Clinical practice guidelines for the diagnosis and management of acute sensorineural hearing loss.

OBJECTIVE: Acute sensorineural hearing loss represents a spectrum of conditions characterized by sudden onset hearing loss. The "Clinical Practice Guidelines for the Diagnosis and Management of Acute Sensorineural Hearing Loss" were issued as the first clinical practice guidelines in Japan outlining the standard diagnosis and treatment. The purpose of this article is to strengthen the guidelines by adding the scientific evidence including a systematic review of the latest publications, and to widely introduce the current treatment options based on the scientific evidence. METHODS: The clinical practice guidelines were completed by 1) retrospective data analysis (using nationwide survey data), 2) systematic literature review, and 3) selected clinical questions (CQs). Additional systematic review of each disease was performed to strengthen the scientific evidence of the diagnosis and treatment in the guidelines. RESULTS: Based on the nationwide survey results and the systematic literature review summary, the standard diagnosis flowchart and treatment options, including the CQs and recommendations, were determined. CONCLUSION: The guidelines present a summary of the standard approaches for the diagnosis and treatment of acute sensorineural hearing loss. We hope that these guidelines will be used in medical practice and that they will initiate further research.

Map plasticity following noise exposure in auditory cortex of rats: implications for disentangling neural correlates of tinnitus and hyperacusis.

Introduction: Both tinnitus and hyperacusis, likely triggered by hearing loss, can be attributed to maladaptive plasticity in auditory perception. However, owing to their co-occurrence, disentangling their neural mechanisms proves difficult. We hypothesized that the neural correlates of tinnitus are associated with neural activities triggered by low-intensity tones, while hyperacusis is linked to responses to moderate- and high-intensity tones. Methods: To test these hypotheses, we conducted behavioral and electrophysiological experiments in rats 2 to 8 days after traumatic tone exposure. Results: In the behavioral experiments, prepulse and gap inhibition tended to exhibit different frequency characteristics (although not reaching sufficient statistical levels), suggesting that exposure to traumatic tones led to acute symptoms of hyperacusis and tinnitus at different frequency ranges. When examining the auditory cortex at the thalamocortical recipient layer, we observed that tinnitus symptoms correlated with a disorganized tonotopic map, typically characterized by responses to low-intensity tones. Neural correlates of hyperacusis were found in the cortical recruitment function at the multi-unit activity (MUA) level, but not at the local field potential (LFP) level, in response to moderate- and high-intensity tones. This shift from LFP to MUA was associated with a loss of monotonicity, suggesting a crucial role for inhibitory synapses. Discussion: Thus, in acute symptoms of traumatic tone exposure, our experiments successfully disentangled the neural correlates of tinnitus and hyperacusis at the thalamocortical recipient layer of the auditory cortex. They also suggested that tinnitus is linked to central noise, whereas hyperacusis is associated with aberrant gain control. Further interactions between animal experiments and clinical studies will offer insights into neural mechanisms, diagnosis and treatments of tinnitus and hyperacusis, specifically in terms of long-term plasticity of chronic symptoms.

Hearing loss-related altered neuronal activity in the inferior colliculus.

Hearing loss is well known to cause plastic changes in the central auditory system and pathological changes such as tinnitus and hyperacusis. Impairment of inner ear functions is the main cause of hearing loss. In aged individuals, not only inner ear dysfunction but also senescence of the central nervous system is the cause of malfunction of the auditory system. In most cases of hearing loss, the activity of the auditory nerve is reduced, but that of the successive auditory centers is increased in a compensatory way. It has been reported that activity changes occur in the inferior colliculus (IC), a critical nexus of the auditory pathway. The IC integrates the inputs from the brainstem and drives the higher auditory centers. Since abnormal activity in the IC is likely to affect auditory perception, it is crucial to elucidate the neuronal mechanism to induce the activity changes of IC neurons with hearing loss. This review outlines recent findings on hearing-loss-induced plastic changes in the IC and brainstem auditory neuronal circuits and discusses what neuronal mechanisms underlie hearing-loss-induced changes in the activity of IC neurons. Considering the different causes of hearing loss, we discuss age-related hearing loss separately from other forms of hearing loss (non-age-related hearing loss). In general, the main plastic change of IC neurons caused by both age-related and non-age-related hearing loss is increased central gain. However, plastic changes in the IC caused by age-related hearing loss seem to be more complex than those caused by non-age-related hearing loss.

