 24 h, 2 wks or 8 wks after exposure for 2 h to octave-band noise (8-16 kHz) at either 90, 94 or 98 dB SPL, to compare with analogous post-exposure results in CBA/CaJ at 98 or 101 dB. We counted pre- and post-synaptic puncta in immunostained cochleas, using machine learning to classify paired (GluA2 and CtBP2) vs. orphan (CtBP2 only) puncta, and batch-processing to quantify immunostaining intensity. At 98 dB, both strains show ongoing loss of ribbons and synapses between 0 and 24 h, followed by partial recovery, however the extent and degree of these changes were greater in C57BL/6J. Much of the synaptic recovery is due to transient reduction in GluA2 intensity in synaptopathic regions. In contrast, CtBP2 intensity showed only transient increases (at 2 wks). Neurofilament staining revealed transient extension of ANF terminals in C57BL/6J, but not in CBA/CaJ, peaking at 24 h and reverting by 2 wks. Thus, although interstrain differences in synapse recovery are dominated by reversible changes in GluA2 receptor levels, the neurite extension seen in C57BL/6J suggests a qualitative difference in regenerative capacity.

Reduced processing efficiency impacts auditory detection of amplitude modulation in children: Evidence from an experimental and modeling study.

Auditory detection of the Amplitude Modulation (AM) of sounds, crucial for speech perception, improves until 10 years of age. This protracted development may not only be explained by sensory maturation, but also by improvements in processing efficiency: the ability to make efficient use of available sensory information. This hypothesis was tested behaviorally on 86 6-to-9-year-olds and 15 adults using AM-detection tasks assessing absolute sensitivity, masking, and response consistency in the AM domain. Absolute sensitivity was estimated by the detection thresholds of a sinusoidal AM applied to a pure-tone carrier; AM masking was estimated as the elevation of AM-detection thresholds produced when replacing the pure-tone carrier by a narrowband noise; response consistency was estimated using a double-pass paradigm where the same set of stimuli was presented twice. Results showed that AM sensitivity improved from childhood to adulthood, but did not change between 6 and 9 years. AM masking did not change with age, suggesting that the selectivity of perceptual AM filters was adult-like by 6 years. However, response consistency increased developmentally, supporting the hypothesis of reduced processing efficiency in early childhood. At the group level, double-pass data of children and adults were well simulated by a model of the human auditory system assuming a higher level of internal noise for children. At the individual level, for both children and adults, double-pass data were better simulated when assuming a sub-optimal decision strategy in addition to differences in internal noise. In conclusion, processing efficiency for AM detection is reduced in childhood. Moreover, worse AM detection was linked to both systematic and stochastic inefficiencies, in both children and adults.

Hidden hearing loss: Fifteen years at a glance.

Hearing loss affects approximately 18% of the population worldwide. Hearing difficulties in noisy environments without accompanying audiometric threshold shifts likely affect an even larger percentage of the global population. One of the potential causes of hidden hearing loss is cochlear synaptopathy, the loss of synapses between inner hair cells (IHC) and auditory nerve fibers (ANF). These synapses are the most vulnerable structures in the cochlea to noise exposure or aging. The loss of synapses causes auditory deafferentation, i.e., the loss of auditory afferent information, whose downstream effect is the loss of information that is sent to higher-order auditory processing stages. Understanding the physiological and perceptual effects of this early auditory deafferentation might inform interventions to prevent later, more severe hearing loss. In the past decade, a large body of work has been devoted to better understand hidden hearing loss, including the causes of hidden hearing loss, their corresponding impact on the auditory pathway, and the use of auditory physiological measures for clinical diagnosis of auditory deafferentation. This review synthesizes the findings from studies in humans and animals to answer some of the key questions in the field, and it points to gaps in knowledge that warrant more investigation. Specifically, recent studies suggest that some electrophysiological measures have the potential to function as indicators of hidden hearing loss in humans, but more research is needed for these measures to be included as part of a clinical test battery.

Functional Hearing Preservation in Cochlear Implantation: The Miami Cocktail Effect.

