Auditory Brainstem Research Articles

Comparison of Click and Level-Specific CE Chirp-Stimulated Auditory Brainstem Responses in Adults with Hearing Loss.

The Claus Elberling Chirp (CE-Chirp) stimulus used in the auditory brainstem responses (ABRs) was developed to compensate for the cochlear wave delay. As a version of broadband CE-Chirp stimulus, the use of level-specific (LS) CE-Chirp stimuli, which are created with varying delay models suitable for the intensity levels at which the sound is transmitted, is becoming increasingly common. The aim of this study was to compare click ABRs with LS CE-Chirp ABR thresholds in adults with sensorineural hearing loss. The research is a cross-sectional, analytical research. Twenty-two adult patients (n = 44 ears) with bilateral sensorineural hearing loss were included in the study. Pure-tone audiometry, click ABR, and LS CE-Chirp ABR tests were performed on adult (13 males and 9 females; 42.86 ± 14.50 years) patients with bilateral sensorineural hearing loss. Click ABR and LS CE-Chirp ABR thresholds were compared in terms of proximity to behavioral hearing thresholds of 2 kHz, 4 kHz, and 2 to 4 kHz averages. Both types of ABR stimuli were able to identify with total hearing loss (n = 6). A significant difference was found between LS CE-Chirp ABR thresholds (53.81 ± 20.28 decibel normal hearing level [dB nHL]) and click ABR thresholds (58.81 ± 19.11 dB nHL) in the other ears (n = 38) with hearing loss (p = 0.00). When both ears were evaluated together and the right and left ears were evaluated separately, no difference was found between LS CE-Chirp ABR thresholds and 4 kHz hearing thresholds (p = 0.66, 0.80, and 0.69, respectively). In adults with hearing loss, the LS CE-Chirp provides ABR thresholds closer to the behavioral hearing thresholds at 2 and 4 kHz compared with the click stimulus. Notably, there was no difference between LS CE-Chirp ABR thresholds and the 4 kHz behavioral hearing thresholds. We concluded that the LS CE-Chirp can be used effectively in the estimation of behavioral hearing thresholds in adults with hearing loss.

MiR-204-5p regulates SIRT1 to promote the endoplasmic reticulum stress-induced apoptosis of inner ear cells in C57BL/6 mice with hearing loss

Purpose This study investigated the effect of miR-204-5p-mediated silencing of SIRT1 on the development of deafness in C57BL/6 mice and the roles of miR-204-5p and SIRT1 in deafness. Methods Auditory brainstem response recordings, H&E staining, and immunohistochemistry were used to observe changes in hearing function and cochlear tissue morphology in 2-month-old and 15-month-old C57BL/6 mice. A senescence model was induced using H2O2 in inner ear cells (HEI-OC1). Changes in HEI-OC1 cell proliferation were detected using the CCK-8 assay, whereas flow cytometry was used to detect changes in apoptosis. MiR-204-5p expression was measured via RT‒qPCR. The SIRT1 agonist RSV and a miR-204-5p inhibitor were used to study changes in ER stress (ERS), proliferation, and apoptosis in HEI-OC1 cells. Western blotting was performed to detect changes in ATF4, CHOP, SIRT1, PERK, p-PERK, Bax, and Bcl-2 protein levels. A dual-luciferase reporter gene assay was carried out to assess the ability of miR-204-5p to target SIRT1. Results Relative miR-204-5p expression levels in the cochleae of aged C57BL/6 mice increased, whereas SIRT1 expression levels decreased, and miR-204-5p and SIRT1 expression levels were negatively correlated. ERS and increased 8-OHDG levels were observed in aged C57BL/6 mice. In a model of inner ear cell aging, H2O2 treatment induced increases in miR-204-5p expression and ERS-mediated apoptosis. MiR-204-5p was found to target SIRT1 and inhibit its expression. SIRT1 activation and a miR-204-5p inhibitor promoted HEI-OC1 cell proliferation and reduced apoptosis. The miR-204-5p inhibitor regulated expression of the ERS proteins PERK, ATF4, and CHOP to upregulate Bcl-2 and downregulate Bax. Conclusion This study identified the roles of miR-204-5p and SIRT1 in deafness in C57BL/6 mice and investigated the loss of cochlear outer hair cells and the involvement of apoptosis and ERS in deafness.

