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.

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.

Efficacy of Hearing Aids on the Cognitive Status of Patients with Alzheimer's Disease and Hearing Loss: A Multicenter Controlled Randomized Trial.

BACKGROUND/OBJECTIVE: This study evaluated the cognitive benefit of hearing aids (HA) in older patients with Alzheimer's disease (AD) and hearing loss (HL) after a 6- and 12-month period of utilization. METHODS: A multicenter double-blind randomized placebo-controlled trial was conducted in patients aged more than 65 years. A group was equipped with active HA for 6 months (active group) and a second group had placebo HA for 6 months (placebo group) followed by a secondary activation phase for a further 6 months (semi crossover procedure). Both groups were retested after a 12-month period. The primary endpoint was the change from baseline of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS Cog) after a 6-month period in both groups and after 6 months of secondary HA activation in the placebo group. A smaller cognitive decline should be obtained with HA use; an increase in ADAS Cog score of less than 6 points was defined a success. RESULTS: Fifty-one patients aged 68 to 99 years were included; 38 attended the 6-month visit: 18 in the active group and 20 in the placebo group. At 6 months, 14 (82.4%) successes were noticed in the active group, and 15 (88.2%) in the placebo group (p = 1.0); delta ADAS Cog in the active group was 1.8±5.3 and 1.3±5.3 in the placebo group (p = 0.8). In the placebo group, after the secondary HA activation, no significant improvement was observed. CONCLUSION: No significant effect of HA use was observed after 6 months of follow-up in patients with AD and HL.

Do Hearing Aids Influence Behavioral and Psychological Symptoms of Dementia and Quality of Life in Hearing Impaired Alzheimer's Disease Patients and Their Caregivers?

BACKGROUND: It has been suggested that age-related hearing loss (ARHL) and Alzheimer's disease (AD) are commonly associated. OBJECTIVE: The Alzheimer Disease, Presbycusis and Hearing Aids (ADPHA) clinical trial assessed the influence of hearing aids (HAs) on patients affected by ARHL and AD, as judged by behavioral symptoms and functional abilities, as well as patient and caregiver quality of life (QoL). METHODS: A multicenter double-blind randomized placebo-controlled trial, with a semi-crossover procedure over 12 months, was conducted from 2006 to 2012. For the first 6 months, the active group was treated with active HAs and the placebo group with inactive HAs. For the last 6 months, HAs in the placebo group were activated. Assessment was conducted at baseline, 6 months, and 12 months. We performed intergroup and intragroup comparisons. Behavioral symptoms were assessed by neuropsychiatric inventory (NPI), functional abilities by instrumental activities of daily living, and QoL by Zarit, Alzheimer's disease related quality of life, and simplified Duke scales. RESULTS: Fifty-one patients were included and randomized: 22 in active group (mean NPI 17.6; mean age 83±6.2) and 26 in placebo group (mean NPI 25.8; mean age 82.3±7.2) were fitted with HAs. At 6-month follow-up, all scores worsened without significant difference between the two groups. In placebo group, activation of HAs had no effect on the change of these scores. CONCLUSION: These findings do not provide evidence of improvement in behavioral symptoms, functional status, or QoL of hearing impaired AD patients and their caregivers after 6 months of HA use. However, we cannot exclude that HAs may have a positive effect in patients aged less than 75 years.

Function and plasticity of the medial olivocochlear system in musicians: a review.

The outer hair cells of the organ of Corti are the target of abundant efferent projections from the olivocochlear system. This peripheral efferent auditory subsystem is currently thought to be modulated by central activity via corticofugal descending auditory system, and to modulate active cochlear micromechanics. Although the function of this efferent subsystem remains unclear, physiological, psychophysical, and modeling data suggest that it may be involved in ear protection against noise damage and auditory perception, especially in the presence of background noise. Moreover, there is mounting evidence that its activity is modulated by auditory and visual attention. A commonly used approach to measure olivocochlear activity noninvasively in humans relies on the suppression of otoacoustic emissions by contralateral noise. Previous studies have found substantial interindividual variability in this effect, and statistical differences have been observed between professional musicians and non-musicians, with stronger bilateral suppression effects in the former. In this paper, we review these studies and discuss various possible interpretations for these findings, including experience-dependent neuroplasticity. We ask whether differences in olivocochlear function between musicians and non-musicians reflect differences in peripheral auditory function or in more central factors, such as top-down attentional modulation.

Repetitive transcranial magnetic stimulation noise levels: methodological implications for tinnitus treatment.

OBJECTIVE: To measure noise levels generated by repetitive transcranial magnetic stimulation. INTERVENTION: Repetitive transcranial magnetic stimulation (rTMS). MAIN OUTCOME MEASURES: rTMS noise levels measured in equivalent continuous sound level (LAeq) and in peak level (LC, peak), as a function of maximum power output of the equipment. METHODS: rTMS noise levels were measured for an active and a corresponding sham coil, as a function of distance and percentage power output of a MagPro X100 system (Medtronic) and compared with occupational noise exposure standards, using parameters classically used for rTMS tinnitus treatment. RESULTS: Significant differences in frequency composition and intensity levels were observed between sham and active coil noises. The active coil noise reached, at 50% power, 96 LAeq (peak at 132 LC, peak), varying by 3.9 LAeq (3.9 LC, peak) per 10% of power increase, whereas the sham coil reached 87 LAeq (114 LC, peak), varying by 3.2 LAeq (3.6 LC, peak) per 10% of power increase. CONCLUSION: rTMS noise levels differ significantly between active and sham coils, and can go beyond the American and European legal occupational noise limits, hence making ear protection a specific issue, particularly relevant to rTMS treatment for tinnitus.

Repetitive transcranial magnetic stimulation: hearing safety considerations.

