Auditory Brainstem Research Articles

L-Ergothioneine slows the progression of age-related hearing loss in CBA/CaJ mice

The naturally occurring amino acid, l-ergothioneine (EGT), has immense potential as a therapeutic, having shown promise in the treatment of other disease models, including neurological disorders. EGT is naturally uptaken into cells via its specific receptor, OCTN1, to be utilized by cells as an antioxidant and anti-inflammatory. In our current study, EGT was administered over a period of 6 months to 25–26-month-old CBA/CaJ mice as a possible treatment for age-related hearing loss (ARHL), since presbycusis has been linked to higher levels of cochlear oxidative stress, apoptosis, and chronic inflammation. Results from the current study indicate that EGT can prevent aging declines of some key features of ARHL. However, we found a distinct sex difference for the response to the treatments, for hearing – Auditory Brainstem Responses (ABRs) and Distortion Product Otoacoustic Emissions (DPOAEs). Males exhibited lower threshold declines in both low dose (LD) and high dose (HD) test groups throughout the testing period and did not display some of the characteristic aging declines in hearing seen in Control animals. In contrast, female mice did not show any therapeutic effects with either treatment dose. Further confirming this sex difference, EGT levels in whole blood sampling throughout the testing period showed greater uptake of EGT in males compared to females. Additionally, RT-PCR results from three tissue types of the inner ear confirmed EGT activity in the cochlea in both males and females. Males and females exhibited significant differences in biomarkers related to apoptosis (Cas-3), inflammation (TNF-a), oxidative stress (SOD2), and mitochondrial health (PGC1a).These changes were more prominent in males as compared to females, especially in stria vascularis tissue. Taken together, these findings suggest that EGT has the potential to be a naturally derived therapeutic for slowing down the progression of ARHL, and possibly other neurodegenerative diseases. EGT, while effective in the treatment of some features of presbycusis in aging males, could also be modified into a general prophylaxis for other age-related disorders where treatment protocols would include eating a larger proportion of EGT-rich foods or supplements. Lastly, the sex difference discovered here, needs further investigation to see if therapeutic conditions can be developed where aging females show better responsiveness to EGT.

Silk fibroin-gelatin films crosslinked by genipin for regenerating tympanic membrane perforations

The tympanic membrane (TM) integrity is necessary for our normal hearing function. TM perforations pose significant morbidities such as middle ear infection, recurrent otorrhea, hearing loss, and acquired cholesteatoma. Myringoplasty is commonly performed to repair chronic perforations; although various grafts and materials have been utilized to promote TM regeneration, all have associated restrictions. This study aimed to prepare and evaluate the efficacy and feasibility of a tissue-engineered patch based on silk fibroin and gelatin (SF-GT) to improve regeneration. A casting technique was used to make the SF-GT films, using 0–30 v/v% GT, as it is shown that films are remarkably efficient for TM regeneration, easy to mass produce and cheap to make. The surface morphology (SEM), chemical structure (FTIR), crystallinity (XRD), mechanical strength (tensile test), water uptake and in vitro degradation, and cellular biocompatibility (MTT and scratch) were investigated for SF-GT films, and the optimal patch was chosen based on the results (SF-30GT). SF-30GT was used for in vivo studies in a rat model with TM perforations to induce TM regeneration. The morphology of the TM was assessed at days 0, 3, 5, 7, 9 and 11 post-implantation using otoscopy and functional outcomes by auditory brainstem responses (ABRs). This study indicates that compared with the control group (spontaneous healing), the SF-30GT scaffold was more effective in promoting early TM regeneration (complete healing at day 7) and normal hearing (back to 20 dB after healing), suggesting that this scaffold can be a potential substitute for clinical use.

Constructing group sequential tests with data monitoring

Objective:Group sequential tests are procedures for repeatedly analysing accruing data, and aim to reduce test time by stopping data collection as soon as an effect is deemed statistically present or absent. Data monitoring, on the other hand, aims to control statistical power by repeatedly re-estimating sample variance from the accruing data, and then adjusting the sample size accordingly. The current work presents a numerical framework for combining group sequential tests with data monitoring, thus leveraging the best of both methods. Methods:The approach revolves around numerically convolving truncated probability density functions, which leads to numerically tracktable distributions for the sequential test statistic. This then allows conventional power analysis methodologies to be used during the data monitoring procedure, thus keeping the procedure relatively intuitive and transparent. The test operating characteristics of the procedure were evaluated extensively in simulations and in Auditory Brainstem Response data. Results:A good control over statistical power was observed, which was attributed to data monitoring. In some test conditions, however, data monitoring led to inflated type-I error rates and a reduced control over statistical power. This was attributed to sample variance estimation errors, and was largely overcome by initiating data monitoring after at least ∼40-90 samples had accrued and/or by leaving data blinded. Conclusion/Significance:When there is uncertainty regarding the effect size and/or the population variance, then group sequential tests with data monitoring may offer a solution, providing an efficient means to reach an unambiguous test outcome in terms of effect present/absent.

