The human OPA1delTTAG mutation induces adult onset and progressive auditory neuropathy in mice.

Dominant optic atrophy (DOA) is one of the most prevalent forms of hereditary optic neuropathies and is mainly caused by heterozygous variants in OPA1, encoding a mitochondrial dynamin-related large GTPase. The clinical spectrum of DOA has been extended to a wide variety of syndromic presentations, called DOAplus, including deafness as the main secondary symptom associated to vision impairment. To date, the pathophysiological mechanisms underlying the deafness in DOA remain unknown. To gain insights into the process leading to hearing impairment, we have analyzed the Opa1delTTAG mouse model that recapitulates the DOAplus syndrome through complementary approaches combining morpho-physiology, biochemistry, and cellular and molecular biology. We found that Opa1delTTAG mutation leads an adult-onset progressive auditory neuropathy in mice, as attested by the auditory brainstem response threshold shift over time. However, the mutant mice harbored larger otoacoustic emissions in comparison to wild-type littermates, whereas the endocochlear potential, which is a proxy for the functional state of the stria vascularis, was comparable between both genotypes. Ultrastructural examination of the mutant mice revealed a selective loss of sensory inner hair cells, together with a progressive degeneration of the axons and myelin sheaths of the afferent terminals of the spiral ganglion neurons, supporting an auditory neuropathy spectrum disorder (ANSD). Molecular assessment of cochlea demonstrated a reduction of Opa1 mRNA level by greater than 40%, supporting haploinsufficiency as the disease mechanism. In addition, we evidenced an early increase in Sirtuin 3 level and in Beclin1 activity, and subsequently an age-related mtDNA depletion, increased oxidative stress, mitophagy as well as an impaired autophagic flux. Together, these results support a novel role for OPA1 in the maintenance of inner hair cells and auditory neural structures, addressing new challenges for the exploration and treatment of OPA1-linked ANSD in patients.

Validation of a tablet-based application for hearing self-screening in an adult population.

OBJECTIVE: This study evaluated the diagnostic performances of a tablet-based hearing screening test by assisted-test and self-test modes. DESIGN/METHOD: Measurements were performed with the SoTone tests in normal hearing and hearing-impaired adult participants using an Android tablet and calibrated Bluetooth headphones. The duration of assisted- and self-test modes were compared. Receiver operating characteristic (ROC) curves were plotted after calculations of sensitivity and specificity at 20, 30, and 35 dB HL cut-off values. STUDY SAMPLE: 217 participants performed the tests. The effect of test mode (assisted versus self) was compared in a sample of 103 participants. RESULTS: Self-test duration (89 s) was significantly longer than the assisted-test duration (75 s) (p = 0.003, Wilcoxon test). For the 20, 30, and 35 dB HL cut-off values, sensitivity was between 92% and 96%, and specificity was between 79 and 90%. Concordance of results between assisted-test and self-test modes was excellent (Cohen's kappa = 0.81, p < 0.001). CONCLUSIONS: The SoTone hearing screening test is accurate for identifying the presence of a suspected hearing loss at 20 dB HL or more in adults. It can be used either in assisted-test or self-test modes.

Exacerbated age-related hearing loss in mice lacking the p43 mitochondrial T3 receptor.

