Normal Auditory Brainstem Response Research Articles

A new mutation of Sgms1 causes gradual hearing loss associated with a reduced endocochlear potential

Sgms1 encodes sphingomyelin synthase 1, an enzyme in the sphingosine-1-phosphate signalling pathway, and was previously reported to underlie hearing impairment in the mouse. A new mouse allele, Sgms1tm1a, unexpectedly showed normal Auditory Brainstem Response thresholds. We found that the Sgms1tm1a mutation led to incomplete knockdown of transcript to 20% of normal values, which was enough to support normal hearing. The Sgms1tm1b allele was generated by knocking out exon 7, leading to a complete lack of detectable transcript in the inner ear. Sgms1tm1b homozygotes showed largely normal auditory brainstem response thresholds at first, followed by progressive loss of sensitivity until they showed severe impairment at 6 months old. The endocochlear potential was consistently reduced in Sgms1tm1b mutants at 3, 4 and 8 weeks old, to around 80mV compared with around 120mV in control littermates. The stria vascularis showed a characteristic irregularity of marginal cell surfaces and patchy loss of Kcnq1 expression at their apical membrane, and expression analysis of the lateral wall suggested that marginal cells were the most likely initial site of dysfunction in the mutants. Finally, significant association of auditory thresholds with DNA markers within and close to the human SGMS1 gene were found in the 1958 Birth Cohort, suggesting that SGMS1 variants may play a role in the range of hearing abilities in the human population.

A New Mouse Model for Usher Syndrome Crossing Kunming Mice with CBA/J Mice

BackgroundPreviously, we discovered a strain of Kunming mice, referred to as the KMush/ush strain, that exhibited notably abnormal electroretinogram (ERG) readings and elevated thresholds for auditory brainstem responses (ABRs), which resembled the characteristics of Usher Syndrome (USH). We successfully identified the pathogenic genes, Pde6b and Adgrv1, after KMush/ush crossbred with CBA/CaJ mice, referred to as CBA-1ush/ush, CBA-2ush/ush or CBA-2ush/ush. In this investigation, we crossbred KMush/ush and CBA/J mice to establish novel recombinant inbred lines and analysed their phenotypic and genotypic characteristics. MethodsERG readings, ABR testing, fundus morphology, histological examination of the retina and inner ear, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, western blotting, DNA sequence analysis and behavioural experiments were performed to assess the phenotypes and genotypes of the progeny lines. ResultsNo obvious waveforms in the ERG were detected in F1 hybrid mice while normal ABR results were recorded. The F2 hybrids, which were called J1ush/ush or J2ush/ush, exhibited segregated hearing-loss phenotypes. J1ush/ush mice had a retinitis pigmentosa (RP) phenotype with elevated ABR thresholds, whereas J2ush/ush mice exhibited only the RP phenotype. Interestingly, J1ush/ush mice showed significantly higher ABR thresholds than wild-type mice at 28 days post born (P28), and RT-qPCR and DNA-sequencing analysis showed that Adgrv1 gene expression was significantly altered in J1ush/ush mice, but histological analysis showed no significant structural changes in the organ of Corti or spiral ganglia. Further elevation of ABR-related hearing thresholds by P56 manifested only as a reduced density of spiral ganglion cells, which differed significantly from the previous pattern of cochlear alterations in CBA-2ush/ush mice. ConclusionsWe successfully introduced the hearing-loss phenotype of inbred mice with USH into CBA/J mice, which provides a good animal model for future studies on the important physiological roles of the Adgrv1 gene in inner-ear structure and for therapeutic studies targeting Adgrv1-mutated USH.

Alpha9alpha10 knockout mice show altered physiological and behavioral responses to signals in masking noise.

Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (α9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (α9α10KOs) may exhibit more severe MOC-related phenotypes. Like α9KOs, α9α10KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in α9α10KO mice. Wild-type (WT) and α9α10KO mice had similar ABR thresholds and acoustic startle response amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. α9α10KO mice had larger ABR Wave I amplitudes than WTs in quiet and noise. Other ABR metrics of hearing-in-noise function yielded conflicting findings regarding α9α10KO susceptibility to masking effects. α9α10KO mice also had larger startle amplitudes in tone backgrounds than WTs. Overall, α9α10KO mice had grossly normal auditory function in quiet and noise, although their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.

