Distinct changes in brain metabolism in patients with dementia and hearing loss.

INTRODUCTION: Previous studies have reported that hearing loss (HL) is associated with dementia, although the mechanistic underpinnings remain elusive. This study aimed to evaluate the changes in brain metabolism in patients with HL and different types of dementia. METHODS: Patients with cognitive impairment (CI) and HL treated at the university-based memory clinic from May 2016 to October 2021 were included. In total, 108 patients with CI and HL prospectively underwent audiometry, neuropsychological test, magnetic resonance imaging, and 18 F-fluorodeoxyglucose positron emission tomography. Twenty-seven individuals without cognitive impairment and hearing loss were enrolled as a control group. Multivariable regression was performed to evaluate brain regions correlated with each pathology type after adjusting for confounding factors. RESULTS: Multivariable regression analyses revealed that Alzheimer's disease-related CI (ADCI) was associated with hypometabolic changes in the right superior temporal gyrus (STG), right middle temporal gyrus (MTG), and bilateral medial temporal lobe. Lewy body disease-related CI (LBDCI) and vascular CI were associated with hypermetabolic and hypometabolic changes in the ascending auditory pathway, respectively. In the pure ADCI group, the degree of HL was positively associated with abnormal increase of brain metabolism in the right MTG, whereas it was negatively associated with decreased brain metabolism in the right STG in the pure LBDCI group. CONCLUSION: Each dementia type is associated with distinct changes in brain metabolism in patients with HL.

Apparent diffusion coefficient values of the white matter in magnetic resonance imaging of the neonatal brain may help predict outcome in congenital cytomegalovirus infection.

BACKGROUND: White matter change is a well-known abnormality in congenital cytomegalovirus (cCMV) infection, but grading remains challenging and clinical relevance unclear. OBJECTIVE: To investigate if quantitative measurement of white matter apparent diffusion coefficient (ADC) values in magnetic resonance imaging (MRI) of the neonatal brain can predict outcome in cCMV. MATERIALS AND METHODS: A retrospective, single-center observational study, including patients with cCMV who had a neonatal brain MRI with diffusion-weighted imaging, was performed between 2007 and 2020. Regions of interest were systematically placed in the white matter on the ADC maps. Two pediatric radiologists independently scored additional brain abnormalities. Outcome measures were neonatal hearing and cognitive and motor development. Statistical analysis included simple and penalized elastic net regression. RESULTS: Neonatal brain MRI was evaluated in 255 patients (median age 21 days, 25-75 percentiles: 14-28 days, 121 male). Gyral abnormalities were noted in nine patients (3.5%), ventriculomegaly in 24 (9.4%), and subependymal cysts in 58 (22.7%). General white matter ADC was significantly higher in patients with neonatal hearing loss and cognitive and motor impairment (P< 0.05). For neonatal hearing loss, simple logistic regression using only general white matter was the best prediction model, with a receiver operating characteristic area under the curve (AUC)=0.76. For cognitive impairment, interacting elastic net regression, including other brain abnormalities and frontoparietal white matter ADC, performed best, with AUC=0.89. For motor impairment, interacting elastic net regression, including other brain abnormalities and deep anterior frontal white matter performed best, with AUC=0.73. CONCLUSION: Neonatal white matter ADC was significantly higher in patients with clinical impairments. Quantitative ADC measurement may be a useful tool for predicting clinical outcome in cCMV.

Scuba Diving-Induced Inner-Ear Pathology: Imaging Findings of Superior Semicircular Canal and Tegmen Tympani Dehiscence.