Effectiveness of auditory measures in the diagnosis of cochlear synaptopathy and noise-induced hidden hearing loss: a case–control study

Abstract Background Cochlear synaptopathy is a disorder where auditory perceptual impairments, such as speech perception in noise and tinnitus, may not be accurately reflected by audiometric thresholds, even if the audiogram appears normal. It is proposed that the connections between hair cells and the auditory nerve are more susceptible to sound and aging damage than the cochlea’s hair cells. Cochlear synaptopathy can be present in ears with normal audiograms and undamaged hair cells, leading to hidden hearing loss. This study aims to construct electrophysiological and behavioral auditory parameters associated with persons exposed to loudness and having normal audiograms and auditory complaints to identify hidden hearing loss. Results A case–control study was done with forty participants with a documented history of exposure to loud sounds and various auditory complaints, compared to a control group of forty persons who had all been confirmed to have normal audiograms. The chosen behavioral core tests comprised the speech intelligibility in noise test (SPIN), gaps detection in noise (GIN test), and pitch pattern sequence test (PPS). The electrophysiological measures utilized in the study were the auditory brainstem response test (ABR) and electrocochleography (ECochG). The SPIN, PPS, and GIN test results demonstrated statistically significant disparities between the control and case groups. The amplitude ratio of wave I to wave V in ABR and the ratio of EcochG AP to SP demonstrated a statistically significant variance between the two groups. The SPIN test exhibited the highest AUC, signifying its superior diagnostic capability in identifying hidden hearing loss. Conclusion The present study has shown that the SPIN, as a behavioral test, and the EcochG AP amplitude measure, as an electrophysiological test, provide the greatest auditory diagnostic capability for identifying cochlear synaptopathy. Wave I amplitude in the auditory brainstem response (ABR) and the SP/AP ratio in electrocochleography (EcochG) are promising non-behavioral measures of cochlear synaptopathy or hidden hearing loss.

Improved intracochlear biopolymeric drug delivery system: an in vivo study

Background The delivery of drugs into the inner ear is a challenging field of study due to the complex cochlear anatomy and physiology. The creation of an intracochlear device that allows for short- and long-term intracochlear delivery of the drugs with a minimal invasive technology is needed to prevent or treat conditions that can potentially prevent the development of permanent hearing loss. Aim This study intends to test the efficacy of DXM-infused PLGA microneedles created in our laboratory in an in vivo animal model of acute ototoxic injury. Material and Methods Twenty-four male Norway Brown rats were randomized into four groups, three of which groups received an intratympanic injection of ethacrynic acid and kanamycin. Two of these groups underwent the placement of an intracochlear microneedle blended or not with dexamethasone, and two groups underwent implantation of a plain microneedle, one of without prior exposure to the ototoxic agent to confirm in vivo biocompatibility. Animals were then followed with a weekly auditory brainstem response testing until day 28 after surgical intervention. Result and Conclusion Our intracochlear device demonstrated biocompatibility and produced no hearing changes after its implantation in the control group. Inserted DXM-blended microneedles prevented hearing deterioration in those animals exposed to an ototoxic environment.