Evaluation of Neurological and Auditory Development in Children with Congenital Heart Disease using Essence Q Questionnaire and Auditory Brainstem Response (ABR) Test.

The progress of cardiac surgery in children and the increase in the survival of children with Congenital Heart Disease (CHD) has led to consider another issue called a neurodevelopmental disorder. In this study, 53 children with CHD were evaluated in terms of development with the Essence Q questionnaire, Otoacoustic Emission (OAE), and Auditory Brainstem Response (ABR) regarding these patients' hearing and risk factors. The Essence Q scores were also examined. In this prospective, cross-sectional study, the researchers included 53 children diagnosed with CHD. Initially, each child underwent ABR and OAE tests. Subsequently, data on potential risk factors associated with neurodevelopmental delay were collected. A trained project associate administered the Essence Q questionnaire, using parents' information as a guide. Following data collection, this study proceeded with an in-depth analysis of the information. Thirty-six boys (67.92%) and 17 girls (32.08%) with CHD were included in the study. The mean age of children was 26.9810.64 months. The mean Essence Q score for boys was 7.482.57. Moreover, the average score for girls was 2.23 8.11. According to this questionnaire, 39 patients (73.58%) had hyperactivity disorder, 46 patients (86.79%) had behavioral disorders, and ten patients (16.98%) had a motor delay. Unlike previous studies, all patients had normal OAE and ABR hearing. This study demonstrated that factors such as developmental delay in the first year, a known genetic disease, and a history of seizures significantly impacted the Essence Q score. However, elements like prematurity, the use of ventilation, abnormalities on the dorsum, and the number of days post-surgery did not significantly affect the Essence Q score. Essence Q can be a reliable tool in screening for neurodevelopment in children with CHD.

Hearing Screening through Frequency Analysis of Auditory Brainstem Response Using PhysioNet Data

Objectives. Responding to the reality of neonate patients with delayed childhood development due to late diagnosis of and intervention on hearing impairment, this study aims to determine the features based on time-frequency domain of auditory brainstem response (ABR) signals and to test the protocol on ABR signals from PhysioNet.Methods. This is done by pre-processing, performing time-frequency analysis, and characterizing hearing impairment using the dominant features of the ABR. In this study, normal (N) and hearing impaired (HI) ABR adult human signals were acquired from Physionet.org, a publicly available database. Considering its high signal-to-noise ratio, numerous filters and transformations were applied to extract the ABR. Consequently, the features acquired — dominant frequency and bigrams, were used as data classifiers.Results. Initial results using only N classifiers, that is features from the Normal dataset, and bandpass Chebyshev filter with a lower cut-off frequency of 60 Hz show that the tests yielded low to middle sensitivity. Further tests were done to improve the sensitivity that incorporated the HI classifiers, used data filtered with a low cut-off frequency of 300 Hz, and data divided per stimulus intensity level.Conclusion. Conclusions made are 1) data with both N and HI classifiers have higher sensitivity than those using only N classifiers, 2) data with a Chebyshev cut-off frequency of 300 Hz have a higher sensitivity than those with 60 Hz, and 3) data divided per intensity level have a higher sensitivity than data analyzed as a whole, and that features with stimulus intensity in middle ranges have a better distinction between HI and N patients.

Diagnostic Validity of Auditory Brainstem Response for the Initial Screening of Vestibular Schwannoma.

Background and ObjectivesTo investigate the diagnostic validity of auditory brainstem response (ABR) in the screening of vestibular schwannoma (VS).Subjects and MethodsForty patients diagnosed with VS using magnetic resonance imaging who had undergone ABR before treatment between 2005 and 2015 were included. ABR results were considered positive when findings met at least one of the following criteria: 1) absent evoked response, 2) desynchronization of waves other than wave I, 3) interpeak latency (IPL) between waves I and III >2.5 ms, 4) IPL between waves I and V >4.4 ms, 5) wave V interaural latency difference >0.2 ms, and 6) interaural difference in IPL between waves I and V >0.2 ms.ResultsThe overall sensitivity of ABR was 85.0%. For tumors measuring <10 mm, the sensitivity of ABR was 66.7%, whereas it increased to 90.3% for tumors measuring >10 mm. The sensitivity of tumors confined to the internal acoustic canal was 73.3% compared with 100.0% for tumors confined to the cerebellopontine angle. In patients with serviceable hearing, the mean tumor size was 7.8±2.9 mm in patients with a normal ABR and 15.1±9.4 mm in patients with an abnormal ABR, indicating a significant difference (p<0.05).ConclusionsABR alone is insufficient for the screening of VS, bearing the risk of false-negative outcomes when examining small, intracanalicular tumors. However, ABR can be inexpensively applied for the screening of VS measuring >10 mm in patients with serviceable hearing, supporting the need for further active diagnostic and treatment modalities in clinical practice.

