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.

The effect of long-term unilateral deafness on the activation pattern in the auditory cortices of French-native speakers: influence of deafness side.

BACKGROUND: In normal-hearing subjects, monaural stimulation produces a normal pattern of asynchrony and asymmetry over the auditory cortices in favour of the contralateral temporal lobe. While late onset unilateral deafness has been reported to change this pattern, the exact influence of the side of deafness on central auditory plasticity still remains unclear. The present study aimed at assessing whether left-sided and right-sided deafness had differential effects on the characteristics of neurophysiological responses over auditory areas. Eighteen unilaterally deaf and 16 normal hearing right-handed subjects participated. All unilaterally deaf subjects had post-lingual deafness. Long latency auditory evoked potentials (late-AEPs) were elicited by two types of stimuli, non-speech (1 kHz tone-burst) and speech-sounds (voiceless syllable/pa/) delivered to the intact ear at 50 dB SL. The latencies and amplitudes of the early exogenous components (N100 and P150) were measured using temporal scalp electrodes. RESULTS: Subjects with left-sided deafness showed major neurophysiological changes, in the form of a more symmetrical activation pattern over auditory areas in response to non-speech sound and even a significant reversal of the activation pattern in favour of the cortex ipsilateral to the stimulation in response to speech sound. This was observed not only for AEP amplitudes but also for AEP time course. In contrast, no significant changes were reported for late-AEP responses in subjects with right-sided deafness. CONCLUSION: The results show that cortical reorganization induced by unilateral deafness mainly occurs in subjects with left-sided deafness. This suggests that anatomical and functional plastic changes are more likely to occur in the right than in the left auditory cortex. The possible perceptual correlates of such neurophysiological changes are discussed.

Speech restoration: an interactive process.

PURPOSE: This study investigates the ability to understand degraded speech signals and explores the correlation between this capacity and the functional characteristics of the peripheral auditory system. METHOD: The authors evaluated the capability of 50 normal-hearing native French speakers to restore time-reversed speech. The task required them to transcribe two-syllable items containing temporal reversions of variable sizes, ranging from no reversion to complete reversion, increasing by half-syllable steps. In parallel, the functionality of each participant's auditory efferent system was evaluated using contralateral suppression of click-evoked otoacoustic emissions. RESULTS: Perceptual accuracy for time-reversed speech diminished when the size of the applied temporal distortion increased. A lexical benefit was evident, and an important interindividual variability in performance was observed. Functional exploration of the auditory system revealed that speech restoration performances correlated with the suppression strength of the participant's auditory efferent system. CONCLUSIONS: These results suggest a clear relation between the functional asymmetry of the auditory efferent pathway (the right-side activity is greater than the left-side activity in right-handed participants) and the comprehension of acoustically distorted speech in normal-hearing participants. Further experiments are needed to better specify how the functionality of the medial olivocochlear bundle can cause phonological activation to be more efficient.

Implicit Processing of Pitch in Postlingually Deafened Cochlear Implant Users.

Cochlear implant (CI) users can only access limited pitch information through their device, which hinders music appreciation. Poor music perception may not only be due to CI technical limitations; lack of training or negative attitudes toward the electric sound might also contribute to it. Our study investigated with an implicit (indirect) investigation method whether poorly transmitted pitch information, presented as musical chords, can activate listeners' knowledge about musical structures acquired prior to deafness. Seven postlingually deafened adult CI users participated in a musical priming paradigm investigating pitch processing without explicit judgments. Sequences made of eight sung-chords that ended on either a musically related (expected) target chord or a less-related (less-expected) target chord were presented. The use of a priming task based on linguistic features allowed CI patients to perform fast judgments on target chords in the sung music. If listeners' musical knowledge is activated and allows for tonal expectations (as in normal-hearing listeners), faster response times were expected for related targets than less-related targets. However, if the pitch percept is too different and does not activate musical knowledge acquired prior to deafness, storing pitch information in a short-term memory buffer predicts the opposite pattern. If transmitted pitch information is too poor, no difference in response times should be observed. Results showed that CI patients were able to perform the linguistic task on the sung chords, but correct response times indicated sensory priming, with faster response times observed for the less-related targets: CI patients processed at least some of the pitch information of the musical sequences, which was stored in an auditory short-term memory and influenced chord processing. This finding suggests that the signal transmitted via electric hearing led to a pitch percept that was too different from that based on acoustic hearing, so that it did not automatically activate listeners' previously acquired musical structure knowledge. However, the transmitted signal seems sufficiently informative to lead to sensory priming. These findings are encouraging for the development of pitch-related training programs for CI patients, despite the current technological limitations of the CI coding.

Evidence of a tonotopic organization of the auditory cortex in cochlear implant users.