The Effects of Memantine on Cisplatin-induced Ototoxicity

Introduction: We aimed to investigate electrophysiologically and histopathologically, the protective effects of intratympanic memantine, an N-methyl-D-aspartate receptor antagonist, on ototoxicity caused by cisplatin, an anti-neoplastic agent used in many types of cancer. Methods: Thirty-seven guinea pigs with a normal auditory function were randomly allocated to group 1 (Cisplatin; n=8), group 2 (Memantine; n=8), group 3 (Cisplatin+Memantine; n=8), group 4 (Cisplatin+Physiological Serum [PS]; n=8), and group 5 (Control; n=5). Auditory assessments were conducted using distortion product otoacoustic emissions (DPOAE) within a frequency range of 1-32 kHz, and auditory brainstem responses (ABR) within 8-32 kHz. A single dose of cisplatin (12 mg/kg) was administered intraperitoneally, followed by intratympanic administration of 0.2 mL of either memantine or PS to both ears at least half an hour before cisplatin administration. Subsequent auditory evaluations were conducted 72 h after cisplatin administration. Histopathological analyses were performed using light microscopy of the right ear and scanning electron microscopy (SEM) of the left ear. Results: Auditory evaluations conducted before and after treatment revealed significant findings. Specifically, within groups 3 and 4, ABR thresholds were elevated at all frequencies (p=0.00), whereas the DPOAE signal-to-noise ratios were reduced at frequencies of 8, 12, 16, and 24 kHz (p=0.001, p=0.01, p=0.01, and p=0.00, respectively). Histopathologically, both light microscopy and SEM revealed that the cisplatin+memantine group exhibited fewer hair cells and nuclear degeneration in the spiral ganglion than the cisplatin and cisplatin+PS groups. Additionally, the stria vascularis thickness was greater in the cisplatin+memantine group than in cisplatin and cisplatin+PS groups. Conclusion: Despite the negative electrophysiological findings, the histopathological outcomes suggest that intratympanic memantine may have a potential protective effect against cisplatin-induced ototoxicity. However, further investigations are warranted to corroborate these findings and elucidate the underlying mechanisms of action of memantine.

Semicircular canal drug delivery safely targets the inner ear perilymphatic space.

Effective, reproducible, and safe delivery of therapeutics into the inner ear is required for the prevention and treatment of hearing loss. A commonly used delivery method is via the posterior semicircular canal (PSCC); however, its specific targeting within the cochlea remains unclear, impacting precision and reproducibility. To assess safety and target specificity, we conducted in vivo recordings of the pharmacological manipulations delivered through the PSCC. Measurements of auditory brainstem response (ABR), vibrometry, and vestibular behavioral and sensory-evoked potential (VsEP) revealed preserved hearing and vestibular functions after artificial perilymph injections. Injection of curare, a mechanoelectrical transducer (MET) channel blocker that affects hearing when in the endolymph, had no effect on ABR or VsEP thresholds. Conversely, injection of CNQX, an AMPA receptor blocker, or lidocaine, a Na+ channel blocker, which affects hearing when in the perilymph, significantly increased both thresholds, indicating that PSCC injections selectively target the perilymphatic space. In vivo tracking of gold nanoparticles confirmed their exclusive distribution in the perilymph during PSCC injection, supporting the pharmacological finding. Together, PSCC injection is a safe method for inner ear delivery, specifically targeting the perilymphatic space. Our findings will allow for precise delivery of therapeutics within the inner ear for therapeutic and research purposes.

Analysis of Adherence to AAO-HNSF Clinical Practice Guidelines for Sudden Hearing Loss.

