Auditory Brainstem Response Analysis Research Articles

A mouse model of autoimmune inner ear disease without endolymphatic hydrops

Autoimmune inner ear disease (AIED) is an organ-specific disease characterized by irreversible, prolonged, and progressive hearing and equilibrium dysfunctions. The primary symptoms of AIED include asymmetric sensorineural hearing loss accompanied by vertigo, aural fullness, and tinnitus. AIED is divided into primary and secondary types. Research has been conducted using animal models of rheumatoid arthritis (RA), a cause of secondary AIED. However, current models are insufficient to accurately analyze vestibular function, and the mechanism underlying the onset of AIED has not yet been fully elucidated. Elucidation of the mechanism of AIED onset is urgently needed to develop effective treatments. In the present study, we analyzed the pathogenesis of vertigo in autoimmune diseases using a mouse model of type II collagen-induced RA. Auditory brain stem response analysis demonstrated that the RA mouse models exhibited hearing loss, which is the primary symptom of AIED. In addition, our vestibulo-oculomotor reflex analysis, which is an excellent vestibular function test, accurately captured vertigo symptoms in the RA mouse models. Moreover, our results revealed that the cause of hearing loss and vestibular dysfunction was not endolymphatic hydrops, but rather structural destruction of the organ of Corti and the lateral semicircular canal ampulla due to an autoimmune reaction against type II collagen. Overall, we were able to establish a mouse model of AIED without endolymphatic hydrops. Our findings will help elucidate the mechanisms of hearing loss and vertigo associated with AIED and facilitate the development of new therapeutic methods.

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.

Long-term exposure to high-concentration dexamethasone in the inner ear via intratympanic administration

The first-line treatment for inner ear disorders is usually oral/systemic steroids. Intratympanic steroid therapy is an alternative option; however, it requires multiple office visits owing to the short residence time of steroids in the inner ear (systemic: 24 h, intratympanic: 2–3 h). Therefore, intratympanic injections of higher steroid concentrations could result in longer drug exposure, providing better treatment outcomes. This study aimed to develop a prototype for high-concentration steroids and examine their safety and feasibility in vivo. Using wild-type Institute for Cancer Research mice, high-concentration steroids (50 mg/mL dexamethasone), typical steroid concentrations (3.3 mg/mL dexamethasone), and sterile saline were administrated into the middle ear cavity via tympanic membrane injection. Auditory brainstem response analysis, vestibular function tests, and morphological analyses were performed to examine the safety and utility of High-conc Dex. One month post-injection, the frequency-averaged auditory brainstem response thresholds of high-dose dexamethasone-treated mice were not significantly different from those of low-dose dexamethasone- and saline-treated mice at all tested frequencies. Furthermore, the total points on vestibular function tests were similar between the three groups. Morphologically, no damage to the inner ear/middle ear mucosa was observed in all groups. Two months post-injection, dexamethasone could still be detected in the high-dose dexamethasone group. Altogether, our data successfully demonstrates the feasibility and safety of high-dose dexamethasone for in vivo use in the middle ear and ensure that the drug localizes to the inner ear. Further research is warranted to develop this new treatment strategy and further characterize its effects in vivo.

Lack of collagen α6(IV) chain in mice does not cause severe-to-profound hearing loss or cochlear malformation, a distinct phenotype from nonsyndromic hearing loss with COL4A6 missense mutation.

