Novel Pathogenic Variants in PJVK, the Gene Encoding Pejvakin, in Subjects with Autosomal Recessive Non-Syndromic Hearing Impairment and Auditory Neuropathy Spectrum Disorder

Pathogenic variants in the PJVK gene cause the DFNB59 type of autosomal recessive non-syndromic hearing impairment (AR-NSHI). Phenotypes are not homogeneous, as a few subjects show auditory neuropathy spectrum disorder (ANSD), while others show cochlear hearing loss. The numbers of reported cases and pathogenic variants are still small to establish accurate genotype-phenotype correlations. We investigated a cohort of 77 Spanish familial cases of AR-NSHI, in whom DFNB1 had been excluded, and a cohort of 84 simplex cases with isolated ANSD in whom OTOF variants had been excluded. All seven exons and exon-intron boundaries of the PJVK gene were sequenced. We report three novel DFNB59 cases, one from the AR-NSHI cohort and two from the ANSD cohort, with stable, severe to profound NSHI. Two of the subjects received unilateral cochlear implantation, with apparent good outcomes. Our study expands the spectrum of PJVK mutations, as we report four novel pathogenic variants: p.Leu224Arg, p.His294Ilefs*43, p.His294Asp and p.Phe317Serfs*20. We review the reported cases of DFNB59, summarize the clinical features of this rare subtype of AR-NSHI and discuss the involvement of PJVK in ANSD.

The Relationship Between Tinnitus Pitch, Audiogram Edge Frequency, and Auditory Stream Segregation Abilities in Individuals With Tinnitus

Purpose Around 80%–93% of the individuals with tinnitus have hearing loss. Researchers have found that tinnitus pitch was related to the frequencies of hearing loss, but unclear about the relationship between tinnitus pitch and audiometry edge frequency. The comorbidity of tinnitus and speech perception in noise problems had also been reported, but the relationship between tinnitus pitch and speech perception in noise had seldom been investigated. This study was designed to estimate the relationship between tinnitus pitch, audiogram edge frequency, and speech perception in noise. The speech perception in noise was measured using auditory stream segregation paradigm. Method Thirteen individuals with bilateral mild-to-severe tonal tinnitus and minimal-to-mild cochlear hearing loss were selected. Thirteen individuals with hearing loss without tinnitus were also selected. The audiogram of each participant with tinnitus was matched with that of the participant without tinnitus. Tinnitus pitch of the participants with tinnitus was measured and compared with audiogram edge frequency. The stream segregation thresholds were calculated at the participants' admitted tinnitus pitch and one octave below the tinnitus pitch. The stream segregation thresholds were estimated at fission and fusion boundary using pure-tone stimuli in ABA paradigm. Results High correlation between tinnitus pitch and audiogram edge frequency was noted. Overall stream segregation thresholds were higher for individuals with tinnitus. Higher thresholds indicated poorer stream segregation abilities. Within tinnitus participants, the thresholds were significantly lesser at frequency corresponding to admitted tinnitus pitch than at one octave below the tinnitus pitch. Conclusions The information from this study may be helpful in educating the patients about the relationship between hearing loss and tinnitus. The findings may also account for speech-perception-in-noise difficulties often reported by the individuals with tinnitus.

Mechanisms of Spectrotemporal Modulation Detection for Normal- and Hearing-Impaired Listeners

Spectrotemporal modulations (STM) are essential features of speech signals that make them intelligible. While their encoding has been widely investigated in neurophysiology, we still lack a full understanding of how STMs are processed at the behavioral level and how cochlear hearing loss impacts this processing. Here, we introduce a novel methodological framework based on psychophysical reverse correlation deployed in the modulation space to characterize the mechanisms underlying STM detection in noise. We derive perceptual filters for young normal-hearing and older hearing-impaired individuals performing a detection task of an elementary target STM (a given product of temporal and spectral modulations) embedded in other masking STMs. Analyzed with computational tools, our data show that both groups rely on a comparable linear (band-pass)–nonlinear processing cascade, which can be well accounted for by a temporal modulation filter bank model combined with cross-correlation against the target representation. Our results also suggest that the modulation mistuning observed for the hearing-impaired group results primarily from broader cochlear filters. Yet, we find idiosyncratic behaviors that cannot be captured by cochlear tuning alone, highlighting the need to consider variability originating from additional mechanisms. Overall, this integrated experimental-computational approach offers a principled way to assess suprathreshold processing distortions in each individual and could thus be used to further investigate interindividual differences in speech intelligibility.