To assess adherence to the 2019 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNSF) guidelines for the diagnosis and management of sudden hearing loss (SHL) and sudden sensorineural hearing loss (SSNHL). Retrospective cohort. TriNetX, a de-identified healthcare database. Evaluation focused on the percentage of patients undergoing proper guideline-adherent workup and treatment for SHL. Key measures include audiogram testing within 2 weeks for distinguishing SSNHL from CHL. For SSNHL patients, MRI or auditory brainstem response (ABR) testing should be obtained, and steroids and/or hyperbaric oxygen may be offered within 2 weeks. There were 24,203 SHL patients, 59.1% (n = 14,309) of whom underwent recommended audiogram testing, with 35.8% (n = 8,674) completing it within 2 weeks. Overall, 3,107 were diagnosed with unilateral SSNHL, 104 with unilateral conductive hearing loss (CHL), 121 with mixed hearing loss, and 10,977 were lost to follow-up. Among 3,107 SSNHL cases, just 25.5% (n = 791) obtained MRI/ABR within 1 month, and vestibular schwannoma was diagnosed in 3.5% (n = 28). Additionally, steroids were prescribed to 54.5% (n = 1,692), and <0.3% (n ≤ 10) received hyperbaric oxygen. In accordance with strong recommendations against or insufficient evidence to support the following diagnostics and treatments, 2.0% (n = 63) underwent a CT scan, less than 0.3% (n ≤ 10) were prescribed vasodilators or thrombolytics, and 3.5% (n = 108) were on antivirals. There is a significant opportunity for improvement in evaluating patients with SHL, specifically SSNHL. Proper adherence to guidelines may improve screening, detection, and management of neurotologic pathologies, including vestibular schwannoma.

Infantile Krabbe disease (0-12 months), progression, and recommended endpoints for clinical trials.

Krabbe disease is due to deficiency of galactocerebrosidase, resulting in progressive neurodegeneration due to demyelination. The purpose of this study is to document disease progression in the newly classified infantile-onset (0-12 months). We evaluated the outcomes of hematopoietic stem cell transplantation (HSCT) and described meaningful clinical endpoints. Patients with infantile Krabbe disease were prospectively evaluated between 2000 and 2022. All patients underwent comprehensive and standardized protocols. Descriptive statistics and Kaplan-Meier survival curves were used for analysis. One hundred and thirty-seven children with infantile Krabbe disease were included (68 males and 69 females). Of the 137, 96 were not treated and 41 underwent hematopoietic stem cell transplantation. Twenty-three were asymptomatic and 18 symptomatic. Initial symptoms included irritability, developmental delay or loss of milestones, feeding difficulties, spasticity, and reflux with an average survival of 2.2. Abnormalities in nerve conduction studies, auditory brainstem responses, and brain MRIs were evident in both groups of patients. Age at transplantation and signs and symptoms determined functional outcomes. Symptomatic and asymptomatic transplanted patients showed an increase in galactocerebrosidase and a decrease in psychosine, but did not reach the normal range. The median survival for transplanted symptomatic patients was 5 years while asymptomatic was extended to 15.5 years. Infantile Krabbe disease with onset before 12 months is rapidly progressive. Irreversible brain damage occurs unless timely HSCT is performed. HSCT does not prevent the progression of peripheral nerve disease. This study can be used to monitor patients and evaluate the effects of future therapies.

Effects of the two-pore potassium channel subunit Task5 on neuronal function and signal processing in the auditory brainstem

Processing of auditory signals critically depends on the neuron’s ability to fire brief, precisely timed action potentials (APs) at high frequencies and high fidelity for prolonged times. This requires the expression of specialized sets of ion channels to quickly repolarize neurons, prevent aberrant AP firing and tightly regulate neuronal excitability. Although critically important, the regulation of neuronal excitability has received little attention in the auditory system. Neuronal excitability is determined to a large extent by the resting membrane potential (RMP), which in turn depends on the kind and number of ion channels open at rest; mostly potassium channels. A large part of this resting potassium conductance is carried by two-pore potassium channels (K2P channels). Among the K2P channels, the subunit Task5 is expressed almost exclusively in the auditory brainstem, suggesting a specialized role in auditory processing. However, since it failed to form functional ion channels in heterologous expression systems, it was classified “non-functional” for a long time and its role in the auditory system remained elusive. Here, we generated Task5 knock-out (KO) mice. The loss of Task5 resulted in changes in neuronal excitability in bushy cells of the ventral cochlear nucleus (VCN) and principal neurons of the medial nucleus of the trapezoid body (MNTB). Moreover, auditory brainstem responses (ABRs) to loud sounds were altered in Tasko5-KO mice. Thus, our study provides evidence that Task5 is indeed a functional K2P subunit and contributes to sound processing in the auditory brainstem.

