Auditory Nerve Dysfunction Research Articles

Peripheral Auditory Nerve Impairment in a Mouse Model of Syndromic Autism.

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (Mef2c-Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c-Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types; and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments.SIGNIFICANCE STATEMENT This is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human MEF2C haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.

Identifying three otopathologies in humans

ObjectivesHearing-in-noise (HIN) is a primary complaint of both the hearing impaired and the hearing aid user. Both auditory nerve (AN) function and outer hair cell (OHC) function are thought to contribute to HIN, but their relative contributions are still being elucidated. OHCs play a critical role in HIN by fine tuning the motion of the basilar membrane. Further, animal studies suggest that cochlear (auditory) synaptopathy, which is the loss of synaptic contact between hair cells and the AN, may be another cause of HIN difficulty. While there is evidence that cochlear synaptopathy occurs in animal models, there is debate as to whether cochlear synaptopathy is clinically significant in humans, which may be due to disparate methods of measuring noise exposure in humans and our high variability in susceptibility to noise damage. Rather than use self-reported noise exposure to define synaptopathic groups, this paper assumes that the general population exhibits a range of noise exposures and resulting otopathologies and defines cochlear synaptopathy “operationally” as low CAP amplitude accompanied by normal DPOAE levels in persons with low pure tone averages. The first question is whether the standard audiogram detects AN dysfunction and OHC dysfunction? The second question is whether HIN performance is primarily dependent on AN function, OHC function, or both functions? DesignAdult subjects have been recruited to participate in an ongoing study and variables such as age, self-reported gender, pure tone audiometry (0.25–20 kHz), subjective perception of HIN difficulty, Quick Speech-in Noise (QuickSIN) test, 45% time compressed word recognition (WR) in 10% reverberation and WR in the presence of ipsilateral speech-weighted noise have been collected. These variables were correlated with OHC function measured by distortion-product otoacoustic emission (DPOAE) signal to-noise-ratio (SNR), and AN function measured by compound action potential (CAP) peak amplitude and ratio to summating potential measured using electrocochleography. ResultsSynaptopathy, by this operational definition, may be present in as many as 30% of individuals with normal hearing. Persons hearing within normal limits may exhibit HIN difficulties, and persons with hearing within normal limits may exhibit two distinct types of otopathologies undetected by the standard audiogram (a.k.a. hidden hearing loss) namely operational cochlear synaptopathy and OHC dysfunction. AN untuning secondary to OHC dysfunction is a third otopathology that occurs in subjects with a Mild–Moderate sensorineural hearing loss (SNHL). Clinical norms for each of these otopathologies are presented. Finally, the data show that operational cochlear synaptopathy does not correlate with HIN dysfunction. Rather, HIN performance is primarily governed by OHC function, while AN untuning also plays a lesser but statistically significant role. ConclusionsThe results of this study suggest the following: (1) persons hearing within normal limits may exhibit HIN difficulties; (2) persons hearing within normal limits may exhibit undetected otopathologies, namely AN dysfunction and OHC dysfunction; (3) AN untuning secondary to OHC dysfunction occurs in subjects with Mild–Moderate SNHL; (4) HIN performance is primarily governed by OHC function rather than AN function.

A multi-metric approach to characterizing mouse peripheral auditory nerve function using the auditory brainstem response

BackgroundThe auditory brainstem response (ABR), specifically wave I, is widely used to noninvasively measure auditory nerve (AN) function. Recent work in humans has introduced novel electrocochleographic measures to comprehensively characterize AN function that emphasize suprathreshold processing and estimate neural synchrony. New MethodThis study establishes new tools for evaluating AN function in vivo in adult mice using tone-evoked ABRs obtained from young-adult CBA/CaJ mice, adapting the approach previously introduced in humans. Six metrics are obtained from ABR wave I at suprathreshold stimulus levels. ResultsChange-point analyses show that the metrics’ rate of change with stimulus level differs between moderate and high suprathreshold levels, suggesting that this approach can potentially characterize the presence of heterogeneous AN fiber types. Comparison with existing methodsTraditional ABR approaches focus on response thresholds and averaged amplitudes/latencies. In contrast, our multi-metric approach, which uses single-trial data and suprathreshold stimuli, provides novel information and identifies evidence of neural synchrony deficits and changes in the heterogeneity of AN fibers underlying AN behavior. ConclusionThe techniques reported here provide a novel tool to assess changes in AN function in vivo in a commonly used animal model. A benchmark of most current hearing research is the transition from animal to human studies. Here we established a translational objective approach, applying methods that were first developed in humans to animals. This approach enables researchers to identify changes in AN function arising from the animal models with well-characterized pathology, and predict similar pathological changes in human AN dysfunction and hearing loss.

