Auditory function in Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD; MIM 312080), an inherited defect of central nervous system myelin formation, affects individuals in many ways, including their hearing and language abilities. The aim of this study was to assess the auditory abilities in 18 patients with PMD by examining the functional processes along the central auditory pathways using auditory brainstem responses (ABR) and cortical auditory evoked potentials (CAEP) in response to speech sounds. The significant ABR anomalies confirm the existence of dyssynchrony previously described at the level of the brainstem in patients with PMD. Despite the significant auditory dyssynchrony observed at the level of the brainstem, CAEPs were present in most patients, albeit somehow abnormal in terms of morphology and latency, resembling a type of auditory neuropathy spectrum disorder.

Flow cytometry for receptor analysis from ex-vivo brain tissue in adult rat.

BACKGROUND: Flow cytometry allows single-cell analysis of peripheral biological samples and is useful in many fields of research and clinical applications, mainly in hematology, immunology, and oncology. In the neurosciences, the flow cytometry separation method was first applied to stem cell extraction from healthy or cerebral tumour tissue and was more recently tested in order to phenotype brain cells, hippocampal neurogenesis, and to detect prion proteins. However, it remains sparsely applied in quantifying membrane receptors in relation to synaptic plasticity. NEW METHOD: We aimed to optimize a flow cytometric procedure for receptor quantification in neurons and non-neurons. A neural dissociation process, myelin separation, fixation, and membrane permeability procedures were optimized to maximize cell survival and analysis in hippocampal tissue obtained from adult rodents. We then aimed to quantify membrane muscarinic acetylcholine receptors (mAChRs) in rats with and without bilateral vestibular loss (BVL). RESULTS: mAChR's were quantified for neuronal and non-neuronal cells in the hippocampus and striatum following BVL. At day 30 but not at day 7 following BVL, there was a significant increase (P ≤ 0.05) in the percentage of neurons expressing M2/4 mAChRs in both the hippocampus and the striatum. CONCLUSION: Here, we showed that flow cytometry appears to be a reliable method of membrane receptor quantification in ex-vivo brain tissue.

Hidden hearing loss and endbulbs of Held: Evidence for central pathology before detection of ABR threshold increases.

Reductions in sound-evoked activity in the auditory nerve due to hearing loss have been shown to cause pathological changes in central auditory structures. Hearing loss due strictly to the aging process are less well documented. In this study of CBA/CaH mice, we provide evidence for age-related pathology in the endbulb of Held, a large axosomatic ending arising from myelinated auditory nerve fibers. Endbulbs are known to be involved in the processing of temporal cues used for sound localization and speech comprehension. Hearing thresholds as measured by auditory brainstem response (ABR) thresholds remained stable up to one year, whereas suprathreshold amplitudes of early ABR waves decreased by up to 50% in older mice, similar to that reported for age-related cochlear synaptopathy (Sergeyenko et al., 2013). The reduction of ABR response magnitude with age correlated closely in time with the gradual atrophy of endbulbs of Held, and is consistent with the hypothesis that endbulb integrity is dependent upon normal levels of spike activity in the auditory nerve. These results indicate that central auditory pathologies emerge as consequence of so-called "hidden" hearing loss and suggest that such brain changes require consideration when devising therapeutic interventions.

Auditory Pathway Features Determined by DTI in Subjects with Unilateral Acoustic Neuroma.

PURPOSE: In the studies concerning the pathology of the auditory pathway in the vestibulocochlear system, few use advanced neuroimaging applications of magnetic resonance imaging (MRI) such as diffusion tensor imaging (DTI). Those who did use reported DTI changes only at the lateral lemniscus and inferior colliculus level. The aim of our study was to determine diffusion changes in the bilateral auditory pathways of subjects with unilateral acoustic neuroma (AN) and compare them with healthy controls. MATERIAL AND METHODS: A total of 15 subjects with unilateral AN along with 11 controls underwent routine MRI and DTI. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values obtained from the lateral lemniscus, inferior colliculus, corpus geniculatum mediale, and Heschl's gyrus of the auditory pathway were then compared. RESULTS: The subjects' ADC values measured from the contralateral side were significantly higher at the lateral lemniscus, inferior colliculus, and corpus geniculatum mediale compared with those of the controls. Also, decreased FA values were noted at the inferior colliculus for both the contralateral and ipsilateral sides. The highest ADC values were detected in the inferior colliculus of the auditory pathway. CONCLUSIONS: In the auditory pathway of subjects with AN, the contralateral side is more affected than the ipsilateral side, the most affected region being the inferior colliculus. DTI is an advanced neuroimaging technique that can be used to determine the presence of microstructural damage to the auditory pathway in subjects with AN, whereas conventional MRI is not sensitive enough to detect damage.