Impaired brainstem auditory evoked potentials after in utero exposure to high dose paracetamol exposure

Paracetamol is an analgesic and antipyretic medication regarded as the safest over-the-counter pain and fever relief option during pregnancy. Paracetamol and its metabolites are known to reach the developing fetus through direct placental transfer and can cross the blood brain barrier. Several recent, large-scale epidemiologic studies suggest that in utero paracetamol exposure can increase the risk of neurodevelopmental conditions, including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and developmental delay (DD). Since auditory processing deficits are a common feature of ASD, we hypothesized that animals exposed to paracetamol in utero will have impaired auditory brainstem function. We investigated this hypothesis by recording and analyzing click-evoked auditory brainstem responses (ABR) at postnatal day 21 and 29 in Sprague-Dawley rats. In utero exposure to high dose paracetamol exposure had no impact on body or brain weight. However, high dose paracetamol exposure did significantly delay ear opening and resulted in elevated ABR thresholds, and longer wave and interwave latencies. These changes in wave latency extended to the highest click intensity tested but were most severe near threshold. This data suggests that development and function of the auditory brainstem may be impacted by high dose paracetamol exposure and that simple, non-invasive tests of auditory function have utility as an early screening tool for neurodevelopmental disorders.

MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss.

Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1-knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1-knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans.

Oxidative and endoplasmic reticulum stress in diabetes-related hearing loss: Protective effects of thioredoxin

Diabetes mellitus (DM) induces complex physiological changes in the inner ear environment. This study investigates the roles of oxidative stress (OS) and endoplasmic reticulum stress (ERS) in diabetic hearing loss and explores the potential of thioredoxin (Trx) in regulating OS, ERS, and apoptosis-related factors to mitigate the progression of hearing impairment. We conducted auditory and serological assessments in 63 patients with type 2 diabetes and 30 healthy controls. Type 2 diabetes models were induced in wild-type and Trx transgenic (Tg) mice, with auditory brainstem response (ABR) used to evaluate hearing changes. Cochlear tissues were isolated to analyse markers of apoptosis, OS, and ERS. Both patients with diabetes and mouse models exhibited hearing loss, alongside increased serum levels of Trx1, TXNIP, and AOPP, indicating oxidative damage. H&E and succinate dehydrogenase (SDH) staining revealed varying degrees of hair cell loss from the base to the apex of the cochlea in diabetic mice, with decreased expression of the hair cell protein prestin gene. Notably, Tg mice showed significant delay in hearing loss progression. In vitro, advanced glycation end-products (AGEs) induced OS and ERS in cochlear-like HEI-OC1 cells, while Trx overexpression enhanced Nrf2 activity, alleviating AGE-induced cellular stress. In conclusion, Trx exhibits protective effects against diabetes-related hearing loss, potentially by enhancing Nrf2/HO-1/SOD2 function to reduce OS and ERS.

Fundamental frequency predominantly drives talker differences in auditory brainstem responses to continuous speech.

Deriving human neural responses to natural speech is now possible, but the responses to male- and female-uttered speech have been shown to differ. These talker differences may complicate interpretations or restrict experimental designs geared toward more realistic communication scenarios. This study found that when a male talker and a female talker had the same fundamental frequency, auditory brainstem responses (ABRs) were very similar. Those responses became smaller and later with increasing fundamental frequency, as did click ABRs with increasing stimulus rates. Modeled responses suggested that the speech and click ABR differences were reasonably predicted by peripheral and brainstem processing of stimulus acoustics.

Resistance to age-related hearing loss in the echolocating big brown bat (Eptesicus fuscus).

