Therapeutic Function of Liraglutide for Mitigation of Blast-Induced Hearing Damage: An Initial Investigation in Animal Model of Chinchilla.

INTRODUCTION: Auditory injuries induced by repeated exposures to blasts reduce the operational performance capability and the life quality of military personnel. The treatment for blast-induced progressive hearing damage is lacking. We have recently investigated the therapeutic function of liraglutide, a glucagon-like peptide-1 receptor agonist, to mitigate blast-induced hearing damage in the animal model of chinchilla, under different blast intensities, wearing earplugs (EPs) or not during blasts, and drug-treatment plan. The goal of this study was to investigate the therapeutical function of liraglutide by comparing the results obtained under different conditions. MATERIALS AND METHODS: Previous studies on chinchillas from two under-blast ear conditions (EP/open), two blast plans (G1: 6 blasts at 3-5 psi or G2:3 blasts at 15-25 psi), and three treatment plans (blast control, pre-blast drug treatment, and post-blast drug treatment) were summarized. The auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and middle latency response (MLR) recorded within 14 days after the blasts were used. Statistical analysis was performed to evaluate the effect of liraglutide under different conditions. RESULTS: ABR threshold shifts indicated that the conditions of the EP and open ears were substantially different. Results from EP chinchillas indicated that the pre-blast treatment reduced the acute ABR threshold elevation on the day of blasts, and the significance of such an effect increased with the blast level. Liraglutide-treated open chinchillas showed lower ABR threshold shifts at the later stage of the experiment regardless of the blast levels. The DPOAE was less damaged after G2 blasts compared to G1 when pre-blast liraglutide was administrated. Lower post-blast MLR amplitudes were observed in the pre-blast treatment groups. CONCLUSIONS: This study indicated that the liraglutide mitigated the blast-induced auditory injuries. In EP ears, the pre-blast administration of liraglutide reduced the severity of blast-induced acute damage in ears with EP protection, especially under G2. In animals with open ears, the effect of liraglutide on the restoration of hearing increased with time. The liraglutide potentially benefits post-blast hearing through multiple approaches with different mechanics.

Relationships between the expectations based on the regularity of preceding sound sequences and the medial olivocochlear reflex.

Rhythms are the most natural cue for temporal anticipation because many sounds in our living environment have rhythmic structures. Humans have cortical mechanisms that can predict the arrival of the next sound based on rhythm and periodicity. Herein, we showed that temporal anticipation, based on the regularity of sound sequences, modulates peripheral auditory responses via efferent innervation. The medial olivocochlear reflex (MOCR), a sound-activated efferent feedback mechanism that controls outer hair cell motility, was inferred noninvasively by measuring the suppression of otoacoustic emissions (OAE). First, OAE suppression was compared between conditions in which sound sequences preceding the MOCR elicitor were presented at regular (predictable condition) or irregular (unpredictable condition) intervals. We found that OAE suppression in the predictable condition was stronger than that in the unpredictable condition. This implies that the MOCR is strengthened by the regularity of preceding sound sequences. In addition, to examine how many regularly presented preceding sounds are required to enhance the MOCR, we compared OAE suppression within stimulus sequences with 0-3 preceding tones. The OAE suppression was strengthened only when there were at least three regular preceding tones. This suggests that the MOCR was not automatically enhanced by a single stimulus presented immediately before the MOCR elicitor, but rather that it was enhanced by the regularity of the preceding sound sequences.

The Origin Along the Cochlea of Otoacoustic Emissions Evoked by Mid-Frequency Tone Pips.

PURPOSE: Tone-pip-evoked otoacoustic emissions (PEOAEs) are transient-evoked otoacoustic emissions (OAEs) that are hypothesized to originate from reflection of energy near the best-frequency (BF) cochlear place of the stimulus frequency. However, individual PEOAEs have energy with a wide range of delays. We sought to determine whether some PEOAE energy is consistent with having been generated far from BF. METHODS: PEOAEs from 35 and 47 dB SPL tone pips were obtained by removing pip-stimulus energy by subtracting the ear-canal sound pressure from scaled-down 59 dB SPL tone pips (which evoke relatively small OAEs). PEOAE delays were measured at each peak in the PEOAE absolute-value waveforms. While measuring PEOAEs and auditory-nerve compound action potentials (CAPs), amplification was blocked sequentially from apex to base by cochlear salicylate perfusion. The perfusion time when a CAP was reduced identified when the perfusion reached the tone-pip BF place. The perfusion times when each PEOAE peak was reduced identified where along the cochlea it received cochlear amplification. PEOAEs and CAPs were measured simultaneously using one pip frequency in each ear (1.4 to 4 kHz across 16 ears). RESULTS: Most PEOAE peaks received amplification primarily between the BF place and 1-2 octaves basal of the BF place. PEOAE peaks with short delays received amplification basal of BF place. PEOAE peaks with longer delays sometimes received amplification apical of BF place, consistent with previous stimulus-frequency-OAE results. CONCLUSION: PEOAEs provide information about cochlear amplification primarily within ~ 1.5 octave of the tone-pip BF place, not about regions > 3 octaves basal of BF.