Congenital hearing loss affects 1 in every 1000 births, with genetic mutations contributing to more than 50% of all cases. X-linked nonsyndromic hereditary hearing loss is associated with six loci (DFNX1-6) and five genes. Recently, the missense mutation (c.1771G>A, p.Gly591Ser) in COL4A6, encoding the basement membrane (BM) collagen α6(IV) chain, was shown to be associated with X-linked congenital nonsyndromic hearing loss with cochlear malformation. However, the mechanism by which the COL4A6 mutation impacts hereditary hearing loss has not yet been elucidated. Herein, we investigated Col4a6 knockout (KO) effects on hearing function and cochlear formation in mice. Immunohistochemistry showed that the collagen α6(IV) chain was distributed throughout the mouse cochlea within subepithelial BMs underlying the interdental cells, inner sulcus cells, basilar membrane, outer sulcus cells, root cells, Reissner’s membrane, and perivascular BMs in the spiral limbus, spiral ligament, and stria vascularis. However, the click-evoked auditory brainstem response analysis did not show significant changes in the hearing threshold of Col4a6 KO mice compared with wild-type (WT) mice with the same genetic background. In addition, the cochlear structures of Col4a6 KO mice did not exhibit morphological alterations, according to the results of high-resolution micro-computed tomography and histology. Hence, loss of Col4a6 gene expression in mice showed normal click ABR thresholds and normal cochlear formation, which differs from humans with the COL4A6 missense mutation c.1771G>A, p.Gly591Ser. Therefore, the deleterious effects in the auditory system caused by the missense mutation in COL4A6 are likely due to the dominant-negative effects of the α6(IV) chain and/or α5α6α5(IV) heterotrimer with an aberrant structure that would not occur in cases with loss of gene expression.

Pasireotide protects mammalian cochlear hair cells from gentamicin ototoxicity by activating the PI3K\u2013Akt pathway

Gentamicin is a widely used antibiotic for the treatment of gram-negative bacterial infections; however, its use often results in significant and permanent hearing loss. Hearing loss resulting from hair cell (HC) degeneration affects millions of people worldwide, and one major cause is the loss of sensory HCs in the inner ear due to aminoglycoside exposure. Strategies to overcome the apparently irreversible loss of HCs in mammals are crucial for hearing protection. Here, we report that the somatostatin analog pasireotide protects mouse cochlear HCs from gentamicin damage using a well-established in vitro gentamicin-induced HC loss model and that the otoprotective effects of pasireotide are due to Akt up-regulation via the PI3K–Akt signal pathway activation. We demonstrate active caspase signal in organ of Corti (OC) explants exposed to gentamicin and show that pasireotide treatment activates survival genes, reduces caspase signal, and increases HC survival. The neuropeptide somatostatin and its selective analogs have provided neuroprotection by activating five somatostatin receptor (SSTR1–SSTR5) subtypes. Pasireotide has a high affinity for SSTR2 and SSTR5, and the addition of SSTR2- and SSTR5-specific antagonists leads to a loss of protection. The otoprotective effects of pasireotide were also observed in a gentamicin-injured animal model. In vivo studies have shown that 13 days of subcutaneous pasireotide application prevents gentamicin-induced HC death and permanent hearing loss in mice. Auditory brainstem response analysis confirmed the protective effect of pasireotide, and we found a significant threshold shift at all measured frequencies (4, 8, 16, 24, and 32 kHz). Together, these findings indicate that pasireotide is a novel otoprotective peptide acting via the PI3K–Akt pathway and may be of therapeutic value for HC protection from ototoxic insults.

Intrauterine Lipopolysaccharide-Induced Chorioamnionitis in a Sheep: Does It Affect the Auditory System?

Fetal exposure to in utero inflammation such as chorioamnionitis is related to central nervous system injury. We hypothesized that chorioamnionitis can provoke inflammatory changes in the perilymph and alter hearing outcome. Pregnant ewes were randomized into 2 groups: intrauterine injection with lipopolysaccharide (LPS; n = 19) or saline (n = 21). In the first experiment, fetal perilymph samples were taken for cytokine analysis. In the second experiment, consecutive bone-conducted auditory brain stem responses were obtained from 1 to 7 months after birth. Perilymph samples showed a significant elevation in interleukin 8 in the LPS group. Auditory brain stem response analysis demonstrated higher response thresholds and a prolongation of absolute peak V and interpeak intervals I to V and III to V in the LPS group compared to sham treatment. Our study confirms the hypothesis that an intrauterine inflammation by LPS can result in a fetal perilymphatic inflammatory response and functional impaired hearing outcomes after birth in a sheep model.

Noise Trauma Induced Neural Plasticity Throughout the Auditory System of Mongolian Gerbils: Differences between Tinnitus Developing and Non-Developing Animals.