Prediction of auditory brain stem responses damage in patients with head-and-neck cancers receiving radiotherapy using the functional assays of normal tissue complication probability models.

The purpose of this study was to set four NTCP models on clinical data and develop a model that calculates the possibility of hearing damage due to irradiation of healthy and at-risk brainstem tissue. ABR tests were performed on 50 head-and-neck cancer patients three years after radiotherapy for evaluation of lesions in a part of the auditory nerve or the auditory pathway in the brainstem. It indicated a significant difference in the latency of the waves assessed by the ABR test between the two groups. The paired sample t-test indicated the latency time of waves I, III, V, I-III, and I-V (P < 0.001) in the right ear, and in the left ear latency time of waves III, V, I-III, I-V, and III-V (P < 0.001) were significantly higher in the case group's ear than those in the control group. The confidence interval of the fitted parameters was 95% for NTCP models. ABR test's binary outcome with differential dose-volume histograms (dDVHs) was calculated and imported as input to the NTCP modeling. The values of the parameters n = 2.3-2.9 and the value s = 1 were obtained, which indicated that the brainstem organ is seriality. The best model ranked for the prediction of brainstem hearing damage was the logit model, which had the lowest Akaike value. The nervousness of the auditory organ of the brainstem (VIII nerve) can be declared as one of the reasons for being independent of the received dose.

Midlife Speech Perception Deficits: Impact of Extended High-Frequency Hearing, Peripheral Neural Function, and Cognitive Abilities.

The objectives of the present study were to investigate the effects of age-related changes in extended high-frequency (EHF) hearing, peripheral neural function, working memory, and executive function on speech perception deficits in middle-aged individuals with clinically normal hearing. We administered a comprehensive assessment battery to 37 participants spanning the age range of 20 to 56 years. This battery encompassed various evaluations, including standard and EHF pure-tone audiometry, ranging from 0.25 to 16 kHz. In addition, we conducted auditory brainstem response assessments with varying stimulation rates and levels, a spatial release from masking (SRM) task, and cognitive evaluations that involved the Trail Making test (TMT) for assessing executive function and the Abbreviated Reading Span test (ARST) for measuring working memory. The results indicated a decline in hearing sensitivities at EHFs and an increase in completion times for the TMT with age. In addition, as age increased, there was a corresponding decrease in the amount of SRM. The declines in SRM were associated with age-related declines in hearing sensitivity at EHFs and TMT performance. While we observed an age-related decline in wave I responses, this decline was primarily driven by age-related reductions in EHF thresholds. In addition, the results obtained using the ARST did not show an age-related decline. Neither the auditory brainstem response results nor ARST scores were correlated with the amount of SRM. These findings suggest that speech perception deficits in middle age are primarily linked to declines in EHF hearing and executive function, rather than cochlear synaptopathy or working memory.