Exploring the Influence of Extended High-Frequency Hearing on Cochlear Functioning at Lower Frequencies.

PURPOSE: Diminished basal cochlear function, as indicated by elevated hearing thresholds in the extended high frequencies (EHFs), has been associated with lower levels of click-evoked and distortion-product otoacoustic emissions measured at lower frequencies. However, stimulus-frequency otoacoustic emissions (SFOAEs) at low-probe levels are reflection-source emissions that do not share the same generation mechanism as distortion-source emissions. The primary objective of the present study was to examine the influence of hearing thresholds in the EHFs on SFOAEs measured at lower frequencies. METHOD: SFOAEs were recorded from both ears in 45 individuals with normal hearing thresholds in the conventional audiometric frequencies (0.25-8 kHz). Hearing thresholds were also measured at EHFs (10, 12.5, and 16 kHz). SFOAE magnitudes and signal-to-noise ratios (SNRs) were averaged across 1, 2, and 4 kHz probe frequencies and also averaged for high-probe frequencies (2 and 4 kHz). RESULTS: SFOAE magnitudes and SNRs were significantly higher for ears with better EHF hearing relative to poorer EHF hearing, categorized based on the median split. In addition, hearing in the EHFs significantly contributed to the variance in all SFOAE measures, except for the high-frequency SFOAE magnitudes model. However, hearing thresholds at the probe frequencies did not significantly contribute to the variance in SFOAEs. CONCLUSIONS: The study findings suggest that alterations in the basal cochlea, as revealed by EHF hearing thresholds, could be associated with diminished cochlear functioning in relatively apical regions, shown by SFOAEs at lower frequencies, in individuals with normal audiograms. These findings underscore the significance of considering EHF thresholds in audiological evaluations, as alterations in these frequencies may reflect broader cochlear health status.

[Pulsed DPOAEs in serial measurements : Combined analysis paradigm of simultaneously occurring changes in hearing thresholds and DPOAEs. German version]. / Gepulste DPOAE in Verlaufsmessungen : Kombiniertes Analyseparadigma von gleichzeitig auftretenden Veränderungen in Hörschwellen und DPOAE.

BACKGROUND: To date, there is no consensus on how to standardize the assessment of ototoxicity in serial measurements. For the diagnosis of damage to the cochlear amplifier, measurement methods are required that have the highest possible test-retest reliability and validity for detecting persistent damage. Estimated distortion-product thresholds (LEDPT) based on short-pulse distortion-product otoacoustic emission (DPOAE) level maps use individually optimal DPOAE stimulus levels and allow reliable quantitative estimation of cochlea-related hearing loss. MATERIALS AND METHODS: Hearing thresholds were estimated objectively using LEDPT and subjectively using modified Békésy tracking audiometry (LTA). Recordings were performed seven times within three months at 14 frequencies (f2 = 1-14 kHz) in 20 ears (PTA4 (0.5-4 kHz) < 20 dB HL). Reconstruction of the DPOAE growth behavior as a function of the stimulus levels L1, L2 was performed on the basis of 21 DPOAE amplitudes. A numerical fit of a nonlinear mathematical function to the three-dimensional DPOAE growth function yielded LEDPT for each stimulus frequency. For the combined analysis, probability distributions of hearing thresholds (LTA, LEDPT), DPOAE levels (LDP), and combinations thereof were determined. RESULTS: LTA and LEDPT each exhibited a test-retest reliability with a median of absolute differences (AD) of 3.2 dB and 3.3 dB, respectively. Combining LEDPT, LDP, and LTA into a single parameter yielded a significantly smaller median AD of 2.0 dB. CONCLUSION: It is expected that an analysis paradigm based on a combination of LEDPT, suprathreshold LDP, and fine-structure-reduced LTA would achieve higher test performance (sensitivity and specificity), allowing reliable detection of pathological or regenerative changes in the outer hair cells.