OBJECTIVE: To investigate if pharmacological treatment with prednisone and L-N-acetylcysteine (STE + NAC) influence functional hearing preservation in cochlear implant (CI) surgery. STUDY DESIGNS: Preimplantation and postimplantation longitudinal case-control study. SETTING: Tertiary referral center. PATIENTS: Pediatric and adult recipients of CI with preimplantation functional hearing defined as an average of air-conducted thresholds at 125, 250, and 500 Hz (low-frequency pure-tone average [LFPTA]) <80 dB. INTERVENTIONS: Preimplantation and postimplantation audiometry. Weight-adjusted oral prednisone and L-N-acetylcysteine starting 2 days before surgery (Miami cocktail). Prednisone was continued for 3 days and L-N-acetylcysteine for 12 days after surgery, respectively. Cochlear implantation with conventional length electrodes. MAIN OUTCOME MEASURES: Proportion of patients with LFPTA <80 dB, and LFPTA change at 1-year postimplantation. RESULTS: All 61 patients received intratympanic and intravenous dexamethasone intraoperatively, with 41 patients receiving STE + NAC and 20 patients not receiving STE + NAC. At 1-year postimplantation, the proportion of functional hearing preservation was 83% in the STE + NAC group compared with 55% of subjects who did not receive STE + NAC ( p = 0.0302). The median LFPTA change for STE + NAC-treated and not treated subjects was 8.33 dB (mean, 13.82 ± 17.4 dB) and 18.34 dB (mean, 26.5 ± 23.4 dB), respectively ( p = 0.0401, Wilcoxon rank test). Perioperative STE + NAC treatment resulted in 10 dB of LFPTA better hearing than when not receiving this treatment. Better low-frequency preimplantation hearing thresholds were predictive of postimplantation functional hearing. No serious side effects were reported. CONCLUSION: Perioperative STE + NAC, "The Miami Cocktail," was safe and superior to intraoperative steroids alone in functional hearing preservation 1-year after cochlear implantation.

The perception of ultrasonic vocalizations by laboratory mice following intense noise exposures.

Noise-induced hearing loss interacts with age, sex, and listening conditions to affect individuals' perception of ecologically relevant stimuli like speech. The present experiments assessed the impact of age and sex on vocalization detection by noise-exposed mice trained to detect a downsweep or complex ultrasonic vocalization in quiet or in the presence of a noise background. Daily thresholds before and following intense noise exposure were collected longitudinally and compared across several factors. All mice, regardless of age, sex, listening condition, or stimulus type showed their poorest behavioral sensitivity immediately after the noise exposure. There were varying degrees of recovery over time and across factors. Old-aged mice had greater threshold shifts and less recovery compared to middle-aged mice. Mice had larger threshold shifts and less recovery for downsweeps than for complex vocalizations. Female mice were more sensitive, had smaller post-noise shifts, and had better recovery than males. Thresholds in noise were higher and less variable than thresholds in quiet, but there were comparable shifts and recovery. In mice, as in humans, the perception of ecologically relevant stimuli suffers after an intense noise exposure, and results differ from simple tone detection findings.

[Study on gene therapy for DPOAE and ABR threshold changes in adult Otof-/- mice].

Objective:This study aims to analyze the threshold changes in distortion product otoacoustic emissions（DPOAE） and auditory brainstem response（ABR） in adult Otof-/- mice before and after gene therapy, evaluating its effectiveness and exploring methods for assessing hearing recovery post-treatment. Methods:At the age of 4 weeks, adult Otof-/- mice received an inner ear injection of a therapeutic agent containing intein-mediated recombination of the OTOF gene, delivered via dual AAV vectors through the round window membrane（RWM）. Immunofluorescence staining assessed the proportion of inner ear hair cells with restored otoferlin expression and the number of synapses.Statistical analysis was performed to compare the DPOAE and ABR thresholds before and after the treatment. Results:AAV-PHP. eB demonstrates high transduction efficiency in inner ear hair cells. The therapeutic regimen corrected hearing loss in adult Otof-/- mice without impacting auditory function in wild-type mice. The changes in DPOAE and ABR thresholds after gene therapy are significantly correlated at 16 kHz. Post-treatment,a slight increase in DPOAE was observeds,followed by a recovery trend at 2 months post-treatment. Conclusion:Gene therapy significantly restored hearing in adult Otof-/- mice, though the surgical delivery may cause transient hearing damage. Precise and gentle surgical techniques are essential to maximize gene therapy's efficacy.

Multisession anodal epidural direct current stimulation of the auditory cortex delays the progression of presbycusis in the Wistar rat.