BACKGROUND: Age-related hearing loss (ARHL), also known as presbycusis, is the most common sensory impairment seen in elderly people. However, the cochlear aging process does not affect people uniformly, suggesting that both genetic and environmental (e.g., noise, ototoxic drugs) factors and their interaction may influence the onset and severity of ARHL. Considering the potential links between thyroid hormone, mitochondrial activity, and hearing, here, we probed the role of p43, a N-terminally truncated and ligand-binding form of the nuclear receptor TRα1, in hearing function and in the maintenance of hearing during aging in p43-/- mice through complementary approaches, including in vivo electrophysiological recording, ultrastructural assessments, biochemistry, and molecular biology. RESULTS: We found that the p43-/- mice exhibit no obvious hearing loss in juvenile stages, but that these mice developed a premature, and more severe, ARHL resulting from the loss of cochlear sensory outer and inner hair cells and degeneration of spiral ganglion neurons. Exacerbated ARHL in p43-/- mice was associated with the early occurrence of a drastic fall of SIRT1 expression, together with an imbalance between pro-apoptotic Bax, p53 expression, and anti-apoptotic Bcl2 expression, as well as an increase in mitochondrial dysfunction, oxidative stress, and inflammatory process. Finally, p43-/- mice were also more vulnerable to noise-induced hearing loss. CONCLUSIONS: These results demonstrate for the first time a requirement for p43 in the maintenance of hearing during aging and highlight the need to probe the potential link between human THRA gene polymorphisms and/or mutations and accelerated age-related deafness or some adult-onset syndromic deafness.

[Early management of presbycusis: recommendations from the French Society of Otorhinolaryngology and Head and Neck Surgery, the French Society of Audiology, and the French Society of Geriatrics and Gerontology]. / Recommandations de la Société française d'otorhinolaryngologie et de chirurgie de la face et du cou, la Société française d'audiologie et la Société française de gériatrie et gérontologie pour la prise en charge précoce de la presbyacousie.

INTRODUCTION: Presbycusis is the physiological decrease in hearing due to advancing age and begins well before the sixth decade. These recommendations recall the principles of early diagnosis of presbycusis and the means of optimal rehabilitation as soon as the first symptoms appear. MATERIAL AND METHODS: The recommendations are based on a systematic analysis of the literature carried out by a multidisciplinary group of doctors and audioprosthetists from all over France. They are graded A, B, C or expert opinion according to decreasing level of scientific evidence. RESULTS: The diagnosis of presbycusis is more difficult at the beginning of its evolution but a certain number of tools are available for its early diagnosis and its management in face-to-face or even distance learning. CONCLUSION: In case of a clinical profile suggestive of presbycusis in a young subject, especially if there are several family cases, it is recommended to propose a genetic investigation. It is recommended to perform free-field speech audiometry in noise to measure intelligibility in an environment as close as possible to reality. Questionnaires can be used in addition to audiometry to best assess the patient's disability. It is recommended that hearing rehabilitation with a hearing aid or cochlear implant may slow or prevent cognitive decline. Combined auditory and cognitive rehabilitation should be offered regardless of the time elapsed since the fitting. It is recommended to integrate programs accessible via smartphones, tablets or the Internet, integrating different training domains in addition to face-to-face sessions.

Early management of presbycusis: recommendations from the French Society of Otorhinolaryngology and Head and Neck Surgery, the French Society of Audiology, and the French Society of Geriatrics and Gerontology.

INTRODUCTION: Presbycusis is the physiological decrease in hearing due to advancing age and begins well before the sixth decade. These recommendations recall the principles of early diagnosis of presbycusis and the means of optimal rehabilitation as soon as the first symptoms appear. MATERIAL AND METHODS: The recommendations are based on a systematic analysis of the literature carried out by a multidisciplinary group of ENT physicians, audiologists, geriatricians and hearing specialists from all over France. They are classified as grade A, B, C or professional agreement according to a decreasing level of scientific evidence. RESULTS: The diagnosis of presbycusis is more difficult at the beginning of its evolution but a certain number of tools are available for its early diagnosis and its face-to-face or remote management. CONCLUSION: In the case of a clinical profile suggestive of presbycusis in a young subject, especially if there are several family cases, it is recommended to propose a genetic investigation. Free-field speech audiometry in noise is recommended to measure intelligibility in a realistic environment. Questionnaires in addition to audiometric tests would allow the best assessment of the patient's disability. Hearing rehabilitation with a hearing aid or cochlear implant may slow or prevent cognitive decline. Combined auditory and cognitive rehabilitation should be offered regardless of the time since the hearing was fitting. It is recommended to integrate programs accessible via smartphones, tablets or the Internet, that include different training domains to complement face-to-face sessions.