Randomized Trial to Increase Speech Sound Differentiation in Infants Born Preterm

To test whether infant-directed foreign language active learning would specifically increase speech sound differentiation to the intervention language while not decreasing differentiation in response to English. Pilot randomized controlled trial of stable infants born preterm in the newborn intensive care unit with normal auditory brainstem responses, whose parents spoke only English and had no musical training or familial hearing abnormality. Assignment was to 1 of 3 groups: passive exposure to English infant-directed lullabies and readings (English-enrichment, control group) and contingent exposure by active sucking on a sensor-equipped pacifier to either infant-directed French lullabies and readings (English environment, French-contingent learning group) or infant-directed Mandarin lullabies and readings (English environment, Chinese-contingent learning group). The main outcome measures were preintervention and postintervention event-related potentials (ERPs) in response to standardized speech syllables in each language. Forty-one subjects completed the study, including 15 in the English-enrichment control group and 13 each in the French-contingent and Chinese-contingent groups. The median gestational age at birth was 34weeks (IQR, 8.75weeks); postmenstrual age at intervention ranged from 36 to 46weeks and was similar across the 3 groups. Postintervention mean ERP amplitude to pairs of English speech sounds did not differ across the 3 groups; however, ERP amplitude in French sound differentiation was greater in the French-contingent group than in the Chinese-contingent or English-enrichment groups, and ERP amplitude greater in Chinese sound differentiation was greater in the Chinese-contingent group compared with the other 2 groups. Contingent infant-directed foreign language exposure increased speech sound differentiation specific to the intervention language and did not decrease differentiation in response to English. ClinicalTrials.gov: NCT03232931.

Neonatal Hyperbilirubinemia and Cholestasis.

Neonatal Hyperbilirubinemia and Cholestasis.

Auditory evoked potentials as yardstick for tinnitus

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Aiming to evaluate the recent theoretical postulates on tinnitus underscoring the role of thalamocortical neural tracts, the present study: explores middle latency response (MLR) as a possible physiological measure of tinnitus: thus investigates the predicted exaggeration of P&lt;sub&gt;a&lt;/sub&gt;-N&lt;sub&gt;a&lt;/sub&gt;, N&lt;sub&gt;a&lt;/sub&gt;-P&lt;sub&gt;b&lt;/sub&gt; interpeak amplitudes in tinnitus patients and; explores middle latency response (MLR) as a prognostic indicator of tinnitus retraining therapy (TRT), thus evaluates possible decrease in P&lt;sub&gt;a&lt;/sub&gt;-N&lt;sub&gt;a&lt;/sub&gt; and N&lt;sub&gt;a&lt;/sub&gt;-P&lt;sub&gt;b&lt;/sub&gt; amplitude after 2 weeks exposure to tinnitus retraining therapy.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; An experimental group was constructed by randomly assigning 30 patients with mean age 38.5 years and complaining of debilitating tinnitus but with normal hearing for the study. MLR was administered on patients with normal auditory brainstem response (ABR) and otoacoustic emission (OAE) both pre- and post-tinnitus retraining therapy. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Results demonstrated no significant effect on P&lt;sub&gt;a&lt;/sub&gt;, N&lt;sub&gt;a&lt;/sub&gt; and N&lt;sub&gt;b&lt;/sub&gt; absolute and interpeak latencies. However, significantly exaggerated P&lt;sub&gt;a&lt;/sub&gt;-N&lt;sub&gt;a&lt;/sub&gt; and N&lt;sub&gt;a&lt;/sub&gt;-P&lt;sub&gt;b&lt;/sub&gt; interpeak amplitudes between experimental and control groups as well as pre and post therapeutic groups were found.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; This proves that MLR may adequately reflect thalamocortical hyperactivity in cases with distressing tinnitus and demonstrable improvement post TRT warrants the use of MLR as its prognostic indicator.&lt;/p&gt;