Presbycusis or age-related hearing loss (ARHL) is one of the most prevalent chronic health problems facing aging populations. Along the auditory pathway, the stations involved in transmission and processing, function as a system of interconnected feedback loops. Regulating hierarchically auditory processing, auditory cortex (AC) neuromodulation can, accordingly, activate both peripheral and central plasticity after hearing loss. However, previous ARHL-prevention interventions have mainly focused on preserving the structural and functional integrity of the inner ear, overlooking the central auditory system. In this study, using an animal model of spontaneous ARHL, we aim at assessing the effects of multisession epidural direct current stimulation of the AC through stereotaxic implantation of a 1-mm silver ball anode in Wistar rats. Consisting of 7 sessions (0.1 mA/10 min), on alternate days, in awake animals, our stimulation protocol was applied at the onset of hearing loss (threshold shift detection at 16 months). Click- and pure-tone auditory brainstem responses (ABRs) were analyzed in two animal groups, namely electrically stimulated (ES) and non-stimulated (NES) sham controls, comparing recordings at 18 months of age. At 18 months, NES animals showed significantly increased threshold shifts, decreased wave amplitudes, and increased wave latencies after click and tonal ABRs, reflecting a significant, spontaneous ARHL evolution. Conversely, in ES animals, no significant differences were detected in any of these parameters when comparing 16 and 18 months ABRs, indicating a delay in ARHL progression. Electrode placement in the auditory cortex was accurate, and the stimulation did not cause significant damage, as shown by the limited presence of superficial reactive microglial cells after IBA1 immunostaining. In conclusion, multisession DC stimulation of the AC has a protective effect on auditory function, delaying the progression of presbycusis.

Auditory sensitivity and tympanic middle ear in a vocal and a non-vocal frog.

The tympanic middle ear is important for anuran hearing on land. However, many species have partly or entirely lost their tympanic apparatus. Previous studies have compared hearing sensitivities in species that possess and lack tympanic membranes capable of sound production and acoustic communication. However, little is known about how these hearing abilities are comparable to those of mutant species. Here, we compared the eardrum and middle ear anatomies of two sympatric sibling species from a noisy stream habitat, namely the "non-vocal" Hainan torrent frog (Amolops hainanensis) and the "vocal" little torrent frog (Amolops torrentis), the latter of which is capable of acoustic communication. Our results showed that the relative (to head size) eardrum diameter of A. hainanensis was smaller than that of A. torrentis, although the absolute size was not smaller. Unlike A. torrentis, the tympanic membrane area of A. hainanensis was not clearly differentiated from the surrounding skin. The middle ear, however, was well-developed in both species. We measured the auditory brainstem responses (ABRs) of A. hainanensis and compared the ABR thresholds and latencies to those previously obtained for A. torrentis. Our results suggested that these two species exhibited significant differences in hearing sensitivity. A. hainanensis (smaller relative eardrum, nonvocal) had higher ABR thresholds and longer initial response times than A. torrentis (larger relative eardrum, vocal) at lower frequencies. Neurophysiological responses from the brain were obtained for tone pips between 800 Hz and 7,000 Hz, with peak sensitivities found at 3,000 Hz (73 dB SPL) for A. hainanensis, and at 1,800 Hz (61 dB SPL) for A. torrentis. Our results suggest that the non-vocal A. hainanensis has lower hearing sensitivity than its vocal sister species (i.e., A. torrentis), which may be related to differences in tympanic or inner ear structure and morphology.

An eight-year follow-up on auditory outcomes after neonatal hearing screening.

OBJECTIVE: The aim of this study is to assess the neonatal click Auditory Brainstem Response (ABR) results in relation to the subsequently determined mean hearing loss (HL) over 1, 2 and 4 kHz, as well as over 2 and 4 kHz. METHODS: Between 2004-2009, follow-up data were collected from Visual Reinforcement Audiometry (VRA) at 1 and 2 years and playaudiometry at 4 and 8 years of newborns who had failed neonatal hearing screening in the well-baby clinics and who had been referred to a single Speech and Hearing center. Hearing Level data were compared with ABR threshold-levels established during the first months of life. The Two One-Sided Tests equivalence procedure for paired means was applied, using a region of similarity equal to 10 dB. RESULTS: Initially, in 135 out of 172 children referred for diagnostic procedures hearing loss was confirmed in the neonatal period. In 106/135 of the HL children the eight-year follow-up was completed. Permanent conductive HL was established in 5/106 cases; the hearing thresholds were predominantly stable over time. Temporary conductive HL was found in 48/106 cases and the loss disappeared by 4 years of age at the latest. Sensorineural hearing loss (SNHL) was found in 53/106 cases, of which 13 were unilateral and 40 bilateral. ABR levels were equivalent (within a 10 dB range) to VRA levels at age 1 and 2 and play audiometry levels at age 4 and 8, both when VRA and play audiometry were averaged over both frequency ranges. CONCLUSION: Long term follow-up data of children with SNHL suggest that the initial click ABR level established in the first months of life, are equivalent to the hearing threshold measured at the age of 1, 2, 4 and 8 years for both mean frequency ranges. Click ABR can reliably be used as starting point for long-term hearing rehabilitation.