Evaluation of Hearing Loss in Patients with Essential Tremor

ABSTRACT Background: Essential tremor (ET) is a common chronic progressive disease, characterized by postural and action tremor. Abnormalities within the cerebello-thalamocortical pathways are thought to be involved in ET. In some studies, it was reported that there is an association between ET and hearing loss. Objective: In this study, our goal is to examine the electrophysiological changes of the structures forming the auditory pathway in ET cases, and the relationship of these changes with clinical findings and understand if the pathology underlying hearing loss in ET is cochlear or retrocochlear. Materials and Methods: One hundred sequential ET patients who had referred to Mersin University Faculty of Medicine Neurology Department, and 100 healthy individuals that are equivalent in terms of age and gender were conducted to investigate this association. Detailed medical history, neurologic examination, audiologic examination, pure-tone audiometry (PTA), tympanometry, and auditory brainstem response (ABR) analyses also known as brainstem auditory-evoked potentials were applied to all patients and controls. Results: The mean age of patients with ET was 56.38 ± 16.73, and the mean age of individuals in the control group was 56.47 ± 16.86. Nineteen of the patients with ET, and two healthy individuals from the control group had hearing problems (P &lt; 0.001). In this study, there were no significant differences found in audiometric and ABR examinations in terms of hearing loss between the ET group and control group. However, in audiometric and ABR analyses, an increase in hearing loss was found to be correlated with an increase in tremor severity. In PTA test, hearing loss was higher in those with high-intensity tremor severity than in the group with mild tremor severity. This was statistically significant. P (KW) &lt;0.05 Pposthoc &lt; 0.05. In ABR analysis, it was found that there was a statistically significant difference with the increase of tremor severity at the dominant hand with: wave V latencies of the right and left ear; I-V interpeak latencies of the right ear, and III-V interpeak latencies of the right ear. The difference was between mild and moderate tremor groups. Conclusion: This study shows that there could be an impairment in inhibiting the functional transmission in the brainstem of patients with ET.

Impact of Otitis Media With Effusion in Early Age on Auditory Processing Abilities in Children: A Systematic Review and Meta-Analysis.

Objective: Early-onset otitis media with effusion (OME) can affect the development of the auditory nervous system and thus lead to auditory processing abnormalities. This study aims to review the effect of childhood OME on auditory processing abilities in children. Methods: A systematic review of the literature, restricted to the English language from 1990 to 2022 was conducted using search engines like PubMed, Embase, and Google Scholar. After selecting the articles following predefined inclusion and exclusion criteria, the data were extracted and meta-analysis was performed. Results: A total of 10 articles met the inclusion criteria. Children with a history of OME had poorer performance in most behavioral and electrophysiological tests. Pooled analysis of various tests such as the gap in noise test, frequency pattern test (verbal and nonverbal), and latencies of auditory brainstem response-I, V, I to III, and I to V showed a difference between the 2 groups. Conclusion: Childhood OME can significantly affect auditory processing abilities in children.

Intraoperative EABR Testing Predicts Strength of Cochlear Implant Stimulation Optimized After Long-Term Use in Pediatric Malformation Ears.

This study focused on the intensities of cochlear implant (CI) stimulation in pediatric CI users with inner ear malformation or cochlear nerve deficiency (CND). In this population, CI programming is difficult because a large intensity of CI stimulation is required to achieve sufficient hearing, but the excess CI stimuli often induce facial nerve stimulation. We aimed to assess whether the results of intraoperative electrically evoked auditory brainstem responses (EABRs) testing predict maximum current levels of CI stimuli (cC levels) optimized by a behavioral-based method after long-term CI use. A retrospective case review. A tertiary referral CI center. A total of 116 ears with malformations (malformation group) and 63 control ears (control group) from patients younger than 18 years who received CI. The malformation group comprised 23 ears with a common cavity (CC), 26 with incomplete partition type 1 (IP-1), 26 with incomplete partition type 2 (IP-2), and 41 with CND. Diagnostic. Correlation between intraoperative EABR results and cC levels determined by the behavioral-based CI programming after long-term CI use. The CC, IP-1, and CND ears required significantly larger cC levels than the IP-2 ears and control groups. However, the cC levels increased to reach the plateau 1 year after surgery in all groups. Among the malformation group, 79 ears underwent intraoperative EABR testing. Greater than 80% of the CC, IP-1, and IP-2 ears and 54.8% of the CND ears exhibited evoked wave V (eV) and were included in the eV-positive category. Myogenic responses but no eV were observed in 18.2, 15.0, and 35.5% of the CC, IP-1, and CND ears, defined as the myogenic category. No eV or myogenic response was elicited in 9.7% of the CND ears. We focused on minimum current levels that elicited eV (eV levels) in the eV-positive category and maximum current levels that did not elicit any myogenic responses (myogenic levels) in the myogenic category. A significant relationship was detected between the eV levels and the cC levels. When analyzed in each malformation type, the eV levels significantly correlate with the cC levels in the CC and CND ears but not in the IP-1 and IP-2 ears, probably because of slight variation within the IP-1 group and the small number of the IP-2 group. The myogenic category did not show a significant relationship between the myogenic levels and cC levels, but the cC levels were similar to or smaller than the myogenic levels in most ears. This study confirmed that intraoperative EABR testing helps predict the optimal cC levels in malformation ears. EABR-based CI programming immediately after cochlear implantation, followed by behavioral-based CI programming, may allow us to achieve early postoperative optimization of CI maps even in young children with severe malformations.