Subcortical deafness as a subtype of auditory agnosia after injury of bilateral auditory radiations caused by two cerebrovascular accidents – normal auditory brainstem responses with I–VII waves and abolished consciousness of hearing –

Background In central auditory disorders caused by damage of the cerebral hemispheres, there are cortical deafness and auditory agnosia. Although clinical cases of cortical deafness have been reported, little is known about the hearing problems and localized lesions associated with cortical deafness. Aims/objectives The aims of our research are to elucidate lesion sites associated with cortical deafness and to clarify why patients with cerebral lesions are not aware of any sound at all. Materials and methods Three patients diagnosed as having total loss of hearing participated in this study. We conducted pure-tone audiometry, speech audiometry, distortion product otoacoustic emission (DPOAE), auditory brainstem response (ABR), and brain magnetic resonance imaging (MRI) to diagnose cortical deafness with aphasia tests of these patients. Results Our studies showed that waves VI and VII as well as waves I to V have normal peak latencies in ABRs in all three patients. In brain MRI, we found complete damage of proximal parts of bilateral auditory radiations in the three patients. Conclusions We propose ‘subcortical deafness’ as a subtype of auditory agnosia.

Perinatal factors influencing the neonatal hearing screening results

BackgroundPrevious studies have indicated that the majority of cases with “failed” results related to transient evoked otoacoustic emissions (OAE) test have the normal hearing. The present study aimed to assess the possible relationships between perinatal factors and the false-positive OAE results.MethodsA case-control study was carried out in an Iranian Hospital in 2020. Based on the OAE results on the first day of life, newborns were divided into 2 groups; Control group included subjects with “Pass” OAE results. Every neonate with “Fail” OAE result was referred for auditory brainstem response (ABR). Neonates with bilateral fail OAE but normal ABR results (false-positive OAE) were considered as the case group. All recorded data were analyzed to assess the possible correlations between maternal/neonatal factors and the false-positive OAE results.ResultsOne hundred and eighty-one neonates entered the study. Of all included neonates, 87 (48.1%) cases showed bilateral fail OAE and 94 (51.9%) subjects passed the OAE test. Normal ABR results (false-positive OAE) were observed in all cases with bilateral fail OAE. Comparisons of variables affecting the OAE results showed that of all perinatal factors, neonate’s sex (p = 0.046) and cesarean section (p = 0.003) were the only influencing factors that increased the risk of false-positive OAE results.ConclusionBased on the results, the cesarean section delivery and neonate’s male sex increased the risk of false-positive results related to OAE test. Implementing other screening tests such as ABR or Automated ABR as the initial screening test could be suggested for such cases.

The prevalence and clinical characteristics of vestibular schwannoma among patients treated as sudden sensorineural hearing loss: A 10-year retrospective study in southern China.

To review the prevalence and clinical characteristics of vestibular schwannoma (VS) in patients with sudden sensorineural hearing loss (SSNHL) in southern China. This study examined the medical records and MRI findings of all the 1249 patients diagnosed with SSNHL between May 2009 and April 2019 in the Division of Otolaryngology at Peking University Shenzhen Hospital. Among the 1249 patients with SSNHL, VS was found in 14 (1.12%). Among 14 patients, 11 (78.6%) complained of tinnitus and 3 patients (21.4%) complained of dizziness as accompanying symptoms. There was one patient with SSNHL in right ear who had an incidental finding of VS in the contralateral ear. 2 patients (14.3%) had normal auditory brainstem response (ABR) test and 3 patients (21.4%) had hearing recovery. The size of tumors ranged from 6.1mm to 24.2mm, with 7 grade 1 tumors, 4 grade 2 tumors, and 3 grade 3 tumors. The total MRI screening cost was $130,857 and the average MRI cost for identifying a VS patient was $9346. The prevalence of VS among patients treated as SSNHL was 1.12%. Predicting the risk of VS in SSNHL by the audiogram patterns, pure tone audiometry or hearing recovery is not relivable. Compared with ABR, MRI is more suitable for the assessment of VS in patients with SSNHL in China.

Effect of Hyperbilirubinemia on Medial Olivocochlear System in Newborns.