Deprivation from normal sensory input has been shown to alter tonotopic organization of the human auditory cortex. In this context, cochlear implant subjects provide an interesting model in that profound deafness is made partially reversible by the cochlear implant. In restoring afferent activity, cochlear implantation may also reverse some of the central changes related to deafness. The purpose of the present study was to address whether the auditory cortex of cochlear implant subjects is tonotopically organized. The subjects were thirteen adults with at least 3 months of cochlear implant experience. Auditory event-related potentials were recorded in response to electrical stimulation delivered at different intracochlear electrodes. Topographic analysis of the auditory N1 component (approximately 85 ms latency) showed that the locations on the scalp and the relative amplitudes of the positive/negative extrema differ according to the stimulated electrode, suggesting that distinct sets of neural sources are activated. Dipole modeling confirmed electrode-dependent orientations of these sources in temporal areas, which can be explained by nearby, but distinct sites of activation in the auditory cortex. Although the cortical organization in cochlear implant users is similar to the tonotopy found in normal-hearing subjects, some differences exist. Nevertheless, a correlation was found between the N1 peak amplitude indexing cortical tonotopy and the values given by the subjects for a pitch scaling task. Hence, the pattern of N1 variation likely reflects how frequencies are coded in the brain.

Speech auditory brainstem response (speech ABR) characteristics depending on recording conditions, and hearing status: an experimental parametric study.

Speech elicited auditory brainstem responses (Speech ABR) have been shown to be an objective measurement of speech processing in the brainstem. Given the simultaneous stimulation and recording, and the similarities between the recording and the speech stimulus envelope, there is a great risk of artefactual recordings. This study sought to systematically investigate the source of artefactual contamination in Speech ABR response. In a first part, we measured the sound level thresholds over which artefactual responses were obtained, for different types of transducers and experimental setup parameters. A watermelon model was used to model the human head susceptibility to electromagnetic artefact. It was found that impedances between the electrodes had a great effect on electromagnetic susceptibility and that the most prominent artefact is due to the transducer's electromagnetic leakage. The only artefact-free condition was obtained with insert-earphones shielded in a Faraday cage linked to common ground. In a second part of the study, using the previously defined artefact-free condition, we recorded speech ABR in unilateral deaf subjects and bilateral normal hearing subjects. In an additional control condition, Speech ABR was recorded with the insert-earphones used to deliver the stimulation, unplugged from the ears, so that the subjects did not perceive the stimulus. No responses were obtained from the deaf ear of unilaterally hearing impaired subjects, nor in the insert-out-of-the-ear condition in all the subjects, showing that Speech ABR reflects the functioning of the auditory pathways.

Auditory processing disorder in children with reading disabilities: effect of audiovisual training.

Reading disability is associated with phonological problems which might originate in auditory processing disorders. The aim of the present study was 2-fold: first, the perceptual skills of average-reading children and children with dyslexia were compared in a categorical perception task assessing the processing of a phonemic contrast based on voice onset time (VOT). The medial olivocochlear (MOC) system, an inhibitory pathway functioning under central control, was also explored. Secondly, we investigated whether audiovisual training focusing on voicing contrast could modify VOT sensitivity and, in parallel, induce MOC system plasticity. The results showed an altered voicing sensitivity in some children with dyslexia, and that the most severely impaired children presented the most severe reading difficulties. These deficits in VOT perception were sometimes accompanied by MOC function abnormalities, in particular a reduction in or even absence of the asymmetry in favour of the right ear found in average-reading children. Audiovisual training significantly improved reading and shifted the categorical perception curve of certain children with dyslexia towards the average-reading children's pattern of voicing sensitivity. Likewise, in certain children MOC functioning showed increased asymmetry in favour of the right ear following audiovisual training. The training-related improvements in reading score were greatest in children presenting the greatest changes in MOC lateralization. Taken together, these results confirm the notion that some auditory system processing mechanisms are impaired in children with dyslexia and that audiovisual training can diminish these deficits.

Relationship between loudness growth function and auditory steady-state response in normal-hearing subjects.

The present study investigates the relationship between auditory steady-state responses (ASSRs) and loudness growth function. ASSR amplitudes were compared to the perceived loudness level at frequencies of 500 and 2000Hz in 11 normal-hearing subjects. As a first step, loudness growth function was estimated for the two test frequencies. Then ASSR amplitude was recorded for each of the two frequencies at different stimulus intensities, each corresponding to a loudness level as given by the first part of the study. Normalized results show that the ASSR amplitude correlates well with the loudness function (R(2)=0.81). A stepwise multiple linear regression confirmed these results with loudness explaining almost all the ASSR amplitude (loudness R(2)=0.81, p<0.001, f=562 and for intensity f=1.1, p=0.29). The non-linearity of the ASSR amplitude for low loudness levels can be explained by both the active amplification in the cochlea and the noise in the recording. The results suggest that ASSRs can be used for "objective" loudness measurement.

