Correction: Natarajan et al. Noise-Induced Hearing Loss. J. Clin. Med. 2023, 12, 2347.

Error in Table [...].

Tinnitus prevalence, associated characteristics, and related healthcare use in the United States: a population-level analysis.

Background: Tinnitus is a potentially disabling condition with few treatments. We examined the prevalence and characteristics of tinnitus among demographic groups in the United States (US) and assessed associated factors and tinnitus-related healthcare. Methods: We included adults with and without bothersome tinnitus from the nationally representative 2014 National Health Interview Survey (NHIS; raw n = 36,697), the latest year with tinnitus data. We evaluated tinnitus prevalence and characteristics (frequency, severity, duration) overall and among groups defined by sex and race/ethnicity. Logistic regression with adjusted Wald tests were used for comparisons in NHIS-weighted populations by sex and race/ethnicity, and to evaluate associations between demographic/medical characteristics and noise exposure on tinnitus risk. Findings: The US prevalence of tinnitus was 11.2% (95% CI: 10.8%, 11.7%; ∼27 million people) in 2014. Of those with tinnitus, 41.2% always had symptoms and 28.3% had ≥15 years symptom duration; the rates were significantly higher among men vs. women and non-Hispanic (nHW) vs. Hispanic Whites (HW), Blacks, or other ethnicity. Significantly more women vs. men and HW vs. nHW reported severe tinnitus. Sex and race/ethnicity, except Asian, were not significantly associated with tinnitus when age, otologic/medical disorders, and noise exposure were included in the model. Significantly lower rates of all minority groups discussed tinnitus with a doctor compared to nHW, and among those who did, Blacks were significantly less likely to receive tinnitus evaluation than nHWs. Interpretation: Tinnitus prevalence varies across US demographic groups and racial differences were identified in the delivery of tinnitus-related healthcare. Funding: Rich Robbins, Bertarelli Foundation Endowed Professorship.

Immune Profiling of Secreted Factors from Human Vestibular Schwannoma Cells and Tumor-associated Macrophages.

OBJECTIVES: This study compared the immune-related secretory capacity of human vestibular schwannoma (VS) and tumor-assisted macrophages (TAMs) with their normal counterparts (Schwann cells [SC] and peripheral blood monocyte-derived macrophages [Mo-MFs], respectively), and examined relationships with presurgical hearing and tumor size. METHODS: VS tumors (n = 16), auditory nerve (n = 1), blood (n = 9), and great auricular nerves (n = 3) were used. SCs (S100B+ ) and TAMs (CD68+ ) were isolated from VS tissue for culture. The secreted levels of 65 immune-related factors were measured and compared using unpaired t-tests with Welch correction (schwannoma vs. SCs) or Mann-Whitney tests (TAMs and Mo-MFs). Associations between factor concentration and word recognition (WR), pure-tone average (PTA), and tumor size were evaluated with Spearman correlation. RESULTS: Secreted factors with significantly higher concentrations in schwannoma versus SC supernatants included IL-2 and BAFF, whereas MMP-1, IL-6, FGF-2, VEGF-A, MIP-3α, and GRO-α concentrations were significantly higher in TAMs versus Mo-MFs (all p < 0.05). Worse WR was significantly associated with higher secretion of fractalkine, eotaxin-3, CD30, and IL-16 by VS cells; IP-10, eotaxin-3, multiple interleukins, GM-CSF, SCF, and CD30 by TAMs; and TNF-α and MIP-1α by Mo-MFs (all p < 0.05). Worse PTA was significantly correlated with higher secretion of IL-16 by VS cells (p < 0.05). Larger tumor size was significantly correlated with higher secretion of eotaxin by VS cells, and of IL-7, IL-21, and LIF by TAMs (all p = 0.017). CONCLUSIONS: Differential secretion of immune-related factors was observed in schwannoma versus normal SCs and in TAMs versus Mo-MFs, some of which were correlated with worse hearing and larger VS tumors. LEVEL OF EVIDENCE: N/A Laryngoscope, 134:S1-S14, 2024.

miR-431 secreted by human vestibular schwannomas increases the mammalian inner ear's vulnerability to noise trauma.