To evaluate medial olivocochlear efferent system of babies with hyperbilirubinemia with normal auditory brain stem responses. This was a prospective study in a tertiary referral hospital. The study involved 40 hyperbilirubinemic and 44 healthy newborns. Cochlear and auditory activity of participants was evaluated by transient otoacoustic emissions (TOAEs) and brainstem auditory evoked response components (BAER). Medial olivocochlear (MOC) reflex was evoked with contralateral acoustic stimulation and recorded with TOAEs. A comparison of the MOC reflex activity between two groups with Mann Whitney U test revealed that MOC reflex activity were significantly decreased in the hyberbilirubinemic group for both ears (p<.05). This difference was significant for all frequencies in both ears. There was no significant relation between total serum bilirubin level and MOC reflex activity. Hyperbilirubinemic newborns had decreased MOC reflex activity. This may be indicative of future problems in speech discrimination and effective hearing in noisy background. Additional long cohort studies are needed to evaluate the clinical importance of MOC reflex measurements in this group. MOC reflex measurement has the potential to form part of the audiologic evaluation of newborns with hyperbilirubinemia in the future.

Evaluation of dichotic listening performance in normal-hearing, noise-exposed young females

Recent animal studies have shown that intense noise exposures that produce robust temporary threshold shift (TTS) can inflict irreversible damage to the synaptic connections between the inner hair cells and auditory neurons. It was hypothesized that noise-induced cochlear synaptopathy may cause impaired acoustic encoding in the central auditory nervous system leading to impaired speech perception, particularly in challenging listening situations. The aim of the study was to evaluate the influence of high noise exposure background (NEB) on dichotic listening performance, speech-in-noise performance, and auditory brainstem responses (ABR) measured in young females with normal audiograms. The central hypothesis was that individuals with high NEB would exhibit reduced ABR wave I amplitude and subsequently would exhibit poorer performance on speech-in-noise and dichotic listening. In a sample of 32 females (14 with high NEB and 18 with low NEB) aged 18–35 years, the study compared behavioral hearing thresholds (from 250 to 16000 Hz), distortion-product otoacoustic emissions (DPOAEs, 1000–16000 Hz), click-evoked ABR, QuickSIN signal-to-noise ratio (SNR) loss and dichotic digit test (DDT). The results showed no clear association between NEB, and hearing thresholds, DPOAEs, click-evoked ABR measures, and QuickSIN SNR loss. Individuals with high NEB revealed significantly lower DDT scores and evidence of reduced right ear advantage compared to individuals with low NEB. The poorer performance in DDT and the ear asymmetry in DDT scores with normal ABR findings suggest that high NEB might alter the hemispheric organization of speech-sound processing and cognitive control. The clinical significance of the present findings is discussed.

Morphology variations of click-evoked auditory brainstem response with low and high rate stimuli in rat

Background and Aim: The auditory brainstem response (ABR) is one of the most common obj­ective hearing tests conducting in animal and human. The purpose of this study was evalua­ting the morphology variations of ABR wave­forms in rats with low and high rate click sti­muli.&#x0D; Methods: First, rats with ABR thresholds hig­her than 55 dB SPL were excluded and total 81 ears remained in study. Absolute and interpeak latencies of wave I, II, IV were evaluated at low (17.7 Hz) and high rate (88.7 Hz) for click sti­muli at 120 dB SPL.. Results: At low rate stimuli, ABR waveforms showed different morphologies. The most com­mon complex for waves II to IV was wave III placed on downward slope of wave II (71% of cases). Almost the same morphologies were seen at higher rate; but in some waves, it rou­nded and decreased amplitude. For waves IV-V, the most common morphology was equal amp­litude of wave IV and V in low and high rates (35% vs 56%, respectively). Generally, the high rate stimuli didn’t severely change morphology patterns except for later waves. Conclusion: Normal click-evoked ABR could result in different waveforms. Using click sti­muli at low and high rate result in different mor­phology patterns. Recognizing morphology var­iations of ABR waveforms are essential for det­ecting any pathological conditions. The high rate stimuli increased latencies, especially for later waves.

The Summating Potential Is a Reliable Marker of Electrode Position in Electrocochleography: Cochlear Implant as a Theragnostic Probe.