BACKGROUND Superior semicircular canal dehiscence is an inner-ear pathology which presents with vertigo, disequilibrium, and hearing loss. Although the exact etiology of superior semicircular canal dehiscence is unknown, it is thought that an increase in middle-ear pressure disrupts a thin overlying temporal bone. Superior semicircular canal dehiscence is frequently seen in association with dehiscence of the tegmen tympani, which overlies the middle ear. Here, we present a case report of a 52-year-old Puerto Rican man with vertigo, dizziness, vomiting, and mild hearing loss associated with superior semicircular canal and tegmen tympani dehiscence after performing improper scuba diving techniques. CASE REPORT A 52-year-old Puerto Rican man presented to the emergency department with vertigo, dizziness, vomiting, and mild hearing loss in the right ear. The symptoms began shortly after scuba diving with inadequate decompression techniques on ascent. He was treated with recompression therapy with mild but incomplete improvement in symptoms. Bilateral temporal magnetic resonance imaging was suggestive of segmental dehiscence of the right superior semicircular canal and tegmen tympani. High-resolution computed tomography of the temporal bone confirmed right superior semicircular canal and tegmen tympani dehiscence with an intact left inner ear. CONCLUSIONS The increased inner-ear pressure that occurs during scuba diving can lead to dehiscence of the superior semicircular canal and tegmen tympani, causing vertigo and hearing loss. Performance of improper diving techniques can further increase the risk of dehiscence. Therefore, appropriate radiologic evaluation of the inner ear should be performed in such patients.

The dynamics of actin protrusions can be controlled by tip-localized myosin motors.

Class III myosins localize to inner ear hair cell stereocilia and are thought to be crucial for stereocilia length regulation. Mutations within the motor domain of MYO3A that disrupt its intrinsic motor properties have been associated with non-syndromic hearing loss, suggesting that the motor properties of MYO3A are critical for its function within stereocilia. In this study, we investigated the impact of a MYO3A hearing loss mutation, H442N, using both in vitro motor assays and cell biological studies. Our results demonstrate the mutation causes a dramatic increase in intrinsic motor properties, actin-activated ATPase and in vitro actin gliding velocity, as well as an increase in actin protrusion extension velocity. We propose that both "gain of function" and "loss of function" mutations in MYO3A can impair stereocilia length regulation, which is crucial for stereocilia formation during development and normal hearing. Furthermore, we generated chimeric MYO3A constructs that replace the MYO3A motor and neck domain with the motor and neck domain of other myosins. We found that duty ratio, fraction of ATPase cycle myosin is strongly bound to actin, is a critical motor property that dictates the ability to tip localize within filopodia. In addition, in vitro actin gliding velocities correlated extremely well with filopodial extension velocities over a wide range of gliding and extension velocities. Taken together, our data suggest a model in which tip-localized myosin motors exert force that slides the membrane tip-ward, which can combat membrane tension and enhance the actin polymerization rate that ultimately drives protrusion elongation.

Arachnoid Cyst of the Cerebellopontine Angle: A Systematic Literature Review.

OBJECTIVE: The role of surgical management of arachnoid cyst (AC) of the cerebellopontine angle (CPA) is uncertain. This topic has remained controversial with varying contradictory recommendations in the literature, which is limited to mostly case reports. We aimed to provide a comprehensive summary and analysis of symptoms, operative techniques, outcomes, and recurrence of all available surgical cases of AC of the CPA to date. METHODS: A systematic literature search was performed in May 2022 querying several scientific databases. Inclusion criteria specified all studies and case reports of patients with AC located at the CPA for which any relevant surgical procedures were performed. RESULTS: A total of 55 patients from the literature and 5 treated at our institution were included. Mean patient age was 29 years (range, 0.08-79 years), with nearly twice (1.7×) as many female as male patients (37 female, 22 male). Headaches (35%), hearing loss (30%), vertigo (22%), and ataxia (22%) were the most common presentations. Following surgery, 95% experienced symptom improvement, with complete resolution in 64%. Of patients with hearing loss, 44% reported a return to normal. The rate of mortality was 1.69%, and 10% of tumors recurred (mean follow-up 2.3 years [range, 0-15 years]. CONCLUSIONS: Symptomatic AC of the CPA is rare. It exhibits a proclivity for females and commonly manifests with headache, hearing loss, vertigo, and ataxia. While careful selection for surgical candidacy is needed and intervention should be reserved for patients with severe symptoms, surgical decompression is an effective tool for symptom alleviation and recovery.

