Fabrice Giraudet

Hypervulnerability to Sound Exposure through Impaired Adaptive Proliferation of Peroxisomes

A deficiency in pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of human deafness. Pejvakin-deficient (Pjvk(-/-)) mice also exhibit variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggest a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation show that the cochlear sensory hair cells and auditory pathway neurons of Pjvk(-/-) mice and patients are exceptionally vulnerable to sound. Subcellular analysis revealed that pejvakin is associated with peroxisomes and required for their oxidative-stress-induced proliferation. Pjvk(-/-) cochleas display features of marked oxidative stress and impaired antioxidant defenses, and peroxisomes in Pjvk(-/-) hair cells show structural abnormalities after the onset of hearing. Noise exposure rapidly upregulates Pjvk cochlear transcription in wild-type mice and triggers peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the antioxidant activity of peroxisomes protects the auditory system against noise-induced damage.

Hearing Is Normal without Connexin30

Gjb2 and Gjb6, two contiguous genes respectively encoding the gap junction protein connexin26 (Cx26) and connexin 30 (Cx30) display overlapping expression in the inner ear. Both have been linked to the most frequent monogenic hearing impairment, the recessive isolated deafness DFNB1. Although there is robust evidence for the direct involvement of Cx26 in cochlear functions, the contribution of Cx30 is unclear since deletion of Cx30 strongly downregulates Cx26 both in human and in mouse. Thus, it is imperative that any role of Cx30 in audition be clearly evaluated. Here, we developed a new Cx30 knock-out mouse model (Cx30Δ/Δ) in which half of Cx26 expression was preserved. Our results show that Cx30 and Cx26 coordinated expression is dependent on the spacing of their surrounding chromosomic region, and that Cx30Δ/Δ mutants display normal hearing. Thus, in deaf patients with GJB6 deletion as well as in the previous Cx30 knock-out mouse model, defective Cx26 expression is the likely cause of deafness, and in contrast to current opinion, Cx30 is dispensable for cochlear functions.

Patient satisfaction and functional results with the bone-anchored hearing aid (BAHA)

OBJECTIVESnTo assess patient satisfaction with bone-anchored hearing aids (BAHA) and the role of preoperative audiometric testing.nnnPATIENTS AND METHODSnA telephone satisfaction survey was conducted on all patients implanted between June 1, 2005 and February 1, 2008. Patients with unilateral total deafness underwent preoperative audiometric tests in quiet and in noise and stereoaudiometry with and without BAHA. Patients with a conductive hearing loss underwent preoperative audiometric tests in quiet and in noise and real-life testing at home using a headband. A standardized satisfaction questionnaire derived from the Entific BAHA questionnaire was used.nnnRESULTSnTwenty-two out of 26 patients responded to the questionnaire. Ten patients were implanted for conductive hearing loss (CHL) and 12 for unilateral total deafness (UTD). Mean follow-up was 19 months in the UTD group and 21 months in the CHL group. Sixty-seven percent of UTD and 80% of CHL patients reported improved quality of life. The BAHA was worn for more than 4hours per day by 83% of UTD and 100% of CHL patients, and at least 5 days per week by 67% of UTD and 80% of CHL patients.nnnCONCLUSIONnBAHAs provided real benefit in all situations for CHL patients. In UTD, its benefit basically related to noisy environments. In UTD, satisfaction on preoperative stereoaudiometric testing in noise with and without BAHA was predictive of postimplantation satisfaction. In response to the question Would you do it again?, 81% of patients answered Yes.

Mice with a deletion of the major central myelin protein exhibit hypersensitivity to noxious thermal stimuli: involvement of central sensitization

Null mutations in the gene encoding the major myelin protein of the central nervous system, proteolipid protein 1 (PLP1), cause an X-linked form of spastic paraplegia (SPG2) associated with axonal degeneration. While motor symptoms are the best known manifestations of this condition, its somatosensory disturbances have been described but poorly characterized. We carried out a longitudinal study in an animal model of SPG2 - mice carrying a deletion of the Plp1 gene (Plp-null mice). Plp-null mice exhibited severe early-onset thermal hyperalgesia, in the absence of thermal allodynia. We first performed an electrophysiological testing which showed an early decrease in peripheral and spinal conduction velocities in Plp null mice. Such as the abnormal sensitive behaviors, this slowing of nerve conduction was observed before the development of myelin abnormalities at the spinal level, from 3months of age, and without major morphological defects in the sciatic nerve. To understand the link between a decrease in nerve velocity and an increased response to thermal stimuli before the appearance of myelin abnormalities, we focused our attention on the dorsal horn of the spinal cord, the site of integration of somatosensory information. Immunohistochemical studies revealed an early-onset activation of astrocytes and microglia that worsened with age, associated later in age with perturbation of the expression of the sensory neuropeptides calcitonin-gene-related peptide and galanin. Taken together, these results represent complementary data supporting the hypothesis that Plp-null mice suffer from ganglionopathy associated with late onset central demyelination but with few peripheral nerve alterations, induced by the glial-cell-mediated sensitization of the spinal cord. The mechanism suggested here could underlie pain experiments in other leukodystrophies as well as in other non-genetic demyelinating diseases such as multiple sclerosis.