Hearing mediates many behaviours critical for survival in echolocating bats, including foraging and navigation. Although most mammals are susceptible to progressive age-related hearing loss, the evolution of biosonar, which requires the ability to hear low-intensity echoes from outgoing sonar signals, may have selected against the development of hearing deficits in bats. Many echolocating bats exhibit exceptional longevity and rely on acoustic behaviours for survival to old age; however, relatively little is known about the ageing bat auditory system. In this study, we used DNA methylation to estimate the ages of wild-caught big brown bats (Eptesicus fuscus) and measured hearing sensitivity in young and ageing bats using auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). We found no evidence for hearing deficits in bats up to 12.5 years of age, demonstrated by comparable thresholds and similar ABR and DPOAE amplitudes across age groups. We additionally found no significant histological evidence for cochlear ageing, with similar hair cell counts, afferent and efferent innervation patterns in young and ageing bats. Here, we demonstrate that big brown bats show minimal evidence for age-related hearing loss and therefore represent informative models for investigating mechanisms that may preserve hearing function over a long lifetime.

Local delivery of soluble fractalkine (CX3CL1) peptide restores ribbon synapses after noise-induced cochlear synaptopathy

Cochlear ribbon synapses between sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) are vulnerable to rapid and primary damage and/or loss due to noise overexposure. Such damaged ribbon synapses can repair spontaneously in mouse and guinea pig. However, the mechanisms for synaptic repair are unclear. Previously, we have demonstrated a critical role for the fractalkine signaling axis (CX3CL1-CX3CR1) in synaptic repair, wherein noise-damaged ribbon synapses are spontaneously repaired in the presence of fractalkine receptor (CX3CR1) expressed by cochlear macrophages. Here, we examined whether local administration of chemokine fractalkine ligand (CX3CL1 or FKN) in the form of a peptide is effective in restoring synapses and hearing loss after noise-induced cochlear synaptopathy (NICS). Specifically, the efficacy of different isoforms of FKN was evaluated for restoration of loss of IHC ribbon synapses and hearing after NICS. A single transtympanic injection of soluble isoform of FKN (sFKN) peptide at 1 day after synaptopathic noise trauma for 2 hours at 93 decibel sound pressure level led to significant recovery of auditory brainstem response (ABR) thresholds, ABR peak I amplitudes and ribbon synapses in FKN knockout mice when compared to mice injected with membrane-bound FKN peptide (mFKN). Likewise, local treatment with sFKN peptide in FKN wild type mice restored synaptopathic noise-damaged ribbon synapses and ABR peak I amplitudes. Mechanistically, FKN regulates macrophage numbers in the damaged cochlea and in the absence of macrophages, sFKN failed to restore loss of synapses and hearing after NICS. Furthermore, sFKN treatment attenuated cochlear inflammation after NICS without altering the expression of CX3CR1. Finally, injected sFKN peptide was detectable inside the cochlea for 24 h localized to the basilar membrane and spiral lamina near the sensory epithelium. These data provide a proof-of-principle that local delivery of an immune factor, sFKN is effective in restoring ribbon synapses and hearing loss after NICS in a macrophage-dependent manner and highlights the potential of sFKN as an immunotherapy for cochlear synaptopathy due to noise.

Comparison of 4.54% hypertonic saline and 20% mannitol for brain relaxation during auditory brainstem implantation in pediatric patients: a single-center retrospective observational cohort study