Enlarged Vestibular Aqueduct and Associated Inner Ear Malformations: Hearing Loss Prognostic Factors and Data Modeling from an International Cohort.

ACKGROUND: There is a need to operationalize existing clinical data to support precision medicine in progressive hearing loss (HL). By utilizing enlarged vestibular aqueduct (EVA) and its associated inner ear abnormalities as an exemplar, we model data from a large international cohort, confirm prognostic factors for HL, and explore the potential to generate a prediction model to optimize current management paradigms. METHODS: An international retrospective cohort study. Regression analyses were utilized to model frequency-specific HL and identify prognostic factors for baseline average HL severity and progression. Elastic-net regression and machine learning (ML) techniques were utilized to predict future average HL progression based upon routinely measurable clinical, genetic, and radiological data. RESULTS: Higher frequencies of hearing were lost more severely. Prognostic factors for HL were the presence of incomplete partition type 2 (coefficient 12.95 dB, P=.011, 95% CI 3.0-22 dB) and presence of sac signal heterogeneity (P=.009, 95% CI 0.062-0.429) on magnetic resonance imaging. Elastic-net regression outperformed the ML algorithms (R2 0.32, mean absolute error 11.05 dB) with coefficients for baseline average hearing level and the presence of sac heterogeneity contributing the most to prediction outcomes. CONCLUSION: Incomplete partition type 2 and endolymphatic sac signal heterogeneity phenotypes should be monitored closely for hearing deterioration and need for early audiological rehabilitation/cochlear implant. Preliminary prediction models have been generated using routinely collected health data in EVA. This study showcases how international collaborative research can use exemplar techniques to improve precision medicine in relatively rare disease entities.

Diabetes mellitus and hearing loss.

Diabetes mellitus (DM) is a major disease threatening human health and its incidence is increasing year on year. As a chronic complication of DM, hearing loss mostly occurs undetectably. However, the mechanism of this diabetes-related hearing loss (DRHL) remains unclear and there is no effective clinical treatment. Studies of animal or human pathology show that DM causes damage to the blood vessels, spiral ganglion neurons, afferent nerve fibers, the organ of Corti, and the stria vascularis of the inner ear. In recent years, more advances in pathological research have revealed the possible mechanism of DRHL. In addition, a large number of clinical studies suggest that the duration and severity of DM are closely related to the incidence and severity of DRHL. This review focuses on the relationship between DM and hearing loss. The clinical audiological characteristics of diabetic patients, risk factors for DRHL, typical pathology, and potential interventions of DRHL are summarized. This will help reveal the pathogenesis and intervention approaches for DRHL.

Reversal of an existing hearing loss by gene activation in Spns2 mutant mice.

Hearing loss is highly heterogeneous, but one common form involves a failure to maintain the local ionic environment of the sensory hair cells reflected in a reduced endocochlear potential. We used a genetic approach to ask whether this type of pathology can be reversed, using the Spns2tm1a mouse mutant known to show this defect. By activating Spns2 gene transcription at different ages after the onset of hearing loss, we found that an existing auditory impairment can be reversed to give close to normal thresholds for an auditory brainstem response (ABR), at least at low to mid stimulus frequencies. Delaying the activation of Spns2 led to less effective recovery of ABR thresholds, suggesting that there is a critical period for intervention. Early activation of Spns2 not only led to improvement in auditory function but also to protection of sensory hair cells from secondary degeneration. The genetic approach we have used to establish that this type of hearing loss is in principle reversible could be extended to many other diseases using available mouse resources.

Supporting-cell vs. hair-cell survival in the human cochlea: Implications for regenerative therapies.