Auditory and language features in children with 18q deletion: Our experience and a brief review of the literature

Abstract 18q deletion is a rare genetic condition that occurs approximately 1 in 40,000 live births. The aim of this study is to describe four cases of 18q deletion, analyzing their auditory and language skills. A secondary aim is to compare our findings with those reported in the literature in order to propose a standardized assessment protocol and guidelines for auditory treatment and rehabilitation. All children underwent a detailed audiological evaluation including otoscopy, pure-tone audiometry, and auditory brainstem responses. We also administered language and speech tests according to the children’s age and skills. Comorbidities and disease severity varied depending on the genetic mutation. Data from the literature review are consistent with our findings. Therefore, the type of auditory rehabilitation changed among patients. Despite the heterogeneity of phenotypes and severity, hearing loss and stenotic external auditory canals were detected in all our patients with 18q deletion. Accurate diagnosis and follow-up are mandatory to improve auditory and language skills and quality of life. Due to the complexity of the cases, no standardized assessment protocols or treatment can be routinely proposed.

Subcortical auditory system in tinnitus with normal hearing: insights from electrophysiological perspective

PurposeThe mechanism of tinnitus remains poorly understood; however, studies have underscored the significance of the subcortical auditory system in tinnitus perception. In this study, our aim was to investigate the subcortical auditory system using electrophysiological measurements in individuals with tinnitus and normal hearing. Additionally, we aimed to assess speech-in-noise (SiN) perception to determine whether individuals with tinnitus exhibit SiN deficits despite having normal-hearing thresholds.MethodsA total 42 normal-hearing participants, including 22 individuals with chronic subjective tinnitus and 20 normal individuals, participated in the study. We recorded auditory brainstem response (ABR) and speech-evoked frequency following response (sFFR) from the participants. SiN perception was also assessed using the Matrix test.ResultsOur results revealed a significant prolongation of the O peak, which encodes sound offset in sFFR, for the tinnitus group (p < 0.01). The greater non-stimulus-evoked activity was also found in individuals with tinnitus (p < 0.01). In ABR, the tinnitus group showed reduced wave I amplitude and prolonged absolute wave I, III, and V latencies (p ≤ 0.02). Our findings suggested that individuals with tinnitus had poorer SiN perception compared to normal participants (p < 0.05).ConclusionThe deficit in encoding sound offset may indicate an impaired inhibitory mechanism in tinnitus. The greater non-stimulus-evoked activity observed in the tinnitus group suggests increased neural noise at the subcortical level. Additionally, individuals with tinnitus may experience speech-in-noise deficits despite having a normal audiogram. Taken together, these findings suggest that the lack of inhibition and increased neural noise may be associated with tinnitus perception.

Effects of Cochlear Implantation and Steroids on the Aging Guinea Pig Cochlea.

The objective was to determine the effects of older age on hearing preservation after cochlear implantation (CI), and whether steroids improve hearing preservation in older animals. We hypothesized greater hearing preservation would be observed in (1) young animals compared to older animals and (2) older animals receiving steroids compared to no steroids. The secondary objective was to assess levels of fibrosis utilizing optical coherence tomography (OCT). Experimental Animal Study. Laboratory. Three groups of guinea pigs: young (YCI; 8.5 ± 0.5 weeks; n = 10), old (OCI; 19.1 ± 1.0 months; n = 9) and old + steroids (OCI+S; 19.1 ± 1.0 months; n = 9) underwent CI. The OCI+S group received a steroid taper over 7 days starting 2 days before surgery to 4 days after. Auditory brainstem response (ABR) measurements were performed preoperatively and postoperatively. OCT imaging was performed to assess cochleae for extent of fibrotic tissue growth in the scala tympani. The YCI group had significantly better hearing preservation as measured by smaller increases in ABR thresholds [mean shift: 2.79 ± 0.66] compared to the OCI group [mean shift = 12.44 ± 5.6]. The OCI+S group had significantly better hearing preservation [2.66 ± 1.50] compared to the OCI group. No significant differences was seen in fibrosis across groups. Young animals and older animals that received steroids had better hearing after CI than older animals not given steroids, but hearing preservation was not correlated with the level of fibrosis assessed using OCT. This work is the first to investigate differences in hearing preservation by age in an animal model, and supports the protective effects of steroids on hearing preservation in older individuals.