Time-dependent effects of acoustic trauma and tinnitus on extracellular levels of amino acids in the inferior colliculus of rats.

Chronic tinnitus is a debilitating condition with very few management options. Acoustic trauma that causes tinnitus has been shown to induce neuronal hyperactivity in multiple brain areas in the auditory pathway, including the inferior colliculus. This neuronal hyperactivity could be attributed to an imbalance between excitatory and inhibitory neurotransmission. However, it is not clear how the levels of neurotransmitters, especially neurotransmitters in the extracellular space, change over time following acoustic trauma and the development of tinnitus. In the present study, a range of amino acids were measured in the inferior colliculus of rats during acoustic trauma as well as at 1 week and 5 months post-trauma using in vivo microdialysis and high-performance liquid chromatography. Amino acid levels in response to sound stimulation were also measured at 1 week and 5 months post-trauma. It was found that unilateral exposure to a 16 kHz pure tone at 115 dB SPL for 1 h caused immediate hearing loss in all the animals and chronic tinnitus in 58 % of the animals. Comparing to the sham condition, extracellular levels of GABA were significantly increased at both the acute and 1 week time points after acoustic trauma. However, there was no significant difference in any of the amino acid levels measured between sham, tinnitus positive and tinnitus negative animals at 5 months post-trauma. There was also no clear pattern in the relationship between neurochemical changes and sound frequency/acoustic trauma/tinnitus status, which might be due to the relatively poorer temporal resolution of the microdialysis compared to electrophysiological responses.

Engineering olivocochlear inhibition to reduce acoustic trauma.

Efferent brain-stem neurons release acetylcholine to desensitize cochlear hair cells and can protect the inner ear from acoustic trauma. That protection is absent from knockout mice lacking efferent inhibition and is stronger in mice with a gain-of-function point mutation of the hair cell-specific nicotinic acetylcholine receptor. The present work uses viral transduction of gain-of-function receptors to restore acoustic prophylaxis to the knockout mice. Widespread postsynaptic expression of the transgene was visualized in excised tissue with a fluorophore-conjugated peptide toxin that binds selectively to hair cell acetylcholine receptors. Viral transduction into efferent knockout mice reduced the temporary hearing loss measured 1 day post acoustic trauma. The acoustic evoked-response waveform (auditory brain-stem response) recovered more rapidly in treated mice than in control mice. Thus, both cochlear amplification by outer hair cells (threshold shift) and afferent signaling (evoked-response amplitude) in knockout mice were protected by viral transduction of hair cell acetylcholine receptors. Gene therapy to strengthen efferent cochlear feedback could be complementary to existing and future therapies to prevent hearing loss, including ear coverings, hearing aids, single-gene repair, or small-molecule therapies.

PTEN inhibitor bisperoxovanadium protects against noise-induced hearing loss.

Studies have shown that phosphatase and tensin homolog deleted on chromosome ten (PTEN) participates in the regulation of cochlear hair cell survival. Bisperoxovanadium protects against neurodegeneration by inhibiting PTEN expression. However, whether bisperoxovanadium can protect against noise-induced hearing loss and the underlying mechanism remains unclear. In this study, we established a mouse model of noise-induced hearing loss by exposure to 105 dB sound for 2 hours. We found that PTEN expression was increased in the organ of Corti, including outer hair cells, inner hair cells, and lateral wall tissues. Intraperitoneal administration of bisperoxovanadium decreased the auditory threshold and the loss of cochlear hair cells and inner hair cell ribbons. In addition, noise exposure decreased p-PI3K and p-Akt levels. Bisperoxovanadium preconditioning or PTEN knockdown upregulated the activity of PI3K-Akt. Bisperoxovanadium also prevented H2O2-induced hair cell death by reducing mitochondrial reactive oxygen species generation in cochlear explants. These findings suggest that bisperoxovanadium reduces noise-induced hearing injury and reduces cochlear hair cell loss.

