Distortion Product Otoacoustic Emissions Research Articles

Ototoxicity: a high risk to auditory function that needs to be monitored in drug development

Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field – required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use – ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: in vitro (otic cell assays), ex vivo (cochlear explant), and in vivo (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, in vivo otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.

Audiological Characteristics of Vestibular Schwannoma Patients With Normal Pure-Tone Audiometry.

To investigate the audiological characteristics of vestibular schwannoma (VS) patients with normal pure-tone audiometry (PTA) results. A retrospective study. Forty-two VS patients with normal PTA results from October 2016 to October 2022 were included. Normal PTA was defined when the hearing threshold is ≤25 dB hearing loss (HL) in each test frequency and the PTA is ≤25 dB HL. Results of multiple audiological tests such as the auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), multiple auditory steady-state responses threshold (ASSR), and speech discrimination score were retrospectively reviewed. Demographic data of these patients were also been collected. According to our results, the ABR and average ASSR threshold of the affected side were statistically significantly higher in VS patients with normal PTA. ABR waveforms on the affected side also showed more abnormalities. The DPOAE pass rates of the affected side were lower than the unaffected side while the amplitude and signal-to-noise ratio rate was also lower. In addition, we used magnetic resonance imaging 3-dimensional reconstruction images to measure the volume of tumors in these patients. We also found that higher ABR threshold means lager tumor size in patients with normal PTA. VS patients with normal PTA result cannot be assumed to have no impairment of hearing function. ABR, DPOAE, and ASSR results showed the characteristic changes in the affect ear. ABR threshold has the highest sensitivity for hearing abnormalities and is strong relative with tumor size in patients with normal PTA.

Examining the utility of near infrared light as pre-exposure therapy to mitigate temporary noise-induced hearing loss in humans.

This study sought to determine the effect of Occupational Safety and Health Administration (OSHA) compliant noise on auditory health and assess whether pre-noise near infrared (NIR) light therapy can mitigate the effects of noise exposure. Over four visits, participants (n = 30, NCT#: 03834714) with normal hearing completed baseline hearing health assessments followed by exposure to open ear, continuous pink noise at 94 dBA for 15 min. Immediately thereafter, post-noise hearing tests at 3000, 4000, and 6000 Hz and distortion product otoacoustic emissions (DPOAEs) were conducted along with the Modified Rhyme Test (MRT), Masking Level Difference Test (MLD), and Fixed Level Frequency Tests (FLFT) [collectively referred to as the Central and Peripheral Auditory Test Battery (CPATB)] to acquire baseline noise sensitivity profiles. Participants were then randomized to either Active or Sham NIR light therapy for 30 min binaurally to conclude Visit 1. Visit 2 (≥24 and ≤ 48 h from Visit 1) began with an additional 30-min session of Active NIR light therapy or Sham followed by repeat CPATB testing and noise exposure. Post-noise testing was again conducted immediately after noise exposure to assess the effect of NIR light therapy. The remaining visits were conducted following ≥2 weeks of noise rest in a cross-over design (i.e., those who had received Active NIR light therapy in Visits 1 and 2 received Sham therapy in Visits 3 and 4). Recovery hearing tests and DPOAEs were completed at the end of each visit. Participants experienced temporary threshold shifts (TTS) immediately following noise exposure, with a mean shift of 6.79 dB HL (±6.25), 10.61 dB HL (±6.89), and 7.30 dB HL (±7.25) at 3000, 4000, and 6000 Hz, respectively, though all thresholds returned to baseline at 3000, 4000, and 6000 Hz within 75 min of noise exposure. Paradoxically, Active NIR light therapy threshold shifts were statistically higher than Sham therapy at 3000 Hz (p = 0.04), but no other differences were observed at the other frequencies tested. An age sub-analysis demonstrated that TTS among younger adults were generally larger in the Sham therapy group versus Active therapy, though this was not statistically different. There were no differences in CPATB test results across Active or Sham groups. Finally, we observed no changes in auditory function or central processing following noise exposure, suggestive of healthy and resilient inner ears. In this study, locally administered NIR prior to noise exposure did not induce a significant protective effect in mitigating noise-induced TTS. Further exploration is needed to implement effective dosage and administration for this promising otoprotective therapy.

