Psychometric Validation of a Hearing Screening Questionnaire for Preschoolers based on language development evaluation by caregivers.

INTRODUCTION: This study aimed to validate three age-adjusted versions of a Hearing Screening Questionnaire for Preschoolers, in Brazilian Portuguese, based on parents' perception of their children's hearing and oral language. METHODS: Psychometric validation was conducted on three questionnaires, each comprising nine items with Yes/No responses. Three items focused on hearing screening at birth, and six assessed hearing and oral language. The study included 152 parents and their children, who attended day care centers in Belo Horizonte, Brazil. The children were categorized into three age bands: 12 to 18 months, 19 to 35 months, and 36 to 48 months. Audiological assessments, including tympanometry, transient-evoked otoacoustic emissions (TOAE) and pure-tone audiometry (when applicable), were performed on the children. In case of abnormal findings in the previous exams, auditory brainstem response (ABR) testing was conducted. Descriptive data, false alarm, and false-negative analyses were carried out. RESULTS: Considering any type of hearing loss, whether unilateral or bilateral, the questionnaires showed a false-negative rate of 41.17% (7/17 children). However, when considering only bilateral hearing loss, the questionnaire showed a false alarm rate of 31.69% (45/142) and a false-negative rate of 30.0% (3/10). When focusing exclusively on sensorineural hearing loss, the questionnaire identified two children (1.31%), with a false-negative rate of 0% but a false-positive rate of 33.33%. CONCLUSION: Language-development oriented questionnaires allowed quick screening of potential hearing loss in preschoolers. This study found a robust hit rate with these questionnaires. Their validation signifies a promising and cost-effective tool for conducting hearing screenings in preschool children, especially in nations lacking a comprehensive school screening policy.The validated questionnaire affords an easy-to-apply, low-cost and effective instrument for preschool hearing screening.

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.

Preserved Auditory Steady State Response and Envelope-Following Response in Severe Brainstem Dysfunction Highlight the Need for Cross-Checking.

OBJECTIVES: Commercially available auditory steady state response (ASSR) systems are widely used to obtain hearing thresholds in the pediatric population objectively. Children are often examined during natural or induced sleep so that the recorded ASSRs are of subcortical origin, the inferior colliculus being often designated as the main ASSR contributor in these conditions. This report presents data from a battery of auditory neurophysiological objective tests obtained in 3 cases of severe brainstem dysfunction in sleeping children. In addition to ASSRs, envelope-following response (EFR) recordings designed to distinguish peripheral (cochlear nerve) from central (brainstem) were recorded to document the effect of brainstem dysfunction on the two types of phase-locked responses. DESIGN: Results obtained in the 3 children with severe brainstem dysfunctions were compared with those of age-matched controls. The cases were identified as posterior fossa tumor, undiagnosed (UD), and Pelizaeus-Merzbacher-Like Disease. The standard audiological objective tests comprised tympanograms, distortion product otoacoustic emissions, click-evoked auditory brainstem responses (ABRs), and ASSRs. EFRs were recorded using horizontal (EFR-H) and vertical (EFR-V) channels and a stimulus phase rotation technique allowing isolation of the EFR waveforms in the time domain to obtain direct latency measurements. RESULTS: The brainstem dysfunctions of the 3 children were revealed as abnormal (weak, absent, or delayed) ABRs central waves with a normal wave I. In addition, they all presented a summating and cochlear microphonic potential in their ABRs, coupled with a normal wave I, which implies normal cochlear and cochlear nerve function. EFR-H and EFR-V waveforms were identified in the two cases in whom they were recorded. The EFR-Hs onset latencies, response durations, and phase-locking values did not differ from their respective age-matched control values, indicating normal cochlear nerve EFRs. In contrast, the EFR-V phase-locking value and onset latency varied from their control values. Both patients had abnormal but identifiable and significantly phase-locked brainstem EFRs, even in a case with severely distorted ABR central waves. ASSR objective audiograms were recorded in two cases. They showed normal or slightly elevated (explained by a slight transmission loss) thresholds that do not yield any clue about their brainstem dysfunction, revealing the method's lack of sensitivity to severe brainstem dysfunction. CONCLUSIONS: The present study, performed on 3 sleeping children with severe brainstem dysfunction but normal cochlear responses (cochlear microphonic potential, summating potential, and ABR wave I), revealed the differential sensitivity of three auditory electrophysiological techniques. Estimated thresholds obtained by standard ASSR recordings (cases UD and Pelizaeus-Merzbacher-Like Disease) provided no clue to the brainstem dysfunction clearly revealed by the click-evoked ABR. EFR recordings (cases posterior fossa tumor and UD) showed preserved central responses with abnormal latencies and low phase-locking values, whereas the peripheral EFR attributed to the cochlear nerve was normal. The one case (UD) for which the three techniques could be performed confirms this sensitivity gradient, emphasizing the need for applying the Cross-Check Principle by avoiding resorting to ASSR recording alone. The entirely normal EFR-H recordings observed in two cases further strengthen the hypothesis of its cochlear nerve origin in sleeping children.