Loss of auditory activity modifies the location of potassium channel KCNQ5 in auditory brainstem neurons.

KCNQ5/Kv7.5, a low-threshold noninactivating voltage-gated potassium channel, is preferentially targeted to excitatory endings of auditory neurons in the adult rat brainstem. Endbulds of Held from auditory nerve axons on the bushy cells of the ventral cochlear nucleus (VCN) and calyces of Held around the principal neurons in the medial nucleus of the trapezoid body (MNTB) are rich in KCNQ5 immunoreactivity. We have previously shown that this synaptic distribution occurs at about the time of hearing onset. The current study tests whether this localization in excitatory endings depends on the peripheral activity carried by the auditory nerve. Auditory nerve activity was abolished by cochlear removal or intracochlear injection of tetrodotoxin (TTX). Presence of KCNQ5 was analyzed by immunocytochemistry, Western blotting, and quantitative reverse transcription polymerase chain reaction. After cochlear removal, KCNQ5 immunoreactivity was virtually undetectable at its usual location in endbulbs and calyces of Held in the anteroventral CN and in the MNTB, respectively, although it was found in cell bodies in the VCN. The results were comparable after intracochlear TTX injection, which drastically reduced KCNQ5 immunostaining in MNTB calyces and increased immunolabeling in VCN cell bodies. Endbulbs of Held in the VCN also showed diminished KCNQ5 labeling after intracochlear TTX injection. These results show that peripheral activity from auditory nerve afferents is necessary to maintain the subcellular distribution of KCNQ5 in synaptic endings of the auditory brainstem. This may contribute to adaptations in the excitability and neurotransmitter release properties of these presynaptic endings under altered input conditions.

Imaging for cochlear implantation: structuring a clinically relevant report.

Cochlear implantation is a proven treatment for bilateral severe to profound hearing loss. Imaging has an important role in deciding candidacy, providing realistic preoperative counselling, and predicting postoperative outcomes. Imaging also provides information about the potential difficulties a surgeon may encounter during the implantation. High-resolution computed tomography and high-resolution magnetic resonance imaging complement each other in assessing different aspects of the temporal bone and the auditory pathway in such patients. This review provides a structured format for reading pre-cochlear implant imaging studies with special focus on the surgeon's expectations in order to prepare a clinically relevant report. A constant communication between the imaging specialist and the cochlear implant surgeon improves image interpretation and ensures a successful implantation.

Environmental acoustic enrichment promotes recovery from developmentally degraded auditory cortical processing.

It has previously been shown that environmental enrichment can enhance structural plasticity in the brain and thereby improve cognitive and behavioral function. In this study, we reared developmentally noise-exposed rats in an acoustic-enriched environment for ∼4 weeks to investigate whether or not enrichment could restore developmentally degraded behavioral and neuronal processing of sound frequency. We found that noise-exposed rats had significantly elevated sound frequency discrimination thresholds compared with age-matched naive rats. Environmental acoustic enrichment nearly restored to normal the behavioral deficit resulting from early disrupted acoustic inputs. Signs of both degraded frequency selectivity of neurons as measured by the bandwidth of frequency tuning curves and decreased long-term potentiation of field potentials recorded in the primary auditory cortex of these noise-exposed rats also were reversed partially. The observed behavioral and physiological effects induced by enrichment were accompanied by recovery of cortical expressions of certain NMDA and GABAA receptor subunits and brain-derived neurotrophic factor. These studies in a rodent model show that environmental acoustic enrichment promotes recovery from early noise-induced auditory cortical dysfunction and indicate a therapeutic potential of this noninvasive approach for normalizing neurological function from pathologies that cause hearing and associated language impairments in older children and adults.