Introduction: Vestibular schwannoma (VS) is an intracranial tumor that arises on the vestibular branch of cranial nerve VIII and typically presents with sensorineural hearing loss (SNHL). The mechanisms of this SNHL are postulated to involve alterations in the inner ear's microenvironment mediated by the genetic cargo of VS-secreted extracellular vesicles (EVs). We aimed to identify the EV cargo associated with poor hearing and determine whether its delivery caused hearing loss and cochlear damage in a mouse model in vivo. Methods: VS tissue was collected from routinely resected tumors of patients with good (VS-GH) or poor (VS-PH) pre-surgical hearing measured via pure-tone average and word recognition scores. Next-generation sequencing was performed on RNA isolated from cultured primary human VS cells and EVs from VS-conditioned media, stratified by patients' hearing ability. microRNA expression levels were compared between VS-PH and VS-GH samples to identify differentially expressed candidates for packaging into a synthetic adeno-associated viral vector (Anc80L65). Viral vectors containing candidate microRNA were infused to the semicircular canals of mice to evaluate the effects on hearing, including after noise exposure. Results: Differentially expressed microRNAs included hsa-miR-431-5p (enriched in VS-PH) and hsa-miR-192-5p (enriched in VS-GH). Newborn mice receiving intracochlear injection of viral vectors over-expressing hsa-miR-431-GFP, hsa-miR-192-GFP, or GFP only (control) had similar hearing 6 weeks post-injection. However, after acoustic trauma, the miR-431 group displayed significantly worse hearing, and greater loss of synaptic ribbons per inner hair cell in the acoustically traumatized cochlear region than the control group. Conclusion: Our results suggest that miR-431 contributes to VS-associated hearing loss following cochlear stress. Further investigation is needed to determine whether miR-431 is a potential therapeutic target for SNHL.

Potential Ototoxicity of Insulin-like Growth Factor 1 Receptor Signaling Inhibitors: An In Silico Drug Repurposing Study of the Regenerating Cochlear Neuron Transcriptome.

Spiral ganglion neurons (SGNs) connect cochlear hair cells with higher auditory pathways and their degeneration due to drug toxicity (ototoxicity) contributes to hearing loss. This study aimed to identify drug classes that are negatively correlated with the transcriptome of regenerating SGNs. Human orthologs of differentially expressed genes within the regenerating neonatal mouse SGN transcriptome were entered into CMap and the LINCS unified environment and perturbation-driven gene expression was analyzed. The CMap connectivity scores ranged from 100 (positive correlation) to -100 (negative correlation). Insulin-like growth factor 1/receptor (IGF-1/R) inhibitors were highly negatively correlated with the regenerating SGN transcriptome (connectivity score: -98.87). A systematic literature review of clinical trials and observational studies reporting otologic adverse events (AEs) with IGF-1/R inhibitors identified 108 reports (6141 treated patients). Overall, 16.9% of the treated patients experienced any otologic AE; the rate was highest for teprotumumab (42.9%). In a meta-analysis of two randomized placebo-controlled trials of teprotumumab, there was a significantly higher risk of hearing-related (pooled Peto OR [95% CI]: 7.95 [1.57, 40.17]) and of any otologic AEs (3.56 [1.35, 9.43]) with teprotumumab vs. a placebo, whether or not dizziness/vertigo AEs were included. These results call for close audiological monitoring during IGF-1-targeted treatment, with prompt referral to an otolaryngologist should otologic AEs develop.

Comparative Transcriptomic Analysis of Archival Human Vestibular Schwannoma Tissue from Patients with and without Tinnitus.