Prevalence of hearing loss and health vulnerability in children aged 25 to 36 months: an analysis of spatial distribution. / Prevalência de perda auditiva e vulnerabilidade a saúde em crianças de 25 a 36 meses: uma análise da distribuição espacial.

PURPOSE: To analyze the association between hearing loss and health vulnerability in children aged 25 to 36 months. METHODS: Analytical observational cross-sectional study conducted through child hearing screening in nine day-care centers. The screening consisted of anamnesis, otoscopy, tympanometry, transient otoacoustic emissions, and pure tone audiometry. For each exam performed, the 'pass' and 'fail' criteria were established. The children's residential addresses were georeferenced and a choropleth map of the spatial distribution was built, considering the Health Vulnerability Index (HVI). The analysis of the association between the HVI and the variables sex, auditory assessment, and region area of the household was performed using Pearson's Chi-square and Fisher's Exact tests. RESULTS: Ninety-five children of both sexes were evaluated, of which 44.7% presented alterations in at least one of the exams performed, being referred for otorhinolaryngological evaluation and subsequent auditory assessment. Of the observed changes, 36.9% occurred in the tympanometry and 7.8% in the transient otoacoustic emissions. Among children referred for reassessment, 9.7% were diagnosed with conductive hearing loss, 13.6% results within normal limits and 21.4% did not attend for assessment. Of the children who presented the final diagnosis of conductive hearing loss (9.7%), 1.9% were classified as low-risk HVI and 6.8% as medium-risk HVI. There was statistical significance between HVI and the child's place of residence. CONCLUSION: The association between hearing loss and HIV was not statistically significant; however, it was possible to observe that 77.7% of the children with hearing loss resided in sectors with medium- risk HIV.

OBJETIVO: Analisar a associação entre perda auditiva e a vulnerabilidade à saúde em crianças na faixa etária de 25 a 36 meses. MÉTODO: Estudo observacional analítico do tipo transversal realizado por meio da triagem auditiva infantil em nove creches. A triagem constou de anamnese, meatoscopia, timpanometria, emissões otoacústicas transientes e audiometria tonal limiar. Para cada exame realizado foi estabelecido o critério de "passa" e "falha". Os endereços residenciais das crianças foram georreferenciados e foi construído mapa coroplético da distribuição espacial, considerando o Índice de Vulnerabilidade à Saúde (IVS). Foi realizada análise de associação entre o IVS com as variáveis sexo, exames audiológicos e regional de domicílio por meio dos testes Qui-quadrado de Pearson, e Exato de Fisher. RESULTADOS: Foram avaliadas 95 crianças de ambos os sexos, destas, 44,7% apresentaram alteração em pelo menos um dos exames realizados, sendo encaminhadas para avaliação otorrinolaringológica e auditiva. Das alterações observadas 36,9% ocorreram na timpanometria e 7,8% nas emissões otoacústicas transientes. Dentre crianças encaminhadas para avaliação, 9,7% apresentaram diagnóstico de perda auditiva do tipo condutiva, 13,6% resultados dentro da normalidade e 21,4% não compareceram para reavaliação. Das crianças que apresentaram o diagnóstico final de perda auditiva do tipo condutiva (9,7%), 1,9% foi classificado como IVS de risco baixo e 6,8% como IVS de risco médio. Houve significância estatística entre IVS e o local de residência da criança. CONCLUSÃO: Não houve associação com significância estatística entre alteração auditiva e IVS, entretanto foi possível observar que 77,7% das crianças com diagnóstico de perda auditiva residiam em setores censitários de risco médio do IVS.

