OPA1-related auditory neuropathy: site of lesion and outcome of cochlear implantation.

Hearing impairment is the second most prevalent clinical feature after optic atrophy in dominant optic atrophy associated with mutations in the OPA1 gene. In this study we characterized the hearing dysfunction in OPA1-linked disorders and provided effective rehabilitative options to improve speech perception. We studied two groups of OPA1 subjects, one comprising 11 patients (seven males; age range 13-79 years) carrying OPA1 mutations inducing haploinsufficiency, the other, 10 subjects (three males; age range 5-58 years) carrying OPA1 missense mutations. Both groups underwent audiometric assessment with pure tone and speech perception evaluation, and otoacoustic emissions and auditory brainstem response recording. Cochlear potentials were recorded through transtympanic electrocochleography from the group of patients harbouring OPA1 missense mutations and were compared to recordings obtained from 20 control subjects with normal hearing and from 19 subjects with cochlear hearing loss. Eight patients carrying OPA1 missense mutations underwent cochlear implantation. Speech perception measures and electrically-evoked auditory nerve and brainstem responses were obtained after 1 year of cochlear implant use. Nine of 11 patients carrying OPA1 mutations inducing haploinsufficiency had normal hearing function. In contrast, all but one subject harbouring OPA1 missense mutations displayed impaired speech perception, abnormal brainstem responses and presence of otoacoustic emissions consistent with auditory neuropathy. In electrocochleography recordings, cochlear microphonic had enhanced amplitudes while summating potential showed normal latency and peak amplitude consistent with preservation of both outer and inner hair cell activities. After cancelling the cochlear microphonic, the synchronized neural response seen in both normally-hearing controls and subjects with cochlear hearing loss was replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration during rapid stimulation consistent with neural generation. The use of cochlear implant improved speech perception in all but one patient. Brainstem potentials were recorded in response to electrical stimulation in five of six subjects, whereas no compound action potential was evoked from the auditory nerve through the cochlear implant. These findings indicate that underlying the hearing impairment in patients carrying OPA1 missense mutations is a disordered synchrony in auditory nerve fibre activity resulting from neural degeneration affecting the terminal dendrites. Cochlear implantation improves speech perception and synchronous activation of auditory pathways by bypassing the site of lesion.

Reduced phosphatidylinositol 4,5-bisphosphate synthesis impairs inner ear Ca2+ signaling and high-frequency hearing acquisition.

Phosphatidylinositol phosphate kinase type 1γ (PIPKIγ) is a key enzyme in the generation of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] and is expressed at high levels in the nervous system. Homozygous knockout mice lacking this enzyme die postnatally within 24 h, whereas PIPKIγ(+/-) siblings breed normally and have no reported phenotype. Here we show that adult PIPKIγ(+/-) mice have dramatically elevated hearing thresholds for high-frequency sounds. During the first postnatal week we observed a reduction of ATP-dependent Ca(2+) signaling activity in cochlear nonsensory cells. Because Ca(2+) signaling under these conditions depends on inositol-1,4,5-trisphosphate generation from phospholipase C (PLC)-dependent hydrolysis of PI(4,5)P(2), we conclude that (i) PIPKIγ is primarily responsible for the synthesis of the receptor-regulated PLC-sensitive PI(4,5)P(2) pool in the cell syncytia that supports auditory hair cells; (ii) spatially graded impairment of this signaling pathway in cochlear nonsensory cells causes a selective alteration in the acquisition of hearing in PIPKIγ(+/-) mice. This mouse model also suggests that PIPKIγ may determine the level of gap junction contribution to cochlear development.

Evaluating benefits of cochlear implantation in deaf children with additional disabilities.