In this study, we describe differences between neural plasticity in auditory cortex (AC) of animals that developed subjective tinnitus (group T) after noise-induced hearing loss (NIHL) compared to those that did not [group non-tinnitus (NT)]. To this end, our analysis focuses on the input activity of cortical neurons based on the temporal and spectral analysis of local field potential (LFP) recordings and an in-depth analysis of auditory brainstem responses (ABR) in the same animals. In response to NIHL in NT animals we find a significant general reduction in overall cortical activity and spectral power as well as changes in all ABR wave amplitudes as a function of loudness. In contrast, T-animals show no significant change in overall cortical activity as assessed by root mean square analysis of LFP amplitudes, but a specific increase in LFP spectral power and in the amplitude of ABR wave V reflecting activity in the inferior colliculus (IC). Based on these results, we put forward a refined model of tinnitus prevention after NIHL that acts via a top-down global (i.e., frequency-unspecific) inhibition reducing overall neuronal activity in AC and IC, thereby counteracting NIHL-induced bottom-up frequency-specific neuroplasticity suggested in current models of tinnitus development.

Results of the first universal newborn hearing screening in Algeria

Introduction Hearing loss is the most common congenital pathology at birth. Its prevalence increases during the infant period, especially in children at risk. The application of hearing screening in three stages with follow-up of children at risk of developing hearing loss allows to optimize the screening. Goals The aim of this study was to evaluate the prevalence of hearing loss in the neonatal population and identify newborns at risk and to investigate the best way to support infants with such disability from screening to rehabilitation. Materials and methods This prospective study was conducted over a period of 22 months from June 2011 to March 2013, using a systematic screening for deafness in a high-birth-level maternity unit. Results Over a period of 22 months, 17 912 live newborn were born in the maternity ward. The application of screening for deafness at birth allowed us to screen 15 382 newborns, with a coverage rate of 85.9%. We chose a three-stage screening protocol. In the first stage, 15 382 newborns were screened by means of analysis of distortion product of otoacoustic emissions (DPOAE). The screening was negative (presence of DPOAE and absence of hearing loss) in 13 467 newborns, and it was positive (absence of DPOAE and a possibility of hearing loss) for 1915 newborns who were addressed to the second stage of the screening protocol for the analysis of DPOAE again after 1 month of birth. In this second stage of screening, 1516 infants were screened in the ENT Department and 399 infants were lost to follow-up. After the second stage of the screening, 76 infants were addressed to the third stage of the screening protocol, which is also called stage of diagnosis. In this last step, 14 children were lost to follow-up and 62 infants were tested for hearing threshold using analysis of auditory brainstem response. Finally, after verification of the results obtained in the third stage using behavioral audiometry and impedance, 49 children showed hearing loss with a hearing threshold greater than 30 dB. The prevalence of neonatal hearing loss in the maternity unit was 3.2%. There were 27 male and 22 female patients, of whom 29 had bilateral hearing loss and 20 children had unilateral hearing loss. In contrast, the study of the risk factors of hearing loss allowed us to identify those who are present among the detected newborns and to calculate the prevalence of hearing loss among newborns admitted in the neonatal ICU, which was 2.14%. The risk factors most associated with deafness are infections with cytomegalovirus and rubella, damage to the nervous system and craniofacial malformations. The rehabilitation of hearing is based on speech rehabilitation and the use a hearing aid, either conventional prosthesis or cochlear implant. Conclusion Newborn hearing screening using a three-stage protocol is possible. It allows to detect hearing loss earlier to initiate early hearing and language rehabilitation, the only way to guarantee alignment of children born with hearing impairment or with contracted hearing loss during the neonatal period with their peers with normal hearing.