Isolated auditory neuropathy at birth in congenital cytomegalovirus infection

BackgroundCongenital cytomegalovirus (cCMV) infection is the most frequent non-genetic cause of sensorineural hearing-loss (SNHL) (i.e., hearing loss due to a cochlear and/or auditory nerve damage). It is widely accepted that SNHL at birth, when associated to cCMV symptomatic infection involving the central nervous system, benefits from antiviral therapy started in the neonatal period. Conversely, there is no consensus for antiviral treatment in congenitally infected infants diagnosed with isolated SNHL (i.e., SNHL in an otherwise asymptomatic infant) at birth.Our aim was to assess the frequency and the auditory outcome of isolated SNHL at birth due to auditory neuropathy (AN) (i.e., SNHL in a patient with normal cochlear function and auditory nerve dysfunction) in infants with cCMV infection.MethodsWe retrospectively reviewed the clinical history of 60 infants, born at term, with cCMV asymptomatic infection, without additional risk factors for SNHL, and exhibiting bilateral “pass” otoacustic emissions (OAE). None of them underwent antiviral therapy.Hearing thresholds were assessed by means of Auditory Brainstem Responses (ABR). AN affected children were followed up until possible normalization of the hearing thresholds or definitive diagnosis of AN. Each infant diagnosed with monolateral or bilateral AN was classified according to the worst ear threshold.ResultsIn our population, the first ABR was performed at a mean age of 5.00 ± 2.79 (SD) months and AN was diagnosed in 16/60 (26.67%) infants; in 4 infants the AN was defined as mild (4/4 monolateral), moderate in 11 (5/11 bilateral), and severe in 1 (bilateral). The mean age at first ABR was 3.69 ± 2.80 (SD) months in the 16 babies with AN and 5.48 ± 2.66 (SD) months in the 44 infants with normal hearing (p = 0.007). All AN cases spontaneously recovered a normal auditory threshold over time. The mean length of the audiological follow-up was 32.44 ± 17.58 (SD) months (range 5–60 months).ConclusionA delayed maturation of the auditory pathways should be considered when a mild/moderate isolated AN at birth is detected in cCMV infected infants. Prospective studies conducted on larger populations, and with a longer audiological follow-up, are needed to confirm our findings.

Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series.

BackgroundThe most common inherited peripheral neuropathy is Charcot‐Marie‐Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known.MethodsThe aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype‐genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed.ResultsHearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype‐phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4. ConclusionInvolvement of PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN.

Long‑term treatment with salicylate enables NMDA receptors and impairs AMPA receptors in C57BL/6J mice inner hair cell ribbon synapse.

Salicylate is widely used to produce animal models of tinnitus in mice and/or rats. The side effects on auditory function, including hearing loss and tinnitus, are considered the results of the auditory nerve dysfunction. A recent study indicated that chronic treatment with salicylate for several weeks reduces compressed action potential amplitude, which is contradictory to the studies reporting excessive activation of N-methyl-D-aspartate receptors (NMDAR) in tinnitus-induced animals. The specific aims of the experiment were to detect the effect of salicylate on the inner hair cells (IHCs), ribbon synapse, as well as the association between the hearing threshold and the number of mismatched ribbon synapses. In the present study, mice were injected intraperitoneally with a low dose of salicylate (200 mg/kg) for 14 days. The auditory brainstem response and otoacoustic emission were measured to assess auditory function of the mice. The postsynaptic regions of IHC were identified with two types of immunostaining targets: Postsynaptic density protein 95 and Glu2/3. The number of spheres was counted and the synapses were reconstructed in 3-dimensional images. Increases in distortion product otoacoustic emissions amplitudes of the salicylate group were detected, however, an elevation in the hearing threshold was also observed. A mismatch between pre-and post-ribbon synapses was observed. In addition, the cochlear components, including the numbers of outer hair cells and IHCs, were unlikely to be affected by salicylate. IHC ribbon synapses were more susceptible to salicylate stimuli. Furthermore, mismatch of pre- and post-ribbon synapses may indicate a competitive inhibition between NMDAR and α-amino-3-hydroxy-5-methyl-4-isoxa-zole-propionate receptors and dysfunction of ribbon synapses.