OBJECTIVES: Cochlear-implanted deaf children having additional disabilities may develop speech perception and language skills at a slower pace than their implanted peers without such disorders. Nevertheless, it has been shown that, even for these special cases, cochlear implantation (CI) provides benefits for a larger range of neuropsychological functions including social and relational skills. These benefits are frequently mentioned by parents, but rarely objectively measured by tests. This article presents a new evaluation tool aimed at assessing the global benefits offered by CI in these special cases. DESIGN: The new tool has been designed as a closed-format questionnaire, divided into five areas. It is based on observing the frequency of preselected behaviors in daily activities, which imply specific social, neuropsychological, and perceptual skills. The questionnaire has been presented to the parents of 50 deaf children with additional disabilities, before and at least 6 months after CI. RESULTS: The data show significant improvements in all investigated areas. However, not all skills improve in the same way, and only those skills related to language and communication correlate positively with time after implantation. The present article further discusses changes in skills for which parents have higher expectations, such as the preferred communication mode, speech intelligibility, and the ability to communicate on the telephone. CONCLUSIONS: The questionnaire has a simple-to-use format, and it has been proven to be sufficiently sensitive for the detection of changes in each examined area. Because the questionnaire is based on observed behaviors, it can be used even when other existing tests involve tasks that are too complex for these children.

Temporal bone high-resolution computed tomography in non-syndromic unilateral hearing loss in children.

OBJECTIVE: The aim of this study was to disclose possible inner ear abnormalities/pathologies by means of high-resolution computed tomography (HRCT) of the temporal bone (TBHRCT) in children with unilateral hearing loss (UHL). METHODS: Retrospective review of audiological evaluation and TBHRCT in 22 children with UHL. RESULTS: Two thirds of the children showed profound hearing loss. Review of HRCT scans identified inner ear malformations/pathologies in 9 (41%) cases and a high jugular bulb (HJB), always dehiscent with the vestibular aqueduct, in another 5 (22%). Inner ear malformations included enlarged vestibular aqueduct, common cavity and cochleovestibular hypoplasia, while labyrinthine ossification was the detected pathology. In 1 child, the common cavity of the right ear was associated with congenital melanocytic naevus of the left eyelid and lipomeningocele. To the best of our knowledge, this condition has never been described. CONCLUSIONS: The aetiology of UHL may be revealed in more than half of patients by means of TBHRCT. Besides common inner ear abnormalities, TBHRCT should be evaluated carefully to rule out HJB, dehiscences, diverticulum or erosion of inner ear structures.

Primary tumors and tumor-like lesions of the eustachian tube: a systematic review of an emerging entity.

Eustachian tube (ET) primary tumors and tumor-like lesions are rare diseases presenting with common ear, nose and throat symptoms. Pathology can range from developmental anomalies to high malignant neoplasms. Hence this review aimed at suggesting a classification and outline relevant aspects of ET primary tumors and tumor-like lesions, describing clinical findings, diagnostic management and therapeutic approaches. MEDLINE, CINAHL, OVIDSP, HIGHWIRE, and GOOGLE databases were searched from inception to July 2011 for relevant studies. Further papers were identified by examining the reference lists of all included. Sixty-five papers met the inclusion criteria, enclosing 78 cases. Case reports are increasing in the past few years. Benign lesions and tumor-like lesions of ET have been reported. Moreover, melanomas, carcinomas, and sarcomas can affect the ET as a primary site.

BAAV mediated GJB2 gene transfer restores gap junction coupling in cochlear organotypic cultures from deaf Cx26Sox10Cre mice.