The effectiveness of berberine on noise-induced hearing loss: a rat model

SUMMARY OBJECTIVE: Noise-induced hearing loss is a preventable form of hearing loss that has serious social and economic impacts. This study aimed to investigate the protective effect of berberine, a potent antioxidant and anti-inflammatory agent, against Noise-induced hearing loss. METHODS: After applying distortion product otoacoustic emission, 28 female Sprague-Dawley rats were randomly divided into four groups. Group 1 was designated as acoustic trauma group, and rats in this group were exposed to white noise for 12 h at an intensity of 4 kHz 110 dB sound pressure level. Group 2 was the control group. Group 3 was designated as the berberine group, and 100 mg/kg of berberine was administered to rats in this group by intragastric lavage for five consecutive days. Group 4 was designated as the acoustic trauma+berberine group. distortion product otoacoustic emission was repeated on the 6th day of the study and cochlear tissues of rats were dissected for histopathological and immunohistochemical analyses after sacrificing rats. RESULTS: The distortion product otoacoustic emission results showed a significant decrease in signal-noise ratio values at higher frequencies in rats of the trauma group compared to those in other groups. Acoustic trauma caused severe histopathological impairment at cochlear structures together with severe 8-hydroxy-2-deoxyguanosine expression. Rats in the acoustic trauma+berberine group showed mild histopathological changes with mild 8-hydroxy-2-deoxyguanosine expression and better signal-noise ratio values. CONCLUSION: The histopathological and audiological findings of this experimental study showed that berberine provides protection in Noise-induced hearing loss and may have the potential for use in acoustic trauma-related hearing losses.

Protective Effects of Curcumin and N-Acetyl Cysteine Against Noise-Induced Sensorineural Hearing Loss: An Experimental Study.

We investigated the effectiveness of N-acetyl cysteine (NAC) and curcumin, which have known antioxidant and anti-inflammatory effects, in reducing acoustic trauma. We randomly divided 40 adult male rats into four groups: a control group (group 1), a curcumin group (group 2), a NAC group (group 3), and an ethyl alcohol group (group 4). The rats were exposed to 110 dB sound at a frequency of 4 kHz for 2 h to simulate acoustic trauma. Group 1, group 2, group 3, and group 4 received 1 ml saline, 200 mg/kg curcumin, 350 mg/kg NAC, or 1 ml ethyl alcohol, respectively, intraperitoneally 30 min before and 24 and 48 h after acoustic trauma. Distortion product otoacoustic emissions (DPOAEs) were recorded before and after the acoustic trauma, and 72 h after drug administration. In group 2, signal-to-noise ratio (SNR) values in frequencies of 1000 Hz, 1500 Hz, and 4000 Hz decreased in the second measurements when compared to the first, and showed improvements in the third measurements in comparison to the second ones. In group 3, SNR values decreased in the second measurements, but only the values at 6000 Hz were found to be statistically significant (p = 0.007). The values in the third measurements were statistically significant when compared to the second ones. There was a statistically significant difference in the third measurements in both groups 2 and 3, possibly due to curcumin and NAC treatment. This study showed that curcumin and NAC may be effective against noise-induced hearing loss.

Immediate-Early Modifications to the Metabolomic Profile of the Perilymph Following an Acoustic Trauma in a Sheep Model.

The pathophysiological mechanisms of noise-induced hearing loss remain unknown. Identifying biomarkers of noise-induced hearing loss may increase the understanding of pathophysiological mechanisms of deafness, allow for a more precise diagnosis, and inform personalized treatment. Emerging techniques such as metabolomics can help to identify these biomarkers. The objective of the present study was to investigate immediate-early changes in the perilymph metabolome following acoustic trauma. Metabolomic analysis was performed using liquid chromatography coupled to mass spectrophotometry to analyze metabolic changes in perilymph associated with noise-induced hearing loss. Sheep (n = 6) were exposed to a noise designed to induce substantial hearing loss. Perilymph was collected before and after acoustic trauma. Data were analyzed using univariate analysis and a supervised multivariate analysis based on partial least squares discriminant analysis. A metabolomic analysis showed an abundance of 213 metabolites. Four metabolites were significantly changed following acoustic trauma (Urocanate (p = 0.004, FC = 0.48), S-(5'-Adenosyl)-L-Homocysteine (p = 0.06, FC = 2.32), Trigonelline (p = 0.06, FC = 0.46) and N-Acetyl-L-Leucine (p = 0.09, FC = 2.02)). The approach allowed for the identification of new metabolites and metabolic pathways involved with acoustic trauma that were associated with auditory impairment (nerve damage, mechanical destruction, and oxidative stress). The results suggest that metabolomics provides a powerful approach to characterize inner ear metabolites which may lead to identification of new therapies and therapeutic targets.