Utility of Acoustic Change Complex as an Objective Tool to Evaluate Difference Limen for Intensity in Cochlear Hearing Loss and Auditory Neuropathy Spectrum Disorder

Purpose This study aimed to investigate usefulness of acoustic change complex (ACC) as an objective measure of difference limen for intensity (DLI) in auditory neuropathy spectrum disorders (ANSD) and cochlear hearing loss (CHL). Method The study used a multiple static group comparison research design. Twenty normal-hearing individuals (NH), 19 individuals with ANSD, and 23 individuals with CHL underwent DLI measurement using behavioral (psychoacoustic) techniques and ACC. For eliciting ACC, a 500-ms, 1,000-Hz pure tone was presented at 80 dB SPL. Additionally, six variants of this stimulus with intensity increments of 1, 3, 4, 5, 10, and 20 dB starting 250 ms after stimulus onset were used to elicit the ACC. Results The lowest intensity change that produced replicable and clearly identifiable ACC was referred as objective DLI. In comparison to NH and CHL, the behavioral as well as the objective DLI were significantly larger (poorer) in ANSD ( p < .05). Significantly strong positive correlation existed between DLI obtained using behavioral and objective measures ( p < .05). Conclusions ACC could be a useful objective tool to measure DLI in the clinical population, provided the individuals of the clinical population fulfill the prerequisite of the presence of Auditory Long Latency Responses. Supplemental Material https://doi.org/10.23641/asha.12560132

Mechanisms of spectrotemporal modulation detection for normal- and hearing-impaired listeners

Spectrotemporal modulations (STMs) offer a unified framework to probe suprathreshold auditory processing. Here, we introduce a novel methodological framework based on psychophysical reverse-correlation deployed in the modulation space to characterize how STMs are detected by the auditory system and how cochlear hearing loss impacts this processing. Our results show that young normal-hearing (NH) and older hearing-impaired (HI) individuals rely on a comparable non-linear processing architecture involving non-directional band-pass modulation filtering. We demonstrate that a temporal-modulation filter-bank model can capture the strategy of the NH group and that a broader tuning of cochlear filters is sufficient to explain the overall shift toward temporal modulations of the HI group. Yet, idiosyncratic behaviors exposed within each group highlight the contribution and the need to consider additional mechanisms. This integrated experimental-computational approach offers a principled way to assess supra-threshold auditory processing distortions of each individual.

Evidence for a dynorphin-mediated inner ear immune/inflammatory response and glutamate-induced neural excitotoxicity: an updated analysis

Acoustic overstimulation (AOS) is defined as the stressful overexposure to high-intensity sounds. AOS is a precipitating factor that leads to a glutamate (GLU)-induced Type I auditory neural excitotoxicity and an activation of an immune/inflammatory/oxidative stress response within the inner ear, often resulting in cochlear hearing loss. The dendrites of the Type I auditory neural neurons that innervate the inner hair cells (IHCs), and respond to the IHC release of the excitatory neurotransmitter GLU, are themselves directly innervated by the dynorphin (DYN)-bearing axon terminals of the descending brain stem lateral olivocochlear (LOC) system. DYNs are known to increase GLU availability, potentiate GLU excitotoxicity, and induce superoxide production. DYNs also increase the production of proinflammatory cytokines by modulating immune/inflammatory signal transduction pathways. Evidence is provided supporting the possibility that the GLU-mediated Type I auditory neural dendritic swelling, inflammation, excitotoxicity, and cochlear hearing loss that follow AOS may be part of a brain stem-activated, DYN-mediated cascade of inflammatory events subsequent to a LOC release of DYNs into the cochlea. In support of a DYN-mediated cascade of events are established investigations linking DYNs to the immune/inflammatory/excitotoxic response in other neural systems.

The frequency limit of outer hair cell motility measured in vivo

Outer hair cells (OHCs) in the mammalian ear exhibit electromotility, electrically driven somatic length changes that are thought to mechanically amplify sound-evoked vibrations. For this amplification to work, OHCs must respond to sounds on a cycle-by-cycle basis even at frequencies that exceed the low-pass corner frequency of their cell membranes. Using in vivo optical vibrometry we tested this theory by measuring sound-evoked motility in the 13–25 kHz region of the gerbil cochlea. OHC vibrations were strongly rectified, and motility exhibited first-order low-pass characteristics with corner frequencies around 3 kHz– more than 2.5 octaves below the frequencies the OHCs are expected to amplify. These observations lead us to suggest that the OHCs operate more like the envelope detectors in a classical gain-control scheme than like high-frequency sound amplifiers. These findings call for a fundamental reconsideration of the role of the OHCs in cochlear function and the causes of cochlear hearing loss.