Effects of auditory training in individuals with high-frequency hearing loss

OBJECTIVE:To determine the effects of a formal auditory training program on the behavioral, electrophysiological and subjective aspects of auditory function in individuals with bilateral high-frequency hearing loss.METHOD:A prospective study of seven individuals aged 46 to 57 years with symmetric, moderate high-frequency hearing loss ranging from 3 to 8 kHz was conducted. Evaluations of auditory processing (sound location, verbal and non-verbal sequential memory tests, the speech-in-noise test, the staggered spondaic word test, synthetic sentence identification with competitive ipsilateral and contralateral competitive messages, random gap detection and the standard duration test), auditory brainstem response and long-latency potentials and the administration of the Abbreviated Profile of Hearing Aid Benefit questionnaire were performed in a sound booth before and immediately after formal auditory training.RESULTS:All of the participants demonstrated abnormal pre-training long-latency characteristics (abnormal latency or absence of the P3 component) and these abnormal characteristics were maintained in six of the seven individuals at the post-training evaluation. No significant differences were found between ears in the quantitative analysis of auditory brainstem responses or long-latency potentials. However, the subjects demonstrated improvements on all behavioral tests. For the questionnaire, the difference on the background noise subscale achieved statistical significance.CONCLUSION:Auditory training in adults with high-frequency hearing loss led to improvements in figure-background hearing skills for verbal sounds, temporal ordination and resolution, and communication in noisy environments. Electrophysiological changes were also observed because, after the training, some long latency components that were absent pre-training were observed during the re-evaluation.

Modeling and estimation of single-trial event-related potentials using partially observed diffusion processes

This paper proposes a new modeling framework for estimating single-trial event-related potentials (ERPs). Existing studies based on state-space approach use discrete-time random-walk models. We propose to use continuous-time partially observed diffusion process which is more natural and appropriate to describe the continuous dynamics underlying ERPs, discretely observed in noise as single-trials. Moreover, the flexibility of the continuous-time model being specified and analyzed independently of observation intervals, enables a more efficient handling of irregularly or variably sampled ERPs than its discrete-time counterpart which is fixed to a particular interval. We consider the Ornstein–Uhlenbeck (OU) process for the inter-trial parameter dynamics and further propose a nonlinear process of Cox, Ingersoll & Ross (CIR) with a heavy-tailed density to better capture the abrupt changes. We also incorporate a single-trial trend component using the mean-reversion variant, and a stochastic volatility noise process. The proposed method is applied to analysis of auditory brainstem responses (ABRs). Simulation shows that both diffusions give satisfactory tracking performance, particularly of the abrupt ERP parameter variations by the CIR process. Evaluation on real ABR data across different subjects, stimulus intensities and hearing conditions demonstrates the superiority of our method in extracting the latent single-trial dynamics with significantly improved SNR, and in detecting the wave V which is critical for diagnosis of hearing loss. Estimation results on data with variable sampling frequencies and missing single-trials show that the continuous-time diffusion model can capture more accurately the inter-trial dynamics between varying observation intervals, compared to the discrete-time model.

Familial Alström syndrome: a rare cause of bilateral progressive hearing loss ,

IntroductionAlström Syndrome is a rare disease caused by mutations in ALMS1 gene. It is characterized by a progressive degeneration of sensory functions, resulting in visual and audiological impairment, as well as metabolic disturbances such as childhood obesity, hyperinsulinemia, and diabetes mellitus type 2. ObjectiveTo report and discuss the genetic and audiological findings in two siblings with Alstrom syndrome. MethodsThis was a prospective, analytical and descriptive study, using questionnaires, serial audiograms, otoacoustic emissions, and auditory brainstem response analysis, as well as molecular genetic analysis. ResultsBoth patients presented childhood-onset bilateral sensorineural hearing loss, which progressed to moderate impairment in the first case and severe hearing loss in the second. Otoacoustic emissions were absent, and auditory brainstem responses were bilaterally normal in both cases. Conclusionn the present patients, Alström Syndrome began with a neurosensory hearing loss in early childhood that progressed to a profound loss in ten to twenty years. The auditory lesions were cochlear in origen according to the otoacoustic emissions and auditory brainstem responses.© 2014 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Mutanlallemand (mtl) and Belly Spot and Deafness (bsd) Are Two New Mutations of Lmx1a Causing Severe Cochlear and Vestibular Defects