Electrophysiology of Cranial Nerve Testing: Auditory Nerve.

The electrocochleogram and brainstem auditory evoked potentials (BAEPs) are electrophysiologic signals used to assess the auditory nerve. The electrocohleogram includes the cochlear microphonic, the cochlear summating potential, and the eighth nerve compound action potential. It is used predominantly for hearing assessment and for diagnosis of Ménière disease and auditory neuropathy. Brainstem auditory evoked potentials are used for hearing assessment, diagnosis of dysfunction within the cochlea, the auditory nerve, and the brainstem auditory pathways up to the level of the mesencephalon, and intraoperative monitoring of these structures. The earliest BAEP component, wave I, and the eighth nerve compound action potential reflect the same process-the initial depolarization in the distal auditory nerve. Brainstem auditory evoked potential wave II receives contributions from the region of the cochlear nucleus and from the second depolarization in the distal auditory nerve. Wave III and later components are entirely generated rostral to the auditory nerve. Interpretation of BAEP studies is based on waves I, III, and V; auditory nerve dysfunction is manifested as prolongation of the I-III interpeak interval or absence of waves III and V. Eighth nerve tumors can cause a variety of BAEP abnormalities depending on which structures they affect. Adverse intraoperative BAEP changes can have many etiologies, including direct mechanical or thermal injury of tissue, ischemia (including cochlear ischemia or infarction due to compromise of the internal auditory artery), eighth nerve stretch, systemic or localized hypothermia, and artifactual BAEP changes due to technical factors.

Complementary metrics of human auditory nerve function derived from compound action potentials.

Declines in auditory nerve (AN) function contribute to suprathreshold auditory processing and communication deficits in individuals with normal hearing, hearing loss, hyperacusis, and tinnitus. Procedures to characterize AN loss or dysfunction in humans are limited. We report several novel complementary metrics using the compound action potential (CAP), a direct measure of summated AN activity. Together, these metrics may be used to characterize AN function noninvasively in humans. We examined how these metrics change with stimulus intensity and interpreted these changes within a framework of known physiological properties of the basilar membrane and AN. Our results reveal how neural synchrony and the recruitment of AN fibers with longer first-spike latencies likely contribute to the CAP, affect auditory processing, and differ with noise exposure history in younger adults with normal pure-tone thresholds. Moving forward, this new battery of metrics provides a crucial step toward new diagnostics of AN function in humans. NEW & NOTEWORTHY Loss or inactivity of auditory nerve (AN) fibers is thought to contribute to suprathreshold auditory processing deficits, but evidence-based methods to assess these effects are not available. We describe several novel metrics that together may be used to quantify neural synchrony and characterize AN function in humans.

Outer Hair Cell and Auditory Nerve Function in Speech Recognition in Quiet and in Background Noise.