Noninvasive detection of alarming intracranial pressure changes by auditory monitoring in early management of brain injury: a prospective invasive versus noninvasive study

BackgroundIn brain-injured patients intracranial pressure (ICP) is monitored invasively by a ventricular or intraparenchymal transducer. The procedure requires specific expertise and exposes the patient to complications such as malposition, hemorrhage or infection. As inner-ear fluid compartments are connected to the cerebrospinal fluid space, ICP changes elicit subtle changes in the physiology of the inner ear. Notably, we previously demonstrated that the phase of cochlear microphonic potential (CM) generated by sound stimuli rotates with ICP. The aim of our study was to validate the monitoring of CM as a noninvasive method to follow ICP.MethodsNon-invasive measure of CM-phase was compared to ICP recorded invasively in a prospective series of patients with acute brain injury managed in a neuro-intensive care unit. The study focused on patients with varying ICP and normal middle-ear function.ResultsIn the 24 patients with less than 4 days of endotracheal ventilation and whose ICP fluctuated (50-hour data), we demonstrated close correlation between CM-phase rotation and ICP (average 1.26 degrees/mmHg). As a binary classifier, CM phase changes of 7–10 degrees signaled 7.5-mmHg ICP increases with a sensitivity of 83% and 19% fallout.ConclusionReference methods to measure ICP require the surgical placement of a pressure transducer. Noninvasive CM-based monitoring of ICP might be beneficial to early management of brain-injured patients with initially preserved consciousness and to the diagnosis of neurological conditions, whenever invasive monitoring cannot be performed.Trial registrationClinicalTrials.gov NCT01685476, registered on 30 August 2012.

Measurement of endolymphatic pressure.

Endolymphatic pressure measurement is of interest both to researchers in the physiology and pathophysiology of hearing and ENT physicians dealing with Menières disease or similar conditions. It is generally agreed that endolymphatic hydrops is associated with Menières disease and is accompanied by increased hydrostatic pressure. Endolymphatic pressure, however, cannot be measured precisely without endangering hearing, making the association between hydrops and increased endolymphatic pressure difficult to demonstrate. Several integrated in vivo models have been developed since the 1960s, but only a few allow measurement of endolymphatic hydrostatic pressure. Models associating measurement of hydrostatic pressure and endolymphatic potential and assessment of cochlear function are of value to elucidate the pathophysiology of endolymphatic hydrops. The present article presents the main types of models and discusses their respective interest.

Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin

Abstract: Neurotoxicity remains the most common adverse effect of oxaliplatin, limiting its clinical use. In the present study, we developed a mouse model of chronic oxaliplatin‐induced neuropathy, which mimics both sensory and motor deficits observed in patients, in a clinically relevant time course. Repeated oxaliplatin administration in mice induced both cephalic and extracephalic long lasting mechanical and cold hypersensitivity after the first injection as well as delayed sensorimotor deficits and a depression‐like phenotype. Using this model, we report that riluzole prevents both sensory and motor deficits induced by oxaliplatin as well as the depression‐like phenotype induced by cumulative chemotherapeutic drug doses. All the beneficial effects are due to riluzole action on the TREK‐1 potassium channel, which plays a central role in its therapeutic action. Riluzole has no negative effect on oxaliplatin antiproliferative capacity in human colorectal cancer cells and on its anticancer effect in a mouse model of colorectal cancer. Moreover, riluzole decreases human colorectal cancer cell line viability in vitro and inhibits polyp development in vivo. The present data in mice may support the need to clinically test riluzole in oxaliplatin‐treated cancer patients and state for the important role of the TREK‐1 channel in pain perception. HighlightsRiluzole prevents oxaliplatin‐induced neuropathic adverse effects and comorbidities in mice.The TREK‐1 channel plays a central role in riluzole –induced anti neuropathic effect.Riluzole did not alter oxaliplatin‐induced anticancer effect in vitro and in vivo.Riluzole, per se, decreases human colorectal cancer cell line viability in vitro.Riluzole, per se, inhibits colorectal polyp development in mice.