Animal studies have shown that the supporting-cells surviving in the organ of Corti after cochlear insult can be transdifferentiated into hair cells as a treatment for sensorineural hearing loss. Clinical trials of small-molecule therapeutics have been undertaken, but little is known about how to predict the pattern and degree of supporting-cell survival based on audiogram, hearing loss etiology or any other metric obtainable pre-mortem. To address this, we systematically assessed supporting-cell and hair cell survival, as a function of cochlear location in 274 temporal bone cases from the archives at the Massachusetts Eye and Ear and compared the histopathology with the audiograms and hearing-loss etiologies. Results showed that supporting-cell survival was always significantly greater in the apical half than the basal half of the cochlea, that inner pillars were more robust than outer pillars or Deiters' cells, and that total replacement of all supporting cells with a flat epithelium was rare outside of the extreme basal 20% of the cochlea. Supporting cell survival in the basal half of the cochlea was better correlated with the slope of the audiogram than with the mean high-frequency threshold per se: i.e. survival was better with flatter audiograms than with steeply down-sloping audiograms. Cochlear regions with extensive hair cell loss and exceptional supporting cell survival were most common in cases with hearing loss due to ototoxic drugs. Such cases also tended to have less pathology in other functionally critical structures, i.e. spiral ganglion neurons and the stria vascularis.

Mitochondrial alterations in the cochlea of Cdk5rap1-knockout mice with age-related hearing loss.

Previous studies have revealed that age-related hearing loss (AHL) in Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1)-knockout mice is associated with pathology in the cochlea. Here, we aimed to identify mitochondrial alterations in the cochlea of Cdk5rap1-knockout mice with AHL. Mitochondria in the spiral ganglion neurons (SGNs) and hair cells (HCs) were normal despite senescence; however, the mitochondria of types I, II, and IV spiral ligament fibrocytes were ballooned, damaged, and ballooned, respectively, in the stria vascularis. Our results suggest that the accumulation of dysfunctional mitochondria in the lateral wall, rather than the loss of HCs and SGNs, leads to the onset of AHL. Our results provide valuable information regarding the underlying mechanisms of AHL and the relationship between aberrant tRNA modification-induced hearing loss and mitochondrial dysfunction.

Preimplantation genetic testing for hereditary hearing loss in Chinese population.

PURPOSE: To evaluate the clinical validity of preimplantation genetic testing (PGT) to prevent hereditary hearing loss (HL) in Chinese population. METHODS: A PGT procedure combining multiple annealing and looping-based amplification cycles (MALBAC) and single-nucleotide polymorphisms (SNPs) linkage analyses with a single low-depth next-generation sequencing run was implemented. Forty-three couples carried pathogenic variants in autosomal recessive non-syndromic HL genes, GJB2 and SLC26A4, and four couples carried pathogenic variants in rare HL genes: KCNQ4, PTPN11, PAX3, and USH2A were enrolled. RESULTS: Fifty-four in vitro fertilization (IVF) cycles were implemented, 340 blastocysts were cultured, and 303 (89.1%) of these received a definite diagnosis of a disease-causing variant testing, linkage analysis and chromosome screening. A clinical pregnancy of 38 implanted was achieved, and 34 babies were born with normal hearing. The live birth rate was 61.1%. CONCLUSIONS AND RELEVANCE: In both the HL population and in hearing individuals at risk of giving birth to offspring with HL in China, there is a practical need for PGT. The whole genome amplification combined with NGS can simplify the PGT process, and the efficiency of PGT process can be improved by establishing a universal SNP bank of common disease-causing gene in particular regions and nationalities. This PGT procedure was demonstrated to be effective and lead to satisfactory clinical outcomes.

Three-dimensional quantification of fibrosis and ossification after cochlear implantation via virtual re-sectioning: Potential implications for residual hearing.

Hearing preservation may be achieved initially in the majority of patients after cochlear implantation, however, a significant proportion of these patients experience delayed hearing loss months or years later. A prior histological report in a case of delayed hearing loss suggested a potential cochlear mechanical origin of this hearing loss due to tissue fibrosis, and older case series highlight the frequent findings of post-implantation fibrosis and neoosteogenesis though without a focus on the impact on residual hearing. Here we present the largest series (N = 20) of 3-dimensionally reconstructed cochleae based on digitally scanned histologic sections from patients who were implanted during their lifetime. All patients were implanted with multichannel electrodes via a cochleostomy or an extended round window insertion. A quantified analysis of intracochlear tissue formation was carried out via virtual re-sectioning orthogonal to the cochlear spiral. Intracochlear tissue formation was present in every case. On average 33% (SD 14%) of the total cochlear volume was occupied by new tissue formation, consisting of 26% (SD 12%) fibrous and 7% (SD 6%) bony tissue. The round window was completely covered by fibro-osseous tissue in 85% of cases and was associated with an obstruction of the cochlear aqueduct in 100%. The basal part of the basilar membrane was at least partially abutted by the electrode or new tissue formation in every case, while the apical region, corresponding with a characteristic frequency of < 500 Hz, appeared normal in 89%. This quantitative analysis shows that after cochlear implantation via extended round window or cochleostomy, intracochlear fibrosis and neoossification are present in all cases at anatomical locations that could impact normal inner ear mechanics.