BACKGROUND: The guidelines for use of repetitive transcranial magnetic stimulation (rTMS) advise frequent updating of rTMS safety guidelines and recommendations. Although rTMS can produce sound of more than 120 dB C, which is sufficient to induce hearing loss, the effect of rTMS noise on the hearing of both patients and rTMS practitioners is understudied. OBJECTIVE: This study investigated the effects of rTMS noise on subjects' hearing using otoacoustic emissions evoked by clicks (transiently evoked otoacoustic emissions, TEOAEs), which is an objective and sensitive method of cochlear exploration. METHODS: Hearing thresholds and TEOAEs were recorded in 24 normal-hearing healthy subjects before and after a real or sham rTMS session (a single 20-minute session applied to the superior temporal gyrus with 1200 pulses at 100% of the individual motor threshold). RESULTS: No significant difference in hearing thresholds was observed between subjects exposed to real or sham rTMS. However, the difference in TEOAE amplitude between pre- and post-rTMS sessions increased significantly with rTMS noise for those subjects the least protected by earplugs, showing a post-rTMS slight decrease of TEOAE amplitude for high rTMS intensities and hence minor hearing function alteration. However, this correlation was no longer found 1 hour after the rTMS session. CONCLUSIONS: These findings suggest that, even when rTMS is used within normal safety limits and with good hearing protection, rTMS noise can transiently disturb hearing mechanisms in normal-hearing healthy subjects. This transient effect of rTMS on hearing may be an important consideration for Institutional Review Boards when rTMS is used at higher stimulation intensities.

The experience of pleasure before and after hearing rehabilitation.

Hearing loss may lead to major changes in the social and emotional aspects of daily life. This follow-up study investigated the effect of hearing-aid use on emotional experience in adults with hearing impairment. Thirteen individuals with impaired hearing were tested before and after 6 months of hearing-aid use, and were compared with 19 individuals who had worn hearing aids for many years. The participants reported their daily emotional experiences, by completing questionnaires relating to sensory and social pleasure. After 6 months of hearing-aid use, individuals experienced more physical and social pleasure, whereas individuals using hearing aids for long periods of time reported similar levels of pleasure at the beginning and at the end of a 6-month interval. The participants also performed a visual task, in which they rated the intensity of pleasure they experienced in response to emotionally positive and neutral pictures differing in luminance contrast. In this task, pleasure typically decreases with decreasing contrast of the positive images displayed. Once they had been fitted with hearing aids, the participants reported lower levels of pleasure, especially at low contrast. These findings highlight that the anhedonia scales provide a measure sensitive to emotional improvements that accompany the partial restoration of hearing function, although these scales were not specifically designed for hearing-impaired populations. In contrast, the surprising decrease in pleasure ratings for pictures after the introduction of hearing-aid use may be because of the compensation of hearing loss by changes in visual attention functions.

Plasticity of tonotopic maps in humans: influence of hearing loss, hearing aids and cochlear implants.

CONCLUSION: This paper reviews psychoacoustical and electrophysiological evidence for reorganization of the human central auditory system in case of auditory deprivation and rehabilitation. OBJECTIVE: To investigate the plasticity of cortical tonotopic maps in cochlear-damaged subjects. METHODS: Frequency discrimination scores were analysed in subjects with high frequency hearing loss to test for potential perceptual correlates of auditory deprivation- and rehabilitation-induced plasticity. In cochlear implant patients, electrically evoked auditory cortical responses were obtained using EEG to study scalp potential maps. RESULTS: Perceptual changes in frequency discrimination were observed at the lesion-edge frequency of steeply sloping hearing loss. Although these results are not direct proof of cortical plasticity, no peripheral phenomenon has been found to explain them. The reversal of such auditory deprivation-induced plasticity, a phenomenon that may be termed rehabilitation plasticity, can be studied in hearing-impaired subjects fitted with a hearing aid. Cochlear implant subjects provide another interesting model for studying rehabilitation plasticity in that even profound to total deafness is made partially reversible by cochlear implantation. We found that the auditory cortex of deaf subjects with at least 3 months of cochlear implant experience is organized in a way similar to the tonotopy described in normal-hearing subjects.

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.

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.

Vibrant soundbridge versus conventional hearing aid in sensorineural high-frequency hearing loss: a prospective study.

OBJECTIVES: The present study was aimed to compare gain and speech intelligibility measured in quiet and in noise between the Signia hearing aid and the Vibrant Soundbridge (VSB), both devices using the same sound processing technology. PATIENTS: A prospective longitudinal study was performed. Six patients with a steeply sloping high-frequency hearing loss were selected. INTERVENTION: The protocol comprised 3 months' hearing aid use, VSB implantation, and 3 months' VSB use. MAIN OUTCOME MEASURES: Patient performances were evaluated unaided and aided by audiologic assessments, including free-field thresholds and word recognition tasks in quiet and in noise. RESULTS: Statistical analysis revealed a slight decrease in overall frequencies in pure-tone audiometry after surgery; however, this decrease did not exceed 5 dB and was not different from the changes that occurred in the contralateral nonimplanted ear. The measures of aided and unaided hearing thresholds showed statistically significant larger gains with the VSB than with the hearing aid. In quiet, speech performances were poorer unaided than with either device. Because of ceiling effects, statistically significant higher scores with the VSB than with the hearing aid were only observed at the lowest intensity level. In noise, speech intelligibility was reported to be better with the VSB compared with both unaided and with the hearing aid at 5 signal-to-noise ratios. CONCLUSION: This prospective study demonstrated that direct-drive stimulation provided by the VSB allows better speech performances than acoustic stimulation for rehabilitation of patients with steeply sloping high-frequency hearing losses.

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.

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.