The deafness locus DFNB1 contains GJB2, the gene encoding connexin26 and GJB6, encoding connexin30, which appear to be coordinately regulated in the inner ear. In this work, we investigated the expression and function of connexin26 and connexin30 from postnatal day 5 to adult age in double transgenic Cx26(Sox10Cre) mice, which we obtained by crossing connexin26 floxed mice with a deleter Sox10-Cre line. Cx26(Sox10Cre) mice presented with complete connexin26 ablation in the epithelial gap junction network of the cochlea, whereas connexin30 expression was developmentally delayed; immunolabeling patterns for both connexins were normal in the cochlear lateral wall. In vivo electrophysiological measurements in Cx26(Sox10Cre) mice revealed profound hearing loss accompanied by reduction of endocochlear potential, and functional experiments performed in postnatal cochlear organotypic cultures showed impaired gap junction coupling. Transduction of these cultures with a bovine adeno associated virus vector restored connexin26 protein expression and rescued gap junction coupling. These results suggest that restoration of normal connexin levels by gene delivery via recombinant adeno associated virus could be a way to rescue hearing function in DFNB1 mouse models and, in future, lead to the development of therapeutic interventions in humans.

The novel PMCA2 pump mutation Tommy impairs cytosolic calcium clearance in hair cells and links to deafness in mice.

The mechanotransduction process in hair cells in the inner ear is associated with the influx of calcium from the endolymph. Calcium is exported back to the endolymph via the splice variant w/a of the PMCA2 of the stereocilia membrane. To further investigate the role of the pump, we have identified and characterized a novel ENU-induced mouse mutation, Tommy, in the PMCA2 gene. The mutation causes a non-conservative E629K change in the second intracellular loop of the pump that harbors the active site. Tommy mice show profound hearing impairment from P18, with significant differences in hearing thresholds between wild type and heterozygotes. Expression of mutant PMCA2 in CHO cells shows calcium extrusion impairment; specifically, the long term, non-stimulated calcium extrusion activity of the pump is inhibited. Calcium extrusion was investigated directly in neonatal organotypic cultures of the utricle sensory epithelium in Tommy mice. Confocal imaging combined with flash photolysis of caged calcium showed impairment of calcium export in both Tommy heterozygotes and homozygotes. Immunofluorescence studies of the organ of Corti in homozygous Tommy mice showed a progressive base to apex degeneration of hair cells after P40. Our results on the Tommy mutation along with previously observed interactions between cadherin-23 and PMCA2 mutations in mouse and humans underline the importance of maintaining the appropriate calcium concentrations in the endolymph to control the rigidity of cadherin and ensure the function of interstereocilia links, including tip links, of the stereocilia bundle.

Abnormal cochlear potentials from deaf patients with mutations in the otoferlin gene.

Otoferlin is involved in neurotransmitter release at the synapse between inner hair cells (IHCs) and auditory nerve fibres, and mutations in the OTOF gene result in severe to profound hearing loss. Abnormal sound-evoked cochlear potentials were recorded with transtympanic electrocochleography from four children with otoferlin (OTOF) mutations to evaluate physiological effects in humans of abnormal neurotransmitter release from IHCs. The subjects were profoundly deaf with absent auditory brainstem responses and preserved otoacoustic emissions consistent with auditory neuropathy. Two children were compound heterozygotes for mutations c.2732_2735dupAGCT and p.Ala964Glu; one subject was homozygous for mutation p.Phe1795Cys, and one was compound heterozygote for two novel mutations c.1609delG in exon 16 and c.1966delC in exon 18. Cochlear potentials evoked by clicks from 60 to 120 dB peak equivalent sound pressure level were compared to recordings obtained from 16 normally hearing children. Cochlear microphonic (CM) was recorded with normal amplitudes from all but one ear. After cancelling CM, cochlear potentials were of negative polarity with reduced amplitude and prolonged duration compared to controls. These cochlear potentials were recorded as low as 50-90 dB below behavioural thresholds in contrast to the close correlation in controls between cochlear potentials and behavioural threshold. Summating potential was identified in five out of eight ears with normal latency whilst auditory nerve compound action potentials were either absent or of low amplitude. Stimulation at high rates reduced amplitude and duration of the prolonged potentials, consistent with neural generation. This study suggests that mechano-electrical transduction and cochlear amplification are normal in patients with OTOF mutations. The low-amplitude prolonged negative potentials are consistent with decreased neurotransmitter release resulting in abnormal dendritic activation and impairment of auditory nerve firing.