Prevalência de perda auditiva e vulnerabilidade a saúde em crianças de 25 a 36 meses: uma análise da distribuição espacial / Prevalence of hearing loss and health vulnerability in children aged 25 to 36 months: an analysis of spatial distribution

RESUMO Objetivo Analisar a associação entre perda auditiva e a vulnerabilidade à saúde em crianças na faixa etária de 25 a 36 meses. Método Estudo observacional analítico do tipo transversal realizado por meio da triagem auditiva infantil em nove creches. A triagem constou de anamnese, meatoscopia, timpanometria, emissões otoacústicas transientes e audiometria tonal limiar. Para cada exame realizado foi estabelecido o critério de "passa" e "falha". Os endereços residenciais das crianças foram georreferenciados e foi construído mapa coroplético da distribuição espacial, considerando o Índice de Vulnerabilidade à Saúde (IVS). Foi realizada análise de associação entre o IVS com as variáveis sexo, exames audiológicos e regional de domicílio por meio dos testes Qui-quadrado de Pearson, e Exato de Fisher. Resultados Foram avaliadas 95 crianças de ambos os sexos, destas, 44,7% apresentaram alteração em pelo menos um dos exames realizados, sendo encaminhadas para avaliação otorrinolaringológica e auditiva. Das alterações observadas 36,9% ocorreram na timpanometria e 7,8% nas emissões otoacústicas transientes. Dentre crianças encaminhadas para avaliação, 9,7% apresentaram diagnóstico de perda auditiva do tipo condutiva, 13,6% resultados dentro da normalidade e 21,4% não compareceram para reavaliação. Das crianças que apresentaram o diagnóstico final de perda auditiva do tipo condutiva (9,7%), 1,9% foi classificado como IVS de risco baixo e 6,8% como IVS de risco médio. Houve significância estatística entre IVS e o local de residência da criança. Conclusão Não houve associação com significância estatística entre alteração auditiva e IVS, entretanto foi possível observar que 77,7% das crianças com diagnóstico de perda auditiva residiam em setores censitários de risco médio do IVS.

ABSTRACT Purpose To analyze the association between hearing loss and health vulnerability in children aged 25 to 36 months. Methods Analytical observational cross-sectional study conducted through child hearing screening in nine day-care centers. The screening consisted of anamnesis, otoscopy, tympanometry, transient otoacoustic emissions, and pure tone audiometry. For each exam performed, the 'pass' and 'fail' criteria were established. The children's residential addresses were georeferenced and a choropleth map of the spatial distribution was built, considering the Health Vulnerability Index (HVI). The analysis of the association between the HVI and the variables sex, auditory assessment, and region area of the household was performed using Pearson's Chi-square and Fisher's Exact tests. Results Ninety-five children of both sexes were evaluated, of which 44.7% presented alterations in at least one of the exams performed, being referred for otorhinolaryngological evaluation and subsequent auditory assessment. Of the observed changes, 36.9% occurred in the tympanometry and 7.8% in the transient otoacoustic emissions. Among children referred for reassessment, 9.7% were diagnosed with conductive hearing loss, 13.6% results within normal limits and 21.4% did not attend for assessment. Of the children who presented the final diagnosis of conductive hearing loss (9.7%), 1.9% were classified as low-risk HVI and 6.8% as medium-risk HVI. There was statistical significance between HVI and the child's place of residence. Conclusion The association between hearing loss and HIV was not statistically significant; however, it was possible to observe that 77.7% of the children with hearing loss resided in sectors with medium- risk HIV

The SNARE protein SNAP-25 is required for normal exocytosis at auditory hair cell ribbon synapses.