Pathophysiology of Postoperative Hearing Disorders after Vestibular Schwannoma Resection: Insights from Auditory Brainstem Response and Otoacoustic Emissions.

Background: In order to better understand the pathophysiology of surgically induced hearing loss after vestibular schwannoma (VS) surgery, we postoperatively analyzed the hearing status in a series of patients where hearing was at least partially preserved. Methods: Hearing was assessed through tonal audiometry, speech discrimination score, maximum word recognition score (dissyllabic word lists-MaxIS), otoacoustic emissions (OAEs), and auditory brainstem response (ABR). The magnetic resonance imaging (MRI) tumor characterization was also noted. Results: In a series of 24 patients operated on for VS over 5 years, depending on the results of this triple hearing exploration, we could identify, after surgery, patients with either a myelin alteration or partial damage to the acoustic fibers, others with a likely partial cochlear ischemia, and some with partial cochlear nerve ischemia. One case with persisting OAEs and no preoperative ABR recovered hearing and ABR after surgery. Long follow-up (73 ± 57 months) revealed a mean hearing loss of 30 ± 20 dB with a drastic drop of MaxIS. MRI revealed only 25% of fundus invasion. Conclusion: a precise analysis of hearing function, not only with classic audiometry but also with ABR and OEAs, allows for a better understanding of hearing damage in VS surgery.

Intraoperative assessment of cochlear nerve functionality in various vestibular schwannoma scenarios: Lessons learned

The use of cochlear implants (CIs) is on the rise for patients with vestibular schwannoma (VS). Besides CI following tumor resection, new scenarios such as implantation in observed and/or irradiated tumors are becoming increasingly common. A significant emerging trend is the need of intraoperative evaluation of the functionality of the cochlear nerve in order to decide if a CI would be placed. The purpose of this paper is to explore the experience of a tertiary center with the application of the Auditory Nerve Test System (ANTS) in various scenarios regarding VS patients. The results are compared to that of the studies that have previously used the ANTS in this condition.Patients with unilateral or bilateral VS (NF2) who were evaluated with the ANTS prior to considering CI in a tertiary center between 2021 and 2023 were analyzed. The presence of a robust wave V was chosen to define a positive electrical auditory brainstem response (EABR). Two patients underwent promontory stimulation (PromStim) EABR previous to ANTS evaluation.Seven patients, 2 NF-2 and 5 with sporadic VS were included. The initial scenario was simultaneous translabyrinthine (TL) tumor resection and CI in 3 cases while a CI placement without tumor resection was planned in 4 cases. The ANTS was positive in 4 cases, negative in 2 cases, and uncertain in one case. Two patients underwent simultaneous TL and CI, 1 patient simultaneous TL and auditory brainstem implant, 3 patients posterior tympanotomy with CI, and 1 patient had no implant placement. In the 5 patients undergoing CI, sound detection was present. There was a good correlation between the PromStim and ANTS EABR. The literature research yielded 35 patients with complete information about EABR response. There was one false negative and one false positive case; that is, the 28 implanted cases with a present wave V following tumor resection had some degree of auditory perception in all but one case.The ANTS is a useful intraoperative tool to asses CI candidacy in VS patients undergoing observation, irradiation or surgery. A positive strongly predicts at least sound detection with the CI.

The relationship between cleft palate repair technique and audiological outcomes: A retrospective cohort study.