Long-Term Effects of Repetitive Transcranial Magnetic Stimulation on Tinnitus in a Guinea Pig Model.

The auditory phantom sensation of tinnitus is associated with neural hyperactivity. Modulating this hyperactivity using repetitive transcranial magnetic stimulation (rTMS) has shown beneficial effects in human studies. Previously, we investigated rTMS in a tinnitus animal model and showed that rTMS over prefrontal cortex (PFC) attenuated tinnitus soon after treatment, likely via indirect effects on auditory pathways. Here, we explored the duration of these beneficial effects. Acoustic trauma was used to induce hearing loss and tinnitus in guinea pigs. Once tinnitus developed, high-frequency (20 Hz), high-intensity rTMS was applied over PFC for two weeks (weekdays only; 10 min/day). Behavioral signs of tinnitus were monitored for 6 weeks after treatment ended. Tinnitus developed in 77% of animals between 13 and 60 days post-trauma. rTMS treatment significantly reduced the signs of tinnitus at 1 week on a group level, but individual responses varied greatly at week 2 until week 6. Three (33%) of the animals showed the attenuation of tinnitus for the full 6 weeks, 45% for 1-4 weeks and 22% were non-responders. This study provides further support for the efficacy of high-frequency repetitive stimulation over the PFC as a therapeutic tool for tinnitus, but also highlights individual variation observed in human studies.

Circadian Sensitivity of Noise Trauma-Induced Hearing Loss and Tinnitus in Mongolian Gerbils.

Noise-induced hearing loss (HL) has a circadian component: In nocturnal mice, hearing thresholds (HT) have a significantly stronger effect to acoustic trauma when induced during the night compared to rather mild effects on hearing when induced during daytime. Here, we investigate whether such effects are also present in diurnal Mongolian gerbils and determined whether trauma-induced HL correlated with the development of a tinnitus percept in these animals. In particular, we investigated the effects of acoustic trauma (2 kHz, 115 dB SPL, 75 min) on HT and tinnitus development in 34 male gerbils exposed either at 9 AM, 1 PM, 5 PM, or 12 PM. HT was measured by acoustic brainstem response audiometry at defined times 1 day before and 1 week after the trauma. Possible tinnitus percepts were assessed behaviorally by the gap prepulse inhibition of the acoustic startle response at defined times 1 day before and 1 week after the trauma. We found daytime-dependent changes due to trauma in mean HT in a frequency-dependent manner comparable to the results in mice, but the results temporally shifted according to respective activity profiles. Additionally, we found linear correlations of these threshold changes with the strength of the tinnitus percept, with the most prominent correlations in the 5 PM trauma group. Taken together, circadian sensitivity of the HT to noise trauma can also be found in gerbils, and tinnitus strength correlates most strongly with HL only when the trauma is applied at the most sensitive times, which seem to be the evening.

Genetics of noise-induced hearing loss in the mouse model.

Hearing loss is the most common sensory deficit worldwide, with the majority of preventable injury attributed to noise-induced hearing loss (NIHL). Highly conserved cochlear genetics between humans and mice have made this animal model a high-yield candidate for better characterizing the biologic and genetic underpinnings of human NIHL. This review aims to summarize advances in understanding the genetics of noise-induced hearing loss in mouse models dating from the early 1990s. We review the genetic mechanisms underpinning NIHL as understood in the mouse model, including histopathological and phenotypic associations, molecular and cellular mechanisms of changes in cochlear structures, synaptopathy and neuropathy, and transcriptomics. We describe variations in pathophysiology of hearing loss between mouse strains, with particular emphasis on susceptibility of different strains to different mechanisms of damage after acoustic trauma, and the potential of novel targeted therapeutic approaches for NIHL based on understanding of genetic mechanisms. Finally, we review the current state of research on the cochlear transcriptome after noise exposure in the mouse and implications for translation of these findings to humans.