Diffusion tensor imaging and MR morphometry of the central auditory pathway and auditory cortex in aging.

Age-related hearing loss (presbycusis) is caused mainly by the hypofunction of the inner ear, but recent findings point also toward a central component of presbycusis. We used MR morphometry and diffusion tensor imaging (DTI) with a 3T MR system with the aim to study the state of the central auditory system in a group of elderly subjects (>65years) with mild presbycusis, in a group of elderly subjects with expressed presbycusis and in young controls. Cortical reconstruction, volumetric segmentation and auditory pathway tractography were performed. Three parameters were evaluated by morphometry: the volume of the gray matter, the surface area of the gyrus and the thickness of the cortex. In all experimental groups the surface area and gray matter volume were larger on the left side in Heschl's gyrus and planum temporale and slightly larger in the gyrus frontalis superior, whereas they were larger on the right side in the primary visual cortex. Almost all of the measured parameters were significantly smaller in the elderly subjects in Heschl's gyrus, planum temporale and gyrus frontalis superior. Aging did not change the side asymmetry (laterality) of the gyri. In the central part of the auditory pathway above the inferior colliculus, a trend toward an effect of aging was present in the axial vector of the diffusion (L1) variable of DTI, with increased values observed in elderly subjects. A trend toward a decrease of L1 on the left side, which was more pronounced in the elderly groups, was observed. The effect of hearing loss was present in subjects with expressed presbycusis as a trend toward an increase of the radial vectors (L2L3) in the white matter under Heschl's gyrus. These results suggest that in addition to peripheral changes, changes in the central part of the auditory system in elderly subjects are also present; however, the extent of hearing loss does not play a significant role in the central changes.

The neglected neglect: auditory neglect.

Whereas visual and somatosensory forms of neglect are commonly recognized by clinicians, auditory neglect is often not assessed and therefore neglected. The auditory cortical processing system can be functionally classified into 2 distinct pathways. These 2 distinct functional pathways deal with recognition of sound ("what" pathway) and the directional attributes of the sound ("where" pathway). Lesions of higher auditory pathways produce distinct clinical features. Clinical bedside evaluation of auditory neglect is often difficult because of coexisting neurological deficits and the binaural nature of auditory inputs. In addition, auditory neglect and auditory extinction may show varying degrees of overlap, which makes the assessment even harder. Shielding one ear from the other as well as separating the ear from space is therefore critical for accurate assessment of auditory neglect. This can be achieved by use of specialized auditory tests (dichotic tasks and sound localization tests) for accurate interpretation of deficits. Herein, we have reviewed auditory neglect with an emphasis on the functional anatomy, clinical evaluation, and basic principles of specialized auditory tests.

Auditory dysfunction.

Hearing impairment, although uncommon, may occur in patients with a vertebrobasilar artery occlusion disease. The pathogenesis may be an ischemic lesion involving the auditory pathways in the pons and midbrain, the cochlear nucleus, cochlear nerve or the cochlea. The AICA and IAA are the main arteries that supply the peripheral audiovestibular structures of the inner ear and central audiovestibular pathways of the middle cerebellar peduncle and lateral pons.

Neural network modeling of central auditory dysfunction in Alzheimer's disease.

BACKGROUND: Many reports have described that individuals with Alzheimer's disease show neural breakdown in the brainstem nuclei, hippocampus and auditory cortex in the temporal lobe of the brain. However, it is still unclear whether auditory skills mediated by these areas differ across individuals with and without Alzheimer's disease and how these auditory skills are further confounded by reduction in cognitive function in individuals with AD. AIM: The aim of this study is to discover the hidden and nonlinear associations among higher-order auditory and cognitive processes in individuals with and without Alzheimer's disease through artificial neural network analysis. METHODS: The analyses were based on auditory test data obtained from nine clinically confirmed Alzheimer's disease cases and nine age-matched controls. Hearing threshold sensitivity was equivalent across groups, indicating similar peripheral auditory function. Auditory function was evaluated by standardized tests of auditory closure, auditory attention, and auditory figure ground in listeners with and without Alzheimer's disease. The inputs used for analyses were cognitive status and auditory function. The dependent variables were RAU scores computed from scores of auditory tests. RESULTS: Artificial neural networks showed a complex relationship between the input variables (cognitive status and auditory function) that cannot be predicted simply on the basis of cognition differences between individuals with and without Alzheimer's disease. CONCLUSION: The results of this study suggest that central auditory function declines with age, regardless of changes in cognitive function.