BackgroundMannitol is frequently utilized to achieve intracranial brain relaxation during the retrosigmoid approach for auditory brainstem implantation (ABI). Hypertonic saline (HS) is an alternative for reducing intracranial pressure; however, its application during ABI surgery remains under-investigated. We aimed to compare the efficacy and safety between HS and mannitol for maintaining brain relaxation.MethodsThis single-center retrospective cohort study included pediatric patients undergoing ABI surgery from September 2020 to January 2022 who received only 4.54% HS or 20% mannitol for brain relaxation. The analysis involved initial doses, subsequent doses, and dosing intervals of the two hyperosmolar solutions, as well as the time elapsed from meningeal opening to the first ABI electrode placement attempt. Additionally, the analysis encompassed electrolyte testing, hemodynamic variables, urine output, blood transfusion, second surgeries, adverse events, intensive care unit length of stay, and 30-day mortality.ResultsWe analyzed 68 consecutive pediatric patients; 26 and 42 in the HS and mannitol groups, respectively. The HS group exhibited a reduced rate of supplementary use (7.7% vs. 31%) and lower total urine volume. Perioperative outcomes, mortality, and length of intensive care unit stay did not exhibit significant between-group differences, despite transient increases in blood sodium and chloride observed within 2 h after HS infusion.ConclusionsIn pediatric ABI surgery, as an osmotherapy for cerebral relaxation, 4.54% HS demonstrated a lower likelihood of necessitating additional supplementation than 20% mannitol. Furthermore, the diuretic effect of HS was weak and the increase in electrolyte levels during surgery was temporary and slight.

Effectiveness of CI as an alternative to ABI for hearing loss in patients with vestibular schwannomas: A multicenter study in Japan

ObjectiveNF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS), often causing severe damage to the bilateral auditory function. Auditory brainstem implantation (ABI) provides hearing-impaired patients with an opportunity to reacquire auditory sensation through electrical stimulation of auditory neurons in the cochlear nucleus. However, ABI is not covered by public health insurance in Japan, leading to a large difference in financial burden compared to cochlear implantation (CI). The aim of the present study was to demonstrate the effectiveness of CI as an alternative to ABI for hearing reacquisition in patients with profound hearing loss caused by VS. MethodsTo investigate the current situation of ABI and CI for hearing reconstruction in VS patients, we conducted a questionnaire survey of 102 facilities in Japan. Based on the responses to the questionnaire, a multicenter research group consisting of otolaryngologists and neurosurgeons was established. We collected detailed data on patients with VS who underwent ABI (n = 7, all NF2) and CI (n = 14 [nine NF2, and five non-NF2]). ResultsSome sense of hearing was obtained in all patients but one with CI indicating the efficacy of CI and ABI for profound hearing loss caused by VS. The mean hearing levels were 45.4 dB HL in the ABI patients and 32.7 dB HL in the CI patients, indicating that CI was effective as an alternative to ABI. ConclusionThe results of the present study suggest the effectiveness of CI as an alternative to ABI for hearing reacquisition in patients with profound hearing loss caused by VS. Level of evidence4.

Beyond the cochlea: exploring the multifaceted nature of hearing loss in primary mitochondrial diseases

Abstract Primary mitochondrial diseases, with diverse systemic manifestations, often present with auditory impairments due to mitochondrial dysfunction. This study provides an in-depth exploration of auditory deficits in primary mitochondrial diseases, highlighting the impact of various pathogenic variants on both cochlea and neural/central auditory functions. An observational study involving 72 adults with primary mitochondrial diseases was conducted. Participants underwent extensive audiological evaluations including Pure-Tone Audiometry, Tympanometry, Acoustic Reflex Thresholds, Quick Speech-in-Noise Test, Listening in Spatialized Noise-Sentences test, Auditory-evoked Brainstem Responses, and Distortion Product Otoacoustic Emissions. Multivariate Analysis of Covariance and logistic regression analyses assessed the influence of various pathogenic DNA variants, accounting for age, cognitive status via the Montreal Cognitive Assessment, and disease severity through the Newcastle Mitochondrial Disease Adult Scale. Participants with the pathogenic m.3243A&amp;gt;G/T variants (m.3243A&amp;gt;G n=40; m.3243A&amp;gt;T n=1) exhibited significant elevations in Pure-Tone Audiometry thresholds, especially at high frequencies, suggesting cochlea involvement. Notably, the Listening in Spatialized Noise-Sentences test showed significant spatial processing deficits in the m.3243A&amp;gt;G/T group, possibly indicating a unique mutation-specific impact on central auditory processing. Auditory-evoked Brainstem Responses results highlighted a higher likelihood of auditory brainstem response abnormalities in this group, further substantiating neural/central auditory pathway involvement. This study emphasises the heterogeneous nature of hearing impairment in primary mitochondrial diseases, with a genotype-phenotype correlation, particularly in the m.3243A&amp;gt;G/T group. These insights advocate for personalised, genotype-specific auditory assessments and targeted management strategies. Conventional hearing aids and cochlear implants are ineffective for those with central auditory dysfunctions related to mitochondrial mutations. There is an urgent need for innovative rehabilitation strategies catering for both cochlear and neural/central auditory pathways.