Hearing depends on fast and sustained calcium-dependent synaptic vesicle fusion at the ribbon synapses of cochlear inner hair cells (IHCs). The implication of the canonical neuronal SNARE complex in this exocytotic process has so far remained controversial. We investigated the role of SNAP-25, a key component of this complex, in hearing, by generating and analyzing a conditional knockout mouse model allowing a targeted postnatal deletion of Snap-25 in IHCs. Mice subjected to IHC Snap-25 inactivation after hearing onset developed severe to profound deafness because of defective IHC exocytosis followed by ribbon degeneration and IHC loss. Viral transfer of Snap-25 in these mutant mice rescued their hearing function by restoring IHC exocytosis and preventing synapses and hair cells from degeneration. These results demonstrate that SNAP-25 is essential for normal hearing function, most likely by ensuring IHC exocytosis and ribbon synapse maintenance.

NOS1 mutations cause hypogonadotropic hypogonadism with sensory and cognitive deficits that can be reversed in infantile mice.

The nitric oxide (NO) signaling pathway in hypothalamic neurons plays a key role in the regulation of the secretion of gonadotropin-releasing hormone (GnRH), which is crucial for reproduction. We hypothesized that a disruption of neuronal NO synthase (NOS1) activity underlies some forms of hypogonadotropic hypogonadism. Whole-exome sequencing was performed on a cohort of 341 probands with congenital hypogonadotropic hypogonadism to identify ultrarare variants in NOS1. The activity of the identified NOS1 mutant proteins was assessed by their ability to promote nitrite and cGMP production in vitro. In addition, physiological and pharmacological characterization was carried out in a Nos1-deficient mouse model. We identified five heterozygous NOS1 loss-of-function mutations in six probands with congenital hypogonadotropic hypogonadism (2%), who displayed additional phenotypes including anosmia, hearing loss, and intellectual disability. NOS1 was found to be transiently expressed by GnRH neurons in the nose of both humans and mice, and Nos1 deficiency in mice resulted in dose-dependent defects in sexual maturation as well as in olfaction, hearing, and cognition. The pharmacological inhibition of NO production in postnatal mice revealed a critical time window during which Nos1 activity shaped minipuberty and sexual maturation. Inhaled NO treatment at minipuberty rescued both reproductive and behavioral phenotypes in Nos1-deficient mice. In summary, lack of NOS1 activity led to GnRH deficiency associated with sensory and intellectual comorbidities in humans and mice. NO treatment during minipuberty reversed deficits in sexual maturation, olfaction, and cognition in Nos1 mutant mice, suggesting a potential therapy for humans with NO deficiency.

Impaired auditory neural performance, another dimension of hearing loss in type-2 diabetes mellitus.

AIM: To evaluate auditory performance in subjects with poorly controlled type-2 diabetes mellitus, using a simple test battery assessing sensitivity to pure tones and neuronal function. METHODS: Enrolled subjects, aged between 23 and 79 years, reported several auditory dysfunctions. They were tested using pure-tone audiometry, otoacoustic emissions for cochlear-function evaluation, and measurement of middle-ear muscle-reflex thresholds in search of an auditory neuropathy. RESULTS: Compared to the standard established for an age-matched normative population, the distribution of averaged pure-tone thresholds in enrolled subjects shifted by about one standard deviation with respect to the normal distribution, in line with past reports of mild sensorineural hearing impairment in diabetes, even though many diabetic subjects fell well within the normative interval of audiometric thresholds. Otoacoustic emissions showed that pure-tone thresholds correctly predicted the status of cochlear sensory cells that, by amplifying sound, ensure normal hearing sensitivity. Whereas the observed hearing losses should not have affected the acoustic levels above which the protective middle-ear muscle reflex is triggered by intense sounds, this reflex was undetectable in around 40% enrolled subjects, a marker of auditory neuropathy. CONCLUSION: Auditory-neural function should be evaluated to identify diabetic subjects whose hearing is impaired. Simple automatic tests are available for this purpose, for example middle-ear muscle reflex detection, which turns out to be more sensitive than the standard audiogram.