Otitis media with effusion is common in children with cleft palates. This study aimed to investigate the link between palatal closure techniques and audiological outcomes. In this retrospective-prospective cohort study, we examined the relationship between palate repair techniques and hearing outcomes in children with cleft palates. From 2017 to 2022, 190 ears of 95 cleft patients were studied at the Cleft Lip and Palate Department of Shiraz University of Medical Sciences. Variables assessed included the surgical technique, cleft severity, auditory brainstem response (ABR) threshold, and tympanometry configuration. The mean ABR improved from a prepalatoplasty value of 39.51(11.62) decibels (dB) to a postpalatoplasty mean of 26.61(11.60) dB (Cohen's d: 1.12 [95% CI; 0.90-1.34]). Initially, 87.9% of the studied ears exhibited abnormal tympanometry, but this significantly decreased to 47% postsurgery (risk ratio: 4.43 [95% CI; 1.20-16.43]). When compared with Sommerlad intravelar veloplasty, the Nadjmi modified Furlow palatoplasty was associated with a notably lower mean ABR (β: -6.58 [95% CI: -10.43 to -2.73], p-value = .001) and a reduced frequency of abnormal tympanometry (odds ratio [OR]: -1.10; 95% CI: -1.85 to -0.36, p-value = .004). Factors like prepalatoplasty ABR, cleft palate severity, gender, and syndromic did not confound these findings. Although the Nadjmi modified Furlow palatoplasty showed better results, our findings indicate a significant improvement in ABR and tympanometry outcomes for both techniques. Future randomized controlled trials are suggested to confirm the influence of palatal closure techniques on audiological outcomes. 3b.

Newborn Hearing Screening Results for Infants With Prenatal Opioid Exposure in Southern Appalachia.

Infants prenatally exposed to opioids exhibit withdrawal symptomology that introduce physiological noise and can impact newborn hearing screening results. This study compared the referral rate and physiological noise interpreted by number of trials rejected due to artifact on initial newborn hearing screenings of infants with prenatal opioid exposure (POE) and infants with no opioid exposure (NOE). Furthermore, within the POE group, it examined the relationship of referral rates with severity of withdrawal symptomology, and with maternal and infant risk factors. This study used a retrospective cohort design of electronic medical records from six delivery hospitals in South-Central Appalachia. Newborn hearing screenings were conducted using automated auditory brainstem response (ABR) for 334 infants with POE and 226 infants with NOE. Severity of withdrawal symptomology was measured using the Modified Finnegan Neonatal Abstinence Scoring Tool, which includes observation of behaviors that introduce physiological noise. There was no significant difference in newborn hearing screening referral rate between infants with POE and infants with NOE. Referral rate was not affected by maternal or infant risk factors. Infants with POE had statistically significant higher artifact (defined as rejected ABR sweeps) than infants with NOE. There was a strong positive correlation between Finnegan scores and artifact but not referral rates. Sensitivity and specificity analysis indicated artifact decreased substantially after Day 4 of life. Referral rates of infants with POE were similar to those of infants with NOE. Nevertheless, the withdrawal symptomology of infants with POE introduces physiological noise reflected as artifact on ABR, which can affect efficiency of newborn hearing screenings.

Phenotypic spectrum of tinnitus patients bearing rare ANK2 gene variants

PurposeTo describe the clinical, audiological, and psychometric features observed in patients with chronic tinnitus and rare variants in the ANK2 gene.MethodsWe report a case series of 12 patients with chronic tinnitus and heterozygous variants in the ANK2 gene. Tinnitus phenotyping included audiological (standard and high-frequency audiometry, Auditory Brainstem Responses (ABR) and Auditory Middle Latency Responses (AMLR)), psychoacoustic and psychometric assessment by a Visual Analog Scale (VAS) for tinnitus annoyance, the Tinnitus Handicap Inventory (THI), the test on Hypersensitivity to Sound (THS-GÜF), the Patient Health Questionnaire (PHQ-9), the Hospital Anxiety and Depression Scale (HADS) and the Montreal Cognitive Assessment (MoCA).ResultsAll patients reported a persistent, unilateral noise-type tinnitus, mainly described as white noise or narrowband noise. Seven patients (58%) were considered to have extreme phenotype (THI score > 76), and all patients reported some degree of hyperacusis (THS-GÜF score > 18 in 75% of patients). Seven patients scored MoCA < 26, regardless of the age reported, suggesting a mild cognitive disorder. ABR showed no significant differences in latencies and amplitudes between ears with or without tinnitus. Similarly, the latencies of Pa, Pb waves, and NaPa complex in the AMLR did not differ based on the presence of tinnitus. However, there were statistical differences in the amplitudes of Pa waves in AMLR, with significantly greater amplitudes observed in ears with tinnitus.ConclusionPatients with ANK2 variants and severe tinnitus exhibit an endophenotype featuring hyperacusis, persistent noise-like tinnitus, high-frequency hearing loss, and decreased amplitudes in AMLR. However, anxiety, depression, and cognitive symptoms vary among individuals.

4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway.

Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1β. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.

The transcription factor Pou4f3 is essential for the survival of postnatal and adult mouse cochlear hair cells and normal hearing.

