The natural history, clinical outcomes, and genotype-phenotype relationship of otoferlin-related hearing loss: a systematic, quantitative literature review.

Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

Immersive audiomotor game play enhances neural and perceptual salience of weak signals in noise.

All sensory systems face the fundamental challenge of encoding weak signals in noisy backgrounds. Although discrimination abilities can improve with practice, these benefits rarely generalize to untrained stimulus dimensions. Inspired by recent findings that action video game training can impart a broader spectrum of benefits than traditional perceptual learning paradigms, we trained adult humans and mice in an immersive audio game that challenged them to forage for hidden auditory targets in a 2D soundscape. Both species learned to modulate their angular search vectors and target approach velocities based on real-time changes in the level of a weak tone embedded in broadband noise. In humans, mastery of this tone in noise task generalized to an improved ability to comprehend spoken sentences in speech babble noise. Neural plasticity in the auditory cortex of trained mice supported improved decoding of low-intensity sounds at the training frequency and an enhanced resistance to interference from background masking noise. These findings highlight the potential to improve the neural and perceptual salience of degraded sensory stimuli through immersive computerized games.

Fluctuations in Subjective Tinnitus Ratings Over Time: Implications for Clinical Research.

OBJECTIVE: Patients with chronic, subjective tinnitus are often administered a battery of audiometric tests to characterize their tinnitus percept. Even a comprehensive battery, if applied just once, cannot capture fluctuations in tinnitus strength or quality over time. Moreover, subjects experience a learning curve when reporting the detailed characteristics of their tinnitus percept, such that a single assessment will reflect a lack of familiarity with test requirements. We addressed these challenges by programming an automated software platform for at-home tinnitus characterization over a 2-week period. STUDY DESIGN: Prospective case series. SETTING: Tertiary referral center, patients' homes. INTERVENTIONS: Following an initial clinic visit, 25 subjects with chronic subjective tinnitus returned home with a tablet computer and calibrated headphones to complete questionnaires, hearing tests, and tinnitus psychoacoustic testing. We repeatedly characterized loudness discomfort levels and tinnitus matching over a 2-week period. MAIN OUTCOME MEASURES: Primary outcomes included intrasubject variability in loudness discomfort levels, tinnitus intensity, and tinnitus acoustic matching over the course of testing. RESULTS: Within-subject variability for all outcome measures could be reduced by approximately 25 to 50% by excluding initial measurements and by focusing only on tinnitus matching attempts where subjects report high confidence in the accuracy of their ratings. CONCLUSIONS: Tinnitus self-report is inherently variable but can converge on reliable values with extended testing. Repeated, self-directed tinnitus assessments may have implications for identifying malingerers. Further, these findings suggest that extending the baseline phase of tinnitus characterizations will increase the statistical power for future studies focused on tinnitus interventions.

Audiomotor Perceptual Training Enhances Speech Intelligibility in Background Noise.

Sensory and motor skills can be improved with training, but learning is often restricted to practice stimuli. As an exception, training on closed-loop (CL) sensorimotor interfaces, such as action video games and musical instruments, can impart a broad spectrum of perceptual benefits. Here we ask whether computerized CL auditory training can enhance speech understanding in levels of background noise that approximate a crowded restaurant. Elderly hearing-impaired subjects trained for 8 weeks on a CL game that, like a musical instrument, challenged them to monitor subtle deviations between predicted and actual auditory feedback as they moved their fingertip through a virtual soundscape. We performed our study as a randomized, double-blind, placebo-controlled trial by training other subjects in an auditory working-memory (WM) task. Subjects in both groups improved at their respective auditory tasks and reported comparable expectations for improved speech processing, thereby controlling for placebo effects. Whereas speech intelligibility was unchanged after WM training, subjects in the CL training group could correctly identify 25% more words in spoken sentences or digit sequences presented in high levels of background noise. Numerically, CL audiomotor training provided more than three times the benefit of our subjects' hearing aids for speech processing in noisy listening conditions. Gains in speech intelligibility could be predicted from gameplay accuracy and baseline inhibitory control. However, benefits did not persist in the absence of continuing practice. These studies employ stringent clinical standards to demonstrate that perceptual learning on a computerized audio game can transfer to "real-world" communication challenges.

Translational issues in cochlear synaptopathy.