The goal of this study was to describe the contribution of outer hair cells (OHCs) and the auditory nerve (AN) to speech understanding in quiet and in the presence of background noise. Fifty-three human subjects with hearing ranging from normal to moderate sensorineural hearing loss were assayed for both speech in quiet (Word Recognition) and speech in noise (QuickSIN test) performance. Their scores were correlated with OHC function as assessed via distortion product otoacoustic emissions, and AN function as measured by amplitude, latency, and threshold of the VIIIth cranial nerve Compound Action Potential (CAP) recorded during electrocochleography (ECochG). Speech and ECochG stimuli were presented at equivalent sensation levels in order to control for the degree of hearing sensitivity across patients. The results indicated that (1) OHC dysfunction was evident in the lower range of normal audiometric thresholds, which demonstrates that OHC damage can produce “Hidden Hearing Loss,” (2) AN dysfunction was evident beginning at mild levels of hearing loss, (3) when controlled for normal OHC function, persons exhibiting either high or low ECochG amplitudes exhibited no statistically significant differences in neither speech in quiet nor speech in noise performance, (4) speech in noise performance was correlated with OHC function, (5) hearing impaired subjects with OHC dysfunction exhibited better speech in quiet performance at or near threshold when stimuli were presented at equivalent sensation levels. These results show that OHC dysfunction contributes to hidden hearing loss, OHC function is required for optimum speech in noise performance, and those persons with sensorineural hearing loss exhibit better word discrimination in quiet at or near their audiometric thresholds than normal listeners.

Distinction between auditory electrophysiological responses in type 1 and type 2 diabetic animal models

Neurological research has focused recently on determining the molecular mechanisms of common causes of damage to the peripheral and central nervous systems. One of the metabolic systemic diseases that can result in sensorineural hearing loss is diabetic mellitus (DM). In this study, we aimed to compare the auditory electrophysiological responses present in animal models of type 1 and type 2 DM using auditory brainstem response (ABR), auditory middle latency response (AMLR), and transient evoked otoacoustic emission (TEOAE) in animal model. We found that ABR threshold shifts and latency delays were similar in both types of DM. On the other hand, we found that type 2 diabetic mice exhibited more severe dysfunction to the central auditory pathway, as measured AMLRs and the cochlear hair cells, as measured TEOAEs. These results together suggest that hyperglycemia associated with type 1 or type 2 DM causes auditory nerve dysfunction, while hyperinsulinemia associated with type 2 DM causes dysfunction to both the central auditory pathways and cochlear hair cells.

Optic and auditory pathway dysfunction in demyelinating neuropathies

The involvement of optic and auditory pathways has rarely been studied in demyelinating polyneuropathies. We here aimed to study this further in a cohort of patients with acquired and gentic demyelinating neuropathy. We studied eight patients with hereditary neuropathy with liability to pressure palsies (HNPP), six with Charcot-Marie-Tooth disease type 1A (CMT1A), ten with chronic inflammatory demyelinating polyneuropathy (CIDP) and seven with antimyelin-associated glycoprotein (MAG) neuropathy using visual evoked potentials and brainstem auditory evoked potentials. Optic pathway dysfunction was detected in 6/7 anti-MAG neuropathy patients, about half of those with CIDP and HNPP, but only in 1/6 patients with CMT1A. Peripheral auditory nerve dysfunction appeared common in all groups except HNPP. Brainstem involvement was exceptional in all groups. We conclude optic nerve involvement may be frequent in all demyelinating polyneuropathies, particularly anti-MAG neuropathy, except in CMT1A. Peripheral auditory nerves may be spared in HNPP possibly due to absence of local compression. Evidence for central brainstem pathology appeared infrequent in all four studied neuropathies. This study suggests that acquired and genetic demyelinating polyneuropathies may be associated with optic and auditory nerve involvement, which may contribute to neurological disability, and require greater awareness.

Auditory cortical N100 in pre- and post-synaptic auditory neuropathy to frequency or intensity changes of continuous tones

ObjectivesAuditory cortical N100s were examined in ten auditory neuropathy (AN) subjects as objective measures of impaired hearing. MethodsLatencies and amplitudes of N100 in AN to increases of frequency (4–50%) or intensity (4–8dB) of low (250Hz) or high (4000Hz) frequency tones were compared with results from normal-hearing controls. The sites of auditory nerve dysfunction were pre-synaptic (n=3) due to otoferlin mutations causing temperature sensitive deafness, post-synaptic (n=4) affecting other cranial and/or peripheral neuropathies, and undefined (n=3). ResultsAN consistently had N100s only to the largest changes of frequency or intensity whereas controls consistently had N100s to all but the smallest frequency and intensity changes. N100 latency in AN was significantly delayed compared to controls, more so for 250 than for 4000Hz and more so for changes of intensity compared to frequency. N100 amplitudes to frequency change were significantly reduced in ANs compared to controls, except for pre-synaptic AN in whom amplitudes were greater than controls. N100 latency to frequency change of 250 but not of 4000Hz was significantly related to speech perception scores. ConclusionsAs a group, AN subjects’ N100 potentials were abnormally delayed and smaller, particularly for low frequency. The extent of these abnormalities differed between pre- and post-synaptic forms of the disorder. SignificanceAbnormalities of auditory cortical N100 in AN reflect disorders of both temporal processing (low frequency) and neural adaptation (high frequency). Auditory N100 latency to the low frequency provides an objective measure of the degree of impaired speech perception in AN.