A disease-associated mutation in thyroid hormone receptor α1 causes hearing loss and sensory hair cell patterning defects in mice.

Resistance to thyroid hormone due to mutations in THRA, which encodes the thyroid hormone receptor α (TRα1), shows variable clinical presentation. Mutations affecting TRß1 and TRß2 cause deafness in mice and have been associated with deafness in humans. To test whether TRα1 also affects hearing function, we used mice heterozygous for a frameshift mutation in Thra that is similar to human THRA mutations (ThraS1/+ mice) and reduces tissue sensitivity to thyroid hormone. Compared to wild-type littermates, ThraS1/+ mice showed moderate high-frequency sensorineural hearing loss as juveniles and increased age-related hearing loss. Ultrastructural examination revealed aberrant orientation of ~20% of sensory outer hair cells (OHCs), as well as increased numbers of mitochondria with fragmented morphology and autophagic vacuoles in both OHCs and auditory nerve fibers. Molecular dissection of the OHC lateral wall components revealed that the potassium ion channel Kcnq4 was aberrantly targeted to the cytoplasm of mutant OHCs. In addition, mutant cochleae showed increased oxidative stress, autophagy, and mitophagy associated with greater age-related cochlear cell damage, demonstrating that TRα1 is required for proper development of OHCs and for maintenance of OHC function. These findings suggest that patients with THRA mutations may present underdiagnosed, mild hearing loss and may be more susceptible to age-related hearing loss.

French Version of the Antiphasic Digits-in-Noise Test for Smartphone Hearing Screening.

In France 58% of persons with hearing loss still do not wear hearing aids. Pure-tone audiometry is the traditional gold standard in assessment and screening of hearing impairment, but it requires the use of calibrated devices and soundproof booth. The antiphasic digits-in-noise (DIN) test does not require calibrated material and can run on a standard headset or earbuds connected to a smartphone or a computer. The DIN test is highly correlated with pure tone audiometry and has already shown to be effective in hearing loss screening in its English version promoted by the WHO. The aim of the present study was to develop and validate a French version of the antiphasic DIN test for implementation on a national screening test offered as a smartphone app. The audio files recorded from a French native female speaker were selected and normalized in intensity according to their recognition probability. The French DIN test application was then tested on normal hearing- and hearing-impaired subjects. Based on the strong correlation between pure tone audiometry (PTA) and DIN SRT, we calculated ROC curves and Z-score. For PTA > 20 dB HL, a SNR cutoff of 12.9 dB corresponds to a sensitivity and specificity of 0.96 and 0.93, respectively. To detect moderate and more severe hearing loss (PTA > 40 dB HL), the SNR cutoff was -10.9 dB, corresponding to a sensitivity and specificity of 0.99 and 0.83, respectively. The Z-score was calculated to define statistical criteria of normality for speech-in-noise evaluation. While a score of 0 roughly corresponds to the normality (DIN SRT = -15.4 dB SNR), a subject with DIN SRT > -12.2 (Z-score > 2) is ranked in the hearing loss population. Next, the French antiphasic DIN test was implemented in the Höra iOS and Android apps. In total, 19,545 Höra tests were completed and analyzed. Three quarters of them were classified as normal (74 %) and one quarter presented mild (9%) or more severe loss (17%). Together, results argue for the use of the French version of antiphasic DIN test in the general population to improve the screening of hearing-impaired individuals.

Impulse Noise Induced Hidden Hearing Loss, Hair Cell Ciliary Changes and Oxidative Stress in Mice.