Reliable Long-Term Serial Evaluation of Cochlear Function Using Pulsed Distortion-Product Otoacoustic Emissions: Analyzing Levels and Pressure Time Courses.

OBJECTIVES: To date, there is no international standard on how to use distortion-product otoacoustic emissions (DPOAEs) in serial measurements to accurately detect changes in the function of the cochlear amplifier due, for example, to ototoxic therapies, occupational noise, or the development of regenerative therapies. The use of clinically established standard DPOAE protocols for serial monitoring programs appears to be hampered by multiple factors, including probe placement and calibration effects, signal-processing complexities associated with multiple sites of emission generation as well as suboptimal selection of stimulus parameters. DESIGN: Pulsed DPOAEs were measured seven times within 3 months for f2 = 1 to 14 kHz and L2 = 25 to 80 dB SPL in 20 ears of 10 healthy participants with normal hearing (mean age = 32.1 ± 9.7 years). L1 values were computed from individual optimal-path parameters derived from the corresponding individual DPOAE level map in the first test session. Three different DPOAE metrics for evaluating the functional state of the cochlear amplifier were investigated with respect to their test-retest reliability: (1) the interference-free, nonlinear-distortion component level ( LOD ), (2) the time course of the DPOAE-envelope levels, LDP ( t ), and (3) the squared, zero-lag correlation coefficient ( ) between the time courses of the DPOAE-envelope pressures, pDP ( t ), measured in two sessions. The latter two metrics include the two main DPOAE components and their state of interference. RESULTS: Collated over all sessions and frequencies, the median absolute difference for LOD was 1.93 dB and for LDP ( t ) was 2.52 dB; the median of was 0.988. For the low ( f2 = 1 to 3 kHz), mid ( f2 = 4 to 9 kHz), and high ( f2 = 10 to 14 kHz) frequency ranges, the test-retest reliability of LOD increased with increasing signal to noise ratio (SNR). CONCLUSIONS: On the basis of the knowledge gained from this study on the test-retest reliability of pulsed DPOAE signals and the current literature, we propose a DPOAE protocol for future serial monitoring applications that takes into account the following factors: (1) separation of DPOAE components, (2) use of individually optimal stimulus parameters, (3) SNR of at least 15 dB, (4) accurate pressure calibration, (5) consideration of frequency- and level-dependent test-retest reliabilities and corresponding reference ranges, and (6) stimulus levels L2 that are as low as possible with sufficient SNR to capture the nonlinear functional state of the cochlear amplifier operating at its highest gain.

Something in Our Ears Is Oscillating, but What? A Modeller's View of Efforts to Model Spontaneous Emissions.

When David Kemp discovered "spontaneous ear noise" in 1978, it opened up a whole new perspective on how the cochlea works. The continuous tonal sound emerging from most healthy human ears, now called spontaneous otoacoustic emissions or SOAEs, was an unmistakable sign that our hearing organ must be considered an active detector, not just a passive microphone, just as Thomas Gold had speculated some 30 years earlier. Clearly, something is oscillating as a byproduct of that sensitive inbuilt detector, but what exactly is it? Here, we give a chronological account of efforts to model SOAEs as some form of oscillator, and at intervals, we illustrate key concepts with numerical simulations. We find that after many decades there is still no consensus, and the debate extends to whether the oscillator is local, confined to discrete local sources on the basilar membrane, or global, in which an assembly of micro-mechanical elements and basilar membrane sections, coupled by inner ear fluid, interact over a wide region. It is also undecided whether the cochlear oscillator is best described in terms of the well-known Van der Pol oscillator or the less familiar Duffing or Hopf oscillators. We find that irregularities play a key role in generating the emissions. This paper is not a systematic review of SOAEs and their properties but more a historical survey of the way in which various oscillator configurations have been applied to modelling human ears. The conclusion is that the difference between the local and global approaches is not clear-cut, and they are probably not mutually exclusive concepts. Nevertheless, when one sees how closely human SOAEs can be matched to certain arrangements of oscillators, Gold would no doubt say we are on the right track.