Efficacy of Oral Steroids for Acute Acoustic Trauma.

OBJECTIVE: This study aimed to study the effect of steroid treatment on new-onset sensorineural hearing loss (SNHL) in subjects presenting shortly after an audiometry-confirmed acute acoustic trauma (AAT) injury. STUDY DESIGN: This is a case-control study. METHODS: We identified healthy military personnel who presented with AAT injury to the Israeli Defense Forces Medical Corps Otolaryngology/Audiology Services during 2016-2020. Patients were nonrandomly allocated to a treatment arm, where they received steroids (prednisone, 1 mg/kg, 60 mg maximal daily dose), administered for either ≥7 days or <7 days, or to a control arm, in which no treatment was offered besides loud noise avoidance. Audiometries were conducted within 7 days following the AAT and within 1 month later. We compared changes in bone conduction (BC) and air conduction (AC) thresholds at 2-8 kHz. RESULTS: Of the 263 enrolled subjects, 137 (52%) received steroids and 126 (48%) received no treatment. Subjects who were treated early (<24 h) with high-dose steroids and for ≥7 days demonstrated significantly better hearing outcomes, compared with the nontreatment group. Subjects in the steroids group demonstrated 13-14 dB average improvement in BC thresholds at 3 and 4 kHz (p = 0.001) and additional 7-8 dB average improvement in AC thresholds at 6 and 8 kHz, compared with the nontreatment group (p < 0.0001). These observations were more compelling in patients who initially presented with worse hearing losses (>35 dB). No statistically significant differences were observed in AC/BC pure tone average between the two groups. CONCLUSIONS: Early oral steroids are recommended in AAT injuries and were shown to improve hearing outcomes within 1 month.

Predicting secondary endolymphatic hydrops in patients with noise-induced hearing loss.

BACKGROUND: Long-term noise exposure may damage the cochlea and endolymph resorption system, which induces episodic vertigo and/or fluctuating hearing loss in later years. OBJECTIVE: This study adopted clinical symptoms, inner ear test battery, and/or magnetic resonance (MR) imaging to evaluate development of secondary endolymphatic hydrops (EH) in patients with noise-induced hearing loss (NIHL). METHODS: Forty NIHL patients with secondary EH were assigned to Group A. Another 40 age-and sex-matched NIHL patients without EH were assigned to Group B. All patients underwent an inner ear test battery. MR imaging was performed when diagnosis of EH was equivocal via above testing. RESULTS: Group A had significantly higher mean hearing levels (MHLs) than Group B at 1000, 2000, 4000, and 8000 Hz. Both groups displayed a significantly declining sequence of abnormality rates of the inner ear test battery. Under receiver operating characteristic (ROC) curve analysis, the cutoff threshold at 4 kHz for predicting the presence of secondary EH in NIHL patients was 52 dBHL, with a sensitivity of 62% and a specificity of 69%. CONCLUSIONS: NIHL patients revealing a typical 4 kHz dip-type audiogram with dip threshold >52 dBHL may predict development of secondary EH. A longitudinal follow-up coupled with MR imaging is required for confirmation.

Early Noise-Induced Hearing Loss Accelerates Presbycusis Altering Aging Processes in the Cochlea.

Several studies identified hearing loss as a risk factor for aging-related processes, including neurodegenerative diseases, as dementia and age-related hearing loss (ARHL). Although the association between hearing impairment in midlife and ARHL has been widely documented by epidemiological and experimental studies, the molecular mechanisms underlying this association are not fully understood. In this study, we used an established animal model of ARHL (C57BL/6 mice) to evaluate if early noise-induced hearing loss (NIHL) could affect the onset or progression of age-related cochlear dysfunction. We found that hearing loss can exacerbate ARHL, damaging sensory-neural cochlear epithelium and causing synaptopathy. Moreover, we studied common pathological markers shared between hearing loss and ARHL, demonstrating that noise exposure can worsen/accelerate redox status imbalance [increase of reactive oxygen species (ROS) production, lipid peroxidation, and dysregulation of endogenous antioxidant response] and vascular dysfunction [increased expression of hypoxia-inducible factor-1alpha (HIF-1α) and vascular endothelial growth factor C (VEGFC)] in the cochlea. Unveiling the molecular mechanisms underlying the link between hearing loss and aging processes could be valuable to identify effective therapeutic strategies to limit the effect of environmental risk factors on age-related diseases.