Evaluation of Subjective Tinnitus Severity and Distortion Product Otoacoustic Emissions and Extended High-Frequency Audiometry.

Tinnitus is a multifactorial phenomenon with quality-of-life detriments for those affected by it. We aim to establish a relationship between subjective tinnitus severity with objective audiometric data in the extended high frequency (EHF) from 9 to 16 khz and with distortion product otoacoustic emissions (DPOAE). We hypothesize that severe subjective tinnitus as measured by the Tinnitus Handicap Inventory (THI) does not correlate with increased hearing thresholds in the EHF range. Prospective. Single Tertiary Care Center. Patients identified with tinnitus and normal hearing thresholds within standard frequency range (250-8000 Hz) were consented for participation. Those with underlying otologic disease, trauma, radiotherapy, or ototoxic drug use were excluded. The THI questionnaire was given to eligible patients and audiometric test results were collected. THI scores were categorized by severity groups. An n = 20 to 30 was determined to have an effect size of 0.7 with a significance level of P = .05. THI and audiometric data were collected for 38 patients and categorized into mild (n = 18, 47.4%), moderate (n = 8, 21.1%), slight (n = 7, 18.4%), and severe (n = 5, 13.2%) tinnitus severity groups. Mean THI score was 32.3 ± 19.6 with a statistically significant difference in scores by assigned THI severity group (P < .01). There were no significant differences or linear relationship among hearing thresholds in EHF range or DPOAE stratified by subjective tinnitus group (P = .49, r2 = 0.10) CONCLUSION: Subjective tinnitus severity is not predictive of audiometric outcomes. This finding can be used as a counseling tool to help tinnitus patients manage symptoms, expectations, and overall treatment outcomes.

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.

Hearing dysfunction heralds an increase in non-motor burden and a worse quality of life in Parkinson's disease: new insights from non-motor spectrum.

Sensorial non-motor symptoms (NMSs) in Parkinson's disease (PD) still lack appropriate investigation in clinical practice. This study aimed to assess if and to what extent auditory dysfunction is associated with other NMSs in PD and its impact on patient's quality of life (QoL). We selected patients with idiopathic PD, without other concomitant neurological diseases, dementia, or diagnosis of any audiological/vestibular disease. Demographic and clinical data were collected. Patients underwent otoscopic examination, audiological testing with pure tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAEs) and completed Non-Motor Symptoms Scale (NMSS) and Parkinson's Disease Questionnaires-39 (PDQ-39). ANCOVA and partial correlation analysis have been used for statistical analysis. 60 patients were enrolled and completed PTA and DPOAEs. 32 patients with hearing impairment (HI), assessed by PTA, (hearing threshold ≥ 25dB) showed similar disease duration, motor impairment, and staging, compared to patients without HI, but higher scores both in NMSS and in PDQ-39, except for cardiovascular (CV), gastrointestinal (GI), urogenital (U) and sexual function (SF) of NMSS. In addition, DPOAEs showed a significant correlation with higher scores both in NMSS and PDQ-39, except for CV, SF, GI, U and perceptual problem subdomains of NMSS. This study demonstrated that PD patients with HI have a greater burden of NMS and lower related QoL and functioning. Our results highlight the importance to reconsider HI as a NMS, in parallel with the others. HI evaluation, even in asymptomatic patients, may reveal a wider pathology with a worse QoL.

Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study

ObjectiveThe genotype-phenotype relationship in cisplatin-induced ototoxicity remains unclear. By assessing early shifts in distortion product otoacoustic emission (DPOAE) levels after initial cisplatin administration, we aimed to discriminate patients’ susceptibility to cisplatin-induced ototoxicity and elucidate their genetic background. Study DesignA prospective cross-sectional study. SettingTertiary referral hospital in Japan. PatientsTwenty-six patients with head and neck cancer were undergoing chemoradiotherapy with three cycles of 100 mg/m2 cisplatin. InterventionsRepetitive pure-tone audiometry and DPOAE measurements, and blood sampling for DNA extraction were performed. Patients were grouped into early ototoxicity presence or absence based on whether DPOAE level shifts exceeded the corresponding reference limits of the 21-day test interval. Main Outcome MeasuresHearing thresholds after each cisplatin cycle, severity of other adverse events, and polymorphisms in cisplatin-induced ototoxicity-associated genes were compared. ResultsEarly ototoxicity was present in 14 and absent in 12 patients. Ototoxicity presence on DPOAEs was associated with greater progression of hearing loss in frequencies ≥2 kHz throughout therapy and with higher ototoxicity grades compared with ototoxicity absence. Ototoxicity was further associated with grade ≥2 nausea. Ototoxicity presence was genetically associated with the GSTT1 null genotype and G-allele of NFE2L2 rs6721961, whereas ototoxicity absence was associated with the GSTM1 null genotype. Dose-dependent progression of hearing loss was the greatest in the combined genotype pattern of GSTT1 null and the T/G or G/G variants of rs6721961. ConclusionEarly DPOAE changes reflected genetic vulnerability to cisplatin-induced ototoxicity. Hereditary insufficiency of the antioxidant defense system causes severe cisplatin-induced hearing loss and nausea.

Otoacoustic emissions in African mole-rats

African mole-rats display highly derived hearing that is characterized by low sensitivity and a narrow auditory range restricted to low frequencies < 10 kHz. Recently, it has been suggested that two species of these rodents do not exhibit distortion product otoacoustic emissions (DPOAE), which was interpreted as evidence for a lack of cochlear amplification. If true, this would make them unique among mammals. However, both theoretical considerations on the generation of DPOAE as well as previously published experimental evidence challenge this assumption. We measured DPOAE and stimulus-frequency otoacoustic emissions (SFOAE) in three species of African mole-rats (Ansell's mole-rat - Fukomys anselli; Mashona mole-rat - Fukomys darlingi; naked mole-rat - Heterocephalus glaber) and found unexceptional otoacoustic emission values. Measurements were complicated by the remarkably long, narrow and curved external ear canals of these animals, for which we provide a morphological description. Both DPOAE and SFOAE displayed the highest amplitudes near 1 kHz, which corresponds to the region of best hearing in all tested species, as well as to the frequency region of the low-frequency acoustic fovea previously described in Ansell's mole-rat. Thus, the cochlea in African mole-rats shares the ability to generate evoked otoacoustic emission with other mammals.

Serum Prestin Level May Increase Following Music Exposure That Induces Temporary Threshold Shifts: A Pilot Study.

To determine if blood prestin level changes after exposure to music at high sound pressure levels, and if this change is associated with temporary threshold shift (TTS) and/or changes in distortion product (DP) amplitude. Participants were exposed to pop-rock music at 100 dBA for 15 min monaurally through headphones. Pure-tone audiometry, DP amplitude, and blood prestin level were measured before and after exposure. Fourteen adults (9 women; age range: 20 to 54 years, median age = 31 [Interquartile ratio = 6.75]) with normal hearing were included in the study. Mean prestin level increased shortly after exposure to music, then returned to baseline within 1 week, although this trend was not observed in all participants. All participants presented TTS or a decrease in DP amplitude in at least one frequency after music exposure. There was a statistically significant average threshold elevation at 4 min postexposure. Statistically significant DP amplitude shifts were observed at 4 and 6 kHz, 2 min following exposure. Mean baseline serum prestin level (mean: 140.00 pg/mL, 95% confidence interval (CI): 125.92 to 154.07) progressively increased following music exposure, reaching a maximum at 2 hr (mean: 158.29 pg/mL, 95% CI: 130.42 to 186.66) and returned to preexposure level at 1 week (mean: 139.18 pg/mL, 95% CI: 114.69 to 163.68). However, after correction for multiple comparisons, mean prestin level showed no statistically significant increase from baseline at any timepoint. No correlation between maximum blood prestin level change and average TTS or distortion product otoacoustic emission amplitude shift was found. However, in an exploratory analysis, TTS at 6 kHz (the frequency at which maximum TTS occurred) decreased significantly as baseline blood prestin level increased. The results suggest that blood prestin level may change after exposure to music at high sound pressure levels, although statistical significance was not reached in this relatively small sample after correction. Baseline serum prestin level may also predict the degree of TTS. These findings thus suggest that the role of baseline serum prestin level as a proxy marker of cochlear susceptibility to intense music exposure should be further explored.