Identification of a novel mutation in the SLC26A4 gene in an Italian with fluctuating sensorineural hearing loss.

Pendred syndrome is an autosomal recessive disorder characterized by congenital sensorineural deafness, goitre and defective iodide organification. Congenital and profound hearing loss is the hallmark of the syndrome, while goitre and thyroid dysfunction are highly variable even within the same family. Clinical features are due to altered formation of pendrin, a chloride/iodide transporter protein expressed in the inner ear, thyroid gland and kidney. A novel substitution was found in exon 7 of the pendrin encoding gene (SLC26A4) that leads to a stop codon, S314X. The new variation was found in compound heterozygosity with L445W mutation in a hearing impaired patient with bilateral Mondini's dysplasia and goitre.

Comparison of speech perception performance between Sprint/Esprit 3G and Freedom processors in children implanted with nucleus cochlear implants.

OBJECTIVE: To compare speech perception performance in children fitted with previous generation Nucleus sound processor, Sprint or Esprit 3G, and the Freedom, the most recently released system from the Cochlear Corporation that features a larger input dynamic range. STUDY DESIGN: Prospective intrasubject comparative study. SETTING: University Medical Center. SUBJECTS: Seventeen prelingually deafened children who had received the Nucleus 24 cochlear implant and used the Sprint or Esprit 3G sound processor. INTERVENTION: Cochlear implantation with Cochlear device. MAIN OUTCOME MEASURES: Speech perception was evaluated at baseline (Sprint, n = 11; Esprit 3G, n = 6) and after 1 month's experience with the Freedom sound processor. Identification and recognition of disyllabic words and identification of vowels were performed via recorded voice in quiet (70 dB [A]), in the presence of background noise at various levels of signal-to-noise ratio (+10, +5, 0, -5) and at a soft presentation level (60 dB [A]). Consonant identification and recognition of disyllabic words, trisyllabic words, and sentences were evaluated in live voice. Frequency discrimination was measured in a subset of subjects (n = 5) by using an adaptive, 3-interval, 3-alternative, forced-choice procedure. RESULTS: Identification of disyllabic words administered at a soft presentation level showed a significant increase when switching to the Freedom compared with the previously worn processor in children using the Sprint or Esprit 3G. Identification and recognition of disyllabic words in the presence of background noise as well as consonant identification and sentence recognition increased significantly for the Freedom compared with the previously worn device only in children fitted with the Sprint. Frequency discrimination was significantly better when switching to the Freedom compared with the previously worn processor. CONCLUSION: Serial comparisons revealed that that speech perception performance evaluated in children aged 5 to 15 years was superior with the Freedom than previous generations of Nucleus sound processors. These differences are deemed to ensue from an increased input dynamic range, a feature that offers potentially enhanced phonemic discrimination.

Hearing loss features in GJB2 biallelic mutations and GJB2/GJB6 digenic inheritance in a large Italian cohort.

The aim of this study was to describe the clinical features of hearing loss due to mutations on connexin 26/30 coding genes (GJB2/GJB6). Mutations in the GJB2 gene are found to account for approximately 50% of cases of autosomal recessive non-syndromic deafness. Several European studies have estimated that the GJB2 healthy carrier condition involves about 2-4% of the population, with the 35delG mutations being the most common. A 342-kb deletion truncating the GJB6 gene (encoding connexin-30) has been associated with autosomal recessive non-syndromic deafness, mostly as digenic inheritance of the Cx30 deletion/Cx26 mutation. The following retrospective study describes audiological features and genotypes of a large cohort of 376 Italian hearing-impaired patients who underwent genetic screening for the GJB2/GJB6 genes and received follow-up care at our centre between January 2002 and October 2006. Sixteen different genotypes causing deafness in more than 27% of patients with either biallelic mutations or digenic inheritance GJB2/GJB6 were identified. The most frequent mutations were 35delG, M34T, L90P, and R184P.