Conditions Underlying the Appearance of Spontaneous Otoacoustic Emissions in Mammals.

Across the wide range of land vertebrate species, spontaneous otoacoustic emissions (SOAE) are common, but not always found. The reasons for the differences between species of the various groups in their emission patterns are often not well understood, particularly within mammals. This review examines the question as to what determines in mammals whether SOAE are emitted or not, and suggests that the coupling between hair-cell regions diminishes when the space constant of frequency distribution becomes larger. The reduced coupling is assumed to result in a greater likelihood of SOAE being emitted.

Optimal Scale-Invariant Wavelet Representation and Filtering of Human Otoacoustic Emissions.

Otoacoustic emissions (OAEs) are generated in the cochlea and recorded in the ear canal either as a time domain waveform or as a collection of complex responses to tones in the frequency domain (Probst et al. J Account Soc Am 89:2027-2067, 1991). They are typically represented either in their original acquisition domain or in its Fourier-conjugated domain. Round-trip excursions to the conjugated domain are often used to perform filtering operations in the computationally simplest way, exploiting the convolution theorem. OAE signals consist of the superposition of backward waves generated in different cochlear regions by different generation mechanisms, over a wide frequency range. The cochlear scaling symmetry (cochlear physics is the same at all frequency scales), which approximately holds in the human cochlea, leaves its fingerprints in the mathematical properties of OAE signals. According to a generally accepted taxonomy (Sher and Guinan Jr, J Acoust Soc Am 105:782-798, 1999), OAEs are generated either by wave-fixed sources, moving with frequency according with the cochlear scaling (as in nonlinear distortion) or by place-fixed sources (as in coherent reflection by roughness). If scaling symmetry holds, the two generation mechanisms yield OAEs with different phase gradient delay: almost null for wave-fixed sources, and long (and scaling as 1/f) for place-fixed sources. Thus, the most effective representation of OAE signals is often that respecting the cochlear scale-invariance, such as the time-frequency domain representation provided by the wavelet transform. In the time-frequency domain, the elaborate spectra or waveforms yielded by the superposition of OAE components from different generation mechanisms assume a much clearer 2-D pattern, with each component localized in a specific and predictable region. The wavelet representation of OAE signals is optimal both for visualization purposes and for designing filters that effectively separate different OAE components, improving both the specificity and the sensitivity of OAE-based applications. Indeed, different OAE components have different physiological meanings, and filtering dramatically improves the signal-to-noise ratio.

Covid-19 infection in pregnant women: Auditory evaluation in infants.

 Recent studies showed that COVID-19 infection can affect cochleo-vestibular system. The possibility of a vertical transmission is controversial. Some studies suggested that it is possible but unlikely, others find no evidence of vertical transmission. The objective of this study was to investigate whether exposure to COVID-19 during pregnancy or at birth has an impact on the hearing of the offspring. As part of the national hearing screening program, we performed in all newborns between January 2022 and February 2023, TEOAEs (Transient Evoked Otoacoustic Emissions) at birth and at 3 months. For those "REFER" at the third month test, we performed aABR (Automatic Auditory Brainstem Response) at 6 months. We analysed separately result between infants born to COVID-positive mothers during pregnancy and those born to COVID-negative mothers. To statistical verify differences we performed "Chi-square test". We enrolled a total of 157 infants, of whom 16 were born to mothers who had a molecular PCR test positive for COVID-19. In the latter we tested a total of 32 ears and only 1 ear (3,1%) resulted "REFER". On the other hand, in the control group we tested a total of 282 ears and 22 (7,8%) were found to be "REFER". Our study showed no significant differences in audiological assessment between newborns exposed to COVID-19 infection during pregnancy or at birth compared to the unexposed group. However, further studies with a larger patient's sample will be necessary for a more comprehensive evaluation.

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

OBJECTIVE: 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. STUDY DESIGN: Prospective. SETTING: Single Tertiary Care Center. METHODS: 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. RESULTS: 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.

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.

BACKGROUND: 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). METHODS: 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. RESULTS: 60 patients were enrolled and completed PTA and DPOAEs. 32 patients with hearing impairment (HI), assessed by PTA, (hearing threshold ≥ 25 dB) 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. CONCLUSION: 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.