Hair cells (HCs) of the cochlea are responsible for sound transduction and hearing perception in mammals. Genetic mutations in the transcription factor Pou4f3 cause non-syndromic autosomal dominant hearing loss in humans (DFNA15) which varies in the age of onset depending on the individual mutation. Mouse models with germline deletion or mutations in Pou4f3 have previously demonstrated its critical role in the maturation and survival of cochlear HCs during embryonic development. However, the role of Pou4f3 in auditory function and in the survival or maintenance of cochlear HCs after birth and during adulthood has not been studied. Therefore, using the inducible CreER-loxP system, we deleted Pou4f3 from mouse cochlear HCs at different postnatal ages, relevant to specific stages of HC maturation and hearing function. Elevated auditory brainstem response thresholds and significant HC loss were detected in mice with Pou4f3 deletion compared to their control littermates, regardless of the age when Pou4f3 was deleted. However, HC loss occurred more rapidly when Pou4f3 was deleted from immature HCs. Additionally, HC loss caused by Pou4f3 deletion did not affect the number of cochlear supporting cells, but caused a delayed loss of spiral ganglion neurons at 4 months after the deletion. In conclusion, Pou4f3 is necessary for the survival of cochlear HCs and normal hearing at all postnatal ages regardless of their maturation state. Our data also suggest that Pou4f3 indirectly regulates the survival of spiral ganglion neurons.

Auditory brainstem responses are resistant to pharmacological modulation in Sprague Dawley wild-type and Neurexin1α knockout rats

Sensory processing in the auditory brainstem can be studied with auditory brainstem responses (ABRs) across species. There is, however, a limited understanding of ABRs as tools to assess the effect of pharmacological interventions. Therefore, we set out to understand how pharmacological agents that target key transmitter systems of the auditory brainstem circuitry affect ABRs in rats. Given previous studies, demonstrating that Nrxn1α KO Sprague Dawley rats show substantial auditory processing deficits and altered sensitivity to GABAergic modulators, we used both Nrxn1α KO and wild-type littermates in our study. First, we probed how different commonly used anesthetics (isoflurane, ketamine/xylazine, medetomidine) affect ABRs. In the next step, we assessed the effects of different pharmacological compounds (diazepam, gaboxadol, retigabine, nicotine, baclofen, and bitopertin) either under isoflurane or medetomidine anesthesia. We found that under our experimental conditions, ABRs are largely unaffected by diverse pharmacological modulation. Significant modulation was observed with (i) nicotine, affecting the late ABRs components at 90 dB stimulus intensity under isoflurane anesthesia in both genotypes and (ii) retigabine, showing a slight decrease in late ABRs deflections at 80 dB stimulus intensity, mainly in isoflurane anesthetized Nrxn1α KO rats. Our study suggests that ABRs in anesthetized rats are resistant to a wide range of pharmacological modulators, which has important implications for the applicability of ABRs to study auditory brainstem physiology.

Assessment of Peripheral and Central Auditory Processing after Treatment for Idiopathic Sudden Sensorineural Hearing Loss.

Introduction When cases of idiopathic sudden sensorineural hearing loss (SSNHL) are treated successfully, most clinicians assume the normality and symmetry of the auditory processing. This assumption is based on the recovery of the detection ability on the part of the patients, but the auditory processing involves much more than detection alone. Since certain studies have suggested a possible involvement of the central auditory system during the acute phase of sudden hearing loss, the present study hypothesized that auditory processing would be asymmetric in people who have experienced sudden hearing loss. Objective To assess the physiologic and electrophysiological conditions of the cochlea and central auditory system, as well as behavioral discrimination, of three primary aspects of sound (intensity, frequency, and time) in subjects with normal ears and ears treated successfully for SSNHL. Methods The study included 19 SSNHL patients whose normal and treated ears were assessed for otoacoustic emissions, speech auditory brainstem response, intensity and pitch discrimination, and temporal resolution in a within-subject design. Results The otoacoustic emissions were poorer in the treated ears compared to the normal ears. Ear- and sex-dependent differences were observed regarding otoacoustic emissions and pitch discrimination. Conclusion The asymmetrical processing observed in the present study was not consistent with the hearing threshold values, which might suggest that the central auditory system would be affected regardless of the status of the peripheral hearing. Further experiments with larger samples, different recovery scenarios after treatment, and other assessments are required.