Review of blast noise and the auditory system.

The auditory system is particularly vulnerable to blast injury due to the ear's role as a highly sensitive pressure transducer. Over the past several decades, studies have used a variety of animal models and experimental procedures to recreate blast-induced acoustic trauma. Given the developing nature of this field and our incomplete understanding of molecular mechanisms underlying blast-related auditory disturbances, an updated discussion about these studies is warranted. Here, we comprehensively review well-established blast-related auditory pathology including tympanic membrane perforation and hair cell loss. In addition, we discuss important mechanistic studies that aim to bridge gaps in our current understanding of the molecular and microstructural events underlying blast-induced cochlear, auditory nerve, brainstem, and central auditory system damage. Key findings from the recent literature include the association between endolymphatic hydrops and cochlear synaptic loss, blast-induced neuroinflammatory markers in the peripheral and central auditory system, and therapeutic approaches targeting biochemical markers of blast injury. We conclude that blast is an extreme form of noise exposure. Blast waves produce cochlear damage that appears similar to, but more extreme than, the standard noise exposure protocols used in auditory research. However, experimental variations in studies of blast-induced acoustic trauma make it challenging to compare and interpret data across studies.

Blast injury on harbour porpoises (Phocoena phocoena) from the Baltic Sea after explosions of deposits of World War II ammunition.

Harbour porpoises are under pressure from increasing human activities. This includes the detonation of ammunition that was dumped in large amounts into the sea during and after World War II. In this context, forty-two British ground mines from World War II were cleared by means of blasting in the period from 28 to 31 August 2019 by a NATO unit in the German Exclusive Economic Zone within the marine protected area of Fehmarn Belt in the Baltic Sea, Germany. Between September and November 2019, 24 harbour porpoises were found dead in the period after those clearing events along the coastline of the federal state of Schleswig-Holstein and were investigated for direct and indirect effects of blast injury. Health evaluations were conducted including examinations of the brain, the air-filled (lungs and gastrointestinal tract) and acoustic organs (melon, acoustic fat in the lower jaw, ears and their surrounding tissues). The bone structure of the tympano-periotic complexes was examined using high-resolution peripheral quantitative computed tomography (HR-pQCT). In 8/24 harbour porpoises, microfractures of the malleus, dislocation of middle ear bones, bleeding, and haemorrhages in the melon, lower jaw and peribullar acoustic fat were detected, suggesting blast injury. In addition, one bycaught animal and another porpoise with signs of blunt force trauma also showed evidence of blast injury. The cause of death of the other 14 animals varied and remained unclear in two individuals. Due to the vulnerability and the conservation status of harbour porpoise populations in the Baltic Sea, noise mitigation measures must be improved to prevent any risk of injury. The data presented here highlight the importance of systematic investigations into the acute and chronic effects of blast and acoustic trauma in harbour porpoises, improving the understanding of underwater noise effects and herewith develop effective measures to protect the population level.

A Prospective Study to Elucidate the Efficacy of 4 Oral Prednisolone Regimens in Acute Acoustic Trauma.