Vestibular schwannoma (VS) is an intracranial tumor that commonly presents with tinnitus and hearing loss. To uncover the molecular mechanisms underlying VS-associated tinnitus, we applied next-generation sequencing (Illumina HiSeq) to formalin-fixed paraffin-embedded archival VS samples from nine patients with tinnitus (VS-Tin) and seven patients without tinnitus (VS-NoTin). Bioinformatic analysis was used to detect differentially expressed genes (DEG; i.e., ≥two-fold change [FC]) while correcting for multiple comparisons. Using RNA-seq analysis, VS-Tin had significantly lower expression of GFAP (logFC = -3.04), APLNR (logFC = -2.95), PREX2 (logFC = -1.44), and PLVAP (logFC = -1.04; all p < 0.01) vs. VS-NoTin. These trends were validated by using real-time RT-qPCR. At the protein level, immunohistochemistry revealed a trend for less PREX2 and apelin expression and greater expression of NLRP3 inflammasome and CD68-positive macrophages in VS-Tin than in VS-NoTin, suggesting the activation of inflammatory processes in VS-Tin. Functional enrichment analysis revealed that the top three protein categories-glycoproteins, signal peptides, and secreted proteins-were significantly enriched in VS-Tin in comparison with VS-NoTin. In a gene set enrichment analysis, the top pathway was allograft rejection, an inflammatory pathway that includes the MMP9, CXCL9, IL16, PF4, ITK, and ACVR2A genes. Future studies are needed to examine the importance of these candidates and of inflammation in VS-associated tinnitus.

Associations of Tinnitus Incidence with Use of Tumor Necrosis Factor-Alpha Inhibitors among Patients with Autoimmune Conditions.

Tumor necrosis factor-alpha (TNFα) may promote neuroinflammation prompting tinnitus. This retrospective cohort study evaluated whether anti-TNFα therapy influences incident tinnitus risk among adults with autoimmune disorders and no baseline tinnitus selected from a US electronic health records database (Eversana; 1 January 2010-27 January 2022). Patients with anti-TNFα had ≥90-day history pre-index (first autoimmune disorder diagnosis) and ≥180-day follow-up post-index. Random samples (n = 25,000) of autoimmune patients without anti-TNFα were selected for comparisons. Tinnitus incidence was compared among patients with or without anti-TNFα therapy, overall and among at-risk age groups or by anti-TNFα category. High-dimensionality propensity score (hdPS) matching was used to adjust for baseline confounders. Compared with patients with no anti-TNFα, anti-TNFα was not associated with tinnitus risk overall (hdPS-matched HR [95% CI]: 1.06 [0.85, 1.33]), or between groups stratified by age (30-50 years: 1 [0.68, 1.48]; 51-70 years: 1.18 [0.89, 1.56]) or anti-TNFα category (monoclonal antibody vs. fusion protein: 0.91 [0.59, 1.41]). Anti-TNFα was not associated with tinnitus risk among those treated for ≥6 months (hdPS-matched HR [95% CI]: 0.96 [0.69, 1.32]) or ≥12 (1.03 [0.71, 1.5]), or those with RA (1.16 [0.88, 1.53]). Thus, in this US cohort study, anti-TNFα therapy was not associated with tinnitus incidence among patients with autoimmune disorders.

Noise-Induced Hearing Loss.

Noise-induced hearing loss (NIHL) is the second most common cause of sensorineural hearing loss, after age-related hearing loss, and affects approximately 5% of the world's population. NIHL is associated with substantial physical, mental, social, and economic impacts at the patient and societal levels. Stress and social isolation in patients' workplace and personal lives contribute to quality-of-life decrements which may often go undetected. The pathophysiology of NIHL is multifactorial and complex, encompassing genetic and environmental factors with substantial occupational contributions. The diagnosis and screening of NIHL are conducted by reviewing a patient's history of noise exposure, audiograms, speech-in-noise test results, and measurements of distortion product otoacoustic emissions and auditory brainstem response. Essential aspects of decreasing the burden of NIHL are prevention and early detection, such as implementation of educational and screening programs in routine primary care and specialty clinics. Additionally, current research on the pharmacological treatment of NIHL includes anti-inflammatory, antioxidant, anti-excitatory, and anti-apoptotic agents. Although there have been substantial advances in understanding the pathophysiology of NIHL, there remain low levels of evidence for effective pharmacotherapeutic interventions. Future directions should include personalized prevention and targeted treatment strategies based on a holistic view of an individual's occupation, genetics, and pathology.