Onset coding is degraded in auditory nerve fibers from mutant mice lacking synaptic ribbons.

Synaptic ribbons, found at the presynaptic membrane of sensory cells in both ear and eye, have been implicated in the vesicle-pool dynamics of synaptic transmission. To elucidate ribbon function, we characterized the response properties of single auditory nerve fibers in mice lacking Bassoon, a scaffolding protein involved in anchoring ribbons to the membrane. In bassoon mutants, immunohistochemistry showed that fewer than 3% of the hair cells' afferent synapses retained anchored ribbons. Auditory nerve fibers from mutants had normal threshold, dynamic range, and postonset adaptation in response to tone bursts, and they were able to phase lock with normal precision to amplitude-modulated tones. However, spontaneous and sound-evoked discharge rates were reduced, and the reliability of spikes, particularly at stimulus onset, was significantly degraded as shown by an increased variance of first-spike latencies. Modeling based on in vitro studies of normal and mutant hair cells links these findings to reduced release rates at the synapse. The degradation of response reliability in these mutants suggests that the ribbon and/or Bassoon normally facilitate high rates of exocytosis and that its absence significantly compromises the temporal resolving power of the auditory system.

Pitch discrimination in cerebellar patients: evidence for a sensory deficit.

In the last two decades, a growing body of research showing cerebellar involvement in an increasing number of nonmotor tasks and systems has prompted an expansion of speculations concerning the function of the cerebellum. Here, we tested the predictions of a hypothesis positing cerebellar involvement in sensory data acquisition. Specifically, we examined the effect of global cerebellar degeneration on primary auditory sensory function by means of a pitch discrimination task. The just noticeable difference in pitch between two tones was measured in 15 healthy controls and in 15 high functioning patients afflicted with varying degrees of global cerebellar degeneration caused by hereditary, idiopathic, paraneoplastic, or postinfectious pancerebellitis. Participants also performed an auditory detection task assessing sustained attention, a test of verbal auditory working memory, and an audiometric test. Patient pitch discrimination thresholds were on average five and a half times those of controls and were proportional to the degree of cerebellar ataxia assessed independently. Patients and controls showed normal hearing thresholds and similar performance in control tasks in sustained attention and verbal auditory working memory. These results suggest there is an effect of cerebellar degeneration on primary auditory function. The findings are consistent with other recent demonstrations of cerebellar-related sensory impairments, and with robust cerebellar auditorily evoked activity, confirmed by quantitative meta-analysis, across a range of functional neuroimaging studies dissociated from attention, motor, affective, and cognitive variables. The data are interpreted in the context of a sensory hypothesis of cerebellar function.

Evaluation of inner hair cell and nerve fiber loss as sufficient pathologies underlying auditory neuropathy.

Auditory neuropathy is a hearing disorder characterized by normal function of outer hair cells, evidenced by intact cochlear microphonic (CM) potentials and otoacoustic emissions (OAEs), with absent or severely dys-synchronized auditory brainstem responses (ABRs). To determine if selective lesions of inner hair cells (IHCs) and auditory nerve fibers (ANFs) can account for these primary clinical features of auditory neuropathy, we measured physiological responses from chinchillas with large lesions of ANFs (about 85%) and IHCs (45% loss in the apical half of the cochlea; 73% in the basal half). Distortion product OAEs and CM potentials were significantly enhanced, whereas summating potentials and compound action potentials (CAPs) were significantly reduced. CAP threshold was elevated by 7.5dB, but response synchrony was well preserved down to threshold levels of stimulation. Similarly, ABR threshold was elevated by 5.6dB, but all waves were present and well synchronized down to threshold levels in all animals. Thus, large lesions of IHCs and ANFs reduced response amplitudes but did not abolish or severely dys-synchronize CAPs or ABRs. Pathologies other than or in addition to ANF and IHC loss are likely to account for the evoked potential dys-synchrony that is a clinical hallmark of auditory neuropathy in humans.