A novel missense mutation in the Connexin 26 gene associated with autosomal recessive nonsyndromic sensorineural hearing loss in a consanguineous Tunisian family.

Nonsyndromic sensorineural hearing impairment is inherited in a predominantly autosomal recessive manner in up to 70% of cases. The gene more often involved is GJB2, encoding the gap junction protein Connexin 26. We report here a novel missense mutation in the GJB2 gene found in a Tunisian family. A homozygous change C/G at nucleotide 263 was detected in the 4-year-old girl of this family, affected by congenital moderate hearing loss. This transversion leads to the replacement of a highly conserved alanine with glycine at codon 88 (A88G). The consanguineous parents of the child are healthy carriers of the mutation.

Cochlear implantation in deaf children with associated disabilities: challenges and outcomes.

The issue of cochlear implantation in deaf children with associated disabilities is an emerging subject. Currently, there is no consensus on whether to implant children with multiple impairments; moreover, it may be difficult to evaluate these children with standard tests pre- or post-implantation. In addition, these children often have poor speech perception and language skills, making assessment more difficult. Despite these factors, these children often receive important benefits in daily life, with an overall improvement in quality of life. In the present study, post-implant outcomes of 23 profoundly deaf children with neuropsychiatric disorders were analysed, using objective measures of speech perception, and a questionnaire administered to the parents, aimed at evaluating the benefits in daily life after implantation. The results were quite variable, but overall positive, in terms of speech perception, communication abilities, and improvement in quality of life. The findings add an additional piece of evidence to support the effectiveness of cochlear implantation in these special cases.

A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy.

Autosomal recessive nonsyndromic hearing impairment (NSHI) is a heterogeneous condition, for which 53 genetic loci have been reported, and 29 genes have been identified to date. One of these, OTOF, encodes otoferlin, a membrane-anchored calcium-binding protein that plays a role in the exocytosis of synaptic vesicles at the auditory inner hair cell ribbon synapse. We have investigated the prevalence and spectrum of deafness-causing mutations in the OTOF gene. Cohorts of 708 Spanish, 83 Colombian, and 30 Argentinean unrelated subjects with autosomal recessive NSHI were screened for the common p.Gln829X mutation. In compound heterozygotes, the second mutant allele was identified by DNA sequencing. In total, 23 Spanish, two Colombian and two Argentinean subjects were shown to carry two mutant alleles of OTOF. Of these, one Colombian and 13 Spanish subjects presented with auditory neuropathy. In addition, a cohort of 20 unrelated subjects with a diagnosis of auditory neuropathy, from several countries, was screened for mutations in OTOF by DNA sequencing. A total of 11 of these subjects were shown to carry two mutant alleles of OTOF. In total, 18 pathogenic and four neutral novel alleles of the OTOF gene were identified. Haplotype analysis for markers close to OTOF suggests a common founder for the novel c.2905_2923delinsCTCCGAGCGCA mutation, frequently found in Argentina. Our results confirm that mutation of the OTOF gene correlates with a phenotype of prelingual, profound NSHI, and indicate that OTOF mutations are a major cause of inherited auditory neuropathy.

Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy.