Micro-optical coherence tomography of the mammalian cochlea.

The mammalian cochlea has historically resisted attempts at high-resolution, non-invasive imaging due to its small size, complex three-dimensional structure, and embedded location within the temporal bone. As a result, little is known about the relationship between an individual's cochlear pathology and hearing function, and otologists must rely on physiological testing and imaging methods that offer limited resolution to obtain information about the inner ear prior to performing surgery. Micro-optical coherence tomography (µOCT) is a non-invasive, low-coherence interferometric imaging technique capable of resolving cellular-level anatomic structures. To determine whether µOCT is capable of resolving mammalian intracochlear anatomy, fixed guinea pig inner ears were imaged as whole temporal bones with cochlea in situ. Anatomical structures such as the tunnel of Corti, space of Nuel, modiolus, scalae, and cell groupings were visualized, in addition to individual cell types such as neuronal fibers, hair cells, and supporting cells. Visualization of these structures, via volumetrically-reconstructed image stacks and endoscopic perspective videos, represents an improvement over previous efforts using conventional OCT. These are the first µOCT images of mammalian cochlear anatomy, and they demonstrate µOCT's potential utility as an imaging tool in otology research.

Notch signaling and Atoh1 expression during hair cell regeneration in the mouse utricle.

The mammalian vestibular epithelium has a limited capacity for spontaneous hair cell regeneration. The mechanism underlying the regeneration is not well understood. Because the Notch signaling pathway mediates the formation of the sensory epithelial mosaic patterning during ear development, it may also play a role in hair cell regeneration in the mature mammalian vestibular epithelium after a lesion. To investigate the process of spontaneous regeneration in the vestibular epithelium vis-à-vis changes in Notch signaling, we induced a unilateral lesion by infusing streptomycin into the mouse posterior semicircular canal, and examined Notch signaling molecules and their mRNA expression levels by immunohistochemistry and quantitative real-time polymerase chain reaction (qRTPCR), respectively. We detected Jagged1 in supporting cells in both normal and lesioned utricles. Atoh1, a marker for early developing hair cells, was absent in the intact mature tissue, but re-appeared after the lesion. Many cells were either positive for both Atoh1 and myosin VIIa, or for one of them. qRTPCR data showed a post trauma decrease of Hes5 and an increase in Atoh1. Atoh1 up-regulation may either be a result of Hes5 down-regulation or mediated by another signaling pathway.

Visualization of spiral ganglion neurites within the scala tympani with a cochlear implant in situ.

Current cochlear histology methods do not allow in situ processing of cochlear implants. The metal components of the implant preclude standard embedding and mid-modiolar sectioning, and whole mounts do not have the spatial resolution needed to view the implant within the scala tympani. One focus of recent auditory research is the regeneration of structures within the cochlea, particularly the ganglion cells and their processes, and there are multiple potential benefits to cochlear implant users from this work. To facilitate experimental investigations of auditory nerve regeneration performed in conjunction with cochlear implantation, it is critical to visualize the cochlear tissue and the implant together to determine if the nerve has made contact with the implant. This paper presents a novel histological technique that enables simultaneous visualization of the in situ cochlear implant and neurofilament-labeled nerve processes within the scala tympani, and the spatial relationship between them.

Brain lesions and their implications in criminal responsibility.

For over 200 years, Western courts have considered pleas of "not guilty by reason of insanity" (NGRI) for defendants in possession of a mental defect rendering them unable to understand the wrongfulness of their act. Until recently, determining the mental state of a defendant has fallen largely upon the shoulders of court psychologists and experts in psychiatry for qualitative assessments related to NGRI pleas and mitigation at sentencing. However, advances in neuroscience--particularly neurological scanning techniques such as magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), computed tomography scanning (CT), and positron emission tomography scanning (PET)--may provide additional, pertinent biological evidence as to whether an organically based mental defect exists. With increasing frequency, criminal defense attorneys are integrating neuroimaging data into hearings related to determinations of guilt and sentencing mitigation. This is of concern, since not all brain lesions and abnormalities indicate a compromised mental state that is relevant to knowing whether the act was wrong at the time of commission, and juries may be swayed by neuroscientific evidence that is not relevant to the determination of the legal question before them. This review discusses historical and modern cases involving the intersection of brain lesions and criminality, neuroscientific perspectives of how particular types of lesions may contribute to a legally relevant mental defect, and how such evidence might best be integrated into a criminal trial.