A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss

Inhibition of Notch signalling with a gamma-secretase inhibitor (GSI) induces mammalian hair cell regeneration and partial hearing restoration. In this proof-of-concept Phase I/IIa multiple-ascending dose open-label trial (ISRCTN59733689), adults with mild-moderate sensorineural hearing loss received 3 intratympanic injections of GSI LY3056480, in 1 ear over 2 weeks. Phase I primary outcome was safety and tolerability. Phase lla primary outcome was change from baseline to 12 weeks in average pure-tone air conduction threshold across 2,4,8 kHz. Secondary outcomes included this outcome at 6 weeks and change from baseline to 6 and 12 weeks in pure-tone thresholds at individual frequencies, speech reception thresholds (SRTs), Distortion Product Otoacoustic Emissions (DPOAE) amplitudes, Signal to Noise Ratios (SNRs) and distribution of categories normal, present-abnormal, absent and Hearing Handicap Inventory for Adults/Elderly (HHIA/E). In Phase I (N = 15, 1 site) there were no severe nor serious adverse events. In Phase IIa (N = 44, 3 sites) the average pure-tone threshold across 2,4,8 kHz did not change from baseline to 6 and 12 weeks (estimated change −0.87 dB; 95% CI −2.37 to 0.63; P = 0.252 and −0.46 dB; 95% CI −1.94 to 1.03; P = 0.545, respectively), nor did the means of secondary measures. DPOAE amplitudes, SNRs and distribution of categories did not change from baseline to 6 and 12 weeks, nor did SRTs and HHIA/E scores. Intratympanic delivery of LY3056480 is safe and well-tolerated; the trial’s primary endpoint was not met.

Distortion Product Otoacoustic Emissions changes after administration of Sildenafil in animal model

Distortion Product Otoacoustic Emissions changes after administration of Sildenafil in animal model

Comparison of Two Clinical Devices for the Measurement of Distortion Product Otoacoustic Emissions in Normal-Hearing Adults.

Otoacoustic emissions (OAEs) are low-intensity sounds generated by the cochlea and associated with the function of the outer hair cells. Since OAE measurements do not require active participation of a listener, OAEs are considered an objective measure of cochlear function. While distortion-product OAEs (DPOAEs) are commonly used in clinical practice, limited information is available on the performance of various clinical devices. This study compared two commercial clinical devices, Titan and Eclipse from Interacoustics, and collected normative data for DPOAEs in people with normal hearing. The data collection and analysis were focused on signal and noise amplitudes as well as signal-to-noise ratios (SNRs). Sixty-three participants with normal hearing (age 23.2±2.0 years) were included in the study. DPOAEs were measured at 31 frequencies ranging from 500 to 10,000 Hz. DPOAE amplitude differed across frequencies. Additionally, a high number of unreliable responses were observed at the edge frequencies (<828 Hz and >6,072 Hz). There were no significant differences between the two devices in terms of DPOAE amplitudes, but the recorded-noise levels (amplitude) differed significantly. SNRs of the recorded OAEs were frequency dependent (higher frequencies showed larger SNRs), and significant differences in terms of SNR were found between the two devices. Despite the above-mentioned differences, the OAEs recorded with both devices met the pass criteria for the SNR (≥6 dB) consistently across frequencies, and thus the differences do not compromise the test outcomes. The frequency dependence of the OAE amplitudes and the corresponding SNRs may be relevant for clinical practice.

Early-Onset Hearing Loss in Mouse Models of Alzheimer's Disease and Increased DNA Damage in the Cochlea.