Hyperacusis and Phonophobia in Williams Syndrome

Event Abstract Back to Event Hyperacusis and Phonophobia in Williams Syndrome O. Zarchi1*, J. Attias1 and D. Gothelf1, 2 1 Schneider Children's Medical Center of Israel, The Behavioral Neurogenetics Center, Israel 2 Tel Aviv University, Sackler Faculty of Medicine, Israel Hyperacusis and phonophobia are among the most salient features of Williams syndrome (WS) and affect the life of most children carrying the syndrome. We have investigated the clinical characteristics and neuroaudiological pathways mediating the hyperacusis in 49 children and adolescents with WS. Compared to controls, subjects with WS showed 20dB lower discomfort level thresholds, high-frequency cochlear hearing, distortion products otoacoustic emission, higher prevalence of ipsilateral acoustic reflex (AR) absence, and prolonged wave I latency of the BAER. Subjects with WS also showed increased suppression effect of the MOC reflex. The findings of the study suggest that hyperacusis in WS is associated with a highfrequency hearing loss resembling the configuration of noise induced hearing loss. The hyperacusis and hearing loss in WS may stem from a deficiency in AR, resulting from auditory nerve dysfunction. Hyperexcitability of the medial olivocochlear efferent system coupled with AR absence further enhance hyperacusis in subjects with WS. Additionally, we present preliminary results suggesting abnormal central auditory processing in WS as evident by mismatch negativity ERP findings. Conference: 12th International Professional Conference on Williams Syndrome, Garden Grove,CA, United States, 13 Jul - 14 Jul, 2008. Presentation Type: Oral Presentation Topic: SESSION 5: Anxiety and Other Psychiatric Problems Citation: Zarchi O, Attias J and Gothelf D (2009). Hyperacusis and Phonophobia in Williams Syndrome. Conference Abstract: 12th International Professional Conference on Williams Syndrome. doi: 10.3389/conf.neuro.09.2009.07.017 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Apr 2009; Published Online: 30 Apr 2009. * Correspondence: O. Zarchi, Schneider Children's Medical Center of Israel, The Behavioral Neurogenetics Center, Petach Tikvah, Israel, omer_zar@yahoo.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers O. Zarchi J. Attias D. Gothelf Google O. Zarchi J. Attias D. Gothelf Google Scholar O. Zarchi J. Attias D. Gothelf PubMed O. Zarchi J. Attias D. Gothelf Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

The Impact of Petrosal Vein Preservation on Postoperative Auditory Function in Surgery of Petrous Apex Meningiomas

The importance of preserving the superior petrosal vein has received increasing attention in the surgical treatment of pathologies involving the petrous apex. Recent reports have associated postoperative auditory nerve dysfunction with petrosal vein sacrifice. However, there is no systematic clinical study available thus far focusing on the postoperative auditory function after petrosal vein obliteration. In 55 patients with meningiomas involving the petrous apex, pre- and intraoperative findings including petrosal vein sectioning were analyzed retrospectively concerning their impact on postoperative auditory function. The petrosal vein was preserved in 26 (47%) cases. In 27 (49%) cases, this vein was not preserved. Hearing loss occurred in 11% of all cases. In the preserved-vein group, postoperative hearing loss occurred in 3 of 26 (11%) cases and in the sacrificed-vein group in 3 of 27 (11%) cases. Sacrifice of the petrosal vein during surgery of petrous apex meningiomas seems not to have an impact on postoperative auditory function.