Spinocerebellar ataxia type 4 (SCA4): Initial pathoanatomical study reveals widespread cerebellar and brainstem degeneration.

Spinocerebellar ataxia type 4 (SCA4), also known as 'hereditary ataxia with sensory neuropathy', represents a very rare, progressive and untreatable form of an autosomal dominant inherited cerebellar ataxia (ADCA). Due to a lack of autopsy cases, no neuropathological or clinicopathological studies had yet been performed in SCA4. In the present study, the first available cerebellar and brainstem tissue of a clinically diagnosed and genetically-confirmed German SCA4 patient was pathoanatomically studied using serial thick sections. During this systematic postmortem investigation, along with an obvious demyelinization of cerebellar and brainstem fiber tracts we observed widespread cerebellar and brainstem neurodegeneration with marked neuronal loss in the substantia nigra and ventral tegmental area, central raphe and pontine nuclei, all auditory brainstem nuclei, in the abducens, principal trigeminal, spinal trigeminal, facial, superior vestibular, medial vestibular, interstitial vestibular, dorsal motor vagal, hypoglossal, and prepositus hypoglossal nuclei, as well as in the nucleus raphe interpositus, all dorsal column nuclei, and in the principal and medial subnuclei of the inferior olive. Severe neuronal loss was seen in the Purkinje cell layer of the cerebellum, in the cerebellar fastigial nucleus, in the red, trochlear, lateral vestibular, and lateral reticular nuclei, the reticulotegmental nucleus of the pons, and the nucleus of Roller. In addition, immunocytochemical analysis using the anti-polyglutamine antibody 1C2 failed to detect any polyglutamine-related immunoreactivity in the central nervous regions of this SCA4 patient studied. In view of the known functional role of affected nuclei and related fiber tracts, the present findings not only offer explanations for the well-known disease symptoms of SCA4 patients (i.e. ataxic symptoms, dysarthria and somatosensory deficits), but for the first time help to explain why diplopia, gaze-evoked nystagmus, auditory impairments and pathologically altered brainstem auditory evoked potentials, saccadic smooth pursuits, impaired somatosensory functions in the face, and dysphagia may occur during the course of SCA4. Finally, the results of our immunocytochemical studies support the concept that SCA4 is not a member of the CAG-repeat or polyglutamine diseases.

Auditory neuropathy: a potentially under-recognized neonatal intensive care unit sequela.

Auditory neuropathy (AN) is a hearing disorder that affects newborns. Those with high-risk neonatal histories, family history of childhood hearing loss, and hyperbilirubinemia are at greatest risk. Current neonatal intensive care unit (NICU) hearing screening methods that rely only on otoacoustic emissions will fail to detect this disorder. Auditory neuropathy differs from conductive hearing loss and sensorineural hearing loss; a specific constellation of findings on audiologic evaluation are diagnostic of this disorder. The pathophysiology of AN is unclear; however, it may be caused by demyelinization or degeneration at points along the auditory pathway. The actual incidence of AN is unknown; it is more prevalent in high-risk infants. The course of AN varies widely among patients. Current management ranges from close monitoring of the child's development to cochlear implantation. Neonatal intensive care unit nurses need to be aware of this disorder to help support and educate at-risk families and to alert them of the need to monitor hearing and language development in their infants.

"Auditory neuropathy": physiologic and pathologic evidence calls for more diagnostic specificity.