There is considerable interest in whether sensory deficiency is associated with the development of Alzheimer's disease (AD). Notably, the relationship between hearing impairment and AD is of high relevance but still poorly understood. In this study, we found early-onset hearing loss in two AD mouse models, 3xTgAD and 3xTgAD/Polβ+/-. The 3xTgAD/Polβ+/- mouse is DNA repair deficient and has more humanized AD features than the 3xTgAD. Both AD mouse models showed increased auditory brainstem response (ABR) thresholds between 16 and 32 kHz at 4 weeks of age, much earlier than any AD cognitive and behavioral changes. The ABR thresholds were significantly higher in 3xTgAD/Polβ+/- mice than in 3xTgAD mice at 16 kHz, and distortion product otoacoustic emission signals were reduced, indicating that DNA damage may be a factor underlying early hearing impairment in AD. Poly ADP-ribosylation and protein expression levels of DNA damage markers increased significantly in the cochlea of the AD mice but not in the adjacent auditory cortex. Phosphoglycerate mutase 2 levels and the number of synaptic ribbons in the presynaptic zones of inner hair cells were decreased in the cochlea of the AD mice. Furthermore, the activity of sirtuin 3 was downregulated in the cochlea of these mice, indicative of impaired mitochondrial function. Taken together, these findings provide new insights into potential mechanisms for hearing dysfunction in AD and suggest that DNA damage in the cochlea might contribute to the development of early hearing loss in AD.

Cochlear zinc signaling dysregulation is associated with noise-induced hearing loss, and zinc chelation enhances cochlear recovery

Exposure to loud noise triggers sensory organ damage and degeneration that, in turn, leads to hearing loss. Despite the troublesome impact of noise-induced hearing loss (NIHL) in individuals and societies, treatment strategies that protect and restore hearing are few and insufficient. As such, identification and mechanistic understanding of the signaling pathways involved in NIHL are required. Biological zinc is mostly bound to proteins, where it plays major structural or catalytic roles; however, there is also a pool of unbound, mobile (labile) zinc. Labile zinc is mostly found in vesicles in secretory tissues, where it is released and plays a critical signaling role. In the brain, labile zinc fine-tunes neurotransmission and sensory processing. However, injury-induced dysregulation of labile zinc signaling contributes to neurodegeneration. Here, we tested whether zinc dysregulation occurs and contributes to NIHL in mice. We found that ZnT3, the vesicular zinc transporter responsible for loading zinc into vesicles, is expressed in cochlear hair cells and the spiral limbus, with labile zinc also present in the same areas. Soon after noise trauma, ZnT3 and zinc levels are significantly increased, and their subcellular localization is vastly altered. Disruption of zinc signaling, either via ZnT3 deletion or pharmacological zinc chelation, mitigated NIHL, as evidenced by enhanced auditory brainstem responses, distortion product otoacoustic emissions, and number of hair cell synapses. These data reveal that noise-induced zinc dysregulation is associated with cochlear dysfunction and recovery after NIHL, and point to zinc chelation as a potential treatment for mitigating NIHL.

Development and Validation of an Efficient and Safe Loud Music Exposure Paradigm.

The purpose of this study was to develop a time-efficient music exposure and testing paradigm that safely creates temporary cochlear dysfunction that could be used in future temporary threshold shift (TTS) studies. A 30-min audio compilation of pop rock music tracks was created. Adult volunteers with normal hearing were then exposed to this music material monaurally through headphones for 30 min at 97 dBA or 15 min at 100 dBA. Levels were measured from the ear of a manikin and are considered to provide an equivalent daily noise dose based on a 3-dB exchange. We assessed the changes in their hearing, by means of distortion product otoacoustic emission (DPOAE) testing, and standard and extended high-frequency pure-tone audiometry before and after exposure. There were 17 volunteers in total. In the first trial, eight volunteers (four females; Mdnage = 31 years [interquartile range, IQR = 4.25]) were included. Although TTS was observed in all eight participants for at least one frequency, a large variation in affected frequencies was observed. To address this issue, the audio material was further remastered to adjust levels across the different frequency bands. Fourteen adults (nine newly recruited and five from the first trial; seven females; Mdnage = 31 years [IQR = 5]) were exposed to the new material. All but two of 17 participants presented clinically significant TTS or decrease in DPOAE amplitude in at least one frequency. Statistically significant average TTS of 7.43 dB was observed at 6 kHz. There were statistically significant average DPOAE amplitude shifts of -2.55 dB at 4 kHz, -4.97 dB at 6 kHz, and -3.14 dB at 8 kHz. No participant presented permanent threshold shift. A monaural music paradigm was developed and shown to induce statistically significant TTS and DPOAE amplitude shifts, without evidence of permanent loss. This realistic and time-efficient paradigm may be considered a viable option for experimental studies of temporary music-induced hearing loss. https://doi.org/10.23641/asha.25016471.