Noise induced hearing loss affects around 5% of the population and acoustic trauma to military personnel accounts for 30% of all injuries inflicted during active service. Initial treatment for acoustic trauma involves administration of steroids, however there are no studies regarding oral steroid regimens for best outcomes. Comparing and elucidating the benefits of four oral steroid regimens on hearing gain in patients with acute acoustic trauma. A prospective study of 4 different steroid regimens was done in 200 soldiers from July 2014 - July 2020. In the first group, oral Prednisolone 60 mg was administered for 6 days, in the second group for 8 days, in the third group for 10 days and in the fourth group for 12 days. Medication was tapered over the next 5 days in all the groups. Data analysed included demographics, Pure Tone Audiograms at admission and at 4 weeks, time of reporting to hospital, onset of treatment and type of treatment given. Multivariate linear regression model was done to consider the risk factors responsible for average hearing gain at all pure tones. Box-and-whisker plot, Mann-Whitney-Wilcoxon test, Kruskal Wallis test, Reciever Operating Characteristic curve were used to analyse the independent samples. p value of < 0.05 was considered statistically significant. Age, time of onset of prednisolone therapy and acoustic trauma due to blast or gunshot injury did not show correlation (R2 = 0.01, 0.01 and 0.35 respectively and p = 0.09, 0.71, 0.80 respectively). Prednisolone therapy, average initial hearing at pure tones were considered as factors responsible for hearing gain as they showed correlation (R2 = 0.22, and 0.34 respectively and p < 0.001 and < 0.01 respectively). Significant hearing gain was found in all groups. The hearing gain was statistically better in group 3 and 4 as compared to group 1 and 2. There was no statistically significant difference in hearing gain between groups 3 and 4. So there was no additional advantage of giving 60 mg oral prednisolone for more than 10 days. The best oral prednisolone regimen recommended is 60 mg/day for 10 days which is tapered over the next 5 days.

LCCL peptide cleavage after noise exposure exacerbates hearing loss and is associated with the monocyte infiltration in the cochlea.

Acoustic trauma induces an inflammatory response in the cochlea, resulting in debilitating hearing function. Clinically, amelioration of inflammation substantially prevents noise-induced hearing loss. The Limulus factor C, Cochlin, and Lgl1 (LCCL) peptide plays an important role in innate immunity during bacteria-induced inflammation in the cochlea. We aimed to investigate the LCCL-induced innate immune response to noise exposure and its impact on hearing function. METHODS: We used Coch (encodes cochlin harboring LCCL peptide) knock-out and p.G88E knock-in mice to compare the immune responses before and after noise exposure. We explored their hearing function and hair cell degeneration. Moreover, we investigated distinct characteristics of immune responses upon noise exposure using flow cytometry and RNA sequencing. RESULTS: One day after noise exposure, the LCCL peptide cleaved from cochlin increased over time in the perilymph space. Both Coch-/- and CochG88E/G88E mutant mice revealed more preserved hearing following acoustic trauma compared to wild-type mice. The outer hair cells were more preserved in Coch-/- than in wild-type mice upon noise exposure. The RNA sequencing data demonstrated significantly upregulated cell migration gene ontology in wild-type mice than in Coch-/- mice following noise exposure, indicating that the infiltration of immune cells was dependent on cochlin. Notably, infiltrated monocytes from blood (C11b+/Ly6G-/Ly6C+) were remarkably higher in wild-type mice than in Coch-/- mice at 1 day after noise exposure. CONCLUSIONS: Noise-induced hearing loss was attributed to over-stimulated cochlin, and led to the cleavage and secretion of LCCL peptide in the cochlea. The LCCL peptide recruited more monocytes from the blood vessels upon noise stimulation, thus highlighting a novel therapeutic target for noise-induced hearing loss.

Endolymphatic Hydrops is a Marker of Synaptopathy Following Traumatic Noise Exposure.

After acoustic trauma, there can be loss of synaptic connections between inner hair cells and auditory neurons in the cochlea, which may lead to hearing abnormalities including speech-in-noise difficulties, tinnitus, and hyperacusis. We have previously studied mice with blast-induced cochlear synaptopathy and found that they also developed a build-up of endolymph, termed endolymphatic hydrops. In this study, we used optical coherence tomography to measure endolymph volume in live CBA/CaJ mice exposed to various noise intensities. We quantified the number of synaptic ribbons and postsynaptic densities under the inner hair cells 1 week after noise exposure to determine if they correlated with acute changes in endolymph volume measured in the hours after the noise exposure. After 2 h of noise at an intensity of 95 dB SPL or below, both endolymph volume and synaptic counts remained normal. After exposure to 2 h of 100 dB SPL noise, mice developed endolymphatic hydrops and had reduced synaptic counts in the basal and middle regions of the cochlea. Furthermore, round-window application of hypertonic saline reduced the degree of endolymphatic hydrops that developed after 100 dB SPL noise exposure and partially prevented the reduction in synaptic counts in the cochlear base. Taken together, these results indicate that endolymphatic hydrops correlates with noise-induced cochlear synaptopathy, suggesting that these two pathologic findings have a common mechanistic basis.