Wideband tympanometry patterns in relation to intracranial pressure.

Wideband tympanometry performs a more thorough analysis of middle-ear mechanics than the conventional single-frequency method with a 226-Hz probe tone. The present work examines the sensitivity of wideband tympanometry to the stiffness of the stapes-annular ligament system in relation to intracranial pressure (ICP) and labyrinthine fluid pressure. Here, body tilt allowed ICP to be set at different values. Sixty-eight ears of volunteers were tested sequentially in upright, supine, head-down (-30°) and upright postures. Energy absorbance of the ear was measured in these postures with a commercially available wideband-tympanometry device between 0.25 and 3 kHz, at ear-canal pressures between -600 and 300 daPa. In each posture, it was possible to find a single (posture-dependent) pressure in the ear canal at which a tympanometric peak occurred at all frequencies below about 1.1 kHz. The average across ears of tympanometric-peak pressure (TPP), close to 0 in upright posture, got increasingly positive, +19 daPa in supine and +27 daPa in head-down positions. The three-dimensional plot of energy absorbance against frequency and pressure displayed an invariant shape, merely shifting with TPP along the pressure axis. Thus, a properly adjusted ear-canal pressure neutralized the effects of ICP on the ear's energy absorbance. Comparisons to published invasive assessments of ICP in the different tested body positions led to the proposed relationship ICP ≈ 15 TPP, likely describing the transformer effect between tympanic membrane and stapes-annular ligament system at quasi-static pressures. With wideband tympanometry, the middle ear may serve as a precision scales for noninvasive ICP measurements.

Decreased Reemerging Auditory Brainstem Responses Under Ipsilateral Broadband Masking as a Marker of Noise-Induced Cochlear Synaptopathy.

OBJECTIVES: In mammals, a 2-hr exposure to an octave-band noise (OBN) at 100 to 108 dB SPL induces loss of synaptic ribbons between inner hair cells and auditory nerve fibers with high thresholds of response (hiT neurons), that encode high-intensity sounds. Here, we tackle the challenge of diagnosing this synaptopathy by a noninvasive functional audiological test, ultimately in humans, despite the expected absence of auditory-threshold elevation and of clear electrophysiological abnormality, hiT neuron contributions being hidden by those of more sensitive and robust neurons. DESIGN: The noise-induced synaptopathy was replicated in mice (at 94, 97, and 100 dB SPL; n = 7, 7, and 8, respectively, against 8 unexposed controls), without long-lasting auditory-threshold elevation despite a twofold decrease in ribbon-synapse number for the 100-dB OBN exposure. Auditory brainstem responses (ABRs) were collected using a simultaneous broadband noise masker just able to erase the ABR response to a 60-dB tone burst. Tone burst intensity was then increased up to 100 dB SPL for eliciting reemerging ABRs (R-ABRs), dependent on hiT neurons as more sensitive neurons are masked. RESULTS: In most ears exposed to 97-dB-SPL and all ears exposed to 100-dB-SPL OBN, contrary to controls, R-ABRs from the overexposed region have vanished, whereas standard ABR distributions widely overlap. CONCLUSIONS: R-ABRs afford an individual noninvasive marker of normal-auditory-threshold cochlear synaptopathy. A simple modification of standard ABRs would allow hidden auditory synaptopathy to be searched in a patient. ABBREVIATIONS: ABR: auditory brainstem response; dB SPL: decibel sound pressure level; DPOAE: distortion-product otoacoustic emission; hiT neuron: high-threshold neuron; IHC: inner hair cell; loT neuron: low-threshold neuron; OBN: octave-band noise; OHC: outer hair cell; PBS: phosphate buffer saline; R-ABR: reemerging ABR.