Recent studies demonstrated that reversible continuous noise exposure may induce a temporary threshold shift (TTS) with a permanent degeneration of auditory nerve fibers, although hair cells remain intact. To probe the impact of TTS-inducing impulse noise exposure on hearing, CBA/J Mice were exposed to noise impulses with peak pressures of 145 dB SPL. We found that 30 min after exposure, the noise caused a mean elevation of ABR thresholds of ~30 dB and a reduction in DPOAE amplitude. Four weeks later, ABR thresholds and DPOAE amplitude were back to normal in the higher frequency region (8-32 kHz). At lower frequencies, a small degree of PTS remained. Morphological evaluations revealed a disturbance of the stereociliary bundle of outer hair cells, mainly located in the apical regions. On the other hand, the reduced suprathreshold ABR amplitudes remained until 4 weeks later. A loss of synapse numbers was observed 24 h after exposure, with full recovery two weeks later. Transmission electron microscopy revealed morphological changes at the ribbon synapses by two weeks post exposure. In addition, increased levels of oxidative stress were observed immediately after exposure, and maintained for a further 2 weeks. These results clarify the pathology underlying impulse noise-induced sensory dysfunction, and suggest possible links between impulse-noise injury, cochlear cell morphology, metabolic changes, and hidden hearing loss.

Speech perception, real-ear measurements and self-perceived hearing impairment after remote and face-to-face programming of hearing aids: A randomized single-blind agreement study.

INTRODUCTION: Current literature does not provide strong evidence that remote programming of hearing aids is effective, despite its increasing use by audiologists. We tested speech perception outcomes, real-ear insertion gain, and changes in self-perceived hearing impairment after face-to-face and remote programming of hearing aids in a randomized multicentre, single-blind crossover study. METHODS: Adult experienced hearing aid users were enrolled during routine follow-up visits to audiology clinics. Hearing aids were programmed both face to face and remotely, then participants randomly received either the face-to-face or remote settings in a blinded manner and were evaluated 5 weeks later. Participants then received the other settings and were evaluated 5 weeks later. RESULTS: Data from 52 out of 60 participants were analysed. We found excellent concordance in performance of hearing aids programmed face to face and remotely for speech understanding in quiet (phonetically balanced kindergarten test - intraclass correlation coefficient of 0.92 (95% confidence interval: 0.87-0.95)), and good concordance in performance for speech understanding in noise (phonetically balanced kindergarten +5 dB signal-to-noise ratio - intraclass correlation coefficient of 0.71 (95% confidence interval: 0.55-0.82)). Face-to-face and remote programming took 10 minutes (±2.9) and 10 minutes (±2.8), respectively. Real-ear insertion gains were highly correlated for input sound at 50, 65 and 80 dB sound pressure levels. The programming type did not affect the abbreviated profile of hearing aid questionnaire scores. CONCLUSIONS: In experienced hearing aid users, face-to-face and remote programming of hearing aids give similar results in terms of speech perception, with no increase in the time spent on patients' care and no difference in self-reported hearing benefit. CLINICALTRIALS.GOV IDENTIFIER: NCT02589561.

ROS-Induced Activation of DNA Damage Responses Drives Senescence-Like State in Postmitotic Cochlear Cells: Implication for Hearing Preservation.

In our aging society, age-related hearing loss (ARHL) has become a major socioeconomic issue. Reactive oxygen species (ROS) may be one of the main causal factors of age-related cochlear cell degeneration. We examined whether ROS-induced DNA damage response drives cochlear cell senescence and contributes to ARHL from the cellular up to the system level. Our results revealed that sublethal concentrations of hydrogen peroxide (H2O2) exposure initiated a DNA damage response illustrated by increased γH2AX and 53BP1 expression and foci formation mainly in sensory hair cells, together with increased levels of p-Chk2 and p53. Interestingly, postmitotic cochlear cells exposed to H2O2 displayed key hallmarks of senescent cells, including dramatically increased levels of p21, p38, and p-p38 expression, concomitant with decreased p19 and BubR1 expression and positive senescence-associated ß-galactosidase labeling. Importantly, the synthetic superoxide dismutase/catalase mimetic EUK-207 attenuated H2O2-induced DNA damage and senescence phenotypes in cochlear cells in vitro. Furthermore, systemic administration of EUK-207 reduced age-related loss of hearing and hair cell degeneration in senescence-accelerated mouse-prone 8 (SAMP8) mice. Altogether, these findings highlight that ROS-induced DNA damage responses drive cochlear cell senescence and contribute to accelerated ARHL. EUK-207 and likely other antioxidants with similar mechanisms of action could potentially postpone cochlear aging and prevent ARHL in humans.