Norepinephrine protects against cochlear outer hair cell damage and noise-induced hearing loss via α2A-adrenergic receptor

BackgroundThe cochlear sympathetic system plays a key role in auditory function and susceptibility to noise-induced hearing loss (NIHL). The formation of reactive oxygen species (ROS) is a well-documented process in NIHL. In this study, we aimed at investigating the effects of a superior cervical ganglionectomy (SCGx) on NIHL in Sprague-Dawley rats.MethodsWe explored the effects of unilateral and bilateral Superior Cervical Ganglion (SCG) ablation in the eight-ten weeks old Sprague-Dawley rats of both sexes on NIHL. Auditory function was evaluated by auditory brainstem response (ABR) testing and Distortion product otoacoustic emissions (DPOAEs). Outer hair cells (OHCs) counts and the expression of α2A-adrenergic receptor (AR) in the rat cochlea using immunofluorescence analysis. Cells culture and treatment, CCK-8 assay, Flow cytometry staining and analysis, and western blotting were to explore the mechanisms of SCG fibers may have a protective role in NIHL.ResultsWe found that neither bilateral nor unilateral SCGx protected the cochlea against noise exposure. In HEI-OC1 cells, H2O2-induced oxidative damage and cell death were inhibited by the application of norepinephrine (NE). NE may prevent ROS-induced oxidative stress in OHCs and NIHL through the α2A-AR.ConclusionThese results demonstrated that sympathetic innervation mildly affected cochlear susceptibility to acoustic trauma by reducing oxidative damage in OHCs through the α2A-AR. NE may be a potential therapeutic strategy for NIHL prevention.

Newborn and Infant Hearing Screening for Early Detection of Hearing Loss in Nairobi, Kenya

Background: Early detection of hearing loss and subsequent intervention leads to better speech, language and educational outcomes giving way to improved socioeconomic prospects in adult life. This can be achieved through establishing universal newborn hearing screening (UNHS) programs. The objectives of this study were to assess the feasibility of implementing a UNHS program and to also determine the prevalence of hearing loss in newborns in Nairobi, Kenya.&#x0D; Materials And Methods: A cross-sectional pilot study was conducted at the National Hospital and a sub-county hospital immunization clinic. A total of 9,963 babies aged 0-3 years, were enrolled in the hearing screening program through convenient sampling over nine months. A case history was administered followed by Distortion Product Oto-acoustic emissions (DPOAEs) and automated auditory brainstem response (AABR) hearing screening.&#x0D; Results: The screening coverage rate was 98.6% (9963/10,104). The referral rate for the initial screen was 3.6% (356/ 9,963), and the return rate for follow-up rescreening was 72% (258 babies out of 356) with a loss to follow-up rate of 28% (98/356). The referral rate of the second screen was 10% (26/258). All 26 babies referred from the second screen returned for diagnostic hearing evaluation and were confirmed to have hearing loss, yielding a prevalence of 3/1000.&#x0D; Conclusions:  Establishing universal newborn and infant hearing screening programs in Kenya is feasible and essential for early  detection and intervention for hearing loss. Data management and efficient follow-up systems are an integral part of achieving  diagnostic confirmation of hearing loss and early intervention.

Cortical Auditory Evoked Potential Indices of Impaired Sensory Gating in People With Chronic Tinnitus.