Notch signaling and Hes labeling in the normal and drug-damaged organ of Corti.

During the development of the inner ear, the Notch cell signaling pathway is responsible for the specification of the pro-sensory domain and influences cell fate decisions. It is assumed that Notch signaling ends during maturity and cannot be reinitiated to alter the fate of new or existing cells in the organ of Corti. This is in contrast to non-mammalian species which reinitiate Delta 1-Notch1 signaling in response to trauma in the auditory epithelium, resulting in hair cell regeneration through transdifferentiation and/or mitosis. We report immunohistochemical data and Western protein analysis showing that in the aminoglycoside-damaged guinea pig organ of Corti, there is an increase in proteins involved in Notch activation occurring within 24h of a chemical hair cell lesion. The signaling response is characterized by the increased presence of Jagged1 ligand in pillar and Deiters cells, Notch1 signal in surviving supporting cell nuclei, and the absence of Jagged2 and Delta-like1. The pro-sensory bHLH protein Atoh1 was absent at all time points following an ototoxic lesion, while the repressor bHLH transcription factors Hes1 and Hes5 were detected in surviving supporting cell nuclei in the former inner and outer hair cell areas, respectively. Notch pathway proteins peaked at 2 weeks, decreased at 1 month, and nearly disappeared by 2 months. These results indicate that the mammalian auditory epithelium retains the ability to regulate Notch signaling and Notch-dependent Hes activity in response to cellular trauma and that the signaling is transient. Additionally, since Hes activity antagonizes the transcription of pro-sensory Atoh1, the presence of Hes after a lesion may prohibit the occurrence of transdifferentiation in the surviving supporting cells.

Response of the flat cochlear epithelium to forced expression of Atoh1.

Following hair cell elimination in severely traumatized cochleae, differentiated supporting cells are often replaced by a simple epithelium with cuboidal or flat appearance. Atoh1 (previously Math1) is a basic helix-loop-helix transcription factor critical to hair cell differentiation during mammalian embryogenesis. Forced expression of Atoh1 in the differentiated supporting cell population can induce transdifferentiation leading to hair cell regeneration. Here, we examined the outcome of adenovirus mediated over-expression of Atoh1 in the non-sensory cells of the flat epithelium. We determined that seven days after unilateral elimination of hair cells with neomycin, differentiated supporting cells are absent, replaced by a flat epithelium. Nerve processes were also missing from the auditory epithelium, with the exception of infrequent looping nerve processes above the habenula perforata. We then inoculated an adenovirus vector with Atoh1 insert into the scala media of the deafened cochlea. The inoculation resulted in upregulation of Atoh1 in the flat epithelium. However, two months after the inoculation, Atoh1-treated ears did not exhibit clear signs of hair cell regeneration. Combined with previous data on induction of supporting cell to hair cell transdifferentiation by forced expression of Atoh1, these results suggest that the presence of differentiated supporting cells in the organ of Corti is necessary for transdifferentiation to occur.

Transdifferentiation and its applicability for inner ear therapy.

During normal development, cells divide, then differentiate to adopt their individual form and function in an organism. Under most circumstances, mature cells cannot transdifferentiate, changing their fate to adopt a different form and function. Because differentiated cells cannot usually divide, the repair of injuries as well as regeneration largely depends on the activation of stem cell reserves. The mature cochlea is an exception among epithelial cell layers in that it lacks stem cells. Consequently, the sensory hair cells that receive sound information cannot be replaced, and their loss results in permanent hearing impairment. The lack of a spontaneous cell replacement mechanism in the organ of Corti, the mammalian auditory sensory epithelium, has led researchers to investigate circumstances in which transdifferentiation does occur. The hope is that this information can be used to design therapies to replace lost hair cells and restore impaired hearing in humans.