Mutanlallemand (mtl) and Belly Spot and Deafness (bsd) are two new spontaneous alleles of the Lmx1a gene in mice. Homozygous mutants show head tossing and circling behaviour, indicative of vestibular defects, and they have short tails and white belly patches of variable size. The analysis of auditory brainstem responses (ABR) showed that mtl and bsd homozygotes are deaf, whereas heterozygous and wildtype littermates have normal hearing. Paint-filled inner ears at E16.5 revealed that mtl and bsd homozygotes lack endolymphatic ducts and semicircular canals and have short cochlear ducts. These new alleles show similarities with dreher (Lmx1a) mutants. Complementation tests between mtl and dreher and between mtl and bsd suggest that mtl and bsd are new mutant alleles of the Lmx1a gene. To determine the Lmx1a mutation in mtl and bsd mutant mice we performed PCR followed by sequencing of genomic DNA and cDNA. The mtl mutation is a single point mutation in the 3′ splice site of exon 4 leading to an exon extension and the activation of a cryptic splice site 44 base pairs downstream, whereas the bsd mutation is a genomic deletion that includes exon 3. Both mutations lead to a truncated LMX1A protein affecting the homeodomain (mtl) or LIM2-domain (bsd), which is critical for LMX1A protein function. Moreover, the levels of Lmx1a transcript in mtl and bsd mutants are significantly down-regulated. Hmx2/3 and Pax2 expression are also down-regulated in mtl and bsd mutants, suggesting a role of Lmx1a upstream of these transcription factors in early inner ear morphogenesis. We have found that these mutants develop sensory patches although they are misshapen. The characterization of these two new Lmx1a alleles highlights the critical role of this gene in the development of the cochlea and vestibular system.

AMPK activation by AICAR induces mitochondrial biogenesis in the inner ear

RationaleThe importance of mitochondrial biogenesis to auditory hair cell physiology or that of the non‐sensory cells in the cochlea is poorly understood. Activation of 5′ AMP activated protein kinase (AMPK) upregulates peroxisome proliferator–activated receptor‐γ coactivator‐1α (PGC‐1α) which, in turn, increases the levels of factors involved in mitochondrial biogenesis and respiration. At the same time, AMPK activation can increase antioxidant expression and reduce reactive oxygen species generation.ObjectiveTo determine whether the AMPK activator 5‐aminoimidazole‐4‐carboxamide‐1‐β‐D‐ribofuranoside (AICAR) can induce mitochondrial biogenesis in the inner ear and protect against noise induced hearing loss.Methods and ResultsAICAR treatment in mice led to higher levels of phosphorylated AMPKα in the cochlea by immunoblot and immunohistochemistry (IHC) analysis. Quantitative real‐time PCR revealed increased PGC‐1α mRNA levels. Extended AICAR treatment increased mitochondrial fission protein 1 and superoxide dismutase 2 protein levels. Auditory brainstem response analysis demonstrated that AICAR treatment accelerated recovery from acoustic trauma.ConclusionThese results demonstrate that mitochondria in the inner ear have the capacity to be dynamically regulated with increasing energy demands.Supported by grants 5R01DC000105 (ALN), 1R01DC010844 (XS), and P30DC005983.

Auditory brainstem response morphology and analysis in very preterm neonatal intensive care unit infants

Analysis of auditory brainstem response (ABR) in very preterm infants can be difficult owing to the poor detectability of the various components of the ABR. We evaluated the ABR morphology and tried to extend the current assessment system. Prospective cohort study. We included 28 preterm very low birth weight infants admitted to the neonatal intensive care unit of Sophia Children's Hospital. ABRs were measured between 26 and 34 weeks postconceptional age. The presence of the following ABR parameters was recorded: the ipsilateral peaks I, III and V, the contralateral peaks III and V, and the response threshold. In 82% of our population, a typical "bow tie" response pattern was present as a sign of early auditory development. This bow tie pattern is the narrowest part of the response wave and is predominantly characterized by the ipsilateral negative peak III. This effect may be emphasized by the contralateral peak III. The bow tie pattern is seen approximately 0.1 milliseconds before the ipsilateral peak III. From 30 weeks postconceptional age onward, a more extensive morphologic pattern is recorded in 90% of the infants. A flow chart was designed to analyze the ABR morphology of preterm infants in an unambiguous stepwise fashion. A typical bow tie pattern preceding peak III seems to be the earliest characteristic of the developing ABR morphology in preterm infants. As ABR characteristics will improve with increasing age, neonatal hearing screening should be postponed until after 34 weeks.