Generalization of the primary tone phase variation method: An exclusive way of isolating the frequency-following response components

The primary tone phase variation (PTPV) technique combines selective sub-averaging with systematic variation of the phases of multitone stimuli. Each response component having a known phase relationship with the stimulus components phases can be isolated in the time domain. The method was generalized to the frequency-following response (FFR) evoked by a two-tone (f 1 and f 2) stimulus comprising both linear and non-linear, as well as transient components. The generalized PTPV technique isolated each spectral component present in the FFR, including those sharing the same frequency, allowing comparison of their latencies. After isolation of the envelope component f 2 - f 1 from its harmonic distortion 2f 2 - 2f 1 and from the transient auditory brainstem response, a computerized analysis of instantaneous amplitudes and phases was applied in order to objectively determine the onset and offset latencies of the response components. The successive activation of two generators separated by 3.7u2009ms could be detected in all (Nu2009=u200912) awake adult normal subjects, but in none (Nu2009=u200910) of the sleeping/sedated children with normal hearing thresholds. The method offers an unprecedented way of disentangling the various FFR subcomponents. These results open the way for renewed investigations of the FFR components in both human and animal research as well as for clinical applications.

Noninvasive in-ear monitoring of intracranial pressure during microgravity in parabolic flights

Among possible causes of visual impairment or headache experienced by astronauts in microgravity or postflight and that hamper their performance, elevated intracranial pressure (ICP) has been invoked but never measured for lack of noninvasive methods. The goal of this work was to test two noninvasive methods of ICP monitoring using in-ear detectors of ICP-dependent auditory responses, acoustic and electric, in acute microgravity afforded by parabolic flights. The devices detecting these responses were handheld tablets routinely used in otolaryngology for hearing diagnosis, which were customized for ICP extraction and serviceable by unskilled operators. These methods had been previously validated against invasive ICP measurements in neurosurgery patients. The two methods concurred in their estimation of ICP changes with microgravity, i.e., 11.0u2009±u20097.7 mmHg for the acoustic method ( n = 7 subjects with valid results out of 30, auditory responses being masked by excessive in-flight noise in 23 subjects) and 11.3u2009±u200910.6 mmHg for the electric method ( n = 10 subjects with valid results out of 10 tested despite the in-flight noise). These results agree with recent publications using invasive access to cerebrospinal fluid in parabolic flights and suggest that acute microgravity has a moderate average effect on ICP, similar to body tilt from upright to supine, yet with some subjects undergoing large effects whereas others seem immune. The electric in-ear method would be suitable for ICP monitoring in circumstances and with subjects such that invasive measurements are excluded. NEW & NOTEWORTHY In-ear detectors of intracranial pressure-dependent auditory responses allow intracranial pressure to be monitored noninvasively during acute microgravity. The average pressure increase during 20-s long sessions in microgravity is 11 mmHg, comparable with an effect of body tilt. However, intersubject variability is large, with subjects who repeatedly experience from nothing to twice the average effect. A systematic in-flight use would allow the relationship between space adaptation syndrome and ICP to be established or dismissed.

Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia

OBJECTIVESnIn patients with Friedreich ataxia (FRDA), mitochondrial failure leads to impaired cellular energetics. Since many FRDA patients have impaired hearing in noise, we investigated the objective consequences on standard auditory brainstem-evoked responses (ABRs).nnnMETHODSnIn 37 FRDA patients, among whom 34 with abnormal standard ABRs, hearing sensitivity, speech-in-noise intelligibility and otoacoustic emissions were controlled. ABR recordings were split into four consecutive segments of the total time frame used for data collection, thus allowing the dynamics of ABR averaging to be observed.nnnRESULTSnMost ears showed features of an auditory neuropathy spectrum disorder with flattened ABRs and impaired speech-in-noise intelligibility contrasting with near-normal hearing sensitivity and normal preneural responses. Yet split-ABRs revealed short-lived wave patterns in 26 out of 68 ears with flattened standard ABRs (38%). While averaging went on, the pattern of waves shifted so that interwave latencies increased by 35% on average.nnnCONCLUSIONSnIn FRDA, the assumption of stationarity used for extracting standard ABRs is invalid. The preservation of early split-ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure.nnnSIGNIFICANCEnThis model of metabolic sensory neuropathy warns against exposure of metabolically-impaired patients to sustained auditory stimulation.