The term "auditory neuropathy" is being used in a rapidly increasing number of papers in the audiology/otolaryngology literature for a variety of individuals (mostly children) who fulfill the following criteria: (1) understanding of speech worse than predicted from the degree of hearing loss on their behavioral audiograms; (2) recordable otoacoustic emissions and/or cochlear microphonic; together with (3) absent or atypical auditory brain stem responses. Because of the general lack of anatomic foundation for the label "auditory neuropathy" as currently used, we review the anatomy of the auditory pathway, the definition of neuropathy and its demyelinating, axonal, and mixed variants. We submit that the diagnostic term "auditory neuropathy" is anatomically inappropriate unless patients have documented evidence for selective involvement of either the spiral ganglion cells or their axons, or of the 8th nerve as a whole. In view of biologic differences between peripheral nerves and white matter tracts in the brain, the term "auditory neuropathy" is inappropriate for pathologies affecting the central auditory pathway in the brainstem and brain selectively. Published reports of patients with "auditory neuropathy" indicate that they are extremely heterogeneous in underlying medical diagnosis, age, severity, test results, and that only a small number have undergone the detailed investigations that would enable a more precise diagnosis of the locus of their pathologies. The electrophysiology of peripheral neuropathies and the deficits expected with pathologies affecting the hair cells, spiral ganglion cells and their axons (auditory neuropathy sensu stricto), and brain stem relays are reviewed. In order to serve patients adequately, including potential candidates for cochlear implants, and to increase knowledge of auditory pathologies, we make a plea for more comprehensive evaluation of patients who fulfill the currently used audiologic criteria for "auditory neuropathy" in an effort to pinpoint the site of their pathologies. We suggest that the term auditory neuropathy be limited to cases in which the locus of pathology is limited to the spiral ganglion cells, their processes, or the 8th nerve, and that the term neural hearing loss be considered for pathologies that affect all higher levels of the auditory pathway, from the brainstem to the auditory cortex.

Deficits of musical timbre perception after unilateral temporal-lobe lesion revealed with multidimensional scaling.

Thirty patients with unilateral temporal lobe excisions and 15 normal control subjects were tested in a task involving judgements of timbre dissimilarity in single tone and melodic conditions. Perceptual correlates of spectral and temporal parameters resulting from changing the number of harmonics and rise-time duration, respectively, were investigated by using a multidimensional scaling technique. The results of subjects with left temporal lobe lesion suggest that they were able to use the spectral and temporal envelopes of tones independently in making perceptual judgements of single tones. In the melodic condition, their results were significantly different from those of normal control subjects, suggesting that left temporal lesions do affect subtle aspects of timbre perception, despite these patients' preserved ability to make discrimination judgements using traditional paradigms. The major finding of this study concerns perceptual ratings obtained by subjects with right temporal lobe lesion, which revealed a disturbed perceptual space in both conditions. The most distorted results were obtained with single tones, in which the temporal parameter was less prominent. Tones were grouped according to their spectral content, but the results did not reflect a coherent underlying perceptual dimension. In general, the data from both patient groups (left lesions and right lesions) showed that the extraction of temporal cues was easier in the melodic than in the single tone condition, suggesting that the different durations and frequencies heard in a musical phrase enhance the importance of certain physical parameters. The findings of the present study replicate and extend previous results showing that timbre perception depends mainly upon the integrity of right neocortical structures, although a contribution of left temporal regions is also apparent. These data also demonstrate that multidimensional techniques are sensitive to more subtle perceptual disturbances that may not be revealed by discrimination paradigms.

Cortical deafness to dissonance.

Ordinary listeners, including infants, easily distinguish consonant from dissonant pitch combinations and consider the former more pleasant than the latter. The preference for consonance over dissonance was tested in a patient, I.R., who suffers from music perception and memory disorders as a result of bilateral lesions to the auditory cortex. In Experiment 1, I.R. was found to be unable to distinguish consonant from dissonant versions of musical excerpts taken from the classical repertoire by rating their pleasantness. I.R.'s indifference to dissonance was not due to a loss of all affective responses to music, however, since she rated the same excerpts as happy or sad, as normal controls do. In Experiment 2, I.R.'s lack of responsiveness to varying degrees of dissonance was replicated with chord sequences which had been used in a previous study using PET, in examining emotional responses to dissonance. A CT scan of I.R.'s brain was co-registered with the PET activation data from normal volunteers. Comparison of I.R.'s scan with the PET data revealed that the damaged areas overlapped with the regions identified to be involved in the perceptual analysis of the musical input, but not with the paralimbic regions involved in affective responses. Taken together, the findings suggest that dissonance may be computed bilaterally in the superior temporal gyri by specialized mechanisms prior to its emotional interpretation.