Meniere's attack - a volume or pressure phenomenon?

Meniere's disease (MD) still raises since its discovery in 1860 pathophysiological and etiopathogenical issues. The main pathophysiological feature that has emerged for decades is an anatomic one, the endolymphatic hydrops (EH), defined by the inflation of the endolymphatic part of the membranous labyrinth. However, the causal relationship between EH and MD has not been proven.Several attempts have been achieved in animals to induce EH. The best known is the blockage of the vestibular duct, which causes a chronic volume inflation of the endolymphatic part. This model is characterized by the discrepancy between electrophysiological findings and scala media inflation. Pressure measurements vary among studies.The endolymphatic infusion model, which attempts to model the acute clinical picture of MD consistently shows pressure equilibration between the endolymphatic and perilymphatic compartments, and rapid recovery of the electrophysiological finding once the injection is stopped.

Auditory biophysics of endolymphatic hydrops.

Audiological tests in patients with Menière's disease reveal abnormal patterns relevant for diagnostic purposes with some success. Electrocochleography, otoacoustic emissions and immittance measurements share a moderate sensitivity but a good specificity. Their potential for monitoring the patients suggests means to understand the characteristic time course of Menière's disease and the pathophysiology behind its attacks. Besides, magnetic resonance imaging now allows direct evaluation of endolymphatic hydrops. One issue is now to understand the links between volume inflation of endolymphatic spaces, which sometimes remains asymptomatic, and the functional signs, in the hope that a better understanding of what triggers the attacks may guide future treatments. This article provides a short review of the possible biophysical significance of audiological tests of Menière's disease, and of the attempts to make sense of functional and imaging data and of the patterns they form when combined.

Subcortical neural generators of the envelope-following response in sleeping children: A transfer function analysis.

Multiple auditory structures, from cochlea to cortex, phase-lock to the envelope of complex stimuli. The relative contributions of these structures to the human surface-recorded envelope-following response (EFR) are still uncertain. Identification of the active contributor(s) is complicated by the fact that even the simplest two-tone (f1&f2) stimulus, targeting its (f2-f1) envelope, evokes additional linear (f1&f2) and non-linear (2f1-f2) phase-locked components as well as a transient auditory brainstem response (ABR). Here, we took advantage of the generalized primary tone phase variation method to isolate each predictable component in the time domain, allowing direct measurements of onset latency, duration and phase discontinuity values from which the involved generators were inferred. Targeting several envelope frequencies (0.22-1 kHz), we derived the EFR transfer functions along a vertical vertex-to-neck and a horizontal earlobe-to-earlobe recording channels, yielding respectively EFR-V and EFR-H waveforms. Subjects (N= 30) were sleeping children with normal electrophysiological thresholds and normal oto-acoustic emissions. Both EFR-H and EFR-V phase-locking values (PLV) transfer functions had a low-pass profile, EFR-V showing a lower cut-off frequency than EFR-H. We also computed the frequency-latency relationships of both EFRs onset latencies. EFR-H data fitted a power-law function incorporating a frequency-dependent traveling wave delay and a fixed one amounting to 1.2 ms. The fitted function nicely fell within five published estimations of the latency-frequency function of the ABR wave-I, thus pointing to a cochlear nerve origin. The absence of phase discontinuity and overall response durations that were equal to that of the stimulus indicated no contribution from a later generator. The recording of an entirely similar EFR-H response in a patient who had severe brainstem encephalitis with a normal, isolated, ABR wave-I but complete absence of later waves, further substantiated a cochlear nerve origin. Modeling of the EFR-V latency-frequency functions indicated a fixed transport time of 2 ms with respect to EFR-H onset, suggesting a cochlear nucleus (CN) origin, here also, without indication for multiple generators. Other features of the EFR-V response pointing to the CN were, at least for the EFR frequency below the cut-off values of the transfer functions, higher PLVs coupled with increased harmonic distortion. Such a behavior has been described in the so-called highly-synchronized neurons of the ventral cochlear nucleus (VCN). The present study compellingly demonstrated the advantage of isolating the EFR in the temporal domain so as to extract detailed spectro-temporal parameters that, combined with orthogonal recording channels, shed new light on the involved neural generators.

Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

Frequency selectivity of tonal language native speakers probed by suppression tuning curves of spontaneous otoacoustic emissions.

Native acquisition of a tonal language (TL) is related to enhanced abilities of pitch perception and production, compared to non-tonal language (NTL) native speakers. Moreover, differences in brain responses to both linguistically relevant and non-relevant pitch changes have been described in TL native speakers. It is so far unclear to which extent differences are present at the peripheral processing level of the cochlea. To determine possible differences in cochlear frequency selectivity between Asian TL speakers and Caucasian NTL speakers, suppression tuning curves (STCs) of spontaneous otoacoustic emissions (SOAEs) were examined in both groups. By presenting pure tones, SOAE levels were suppressed and STCs were derived. SOAEs with center frequencies higher than 4.5 kHz were recorded only in female TL native speakers, which correlated with better high-frequency tone detection thresholds. The suppression thresholds at the tip of the STC and filter quality coefficient Q10dB did not differ significantly between both language groups. Thus, the characteristics of the STCs of SOAEs do not support the presence of differences in peripheral auditory processing between TL and NTL native speakers.

Auditory Brainstem Changes in Timing may Underlie Hyperacusis in a Salicylate-induced Acute Rat Model.

Hyperacusis, an exaggerated, sometimes painful perception of loudness even for soft sounds, is a poorly understood distressing condition. While the involvement of modified gain of central auditory neurons and the influence of nonauditory brain regions are well-documented, the issue of where in the auditory system these abnormalities arise remains open, particularly when hyperacusis comes without sensorineural hearing loss. Here we used acute intraperitoneal administration of sodium salicylate (150 mg/kg) in rats, enough to produce > 10-dB decrease in acoustic startle threshold with mild hearing loss at low frequencies (<10 kHz). Anesthesia, necessary for middle-ear-reflex (MEMR) threshold measurements, abolished the olivocochlear efferent reflex but not the MEMR acting on frequencies < 10 kHz, and its mean threshold increased from 55 dB SPL in controls to 80 dB SPL in salicylate-treated animals 60-90 minutes after injection, with an about 3-dB increase in acoustic energy reaching the cochlea. The mean latencies of auditory brainstem-evoked responses (ABR) conspicuously decreased after salicylate, by 0.25 millisecond at 6 kHz at every level, a frequency-dependent effect absent above 12 kHz. A generic model of loudness based upon cross-frequency coincidence detection predicts that with such timing changes, a transient sound may seem as loud at <40 dB SPL as it does in controls at >60 dB SPL. Candidate circuits able to act at the same time on the startle reflex, the MEMR and ABRs may be serotoninergic, as salicylate is known to increase brain serotonin and 5-HT neurons participate in MEMR and ABR circuits.

Avaliação de Crianças com Indicadores de Risco para Deficiência Auditiva Atendidas em um Serviço de Referência em Triagem Auditiva Neonatal / Evaluation of Children with Risk Indicators for Hearing Loss in a Newborn Hearing Screening Reference Service / Evaluación de Niños con Indicadores de Riesgo para Deficiencia auditiva Atendidas en un Servicio de Referencia en Triagem Auditiva Neonatal

Objetivo: Avaliar a audição de crianças com indicadores de risco para deficiência auditiva que realizaram triagem auditiva neonatal e retornaram para o acompanhamento após seis meses. Métodos: Estudo longitudinal realizado no Serviço de Referência em Triagem Auditiva Neonatal de um hospital universitário com crianças com indicadores de risco para deficiência auditiva. O estudo foi realizado em duas etapas: teste e reteste (quando necessário) e acompanhamento (aos seis meses de idade corrigida). Resultado: Na triagem foram avaliadas 179 crianças. Nesta etapa houve associação entre resultado "falha" em ambas as orelhas e suspeita de síndrome e resultado "falha" e citomegalovirose. Em todas as etapas 12 crianças apresentaram alterações condutivas confirmadas pela imitanciometria, e nenhuma apresentou alteração neurossensorial. Conclusão: A alteração auditiva condutiva foi a mais presente nesta população. Não foram detectadas alterações auditivas neurossensoriais em nenhuma criança avaliada no período do estudo, portanto o monitoramento auditivo dessas crianças deve ser realizado até idades mais avançadas para se detectar eventuais perdas auditivas progressivas ou de origem tardia.