OBJECTIVE: Transtympanic electrocochleography (ECochG) was recorded bilaterally in children and adults with auditory neuropathy (AN) to evaluate receptor and neural generators. METHODS: Test stimuli were clicks from 60 to 120dB p.e. SPL. Measures obtained from eight AN subjects were compared to 16 normally hearing children. RESULTS: Receptor cochlear microphonics (CMs) in AN were of normal or enhanced amplitude. Neural compound action potentials (CAPs) and receptor summating potentials (SPs) were identified in five AN ears. ECochG potentials in those ears without CAPs were of negative polarity and of normal or prolonged duration. We used adaptation to rapid stimulus rates to distinguish whether the generators of the negative potentials were of neural or receptor origin. Adaptation in controls resulted in amplitude reduction of CAP twice that of SP without affecting the duration of ECochG potentials. In seven AN ears without CAP and with prolonged negative potential, adaptation was accompanied by reduction of both amplitude and duration of the negative potential to control values consistent with neural generation. In four ears without CAP and with normal duration potentials, adaptation was without effect consistent with receptor generation. In five AN ears with CAP, there was reduction in amplitude of CAP and SP as controls but with a significant decrease in response duration. CONCLUSIONS: Three patterns of cochlear potentials were identified in AN: (1) presence of receptor SP without CAP consistent with pre-synaptic disorder of inner hair cells; (2) presence of both SP and CAP consistent with post-synaptic disorder of proximal auditory nerve; (3) presence of prolonged neural potentials without a CAP consistent with post-synaptic disorder of nerve terminals. SIGNIFICANCE: Cochlear potential measures may identify pre- and post-synaptic disorders of inner hair cells and auditory nerves in AN.

Cochlear implantation outcome in prelingually deafened young adults. A speech perception study.

The outcome of cochlear implantation in patients with deafness of prelingual onset is largely unpredictable due to high individual variability. This study evaluated speech perception performances in a group of 18 prelingually deafened subjects (aged 13-30 years) which was homogeneous with respect to duration of deafness, hearing aid use before cochlear implantation, mode of communication and administration of auditory-oral speech therapy. Word discrimination length, word and sentence identification, phoneme identification and word and sentence recognition were tested before cochlear implantation and at 6 months, 1, 2 and 3 years of cochlear implant use. Scores on all tests significantly improved after cochlear implantation, although mean values were lower compared to those achieved by postlingually deafened patients. Speech performances on both word and sentence recognition continued to increase over time also beyond 1 year after cochlear implantation. Moreover, scores on sentence recognition tests were significantly higher compared to disyllabic words at 3 years of cochlear implant use. The presence of an auditory input delivered by hearing aids before cochlear implantation associated with auditory-oral therapy and a good level of education may positively influence the cochlear implant outcome in prelingually deafened adults.

Audiological and electrocochleography findings in hearing-impaired children with connexin 26 mutations and otoacoustic emissions.

We recorded cochlear potentials by transtympanic electrocochleography (ECochG) in three hearing-impaired children with GJB2 mutation who showed otoacoustic emissions. Pure tone thresholds, distortion product otoacoustic emissions (DPOAEs) and, auditory brainstem responses (ABRs) were also obtained. Subjects 1 (35delG/35delG) and 3 (M34T/wt) had profound hearing loss and showed the picture of auditory neuropathy (AN) as DPOAEs were detected with absent ABRs in both ears. The hearing impairment found in subject 2 (35delG/35delG) was profound in the right ear and moderate in the left ear. Both DPOAEs and ABRs with normal latencies and morphology were recorded only from the left ear. On the ECochG recording the cochlear microphonic was obtained from all children. No compound action potential (CAP) was detected in subject 1. A neural response was recorded only from the left ear in subject 2 with a threshold corresponding to the audiometric threshold while no CAP was detected on the right side. The ECochG obtained from subject 3 showed a low-amplitude broad negative deflection which was identifiable down to low stimulus levels. This response decreased in amplitude and duration when utilizing a high-rate stimulation paradigm. The amount of amplitude reduction was close to that calculated for normal ears, thus revealing the presence of an adapting neural component. These findings indicate that patients with GJB2 mutations and preserved outer hair cells function could present with the picture of AN. The hearing impairment is underlain by a selective inner hair cell loss or a lesion involving the synapses and/or the auditory nerve terminals. We suggest that neonatal hyperbilirubinemia may play a role in protecting outer hair cells against the damage induced by GJB2 mutations.

Pathogenetic role of the deafness-related M34T mutation of Cx26.

