Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.

Brain voice processing with bilateral cochlear implants: a positron emission tomography study.

Most cochlear implantations are unilateral. To explore the benefits of a binaural cochlear implant, we used water-labelled oxygen-15 positron emission tomography. Relative cerebral blood flow was measured in a binaural implant group (n = 11), while the subjects were passively listening to human voice sounds, environmental sounds non-voice or silence. Binaural auditory stimulation in the cochlear implant group bilaterally activated the temporal voice areas, whereas monaural cochlear implant stimulation only activated the left temporal voice area. Direct comparison of the binaural and the monaural cochlear implant stimulation condition revealed an additional right temporal activation during voice processing in the binaural condition and the activation of a right fronto-parietal cortical network during sound processing that has been implicated in attention. These findings provide evidence that a bilateral cochlear implant stimulation enhanced the spectral cues associated with sound perception and improved brain processing of voice stimuli in the right temporal region when compared to a monaural cochlear implant stimulation. Moreover, the recruitment of sensory attention resources in a right fronto-parietal network allowed patients with bilateral cochlear implant stimulation to enhance their sound discrimination, whereas the same patients with only one cochlear implant stimulation had more auditory perception difficulties.

[Environmental sound management]. / Gestion de la pollution sonore liée à l'environnement.

ENVIRONMENTAL SOUND MANAGEMENT. Pathologies due to a lack of environmental sound management are increasing. The management of environmental sounds - roads, trains, planes, industry - are a major public health challenge concerning the World Health Organization (WHO), the European Union, and public administrations. A good understanding of environmental sounds allows to engage the right prophylactic actions, reducing the production of noise, its propagation and to protect individuals and their home f rom noise. Some regulation has recently been published requiring some sound level measures in decibel even if this notion is much less common than the measure of temperature, for example. European public administration has recommended the establishment of maps of noise, measuring the exposition in one place to environmental sounds, using average level during a period. Physicians must be able to detect symptoms of patients induced by noise management insufficiencies, to treat them, but also to explain the problematic to the patient and to give a strategy to fight efficiently.

GESTION DE LA POLLUTION SONORE LIÉE À L'ENVIRONNEMENT. Le nombre de pathologies liées à une mauvaise gestion sonore est grandissant. La maîtrise du niveau sonore de l'environnement, c'est-à-dire des bruits routiers, ferroviaires, aéroportuaires, industriels, s'avère être un enjeu majeur de santé publique dont s'inquiète l'Organisation mondiale de la santé (OMS), l'Union européenne et les pouvoirs publics. Une meilleure connaissance des enjeux permet d'engager des actions prophylactiques de réduction des émissions sonores nuisibles, de réduire leur transmission dans l'environnement et, en dernier lieu, de protéger l'individu et son habitat des bruits résiduels. Une réglementation se met progressivement en place. Néanmoins, elle repose sur des mesures de niveaux acoustiques en décibels moins connus et courants que la prise de température, par exemple. Les pouvoirs publics européens sont engagés dans une démarche de cartographie des bruits dans les grandes agglomérations reposant sur ces notions d'acoustique. Le médecin doit être en mesure de repérer et d'orienter un patient confronté à une problématique de bruit en la lui expliquant, en plus de l'aider médicalement.

[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.

Arterial spin labeling brain MRI study to evaluate the impact of deafness on cerebral perfusion in 79 children before cochlear implantation.

Age at implantation is considered to be a major factor, influencing outcomes after pediatric cochlear implantation. In the absence of acoustic input, it has been proposed that cross-modal reorganization can be detrimental for adaptation to the new electrical input provided by a cochlear implant. Here, through a retrospective study, we aimed to investigate differences in cerebral blood flow (CBF) at rest prior to implantation in children with congenital deafness compared to normally hearing children. In addition, we looked at the putative link between pre-operative rest-CBF and the oral intelligibility scores at 12 months post-implantation. Finally, we observed the evolution of perfusion with age, within brain areas showing abnormal rest-CBF associated to deafness, in deaf children and in normally hearing children. In children older than 5 years old, results showed a significant bilateral hypoperfusion in temporal regions in deaf children, particularly in Heschl's gyrus, and a significant hyperperfusion of occipital regions. Furthermore, in children older than 5 years old, whole brain voxel-by-voxel correlation analysis between pre-operative rest-CBF and oral intelligibility scores at 12 months post-implantation, showed significant negative correlation localized in the occipital regions: children who performed worse in the speech perception test one year after implantation were those presenting higher preoperative CBF values in these occipital regions. Finally, when comparing mean relative perfusion (extracted from the temporal regions found abnormal on whole-brain voxel-based analysis) across ages in patients and controls, we observed that the temporal perfusion evolution was significantly different in deaf children than in normally hearing children. Indeed, while temporal perfusion increased with age in normally hearing children, it remained stable in deaf children. We showed a critical period around 4 years old, where in the context of auditory deprivation, there is a lack of synaptic activity in auditory regions. These results support the benefits of early cochlear implantation to maximize the effectiveness of auditory rehabilitation and to avoid cross-modal reorganization.

Processing of voices in deafness rehabilitation by auditory brainstem implant.