Hyperacusis in Williams syndrome

Hyperacusis and phonophobia are common, debilitating symptoms in Williams syndrome (WS), yet little is known about their underlying audiologic and neurologic processes. The mothers of 49 subjects with WS were asked to complete the Hyperacusis Screening Questionnaire. Subjects with reported hyperacusis and sufficient developmental capacity underwent comprehensive audiological and brain auditory evoked response (BAER) testing. Findings were compared with those from pair-matched typically developing control subjects. Forty-one of the 49 children with WS (84%) had hyperacusis of moderate to severe degree, which began in infancy. Of these, 21 (mean age 15.8 +/- 5.5 years) were quantitatively tested. Subjects with WS reported discomfort at sound intensities on average 20 dB lower than control subjects. Pure-tone audiometry and distortion products otoacoustic emission test revealed a high-frequency cochlear hearing loss. An absence of ipsilateral acoustic reflex responses to maximum stimulation was significantly more common in the subjects with WS than controls. On BAER testing, the WS group had a significant prolongation in wave I latency. Hyperacusis in Williams syndrome (WS) is associated with a high-frequency hearing loss resembling the configuration of noise-induced hearing loss. The hyperacusis and hearing loss in WS may stem from a deficiency in the acoustic reflex resulting from auditory nerve dysfunction. Additional mechanisms that may mediate hyperacusis in WS and should be evaluated in future studies include recruitment, malformation of the facial canal, and haploinsufficiency of the elastin gene.

Macrophage colony stimulating factor (M-CSF) protects spiral ganglion neurons following auditory nerve injury: morphological and functional evidence

Because hearing disturbance due to auditory nerve dysfunction imposes a formidable burden on human beings, intense efforts have been expended in experimental and clinical studies to discover ways to restore normal hearing. However, the great majority of these investigations have focused on the peripheral process side of bipolar auditory neurons, and very few trials have focused on ways to halt degenerative processes in auditory neurons from the central process side (in the cerebellopontine angle). In the present study, we investigated whether administration of macrophage colony-stimulating factor (M-CSF) could protect auditory neurons in a rat model of nerve injury. The electrophysiological and morphological results of our study indicated that M-CSF could ameliorate both anterograde (Wallerian) and retrograde degeneration in both the CNS and PNS portions of the auditory nerve. We attribute the success of M-CSF therapy to the reported functional dichotomy (having the potential to cause both neuroprotective and neurotoxic effects) of microglia and macrophages. Whether the activities of microglia/macrophages are neuroprotective or neurotoxic may depend upon the nature of the stimulus that activates the cells. In the present study, the neuroprotective effects of M-CSF that were observed could have been due to M-CSF we administered and to M-CSF released from endothelial cells, resident cells of the CNS parenchyma, or infiltrating macrophages. Another possibility is that M-CSF ameliorated apoptotic auditory neuronal death, although this hypothesis remains to be proved in future studies.

Hearing loss as a complication of Paget's disease of bone.

Hearing loss has long been known to be a complication of Paget's disease of bone. Older ideas about the mechanisms of hearing loss are being replaced by a new view based on experimental evidence from patients. Studies reviewed show no evidence of auditory nerve dysfunction and confirm a cochlear site of lesion. A loss of bone mineral density in the cochlear capsule is associated with both a high-tone hearing loss and a low-tone air-bone gap.

Neurophysiologic study of olivopontocerebellar atrophy with or without glutamate dehydrogenase deficiency.

By neurophysiologic investigations, we evaluated 20 patients with olivopontocerebellar atrophy (OPCA), comprising 8 with glutamate dehydrogenase (GDH) deficiency and 12 with normal GDH activity. We found sensorimotor, predominantly sensory axonal neuropathy distally in the legs, and peripheral auditory nerve dysfunction (prolonged wave I but normal interpeak latencies in brainstem auditory evoked response) in GDH-deficient patients. These findings seem distinctive enough to serve as the electrophysiologic marker for diagnosis and monitoring of treatment and progression of the disease. The pattern-reversal visual and median nerve somatosensory evoked responses did not differ among the patients and controls.