Murine cytomegalovirus employs the mixed lineage kinases family to regulate the spiral ganglion neuron cell death and hearing loss.

Cytomegalovirus (CMV)-induced sensorineural hearing loss (SNHL) is a worldwide epidemic. Recent studies have shown that the degree of spiral ganglion neuron (SGN) loss is correlated with hearing loss after CMV infection. We aimed to better understand the pathological mechanisms of CMV-related SGN death and to search for intervention measures. We found that both apoptosis and pyroptosis are involved in CMV-induced SGN death, which may be caused by the simultaneous activation of the p53/JNK and NLRP3/caspase-1 signaling pathways, respectively. Moreover, considering that mixed lineage kinase family (MLK1/2/3) are host restriction factors against viral infection and upstream regulators of the p53/JNK and inflammatory (including NLRP3-caspase1) signaling pathways, we further demonstrated that the MLKs inhibitor URMC-099 exhibited a protective effect against CMV-induced SGN death and hearing loss. These results indicate that MLKs signaling may be a key regulator and promising novel target for preventing apoptosis and even pyroptosis during the CMV infection of SGN cells and for treating hearing loss.

Tramadol-induced apoptosis in auditory hair cells of adult male rats.

Reports have emerged on the sudden opioid-induced auditory hearing loss, and the underlying pathology is not fully understood. The present study aimed to determine the mechanism of action of these drugs in the inner ear. For this purpose, 20 rats were treated with 50 mg/kg tramadol daily for three weeks. Next, the stereological and immunohistochemical alteration of the inner hair cells under chronic exposure to tramadol was evaluated. The results revealed that tramadol induced hair cell degeneration and decreased bipolar neurons of the spiral ganglion and the thickness of stria vascularis. Moreover, immunohistochemistry showed that tramadol caused apoptosis in inner hair cells and bipolar neurons. These findings indicate that tramadol induces apoptosis in auditory hair cells, suggesting that tramadol may cause hearing loss and ototoxicity.

The Natural History of Primary Inner Ear Schwannomas: Outcomes of Long-Term Follow-Up.

OBJECTIVE: To describe the natural history of primary inner ear schwannomas over a long follow-up period. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Patients with primary inner ear schwannomas with serial audiometric and radiologic follow-up. MAIN OUTCOME MEASURES: Patterns of hearing loss, rate of hearing decline, presence of vestibular symptoms, and rate of tumor growth. RESULTS: A total of 12 patients with 13 tumors were identified. The mean duration of follow-up was 7 years. Forty-six percent of tumors were intracochlear, 15% were intravestibular, 23% were transmodiolar, and 15% were intravestibular-cochlear. Hearing loss was the most common presenting symptom, occurring in all patients. Among patients with serviceable hearing (American Academy of Otolaryngology-Head and Neck Surgery Class A or B) at the time of presentation, the average time to decline to a nonserviceable hearing level was 57.3 months (range, 21-117 mo). Hearing loss was sudden in 31% of patients, progressive in 61% and fluctuating in 8%. No patients had intractable vertigo; however, two required vestibular physiotherapy. On initial magnetic resonance imaging, the mean largest tumor dimension was 3.1 mm (standard deviation, 1.2 mm), and the mean largest dimension on most recent magnetic resonance imaging was 4.4 mm (standard deviation, 1.1 mm). Two tumors exhibited no growth over a follow-up of 11.3 and 2.8 years, respectively. Overall, the mean growth was 0.25 mm per year followed. Two patients underwent cochlear implantation with simultaneous tumor resection and had favorable outcomes. CONCLUSION: Long-term follow-up suggests a conservative approach, with possible hearing rehabilitation at the time of deterioration, is a safe management strategy for primary inner ear schwannomas.