Effects of GSM cellular phones on human hearing: the European project "GUARD".

The European multicenter project named GUARD involved nine centers and aimed to assess potential changes in auditory function as a consequence of exposure to low-intensity electromagnetic fields (EMFs) produced by GSM cellular phones. Participants were healthy young adults without any evidence of hearing or ear disorders. Auditory function was assessed immediately before and after exposure to EMFs, and only the exposed ear was tested. The procedure was conducted twice in a double blinded design, once with a genuine EMF exposure and once with a sham exposure (at least 24 h apart). Tests for assessment of auditory function were hearing threshold level (HTL), transient otoacoustic emissions (TEOAE), distortion product otoacoustic emissions (DPOAE), and auditory brainstem response (ABR). The exposure consisted of speech at a typical conversational level delivered via an earphone to one ear, plus genuine or sham EMF exposure. The EMF exposure used the output of a software-controlled consumer cellular phone at full power for 10 min. A system of phone positioning that allowed participants to freely move their heads without affecting exposure was used. Analysis of the data showed there were no effects of exposure to GSM mobile phone signals on the main measures of the status of the auditory system.

The pattern of auditory brainstem response wave V maturation in cochlear-implanted children.

OBJECTIVE: Maturation of acoustically evoked brainstem responses (ABR) in hearing children is not complete at birth but rather continues over the first two years of life. In particular, it has been established that the decrease in ABR wave V latency can be modeled as the sum of two decaying exponential functions with respective time-constants of 4 and 50 weeks [Eggermont, J.J., Salamy, A., 1988a. Maturational time-course for the ABR in preterm and full term infants. Hear Res 33, 35-47; Eggermont, J.J., Salamy, A., 1988b. Development of ABR parameters in a preterm and a term born population. Ear Hear 9, 283-9]. Here, we investigated the maturation of electrically evoked auditory brainstem responses (EABR) in 55 deaf children who recovered hearing after cochlear implantation, and proposed a predictive model of EABR maturation depending on the onset of deafness. The pattern of EABR maturation over the first 2 years of cochlear implant use was compared with the normal pattern of ABR maturation in hearing children. METHODS: Changes in EABR wave V latency over the 2 years following cochlear implant connection were analyzed in two groups of children. The first group (n=41) consisted of children with early-onset of deafness (mostly congenital), and the second (n=14) of children who had become profoundly deaf after 1 year of age. The modeling of changes in EABR wave V latency with time was based on the mean values from each of the two groups, allowing comparison of the rates of EABR maturation between groups. Differences between EABRs elicited at the basal and apical ends of the implant electrode array were also tested. RESULTS: There was no influence of age at implantation on the rate of wave V latency change. The main factor for EABR changes was the time in sound. Indeed, significant maturation was observed over the first 2 years of implant use only in the group with early-onset deafness. In this group maturation of wave V progressed as in the ABR model of [Eggermont, J.J., Salamy, A., 1988a. Maturational time-course for the ABR in preterm and full term infants. Hear Res 33, 35-47; Eggermont, J.J., Salamy, A., 1988b. Development of ABR parameters in a preterm and a term born population. Ear Hear 9, 283-9] of normal hearing children: a sum of two decaying exponential functions, one showing an early rapid decrease in latency and the other a slower decrease. Remarkably, the time-constants fell well within the ranges described by Eggermont and Salamy (i.e., 3.9 and 68 weeks), consistent with the time-course of the neurophysiological mechanisms presumably involved in auditory pathway maturation during the first 2 years of life: i.e., myelination and increased synaptic efficacy. In contrast, relatively little change in wave V was evident in children with late-onset deafness. In agreement with the notion that EABR maturation follows an apex-to-base gradient as described for ABR, we observed that wave V latencies were longer for the basal than the apical end of the implant electrode array and remained so throughout the study period, whatever the time of onset of deafness. CONCLUSIONS: The findings in the early-onset of deafness group support the theory that auditory pathways remain "frozen" during the period of sensory deprivation until cochlear implant rehabilitation restores the normal chronology of maturational processes. In children with late-onset deafness, however, some maturational processes may occur before the onset of deafness, and thus less additional maturation is required during the first two years of implant use resulting in no significant EABR latency changes being observed in this period. The results suggest that the rehabilitation-induced plasticity of the auditory pathways is, in case of late auditory deprivation, unlikely to result in neurophysiological outcomes similar to those observed in children with early auditory deprivation. SIGNIFICANCE: Changes in EABR wave V latency over the first 2 years of cochlear implant use were found to be well fitted by the sum of two decaying exponential functions in children with early-onset deafness. This is in line with the maturation of ABR wave V latency in normal-hearing children over the first two years of life. Further studies are needed to assess whether the differences observed in terms of auditory pathways maturation are associated with consistent differences in terms of language development.