Mutations in the GJB2 gene, which encodes the gap junction protein connexin26 (Cx26), are the major cause of genetic non-syndromic hearing loss. The role of the allelic variant M34T in causing hereditary deafness remains controversial. By combining genetic, clinical, biochemical, electrophysiological and structural modeling studies, we have re-assessed the pathogenetic role of the M34T mutation. Genetic and audiological data indicate that the majority of heterozygous carriers and all five compound heterozygotes exhibited an impaired auditory function. Functional expression in transiently transfected HeLa cells showed that, although M34T was correctly synthesized and targeted to the plasma membrane, it inefficiently formed intercellular channels that displayed an abnormal electrical behavior and retained only 11% of the unitary conductance of the wild-type protein (HCx26wt). Moreover, M34T channels failed to support the intercellular diffusion of Lucifer Yellow and the spreading of mechanically induced intercellular Ca2+ waves. When co-expressed together with HCx26wt, M34T exerted dominant-negative effects on cell-cell coupling. Our findings are consistent with a structural model, predicting that the mutation leads to a constriction of the channel pore. These data support the view that M34T is a pathological variant of Cx26 associated with hearing impairment.

Auditory neuropathy in systemic sclerosis: a speech perception and evoked potential study before and after cochlear implantation.

We report the results of speech perception and electrophysiological evaluation of the auditory periphery performed before and after cochlear implantation in a 18-year-old girl with systemic sclerosis (SS) who presented the clinical picture of auditory neuropathy. Transtympanic electrocochleography (ECochG) in response to 0.1 ms clicks was recorded 1 month before cochlear implantation on both sides while the electrically evoked neural response was obtained intraoperatively in the right ear through cochlear implant stimulation. The ECochG recordings revealed the presence of the cochlear microphonic with normal amplitude and threshold on both sides. A compound action potential was only detected in the left ear at high stimulation intensity, while the electrically evoked neural response was clearly identifiable at all the recording sites during neural response telemetry. Standardized speech perception tests were performed 1 month before cochlear implantation and several times after cochlear implant connection. Speech perception scores were close to chance before cochlear implantation while they showed a remarkable improvement thereafter. The results of this study show that subjects affected by SS could present the clinical picture of auditory neuropathy which is possibly underlain by lesions involving the distal portion of auditory nerve fibers and/or synapses with inner hair cells. The restoration of synchronous neural discharge could be achieved by electrical stimulation through cochlear implant.

Effects of isoflurane on auditory middle latency (MLRs) and steady-state (SSRs) responses recorded from the temporal cortex of the rat.

Auditory steady-state responses (SSRs) are believed to result from superimposition of middle latency responses (MLRs) evoked by individual stimuli during repetitive stimulation. Our previous studies showed that besides linear addition of MLRs, other phenomena, mainly related to the adaptive properties of neural sources, interact in a complex way to generate the SSRs recorded from the temporal cortex of awake rats. The aim of this study was to evaluate the effects of the inhalational general anesthetic, isoflurane, on MLRs and SSRs at several repetition rates (30-60 Hz) recorded from the temporal cortex of rats. Auditory evoked potentials were obtained by means of epidural electrodes in the awake condition and during anesthesia at three isoflurane concentrations (0.38, 0.76 and 1.13 vol.% in oxygen). MLR latency significantly increased during anesthesia in a concentration-dependent manner, while MLR amplitude, even when significantly attenuated with respect to the mean awake baseline value, failed to correlate with isoflurane concentration. SSRs decreased in amplitude and increased in phase during anesthesia in a concentration-dependent manner and the anesthetic-induced decrease of SSR amplitude appeared to be higher than the corresponding MLR attenuation. SSR prediction curves synthesized by linear addition of MLRs failed to predict SSRs in both amplitude and phase. Moreover, phase discrepancies proved to be higher during anesthesia. Our results suggest that MLRs and SSRs recorded from the temporal cortex of the rat exhibit differential sensitivity to isoflurane and that isoflurane could enhance the role of rate-dependent effects in SSR generation.