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

OBJECTIVE: To investigate the audiological characteristics of vestibular schwannoma (VS) patients with normal pure-tone audiometry (PTA) results. STUDY DESIGN: A retrospective study. SETTING: Forty-two VS patients with normal PTA results from October 2016 to October 2022 were included. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The influence of tympanic-membrane orientation on acoustic ear-canal quantities: A finite-element analysis.

Assuming plane waves, ear-canal acoustic quantities, collectively known as wideband acoustic immittance (WAI), are frequently used in research and in the clinic to assess the conductive status of the middle ear. Secondary applications include compensating for the ear-canal acoustics when delivering stimuli to the ear and measuring otoacoustic emissions. However, the ear canal is inherently non-uniform and terminated at an oblique angle by the conical-shaped tympanic membrane (TM), thus potentially confounding the ability of WAI quantities in characterizing the middle-ear status. This paper studies the isolated possible confounding effects of TM orientation and shape on characterizing the middle ear using WAI in human ears. That is, the non-uniform geometry of the ear canal is not considered except for that resulting from the TM orientation and shape. This is achieved using finite-element models of uniform ear canals terminated by both lumped-element and finite-element middle-ear models. In addition, the effects on stimulation and reverse-transmission quantities are investigated, including the physical significance of quantities seeking to approximate the sound pressure at the TM. The results show a relatively small effect of the TM orientation on WAI quantities, except for a distinct delay above 10 kHz, further affecting some stimulation and reverse-transmission quantities.

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.

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.

[Study on gene therapy for DPOAE and ABR threshold changes in adult Otof-/- mice].

Objective:This study aims to analyze the threshold changes in distortion product otoacoustic emissions（DPOAE） and auditory brainstem response（ABR） in adult Otof-/- mice before and after gene therapy, evaluating its effectiveness and exploring methods for assessing hearing recovery post-treatment. Methods:At the age of 4 weeks, adult Otof-/- mice received an inner ear injection of a therapeutic agent containing intein-mediated recombination of the OTOF gene, delivered via dual AAV vectors through the round window membrane（RWM）. Immunofluorescence staining assessed the proportion of inner ear hair cells with restored otoferlin expression and the number of synapses.Statistical analysis was performed to compare the DPOAE and ABR thresholds before and after the treatment. Results:AAV-PHP. eB demonstrates high transduction efficiency in inner ear hair cells. The therapeutic regimen corrected hearing loss in adult Otof-/- mice without impacting auditory function in wild-type mice. The changes in DPOAE and ABR thresholds after gene therapy are significantly correlated at 16 kHz. Post-treatment,a slight increase in DPOAE was observeds,followed by a recovery trend at 2 months post-treatment. Conclusion:Gene therapy significantly restored hearing in adult Otof-/- mice, though the surgical delivery may cause transient hearing damage. Precise and gentle surgical techniques are essential to maximize gene therapy's efficacy.

Swept Along: Measuring Otoacoustic Emissions Using Continuously Varying Stimuli.

At the 2004 Midwinter Meeting of the Association for Research in Otolaryngology, Glenis Long and her colleagues introduced a method for measuring distortion-product otoacoustic emissions (DPOAEs) using primary-tone stimuli whose instantaneous frequencies vary continuously with time. In contrast to standard OAE measurement methods, in which emissions are measured in the sinusoidal steady state using discrete tones of well-defined frequency, the swept-tone method sweeps across frequency, often at rates exceeding 1 oct/s. The resulting response waveforms are then analyzed using an appropriate filter (e.g., by least-squares fitting). Although introduced as a convenient way of studying DPOAE fine structure by separating the total OAE into distortion and reflection components, the swept-tone method has since been extended to stimulus-frequency emissions and has proved an efficient and valuable tool for probing cochlear mechanics. One day-a long time coming-swept tones may even find their way into the audiology clinic.

Occupational Lead Exposure Ototoxicity Evaluated With Distortion-Product Otoacoustic Emissions.