Bcl11b Heterozygosity Leads to Age-Related Hearing Loss and Degeneration of Outer Hair Cells of the Mouse Cochlea

BCL11B/CTIP2 zinc-finger transcription factor is expressed in various types of cells in many different tissues. This study showed that BCL11B is expressed in the nucleus of the outer hair cells of the mouse cochlea, degeneration of which is known to cause deafness and presbycusis or age-related hearing loss (AHL). We tested whether or not Bcl11b heterozygosity would affect AHL in mice. Analysis of auditory brainstem responses revealed AHL in Bcl11b (+/-) heterozygous, but not wild-type, mice, which was evident as early as 3 months after birth. Histological abnormalities were observed in the outer hair cells of the Bcl11b (+/-) mice at 6 months of age with hearing loss. These results suggest that the AHL observed in Bcl11b (+/-) mice is the result of impairment of the outer hair cells and that BCL11B activity is required for the maintenance of outer hair cells and normal hearing.

Risk factors for sensorineural hearing loss in NICU infants compared to normal hearing NICU controls

Objectives To evaluate independent etiologic factors associated with sensorineural hearing loss in infants who have been admitted to the neonatal intensive care unit compared to normal hearing controls. Method Between 2004 and 2009, 3366 infants were admitted to the neonatal intensive care unit of Sophia Children's Hospital, of which 3316 were screened with AABR. A total of 103 infants were referred for auditory brainstem response analysis after failure on neonatal hearing screening. We included all infants diagnosed with sensorineural hearing loss. Each patient was matched with two normal hearing controls from the neonatal intensive care unit of the same gender and postconceptional age. The following risk factors were studied: birth weight, dysmorphic features, APGAR scores (at 1, 5 and 10 min), respiratory distress (IRDS), CMV infection, sepsis, meningitis, cerebral bleeding, cerebral infarction, hyperbilirubinemia requiring phototherapy, peak total bilirubin level, furosemide, dexamethason, vancomycin, gentamycin and tobramycin administration. Results Fifty-eight infants were diagnosed with sensorineural hearing loss: 26 girls and 32 boys. The incidence of dysmorphic features ( P = 0.000), low APGAR score (1 min) ( P = 0.01), sepsis ( P = 0.003), meningitis ( P = 0.013), cerebral bleeding ( P = 0.016) and cerebral infarction ( P = 0.000) were significantly increased in infants with sensorineural hearing loss compared to normal hearing controls ( n = 116). Conclusion Dysmorphic features, low APGAR scores at 1 min, sepsis, meningitis, cerebral bleeding and cerebral infarction are associated with sensorineural hearing loss independent of neonatal intensive care unit admittance.

Deafness and Stria Vascularis Defects in S1P2 Receptor-null Mice

The S1P(2) receptor is a member of a family of G protein-coupled receptors that bind the extracellular sphingolipid metabolite sphingosine 1-phosphate with high affinity. The receptor is widely expressed and linked to multiple G protein signaling pathways, but its physiological function has remained elusive. Here we have demonstrated that S1P(2) receptor expression is essential for proper functioning of the auditory and vestibular systems. Auditory brainstem response analysis revealed that S1P(2) receptor-null mice were deaf by one month of age. These null mice exhibited multiple inner ear pathologies. However, some of the earliest cellular lesions in the cochlea were found within the stria vascularis, a barrier epithelium containing the primary vasculature of the inner ear. Between 2 and 4 weeks after birth, the basal and marginal epithelial cell barriers and the capillary bed within the stria vascularis of the S1P(2) receptor-null mice showed markedly disturbed structures. JTE013, an S1P(2) receptor-specific antagonist, blocked the S1P-induced vasoconstriction of the spiral modiolar artery, which supplies blood directly to the stria vascularis and protects its capillary bed from high perfusion pressure. Vascular disturbance within the stria vascularis is a potential mechanism that leads to deafness in the S1P(2) receptor-null mice.

Knock-in mouse model for resistance to thyroid hormone (RTH): an RTH mutation in the thyroid hormone receptor beta gene disrupts cochlear morphogenesis.