The primary aim of this study was to evaluate whether there is cortical auditory evoked potential (CAEP) evidence of impaired sensory gating in individuals with tinnitus. On the basis of the proposed mechanism of tinnitus generation, including a thalamocortical inhibitory deficit, it was hypothesized that individuals with tinnitus would lack the normal inhibitory effect on the second CAEP response in a paired-click sensory gating paradigm, resulting in larger sensory gating ratios in individuals with tinnitus relative to age-, sex-, and hearing-matched controls. Further, this study assessed the relative predictive influence of tinnitus presence versus other related individual characteristics (hearing loss, age, noise exposure history, and speech perception in noise) on sensory gating. A paired-click CAEP paradigm was used to measure sensory gating outcomes in an independent group's experimental design. Adults who perceived chronic unilateral or bilateral tinnitus were matched with control group counterparts without tinnitus by age, hearing, and sex (n = 18; 10 females, eight males in each group). Amplitude, area, and latency sensory gating ratios were determined for measured P1, N1, and P2 responses evoked by the first and second click in the paradigm and compared between groups by independent t tests. The relative influence of tinnitus (presence/absence), age (in years), noise exposure history (subjective self-report), hearing loss (pure-tone audiometric thresholds), and speech perception in noise (signal to noise ratio-50) on sensory gating was determined based on the proportional reduction in error associated with each variable using multiple regression. A significantly larger was identified in the tinnitus group relative to the control group, consistent with the hypothesis of poorer sensory gating and poorer thalamocortical inhibition in individuals with chronic tinnitus. On the basis of the proportional reduction in error, the influence of tinnitus presence better predicted compared with other related individual characteristics (age, noise exposure history, hearing loss, and speech perception in noise). Results consistent with poorer sensory gating, including a larger , were found for the tinnitus group compared with the controls. This finding supported a thalamocortical inhibitory deficit in the tinnitus group and suggests that individuals with tinnitus may have poorer sensory gating. However, the tinnitus group did differ from controls in meaningful ways including having worse pure-tone thresholds in the extended high-frequency region, lower high-frequency distortion product otoacoustic emissions, and poorer speech perception in noise. Although tinnitus best predicted sensory gating outcomes, the specific effects of tinnitus presence versus absence and other individual characteristics on sensory gating cannot be completely separated.

Risk of hearing loss in non-operated ear due to mastoid drilling

Background: The study purpose is to evaluate the effect of drill-generated high intensity noise on hearing sensitivity in contralateral ear. Methods: Sixty patients who underwent mastoidectomy were studied to see the effect of mastoid drilling on hearing sensitivity in normal ear using pure tone audiometry (PTA) and distortion product otoacoustic emission (OAE) values recorded preoperatively and postoperatively. Results: For PTA, there is no significant hearing loss for 0.25 kHz and 0.50 kHz for all PODs. For 1 kHz, 2 kHz and average PTA there is significant temporary hearing loss from POD 1 to POD 7 which normalizes around POD 30. However, there is significant temporary threshold shift for 4 kHz and 8 kHz from POD 1 to POD 5 and the hearing sensitivity improves to preoperative levels at POD 7. For OAE, 1 kHz, 4 kHz and average OAE there is significant temporary hearing loss from POD 1 to POD 7 which normalizes around POD 30. However, there is significant temporary threshold shift for 2 kHz and 6 kHz from POD 1 to POD 5 and hearing sensitivity improves to preoperative levels at POD 7. There is a significant correlation between drilling duration and PTA averages and OAE averages. Conclusions: Sensorineural hearing loss is more prevalent following modified radical and radical mastoidectomy as compared to canal wall up mastoidectomy. The factors influencing postoperative contralateral ear sensorineural hearing loss are type and size of burr and the duration of burr use.

Effect of Head Position on Distortion Product Otoacoustic Emissions

Abstract Objectives The study aimed to explore the impact of various head positions on the distortion product otoacoustic emissions (DPOAE) amplitudes, identifying the specific DPOAE frequencies showing the effect was also of interest. Materials and Methods DPOAEs were recorded from the right ears of 50 normal-hearing individuals in six head positions, supine, and five sitting positions (head erect, roll left, roll right, pitch backward, and pitch forward). DPOAEs were averaged and measured for their overall and frequency-specific amplitudes at 1 kHz, 1.5 kHz, 2 kHz, 3 kHz, 4 kHz, 6 kHz, and 8 kHz. Statistical Analysis To investigate the statistical significance of the observed mean differences, the data was tested using repeated measures of analysis of variance (ANOVA) following the Shapiro–Wilk normality test. The pair-wise comparison was tested using the Bonferroni post-hoc test and one-sided Bayesian paired sample t-test. Results The results of ANOVA revealed a significant main effect of head posture only at 1 kHz. The Bonferroni post-hoc test and one-sided Bayesian paired sample t-test results showed significantly higher DPOAE amplitude in the head erect compared to the supine position. There were no significant differences between other pairs of head postures. Conclusion Head posture is a trivial influencing factor of DPOAEs and hence, does not require consideration in interpreting DPOAEs.