OBJECTIVES: To evaluate the extent of hearing loss among pottery workers in Mexico exposed to lead. DESIGN: The authors conducted a cross-sectional study including 315 adult pottery workers. Auditory function was evaluated by air conduction pure-tone audiometry (pure-tone average) and distortion-product otoacoustic emission (DPOAE) levels (amplitude and signal-to-noise ratio). Lead exposure was assessed with a single blood sample test and classified as low, medium, and high according to blood lead tertiles. Logistic regression models were calculated for the association between blood lead levels, pure-tone average, and DPOAE records. RESULTS: Median (25th-75th) blood lead levels were 14 µg/dL (7.5-22.6 µg/dL). The audiometric pattern and DPOAE records were similar across blood lead levels groups in all frequencies, and no statistically significant differences were found. Adjusted logistic regression models showed no increase in the odds for hearing thresholds >25 dB (HL) and DPOAE absence associated with blood lead levels, and no dose-response pattern was observed ( p > 0.05). CONCLUSIONS: Given the results from this cross-sectional study, no association was found between blood lead levels and hearing loss assessed with DPOAE. Future longitudinal work should consider chronic lead exposure estimates among underrepresented populations, which can potentially inform safer work practices to minimize the risk of ototoxicity.

A Clinically Viable Medial Olivocochlear Reflex Assay Using Transient-Evoked Otoacoustic Emissions.

OBJECTIVES: The contralateral medial olivocochlear reflex (MOCR) strength may indicate various auditory conditions in humans, but a clinically viable assay and equipment are needed for quick, accurate, and reliable measurements. The first experiment compared an earlier version of the assay, which used a nonlinear-mode chirp stimulus, with a new assay using a linear-mode click stimulus, designed to give reliable MOCR measurements in most normal-hearing ears. The second experiment extended the improved assay on a purpose-built binaural hardware platform that used forward-pressure level (FPL) calibration for both the stimulus and the contralateral MOCR elicitor. DESIGN: Transient-evoked otoacoustic emission (TEOAE) tests were measured with and without a 60-dB SPL MOCR-evoking contralateral broadband noise. The normalized MOCR strength (MOCR%) was derived from the TEOAE responses for each trial pair using the complex pressure difference weighted by the TEOAE magnitude. Experiment 1 compared MOCR% within-subject and across-day using two TEOAE stimuli: nonlinear-mode chirps (50 dB SPL, bandpass 1-5 kHz, 14 ms window delayed by 2 ms) and linear-mode clicks (50 dB SPL, bandpass 0.5-2.5 kHz, 13 ms window delayed by 5 ms). TEOAE responses were analyzed in the 0.5 to 2.5 kHz band. Thirty adult participants with normal hearing (30 ears) completed the study. The TEOAE stimulus was calibrated in situ using spectral flattening, and the contralateral noise was calibrated in a coupler. Twelve TEOAE trial pairs were collected for each participant and condition. Experiment 2 used a purpose-built binaural system. The TEOAE stimuli were linear-mode clicks (50 dB SPL, bandpass 1-3 kHz, 13 ms window delayed by 5 ms), analyzed in the 1 to 3 kHz band over ~12 trial pairs. After a probe refit, an additional trial pair was collected for the two early-stopping signal-to-noise ratio criteria (15 and 20 dB). They were evaluated for single-trial reliability and test time. Nineteen adult participants with normal hearing (38 ears) completed the study. The TEOAE clicks and contralateral elicitor noise were calibrated in situ using FPL and delivered with automated timing. RESULTS: MOCR% for linear-mode clicks was distinguishable from measurement variability in 98% to 100% of participants' ears (both experiments), compared with only 73% for the nonlinear-mode chirp (experiment 1). MOCR detectability was assessed using the MOCR% across-subject/within-subject variance ratio. The ratio in experiment 1 for linear-mode clicks was higher (8.0) than for nonlinear-mode chirps (6.4). The ratio for linear-mode clicks (8.9) in experiment 2 was slightly higher than for the comparable linear-mode stimulus (8.0) in experiment 1. TEOAEs showed excellent reliability with high signal-to-noise ratios in both experiments, but reliability was higher for linear-mode clicks than nonlinear-mode chirps. MOCR reliability for the two stimuli was comparable. The FPL pressure response retest reliability derived from the SPL at the microphone was higher than the SPL retest reliability across 0.4 to 8 kHz. Stable results required 2 to 3 trial pairs for the linear-mode click (experiments 1 and 2) and three for the nonlinear-mode chirp (experiment 1), taking around 2 min on average. CONCLUSIONS: The linear-mode click assay produced measurable, reliable, and stable TEOAE and MOCR results on both hardware platforms in around 2 min per ear. The stimulus design and response window ensured that any stimulus artifact in linear mode was unlikely to confound the results. The refined assay is ready to produce high-quality data quickly for clinical and field studies to develop population norms, recognize diagnostic patterns, and determine risk profiles.