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

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

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

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

Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery.

Exposure to loud noise triggers sensory organ damage and degeneration that, in turn, leads to hearing loss. Despite the troublesome impact of noise-induced hearing loss (NIHL) in individuals and societies, treatment strategies that protect and restore hearing are few and insufficient. As such, identification and mechanistic understanding of the signaling pathways involved in NIHL are required. Biological zinc is mostly bound to proteins, where it plays major structural or catalytic roles; however, there is also a pool of unbound, mobile (labile) zinc. Labile zinc is mostly found in vesicles in secretory tissues, where it is released and plays a critical signaling role. In the brain, labile zinc fine-tunes neurotransmission and sensory processing. However, injury-induced dysregulation of labile zinc signaling contributes to neurodegeneration. Here, we tested whether zinc dysregulation occurs and contributes to NIHL in mice. We found that ZnT3, the vesicular zinc transporter responsible for loading zinc into vesicles, is expressed in cochlear hair cells and the spiral limbus, with labile zinc also present in the same areas. Soon after noise trauma, ZnT3 and zinc levels are significantly increased, and their subcellular localization is vastly altered. Disruption of zinc signaling, either via ZnT3 deletion or pharmacological zinc chelation, mitigated NIHL, as evidenced by enhanced auditory brainstem responses, distortion product otoacoustic emissions, and number of hair cell synapses. These data reveal that noise-induced zinc dysregulation is associated with cochlear dysfunction and recovery after NIHL, and point to zinc chelation as a potential treatment for mitigating NIHL.

Age-Related Deficits in Binaural Hearing: Contribution of Peripheral and Central Effects.

Pure-tone audiograms often poorly predict elderly humans' ability to communicate in everyday complex acoustic scenes. Binaural processing is crucial for discriminating sound sources in such complex acoustic scenes. The compromised perception of communication signals presented above hearing threshold has been linked to both peripheral and central age-related changes in the auditory system. Investigating young and old Mongolian gerbils of both sexes, an established model for human hearing, we demonstrate age-related supra-threshold deficits in binaural hearing using behavioral, electrophysiological, anatomical, and imaging methods. Binaural processing ability was measured as the binaural masking level difference (BMLD), an established measure in human psychophysics. We tested gerbils behaviorally with "virtual headphones," recorded single-unit responses in the auditory midbrain and evaluated gross midbrain and cortical responses using positron emission tomography (PET) imaging. Furthermore, we obtained additional measures of auditory function based on auditory brainstem responses, auditory-nerve synapse counts, and evidence for central inhibitory processing revealed by PET. BMLD deteriorates already in middle-aged animals having normal audiometric thresholds and is even worse in old animals with hearing loss. The magnitude of auditory brainstem response measures related to auditory-nerve function and binaural processing in the auditory brainstem also deteriorate. Furthermore, central GABAergic inhibition is affected by age. Because the number of synapses in the apical turn of the inner ear was not reduced in middle-aged animals, we conclude that peripheral synaptopathy contributes little to binaural processing deficits. Exploratory analyses suggest increased hearing thresholds, altered binaural processing in the brainstem and changed central GABAergic inhibition as potential contributors.

A Guinea Pig Model Suggests That Objective Assessment of Acoustic Hearing Preservation in Human Ears With Cochlear Implants Is Confounded by Shifts in the Spatial Origin of Acoustically Evoked Potential Measurements Along the Cochlear Length.