For the increasing number of cochlear implantations in subjects with residual hearing, hearing preservation, and thus the prevention of implantation trauma, is crucial. A method for monitoring the intracochlear position of a cochlear implant (CI) and early indication of imminent cochlear trauma would help to assist the surgeon to achieve this goal. The aim of this study was to evaluate the reliability of the different electric components recorded by an intracochlear electrocochleography (ECochG) as markers for the cochleotopic position of a CI. The measurements were made directly from the CI, combining intrasurgical diagnostics with the therapeutical use of the CI, thus, turning the CI into a "theragnostic probe." Intracochlear ECochGs were measured in 10 Dunkin Hartley guinea pigs of either sex, with normal auditory brainstem response thresholds. All subjects were fully implanted (4 to 5 mm) with a custom six contact CI. The ECochG was recorded simultaneously from all six contacts with monopolar configuration (retroauricular reference electrode). The gross ECochG signal was filtered off-line to separate three of its main components: compound action potential, cochlear microphonic, and summating potential (SP). Additionally, five cochleae were harvested and histologically processed to access the spatial position of the CI contacts. Both ECochG data and histological reconstructions of the electrode position were fitted with the Greenwood function to verify the reliability of the deduced cochleotopic position of the CI. SPs could be used as suitable markers for the frequency position of the recording electrode with an accuracy of ±1/4 octave in the functioning cochlea, verified by histology. Cochlear microphonics showed a dependency on electrode position but were less reliable as positional markers. Compound action potentials were not suitable for CI position information but were sensitive to "cochlear health" (e.g., insertion trauma). SPs directly recorded from the contacts of a CI during surgery can be used to access the intracochlear frequency position of the CI. Using SP monitoring, implantation may be stopped before penetrating functioning cochlear regions. If the technique was similarly effective in humans, it could prevent implantation trauma and increase hearing preservation during CI surgery. Diagnostic hardware and software for recording biological signals with a CI without filter limitations might be a valuable add-on to the portfolios of CI manufacturers.

A Natural Occurring Mouse Model with Adgrv1 Mutation of Usher Syndrome 2C and Characterization of its Recombinant Inbred Strains

Background/Aims: Our laboratory discovered a Kunming mouse with enormous electroretinogram (ERG) defects. Its auditory brainstem response (ABR) threshold was significantly elevated and closely resembled the features of Usher syndrome (USH). This study sought to cross these USH-like mice (named KM^ush/ush mice) with CBA/CaJ mice to establish recombinant inbred strains and identify their phenotypes and genotypes. Methods: KM^ush/ush mice were crossed with CBA/CaJ mice to establish inbred strains by sibling mating. ERG, ABR, ocular fundus morphology, histological examinations of the retina and inner ear, quantitative real-time polymerase chain reaction, western blotting, and exon sequencing were performed to assess the phenotypes and genotypes of the offspring strains. Results: The F1 hybrids from crossing KM^ush/ush and CBA/CaJ mice had normal ERG and ABR responses. The F2 offspring from intercrossing the F1 mice showed a segregation of the retinitis pigmentosa (RP) and hearing loss phenotypes. The CBA-1^ush/ush mice had an RP phenotype that was characterized by a vanished ERG waveform and loss of the outer nuclear layer. Their Pde6b gene had a nonsense mutation that resulted in the failure of protein production in western blotting. However, the ABR threshold of this strain of mice was normal. The CBA-2^ush/ush mice had normal retinal function and architecture. Their ABR threshold was increased, with a dramatic degeneration of the stereocilia bundles in the outer hair cells of the inner ear. Whole exome sequencing and exon sequencing revealed a deletion of one base pair in exon 31 of the Adgrv1 gene, which would result in the premature termination of protein encoding. The level of Adgrv1 mRNA was reduced in the CBA-2^ush/ush mice. The CBA-3^ush/ush mice had phenotypes of RP, elevated ABR threshold, and degeneration of the stereocilia bundles in the outer hair cells. They were closely associated with the nonsense mutations of Pde6b and Adgrv1, respectively. Conclusion: We isolated a mouse strain with hearing loss from inbred mice with retinal degeneration and established it as a recombinant inbred strain with a spontaneous mutation in Adgrv1, the human Usher syndrome 2C gene. The retinal degeneration was cause by a mutation in Pde6b, while the hearing loss was caused by a mutation in Adgrv1.

Auditory and otologic profile of Alström syndrome: Comprehensive single center data on 38 patients.

Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by mutations in the ALMS1 gene. Hallmark characteristics include childhood onset of severe retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, and cardiomyopathy. Here we comprehensively characterize the auditory and otologic manifestations in a prospective case series of 38 individuals, aged 1.7-37.9 years, with genetically confirmed AS. Hearing loss was preceded by retinal dystrophy in all cases, and had an average age of detection of 7.45 years (range 1.5-15). Audiometric assessments showed mean pure tone averages (0.5, 1, 2, 4 kHz) of 48.6 and 47.5 dB HL in the right and left ears, respectively. Hearing was within normal limits for only 8/74 ears (11%). For the 66 ears with hearing loss, the degree was mild (12%), moderate (54%), or severe (8%). Type of hearing loss was predominantly sensorineural (77%), while three ears had mixed loss, no ears had conductive loss, and type of hearing loss was indeterminate for the remaining 12 ears. Serial audiograms available for 33 patients showed hearing loss progression of approximately 10-15 dB/decade. Our data show that hearing loss associated with AS begins in childhood and is a predominantly symmetric, sensory hearing loss that may progress to a severe degree. Absent otoacoustic emissions, intact speech discrimination, and disproportionately normal auditory brainstem responses suggest an outer hair cell site of lesion. These findings indicate that individuals with AS would benefit from sound amplification and if necessary, cochlear implantation.

Application of objective audiological tests in bilateral tinnitus patients with normal hearing capability

Objective:To analyze the relationship of tinnitus and early stage damage of cochlear, to explore the clinical applied value of distortion product otoacoustic emission(DPOAE) and auditory brainstem response(ABR) in the bilateral tinnitus patients with normal hearing capability. Method:There are 30 cases(60 ears) in the tinnitus group with bilateral tinnitus patients with normal hearing capability, and there are 30 cases(60 ears) in the control group without tinnitus of normal hearing capability. The two groups both test the DPOAE and ABR,and compare the results of the DPOAE and ABR. Result:The passing rate of DPOAE in all frequencies was 100% in the control group,42.67% in the tinnitus group. Significant differences existed between the two groups(P<0.05).The DPOAE could be checked out at all frequencies under 2 kHz except 0.75 kHz in the tinnitus group, and the passing rates of DPOAE were significantly lower than those in control group(P<0.05).There were 3 cases could not be checked out at 0.75 kHz frequency, but there were no significant difference(P>0.05).The DPOAE amplitudes at frequencies of 3 to 8 kHz in tinnitus ears were significantly lower than those in nontinnitus ears(the P value were 0.011,0.013,0.008,0.027 ).Wave Ⅰ,Ⅲ and Ⅴcould be detected in all ears tested at 80 dB nHL. The latencies of WaveⅠin tinnitus group were obviously prolonged.The latencies of Wave Ⅲ and Ⅴ in tinnitus group were also prolonged, but there was no significant difference(P>0.05).The interval between waves Ⅰand Ⅲ,waves Ⅲ and Ⅴand wavesⅠand Ⅴ showed no difference. Conclusion:The maybe cochlear early injury in fractional bilateral tinnitus patients with normal hearing capability, DPOAE and ABR can act as an objective method for diagnosing peripheral tinnitus.

Abnormal mRNA splicing but normal auditory brainstem response (ABR) in mice with the prestin (SLC26A5) IVS2-2A > G mutation

Prestin is critical to OHC somatic motility and hearing sensitivity in mammals. Several mutations of the human SLC26A5 gene have been associated with deafness. However, whether the IVS2-2A>G mutation in the human SLC26A5 gene causes deafness remains controversial. In this study, we created a mouse model in which the IVS2-2A>G mutation was introduced into the mouse Slc26a5 gene by gene targeting. The homozygous Slc26a5 mutant mice were viable and fertile and displayed normal hearing sensitivity by ABR threshold analysis. Whole-mount immunostaining using prestin antibody demonstrated that prestin was correctly targeted to the lateral wall of OHCs, and no obvious hair cell loss occurred in mutant mice. No significant difference in the amount of prestin protein was observed between mutants and controls using western blot analysis. In OHCs isolated from mutants, the NLC was also normal. However, we observed a splicing abnormality in the Slc26a5 mRNA of the mutant mice. Eleven nucleotides were missing from the 5′ end of exon 3 in Slc26a5 mRNA, but the normal ATG start codon in exon 3 was still detected. Thus, the IVS2-2A>G mutation in the Slc26a5 gene is insufficient to cause hearing loss in mice.