Thyroid hormone and the beta isoform of its receptor, Trb, are essential for normal development of the mammalian auditory system. We have analyzed auditory system function and structure in a mouse strain with a targeted Thrb mutation, Thrb(PV), which leads to the loss of binding of thyroid hormone (T3) to the Trb protein. Heterozygosity for the orthologous human THRB(PV) mutation and other similar mutations in human THRB cause resistance to thyroid hormone (RTH), which is occasionally associated with mild sensorineural hearing impairment. Auditory brainstem response analysis of heterozygous Thrb(PV)/+ mice demonstrates that they develop normal hearing. In contrast, Thrb(PV)/Thrb(PV) mice have severe hearing impairment that is already present at 3 weeks of age. This hearing loss is associated with disruption of postnatal morphogenesis of the tectorial membrane and organ of Corti. Comparison with the previously described phenotype of a Thrb -/- knockout strain suggests that Thrb(PV) disrupts the function of other genes that are critical for development and/or maintenance of these structures.

Postoperative Vestibular-evoked Myogenic Potentials in Cases with Vestibular Schwannomas

Although still the subject of discussion, vestibular-evoked myogenic potentials (VEMPs) have been considered to reflect the function of the saccular and, more recently, the cochlear tracts. To accurately determine the precise afferent pathway carrying VEMPs, we studied the outcomes of VEMPs and other examinations in patients with unilateral vestibular schwannomas. Eleven patients with unilateral vestibular schwannomas resected using a middle cranial fossa approach were included in the study. Patients underwent pure-tone threshold audiometry, caloric tests and analysis of auditory brainstem responses (ABRs) and VEMPs pre- and postoperatively. The results were compared with those obtained in patients with intact superior or inferior vestibular and cochlear nerves. Among the 11 patients studied, 4 retained their VEMPs postoperatively. Three of the 10 patients with inferior vestibular schwannomas exhibited normal VEMPs, preserved hearing levels (20 dB HL) and anatomically intact superior vestibular nerves. In all of these cases, ABRs more closely correlated with VEMPs than with caloric responses. In one of the cases with inferior vestibular schwannomas, VEMPs were preserved postoperatively and VEMP latencies were shortened, which indicates the preoperative presence of a conduction block in either the cochlear or superior vestibular nerve. VEMPs may be conducted in both the superior vestibular and cochlear nerves, as well as in the inferior vestibular nerve. Thus, evaluation of saccular nerve function should be performed carefully, especially in cases where hearing is preserved. It appears that cochlear conduction may proceed along two pathways, one direct and the other via the brainstem, but this remains to be verified.

Abnormal auditory brainstem responses for mice treated with mercurial compounds: involvement of excessive nitric oxide

In this paper, we attempted to construct an animal (mouse) model for monitoring the oto-neurotoxicity of mercuric sulfide, comparing its toxicity with the well-known (organic) mercury compound methyl-mercury. Mice were treated with either mercuric sulfide (HgS, 0.1 and 1.0 g/kg per day) or methyl-mercury (MeHg, 0.2, 2.0 and 10 mg/kg per day) by gastric gavage for 7 consecutive days. Analysis of auditory brainstem response (ABR) indicated that significant elevation of the physiological hearing threshold as well as significant prolongation of interwave latency I–V was observed for MeHg — (2.0 and 0.2 mg/kg per day) or HgS — (1.0 g/kg per day, but not 0.1 g/kg per day) treated mice. Further, both MeHg- and HgS-treated animals demonstrated a significant prolongation of interwave latency I–V that increased with an increasing mean blood-Hg level. The oto-neurotoxicity of MeHg (2.0 mg/kg per day) persisted to at least 11 weeks subsequent to the cessation of its administration. The toxic effect of HgS, however, disappeared completely 5 weeks subsequent to the cessation of its administration. These results suggest a correlation between the Hg-elicited hearing dysfunction and the availability of mercury in brain tissue. Both inhibition of Na +/K +-ATPase activity and overproduction of nitric oxide in the brainstem are consistent with an analysis of the physiological hearing threshold and latencies of ABR waveform at all time points throughout the experimental process. Thus, it is proposed that high-dose HgS or MeHg intoxication is associated with a decrease in functional Na +/K +-ATPase activity in the brainstem of affected animals, this presumably arising via excessive nitric oxide production, and suggesting that brainstem damage may play a role in mercury-induced hearing loss.