OBJECTIVES: Our recent empirical findings have shown that the auditory nerve compound action potential (CAP) evoked by a low-level tone burst originates from a narrow cochlear region tuned to the tone burst frequency. At moderate to high sound levels, the origins shift to the most sensitive audiometric regions rather than the extended high-frequency regions of the cochlear base. This means that measurements evoked from extended high-frequency sound stimuli can shift toward the apex with increasing level. Here we translate this study to understand the spatial origin of acoustically evoked responses from ears that receive cochlear implants, an emerging area of research and clinical practice that is not completely understood. An essential step is to first understand the influence of the cochlear implant in otherwise naive ears. Our objective was to understand how function of the high-frequency cochlear base, which can be excited by the intense low-frequency sounds that are frequently used for objective intra- and postoperative monitoring, can be influenced by the presence of the cochlear implant. DESIGN: We acoustically evoked responses and made measurements with an electrode placed near the guinea pig round window. The cochlear implant was not utilized for either electrical stimulation or recording purposes. With the cochlear implant in situ, CAPs were acoustically evoked from 2 to 16 kHz tone bursts of various levels while utilizing the slow perfusion of a kainic acid solution from the cochlear apex to the cochlear aqueduct in the base, which sequentially reduced neural responses from finely spaced cochlear frequency regions. This cochlear perfusion technique reveals the spatial origin of evoked potential measurements and provides insight on what influence the presence of an implant has on acoustical hearing. RESULTS: Threshold measurements at 3 to 11 kHz were elevated by implantation. In an individual ear, thresholds were elevated and lowered as cochlear implant was respectively inserted and removed, indicative of "conductive hearing loss" induced by the implant. The maximum threshold elevation occurred at most sensitive region of the naive guinea pig ear (33.66 dB at 8 kHz), making 11 kHz the most sensitive region to acoustic sounds for guinea pig ears with cochlear implants. Conversely, the acute implantation did not affect the low-frequency, 500 Hz thresholds and suprathreshold function, as shown by the auditory nerve overlapped waveform. As the sound pressure level of the tone bursts increased, mean data show that the spatial origin of CAPs along the cochlear length shifted toward the most sensitive cochlear region of implanted ears, not the extended high-frequency cochlear regions. However, data from individual ears showed that after implantation, measurements from moderate to high sound pressure levels originate in places that are unique to each ear. CONCLUSIONS: Alterations to function of the cochlear base from the in situ cochlear implant may influence objective measurements of implanted ears that are frequently made with intense low-frequency sound stimuli. Our results from guinea pigs advance the interpretation of measurements used to understand how and when residual acoustic hearing is lost in human ears receiving a cochlear implant.

Effect of Stimulus Bandwidth on the Auditory Steady-State Response in Scalp- and Ear-EEG.

OBJECTIVES: The auditory steady-state response (ASSR) enables hearing threshold estimation based on electroencephalography (EEG) recordings. The choice of stimulus type has an impact on both the detectability and the frequency specificity of the ASSR. Amplitude modulated pure tones provide the most frequency-specific ASSR, but responses to pure tones are weak. The ASSR can be enhanced by increasing the bandwidth of the stimulus, but this comes at the cost of a decrease in the frequency specificity of the measured response. The objective of the present study is to investigate the relationship between stimulus bandwidth and ASSR amplitude. DESIGN: The amplitude of ASSR was measured for five types of stimuli: 1 kHz pure tone and band-pass noise with 1/3, 1/2, 1, and 2 octave bandwidths centered at 1 kHz. All stimuli were amplitude modulated with a 40 Hz sinusoid. Responses to all stimulus types were measured at 30, 40, and 50 dB SL. ASSRs were measured concurrently using both conventional scalp-EEG and ear-EEG. RESULTS: Stimulus bandwidth and sound intensity were both found to have a significant effect on the ASSR amplitude for scalp- and ear-EEG recordings. In scalp-EEG ASSRs to all bandwidth stimuli were found to be significantly larger than ASSRs to pure tone at low sound intensity. At higher sound intensities, however, significantly larger responses were only obtained for 1- and 2-octave bandwidth stimuli. In ear-EEG, only the ASSR to 2 octave bandwidth stimulus was significantly larger than the ASSR to amplitude modulated pure tones. CONCLUSIONS: At low presentation levels, even small increases in stimulus bandwidth (1/3 and 1/2 octave) improve the detectability of ASSR in scalp-EEG with little or no impact on the frequency specificity. In comparison, a larger increase in stimulus bandwidth was needed to improve the ASSR detectability in the ear-EEG recordings.