Objective: To evaluate the hearing of children with risk indicators for hearing loss who underwent newborn hearing screening and returned to follow up after six months. Methods: Longitudinal study conducted at the Newborn Hearing Screening Service of a university hospital with children with risk indicators for hearing loss. The study was performed in two stages: test and retest (when necessary) and follow-up (at six months). Results: 179 children were evaluated in the screening. In this stage there was an association between "failed" result in both ears and suspected syndrome and "failed" result and cytomegalovirus. In all the stages, 12 children presented conductive alterations confirmed by the immittanciometry and none presented sensorineural alteration. Conclusion: Conductive hearing loss was more present in this population. No sensorineural hearing loss was detected in any child evaluated during the study period; therefore the auditory monitoring of these children should be performed until later ages to detect any progressive or late-onset hearing loss.

Objetivo:Evaluar la audición de niños con indicadores de riesgo para la deficiencia auditiva que realizaron la tamizaje auditivo neonatal y regresaron para el seguimiento después de seis meses. Métodos:Estudio longitudinal realizado en el Servicio de Referencia enTriage Auditiva Neonatal de un hospital universitario con niños con indicadores de riesgo para la deficiencia auditiva. El estudio fue realizado en dos etapas: prueba y reprueba (cuandonecesario) y seguimiento (a los seis meses de edad corregida). Resultado:En la selección se evaluaron 179 niños. En esta etapa hubo asociación entre resultado "falla" en ambas orejas y sospechosa de síndrome y resultado "falla" y citomegalovirosa. En todas las etapas, 12 niños presentaron alteraciones conductivas confirmadas por la imitanciometría y ninguna presentó alteración neurosensorial. Conclusión: La alteración auditiva conductiva fuela más presente en esta población. No se detectaron alteraciones auditivas neurosensorial en ningún niño evaluado en el período del estudio, por lo que el monitoreo auditivo de estos niños debe ser realizado hasta edades más avanzadas para detectar eventuales pérdidas auditivas progresivas o de origentardío.

Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane.

The function of outer hair cells (OHCs), the mechanical actuators of the cochlea, involves the anchoring of their tallest stereocilia in the tectorial membrane (TM), an acellular structure overlying the sensory epithelium. Otogelin and otogelin-like are TM proteins related to secreted epithelial mucins. Defects in either cause the DFNB18B and DFNB84B genetic forms of deafness, respectively, both characterized by congenital mild-to-moderate hearing impairment. We show here that mutant mice lacking otogelin or otogelin-like have a marked OHC dysfunction, with almost no acoustic distortion products despite the persistence of some mechanoelectrical transduction. In both mutants, these cells lack the horizontal top connectors, which are fibrous links joining adjacent stereocilia, and the TM-attachment crowns coupling the tallest stereocilia to the TM. These defects are consistent with the previously unrecognized presence of otogelin and otogelin-like in the OHC hair bundle. The defective hair bundle cohesiveness and the absence of stereociliary imprints in the TM observed in these mice have also been observed in mutant mice lacking stereocilin, a model of the DFNB16 genetic form of deafness, also characterized by congenital mild-to-moderate hearing impairment. We show that the localizations of stereocilin, otogelin, and otogelin-like in the hair bundle are interdependent, indicating that these proteins interact to form the horizontal top connectors and the TM-attachment crowns. We therefore suggest that these 2 OHC-specific structures have shared mechanical properties mediating reaction forces to sound-induced shearing motion and contributing to the coordinated displacement of stereocilia.