Early cochlear implantation: exploring electrophysiological thresholds and their role in pre-behavioural recommendations.

Studies investigating the relationship between initial electrophysiological thresholds and subsequent behavioural hearing thresholds have demonstrated uncertainty as to whether initial results can provide an accurate estimation of an infant's functional hearing. This estimation must be accurate if a cochlear implant (CI) is to be considered before behavioural audiometry.This study aims to explore the variance between initial electrophysiological thresholds and subsequent behavioural hearing thresholds in infants to determine under which conditions electrophysiological results can be used to support a CI recommendation before behavioural audiology. This is a prospective cohort study of 63 infants with suspected severe to profound hearing loss, referred to the Cochlear Implant Clinic, Melbourne, before 12 months of age. The assessment protocol includes auditory brainstem response, auditory steady state response, tympanometry, and behavioural audiometry. For most infants undergoing CI candidacy evaluation, initial electrophysiological thresholds are an accurate reflection of their subsequent behavioural thresholds. An alternative CI candidacy pathway is recommended for infants who show profound sensorineural hearing loss on initial electrophysiological testing, in the absence of middle ear effusion, prematurity, or auditory neuropathy features, to provide CI recommendations before behavioural thresholds are obtained. This would lead to reduced delay to implantation and improved oral language outcomes.

Pathological mechanisms and candidate therapeutic approaches in the hearing loss of mice carrying human MIR96 mutations.

Progressive hearing loss is a common problem in the human population with no effective therapeutics currently available. However, it has a strong genetic contribution, and investigating the genes and regulatory interactions underlying hearing loss offers the possibility of identifying therapeutic candidates. Mutations in regulatory genes are particularly useful for this, and an example is the microRNA miR-96, a post-transcriptional regulator which controls hair cell maturation. Mice and humans carrying mutations in miR-96 all exhibit hearing impairment, in homozygosis if not in heterozygosis, but different mutations result in different physiological, structural and transcriptional phenotypes. Here we present our characterisation of two lines of mice carrying different human mutations knocked-in to Mir96. We have carried out auditory brainstem response tests to examine their hearing with age and after noise exposure and have used confocal and scanning electron microscopy to examine the ultrastructure of the organ of Corti and hair cell synapses. Bulk RNA-seq was carried out on the organs of Corti of postnatal mice, followed by bioinformatic analyses to identify candidate targets. While mice homozygous for either mutation are profoundly deaf from 2weeks old, the heterozygous phenotypes differ markedly, with only one mutation resulting in hearing impairment in heterozygosis. Investigations of the structural phenotype showed that one mutation appears to lead to synaptic defects, while the other has a much more severe effect on the hair cell stereociliary bundles. Transcriptome analyses revealed a wide range of misregulated genes in both mutants which were notably dissimilar. We used the transcriptome analyses to investigate candidate therapeutics, and tested one, finding that it delayed the progression of hearing loss in heterozygous mice. Our work adds further support for the importance of the gain of novel targets in microRNA mutants and offers a proof of concept for the identification of pharmacological interventions to maintain hearing.