Spiking Pattern of the Mouse Developing Inner Hair Cells Is Mostly Invariant Along the Tonotopic Axis.

During development, the sensory cells of the cochlea, the inner hair cells (IHCs), fire spontaneous calcium action potentials. This activity at the pre-hearing stage allows the IHCs to autonomously excite the auditory nerve fibers and hence, represents an efficient mechanism to shape the tonotopic organization along the ascending auditory pathway. Using calcium imaging, we show that the activity in the developing cochlea consists of calcium waves that propagate across the supporting and sensory cells. Both basal and apical IHCs were characterized by similar spontaneous calcium transients interspaced with silent periods, consistent with bursts of action potentials recorded in patch-clamp. In addition, adjacent auditory hair cells tend to have a synchronized [Ca2+]i activity, irrespective of their location along the base-to-apex gradient of the cochlea. Finally, we show that the mechanical ablation of the inner phalangeal cells (IPCs), a class of supporting cells, reduces the synchronized [Ca2+]i activity between neighboring sensory cells. These findings support the hypothesis that the tonotopic map refinement in higher auditory centers would depend on the synchronization of a discrete number of auditory sensory cells.

Metachronal propagation of motor activity.

A diverse array of biomechanical systems has evolved to satisfy locomotor requirements (reptation, swimming, walking, etc.) and in all cases, successful behabior achievement requires the integrated functioning of various segments, to ensure the appropriate positioning of the different body regions. From comparative studies on a variety of invertebrate and vertebrate organisms, it is now established that the basic motor patterns underlying limb and/or trunk movements during locomotion are driven by central networks of neurons, so-called central pattern generators (CPGs). In limbless animals such as leech, lamprey, snakes... body propulsion is driven by alternate left- right trunk muscle contractions that occur sequentially (or metachronally) along the body length. Here, we highlight some common principles of motor control involving metachronal activity that are shared by multisegmental systems. In a first step we will review systems in which the neural mechanismsthe that underlie modular linear distribution have been extensively studied. Finally, we will review modeling studies that have been performed to better understand the fundamental mechanisms that underlie metachronal propagation.

Comparison of trunk activity during gait initiation and walking in humans.

To understand the role of trunk muscles in maintenance of dynamic postural equilibrium we investigate trunk movements during gait initiation and walking, performing trunk kinematics analysis, Erector spinae muscle (ES) recordings and dynamic analysis. ES muscle expressed a metachronal descending pattern of activity during walking and gait initiation. In the frontal and horizontal planes, lateroflexion and rotation occur before in the upper trunk and after in the lower trunk. Comparison of ES muscle EMGs and trunk kinematics showed that trunk muscle activity precedes corresponding kinematics activity, indicating that the ES drive trunk movement during locomotion and thereby allowing a better pelvis mobilization. EMG data showed that ES activity anticipates propulsive phases in walking with a repetitive pattern, suggesting a programmed control by a central pattern generator. Our findings also suggest that the programs for gait initiation and walking overlap with the latter beginning before the first has ended.

Real time control of a CPG-based model of the human trunk in different walking conditions.

Artificial central pattern generators (CPGs) framework is well adapted to the control of bio-mimetic systems during rhythmic tasks like locomotion. They have the ability to reproduce biological behavior as well as to be used as feedforward controllers for multi-articulated systems. In this paper we present a model of human gait activity based on an oscillator network. The model is especially dedicated to reproduce trunk muscular activities as observed in previous studies, and to fill a lack in trunk modeling in human gait simulation. An offline validation is performed using recorded accelerometer signal that monitors trunk movements during locomotion. We are able to control the model based on this real data and to adapt its pattern to contextual changes (stairs, slope).