Histopathology of Labyrinthitis Ossificans From an Intralabyrinthine Surgical Specimen.

OBJECTIVE: Histologic characterization of labyrinthitis ossificans (LO) has mostly been limited to postmortem samples. In this report, we describe the histology of LO from a surgical specimen obtained from a patient undergoing labyrinthectomy with simultaneous cochlear implantation. PATIENT: A 38-year-old woman initially presenting to the emergency room with acute vertigo, left-sided hearing loss, tinnitus, and aural fullness. INTERVENTIONS: Contrast-enhanced magnetic resonance imaging (MRI) and computerized tomography (CT) were performed for the patient before labyrinthectomy and cochlear implantation. Audiometric testing was performed before and after surgical intervention. Histologic analysis was performed on a specimen obtained from the left lateral semicircular canal (SCC) during surgery. MAIN OUTCOME MEASURES: Preoperative CT and MRI findings, preoperative and postoperative hearing thresholds via air conduction and bone conduction, hematoxylin and eosin (H&E) stain of the surgical sample, and CD45 immunostain of the surgical sample. RESULTS: Preoperative CT and MRI confirmed the diagnosis of isolated LO of the left lateral SCC. Audiometric testing revealed significant improvement in hearing after labyrinthectomy and cochlear implantation. H&E stain demonstrated fibrosis and ossification in the left lateral SCC, and CD45 immunostain was negative. CONCLUSIONS: Histopathology of LO based on a surgical sample is comparable to heterotopic ossification (HO) seen in other human tissue. Given the similarities between LO and HO, agents effective in preventing HO may have utility in preventing LO.

Special manifestations and treatment of rare cases of snoring with special facial features and hearing loss in children.

This current case report describes two rare cases of children with both hearing loss and snoring. Case 1, a 17-month-old male patient, and case 2, an 11-year-old male patient, both presented with nasal obstruction, snoring and hearing loss. Physical examinations showed obvious enlargement of the head circumference and special facial features. The two children underwent otolaryngology examinations, endoscopy, hearing tests, laboratory examinations for bone metabolism markers, cranial computed tomography, X-rays and genome-wide exon sequencing. The first case was diagnosed with craniometaphyseal dysplasia, which was relieved after giving a low-calcium diet. The second case was diagnosed with osteopathia striata with cranial sclerosis by gene sequencing. Snoring improved after medication and the speech and quality of life improved with a hearing aid. Paediatric otolaryngological physicians need to have a deeper understanding of congenital diseases involving the bones. Only by genetic testing to determine the pathogenesis can those children be given the correct treatment, which is of great importance for improving their prognosis.

High jugular bulb with a diverticulum and vestibular aqueduct dehiscence: an anatomical variant to be aware in patients with hearing loss.

PURPOSE: To describe an anatomical variant that should be consider in patients with hearing loss. METHODS: An 8-year-old girl underwent to temporal bone computed tomography for the evaluation of bilateral conductive hearing loss and further assessment of possible enlarged vestibular aqueduct or high jugular bulb on brain magnetic resonance imaging (MRI). RESULTS: CT of temporal bone showed a cystic cavity with bony sclerotic margins extending from the right jugular foramen to the vestibular aqueduct. Bony dehiscence of the jugular foramen with the right carotid canal was also noted. On brain MRI, there was no evidence of enlargement of the endolymphatic duct and sac on T2 thin-section gradient echo sequence. Time of flight MR angiography did not show arterial flow in the cavity. Contrast enhanced MR venography confirmed the presence of a high right jugular bulb with a diverticulum extending into the vestibular aqueduct due to jugular bulb-vestibular aqueduct dehiscence. CONCLUSION: Knowledge of high jugular bulb-vestibular aqueduct dehiscence is important in the assessment of patients with otologic symptoms such as vertigo, tinnitus and hearing loss.