The superior temporal sulcus (STS) is specifically involved in processing the human voice. Profound acquired deafness by post-meningitis ossified cochlea and by bilateral vestibular schwannoma in neurofibromatosis type 2 patients are two indications for auditory brainstem implantation (ABI). In order to objectively measure the cortical voice processing of a group of ABI patients, we studied the activation of the human temporal voice areas (TVA) by PET H(2)(15)O, performed in a group of implanted deaf adults (n=7) with more than two years of auditory brainstem implant experience, with an intelligibility score average of 17%+/-17 [mean+/-SD]. Relative cerebral blood flow (rCBF) was measured in the three following conditions: during silence, while passive listening to human voice, and to non-voice stimuli. Compared to silence, the activations induced by voice and non-voice stimuli were bilaterally located in the superior temporal regions. However, compared to non-voice stimuli, the voice stimuli did not induce specific supplementary activation of the TVA along the STS. The comparison of ABI group with a normal-hearing controls group (n=7) showed that TVA activations were significantly enhanced among controls group. ABI allowed the transmission of sound stimuli to temporal brain regions but lacked transmitting the specific cues of the human voice to the TVA. Moreover, among groups, during silent condition, brain visual regions showed higher rCBF in ABI group, although temporal brain regions had higher rCBF in the controls group. ABI patients had consequently developed enhanced visual strategies to keep interacting with their environment.

Cochlear implant benefits in deafness rehabilitation: PET study of temporal voice activations.

UNLABELLED: Cochlear implants may improve the medical and social prognosis of profound deafness. Nevertheless, some patients have experienced poor results without any clear explanations. One correlate may be an alteration in cortical voice processing. To test this hypothesis, we studied the activation of human temporal voice areas (TVA) using a well-standardized PET paradigm adapted from previous functional MRI (fMRI) studies. METHODS: A PET H(2)(15)O activation study was performed on 3 groups of adult volunteers: normal-hearing control subjects (n = 6) and cochlear-implanted postlingually deaf patients with >2 y of cochlear implant experience, with intelligibility scores in the "Lafon monosyllabic task" >80% (GOOD group; n = 6) or <20% (POOR group; n = 6). Relative cerebral blood flow was measured in 3 conditions: rest, passive listening to human voice, and nonvoice stimuli. RESULTS: Compared with silence, the activations induced by nonvoice stimuli were bilaterally located in the superior temporal regions in all groups. However these activations were significantly and similarly reduced in both cochlear implant groups, whereas control subjects showed supplementary activations. Compared with nonvoice, the voice stimuli induced bilateral activation of the TVA along the superior temporal sulcus (STS) in both the control and the GOOD groups. In contrast, these activations were not detected in the POOR group, which showed only left unilateral middle STS activation. CONCLUSION: These results suggest that PET is an adequate method to explore cochlear implant benefits and that this benefit could be linked to the activation of the TVA.

Abnormal cortical voice processing in autism.

Impairments in social interaction are a key feature of autism and are associated with atypical social information processing. Here we report functional magnetic resonance imaging (fMRI) results showing that individuals with autism failed to activate superior temporal sulcus (STS) voice-selective regions in response to vocal sounds, whereas they showed a normal activation pattern in response to nonvocal sounds. These findings suggest abnormal cortical processing of socially relevant auditory information in autism.

[Medical devices correcting the deafness: Hearing aids and auditory implants]. / Les dispositifs médicaux correcteurs de la surdité : prothèses et implants auditifs.

The management of deafness has become a major public health issue as their lack of detection has a deleterious effect in children and increases the risk factors for aggravation of other pathologies in adults. The detection of deafness remains a real challenge: in the newborn, systematic screening at birth is a good strategy, in adults, much remains to be done. The functional rehabilitation of deafness is based on the use of hearing aids by aerial or bone conduction or of auditory implants. There are three types of auditory implants available: bone anchored hearing implants, middle ear implants and cochlear implants. Many actors, in particular social organizations, can intervene in the financial management of these medical devices.

Effects of noise reduction on AM perception for hearing-impaired listeners.

Noise reduction (NR) systems are commonplace in modern digital hearing aids. Though not improving speech intelligibility, NR helps the hearing-aid user in terms of lowering noise annoyance, reducing cognitive load and improving ease of listening. Previous psychophysical work has shown that NR does in fact improve the ability of normal-hearing (NH) listeners to discriminate the slow amplitude-modulation (AM) cues representative of those found in speech. The goal of this study was to assess whether this improvement of AM discrimination with NR can also be observed for hearing-impaired (HI) listeners. AM discrimination was measured at two audio frequencies of 500 Hz and 2 kHz in a background noise with a signal-to-noise ratio of 12 dB. Discrimination was measured for ten HI and ten NH listeners with and without NR processing. The HI listeners had a moderate sensorineural hearing loss of about 50 dB HL at 2 kHz and normal hearing (≤ 20 dB HL) at 500 Hz. The results showed that most of the HI listeners tended to benefit from NR at 500 Hz but not at 2 kHz. However, statistical analyses showed that HI listeners did not benefit significantly from NR at any frequency region. In comparison, the NH listeners showed a significant benefit from NR at both frequencies. For each condition, the fidelity of AM transmission was quantified by a computational model of early auditory processing. The parameters of the model were adjusted separately for the two groups (NH and HI) of listeners. The AM discrimination performance of the HI group (with and without NR) was best captured by a model simulating the loss of the fast-acting amplitude compression applied by the normal cochlea. This suggests that the lack of benefit from NR for HI listeners results from loudness recruitment.