Understanding the biology of the previously underappreciated sensitivity of cochlear synapses to noise insult, and its clinical consequences, is becoming a mission for a growing number of auditory researchers. In addition, several research groups have become interested in developing therapeutic approaches that can reverse synaptopathy and restore hearing function. One of the major challenges to realizing the potential of synaptopathy rodent models is that current clinical audiometric approaches cannot yet reveal the presence of this subtle cochlear pathology in humans. This has catalyzed efforts, both from basic and clinical perspectives, to investigate novel means for diagnosing synaptopathy and to determine the main functional consequences for auditory perception and hearing abilities. Such means, and a strong concordance between findings in pre-clinical animal models and clinical studies in humans, are important for developing and realizing therapeutics. This paper frames the key outstanding translational questions that need to be addressed to realize this ambitious goal.

Validation of a Self-Administered Audiometry Application: An Equivalence Study.

OBJECTIVES/HYPOTHESIS: To compare hearing measurements made at home using self-administered audiometric software against audiological tests performed on the same subjects in a clinical setting STUDY DESIGN: Prospective, crossover equivalence study METHODS: In experiment 1, adults with varying degrees of hearing loss (N = 19) performed air-conduction audiometry, frequency discrimination, and speech recognition in noise testing twice at home with an automated tablet application and twice in sound-treated clinical booths with an audiologist. The accuracy and reliability of computer-guided home hearing tests were compared to audiologist administered tests. In experiment 2, the reliability and accuracy of pure-tone audiometric results were examined in a separate cohort across a variety of clinical settings (N = 21). RESULTS: Remote, automated audiograms were statistically equivalent to manual, clinic-based testing from 500 to 8,000 Hz (P ≤ .02); however, 250 Hz thresholds were elevated when collected at home. Remote and sound-treated booth testing of frequency discrimination and speech recognition thresholds were equivalent (P ≤ 5 × 10(-5) ). In the second experiment, remote testing was equivalent to manual sound-booth testing from 500 to 8,000 Hz (P ≤ .02) for a different cohort who received clinic-based testing in a variety of settings. CONCLUSION: These data provide a proof of concept that several self-administered, automated hearing measurements are statistically equivalent to manual measurements made by an audiologist in the clinic. The demonstration of statistical equivalency for these basic behavioral hearing tests points toward the eventual feasibility of monitoring progressive or fluctuant hearing disorders outside of the clinic to increase the efficiency of clinical information collection. LEVEL OF EVIDENCE: 2b. Laryngoscope, 126:2382-2388, 2016.

Central Gain Restores Auditory Processing following Near-Complete Cochlear Denervation.

Sensory organ damage induces a host of cellular and physiological changes in the periphery and the brain. Here, we show that some aspects of auditory processing recover after profound cochlear denervation due to a progressive, compensatory plasticity at higher stages of the central auditory pathway. Lesioning >95% of cochlear nerve afferent synapses, while sparing hair cells, in adult mice virtually eliminated the auditory brainstem response and acoustic startle reflex, yet tone detection behavior was nearly normal. As sound-evoked responses from the auditory nerve grew progressively weaker following denervation, sound-evoked activity in the cortex-and, to a lesser extent, the midbrain-rebounded or surpassed control levels. Increased central gain supported the recovery of rudimentary sound features encoded by firing rate, but not features encoded by precise spike timing such as modulated noise or speech. These findings underscore the importance of central plasticity in the perceptual sequelae of cochlear hearing impairment.

Evaluating the perceptual and pathophysiological consequences of auditory deprivation in early postnatal life: a comparison of basic and clinical studies.

Decades of clinical and basic research in visual system development have shown that degraded or imbalanced visual inputs can induce a long-lasting visual impairment called amblyopia. In the auditory domain, it is well established that inducing a conductive hearing loss (CHL) in young laboratory animals is associated with a panoply of central auditory system irregularities, ranging from cellular morphology to behavior. Human auditory deprivation, in the form of otitis media (OM), is tremendously common in young children, yet the evidence linking a history of OM to long-lasting auditory processing impairments has been equivocal for decades. Here, we review the apparent discrepancies in the clinical and basic auditory literature and provide a meta-analysis to show that the evidence for human amblyaudia, the auditory analog of amblyopia, is considerably more compelling than is generally believed. We argue that a major cause for this discrepancy is the fact that most clinical studies attempt to link central auditory deficits to a history of middle ear pathology, when the primary risk factor for brain-based developmental impairments such as amblyopia and amblyaudia is whether the afferent sensory signal is degraded during critical periods of brain development. Accordingly, clinical studies that target the subset of children with a history of OM that is also accompanied by elevated hearing thresholds consistently identify perceptual and physiological deficits that can endure for years after peripheral hearing is audiometrically normal, in keeping with the animal studies on CHL. These studies suggest that infants with OM severe enough to cause degraded afferent signal transmission (e.g., CHL) are particularly at risk to develop lasting central auditory impairments. We propose some practical guidelines to identify at-risk infants and test for the positive expression of amblyaudia in older children.