ASK1 is a novel molecular target for preventing aminoglycoside-induced hair cell death.

Aminoglycoside antibiotics are lifesaving medicines, crucial for the treatment of chronic or drug resistant infections. However, aminoglycosides are toxic to the sensory hair cells in the inner ear. As a result, aminoglycoside-treated individuals can develop permanent hearing loss and vestibular impairment. There is considerable evidence that reactive oxygen species (ROS) production and the subsequent phosphorylation of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38) drives apoptosis in aminoglycoside-treated hair cells. However, treatment strategies that directly inhibit ROS, JNK, or P38 are limited by the importance of these molecules for normal cellular function. Alternatively, the upstream regulator apoptosis signal-regulating kinase 1 (ASK1/MAP3K5) is a key mediator of ROS-induced JNK and P38 activation under pathologic but not homeostatic conditions. We investigated ASK1 as a mediator of drug-induced hair cell death using cochlear explants from Ask1 knockout mice, demonstrating that Ask1 deficiency attenuates neomycin-induced hair cell death. We then evaluated pharmacological inhibition of ASK1 with GS-444217 as a potential otoprotective therapy. GS-444217 significantly attenuated hair cell death in neomycin-treated explants but did not impact aminoglycoside efficacy against P. aeruginosa in the broth dilution test. Overall, we provide significant pre-clinical evidence that ASK1 inhibition represents a novel strategy for preventing aminoglycoside ototoxicity. KEY MESSAGES: ASK1 is an upstream, redox-sensitive regulator of P38 and JNK, which are known mediators of hair cell death. Ask1 knockout does not affect hair cell development in vivo, but significantly reduces aminoglycoside-induced hair cell death in vitro. A small-molecule inhibitor of ASK1 attenuates neomycin-induced hair cell death, and does not impact antibiotic efficacy in vitro. ASK1 may be a novel molecular target for preventing aminoglycoside-induced hearing loss.

Human vestibular schwannoma reduces density of auditory nerve fibers in the osseous spiral lamina.

Hearing loss in patients with vestibular schwannoma (VS) is commonly attributed to mechanical compression of the auditory nerve, though recent studies suggest that this retrocochlear pathology may be augmented by cochlear damage. Although VS-associated loss of inner hair cells, outer hair cells, and spiral ganglion cells has been reported, it is unclear to what extent auditory-nerve peripheral axons are damaged in VS patients. Understanding the degree of damage VSs cause to auditory nerve fibers (ANFs) is important for accurately modeling clinical outcomes of cochlear implantation, which is a therapeutic option to rehabilitate hearing in VS-affected ears. A retrospective analysis of human temporal-bone histopathology was performed on archival specimens from the Massachusetts Eye and Ear collection. Seven patients met our inclusion criteria based on the presence of sporadic, unilateral, untreated VS. Tangential sections of five cochlear regions were stained with hematoxylin and eosin, and adjacent sections were stained to visualize myelinated ANFs and efferent fibers. Following confocal microscopy, peripheral axons of ANFs within the osseous spiral lamina were quantified manually, where feasible, and with a "pixel counting" method, applicable to all sections. ANF density was substantially reduced on the VS side compared to the unaffected contralateral side. In the upper basal turn, a significant difference between the VS side and unaffected contralateral side was found using both counting methods, corresponding to the region tuned to 2000 Hz. Even spiral ganglion cells (SGCs) contralateral to VS were affected by the tumor as the majority of contralateral SGC counts were below average for age. This observation provides histological insight into the clinical observation that unilateral vestibular schwannomas pose a long-term risk of progression of hearing loss in the contralateral ear as well. Our pixel counting method for ANF quantification in the osseous spiral lamina is applicable to other pathologies involving sensorineural hearing loss. Future research is needed to classify ANFs into morphological categories, accurately predict their electrical properties, and use this knowledge to inform optimal cochlear implant programming strategies.