Sharon G. Kujawa

Adding Insult to Injury: Cochlear Nerve Degeneration after “Temporary” Noise-Induced Hearing Loss

Overexposure to intense sound can cause temporary or permanent hearing loss. Postexposure recovery of threshold sensitivity has been assumed to indicate reversal of damage to delicate mechano-sensory and neural structures of the inner ear and no persistent or delayed consequences for auditory function. Here, we show, using cochlear functional assays and confocal imaging of the inner ear in mouse, that acoustic overexposures causing moderate, but completely reversible, threshold elevation leave cochlear sensory cells intact, but cause acute loss of afferent nerve terminals and delayed degeneration of the cochlear nerve. Results suggest that noise-induced damage to the ear has progressive consequences that are considerably more widespread than are revealed by conventional threshold testing. This primary neurodegeneration should add to difficulties hearing in noisy environments, and could contribute to tinnitus, hyperacusis, and other perceptual anomalies commonly associated with inner ear damage.

Acceleration of Age-Related Hearing Loss by Early Noise Exposure: Evidence of a Misspent Youth

Age-related and noise-induced hearing losses in humans are multifactorial, with contributions from, and potential interactions among, numerous variables that can shape final outcome. A recent retrospective clinical study suggests an age–noise interaction that exacerbates age-related hearing loss in previously noise-damaged ears (Gates et al., 2000). Here, we address the issue in an animal model by comparing noise-induced and age-related hearing loss (NIHL; AHL) in groups of CBA/CaJ mice exposed identically (8–16 kHz noise band at 100 dB sound pressure level for 2 h) but at different ages (4–124 weeks) and held with unexposed cohorts for different postexposure times (2–96 weeks). When evaluated 2 weeks after exposure, maximum threshold shifts in young-exposed animals (4–8 weeks) were 40–50 dB; older-exposed animals (≥16 weeks) showed essentially no shift at the same postexposure time. However, when held for long postexposure times, animals with previous exposure demonstrated AHL and histopathology fundamentally unlike unexposed, aging animals or old-exposed animals held for 2 weeks only. Specifically, they showed substantial, ongoing deterioration of cochlear neural responses, without additional change in preneural responses, and corresponding histologic evidence of primary neural degeneration throughout the cochlea. This was true particularly for young-exposed animals; however, delayed neuropathy was observed in all noise-exposed animals held 96 weeks after exposure, even those that showed no NIHL 2 weeks after exposure. Data suggest that pathologic but sublethal changes initiated by early noise exposure render the inner ears significantly more vulnerable to aging.

Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates.

Acoustic overexposure can cause a permanent loss of auditory nerve fibers without destroying cochlear sensory cells, despite complete recovery of cochlear thresholds (Kujawa and Liberman 2009), as measured by gross neural potentials such as the auditory brainstem response (ABR). To address this nominal paradox, we recorded responses from single auditory nerve fibers in guinea pigs exposed to this type of neuropathic noise (4- to 8-kHz octave band at 106 dB SPL for 2 h). Two weeks postexposure, ABR thresholds had recovered to normal, while suprathreshold ABR amplitudes were reduced. Both thresholds and amplitudes of distortion-product otoacoustic emissions fully recovered, suggesting recovery of hair cell function. Loss of up to 30% of auditory-nerve synapses on inner hair cells was confirmed by confocal analysis of the cochlear sensory epithelium immunostained for pre- and postsynaptic markers. In single fiber recordings, at 2 wk postexposure, frequency tuning, dynamic range, postonset adaptation, first-spike latency and its variance, and other basic properties of auditory nerve response were all completely normal in the remaining fibers. The only physiological abnormality was a change in population statistics suggesting a selective loss of fibers with low- and medium-spontaneous rates. Selective loss of these high-threshold fibers would explain how ABR thresholds can recover despite such significant noise-induced neuropathy. A selective loss of high-threshold fibers may contribute to the problems of hearing in noisy environments that characterize the aging auditory system.

Age-Related Cochlear Synaptopathy: An Early-Onset Contributor to Auditory Functional Decline

Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.

Vestibular evoked myogenic potentials show altered tuning in patients with Ménière's disease.

Objective: Acoustic stimulation of the saccule gives rise to a vestibulocollic reflex, the output of which can be measured in the neck as inhibition of activity in the ipsilateral sternocleidomastoid muscle. This vestibular evoked myogenic potential has been promoted as a means of assessing integrity of saccular function. In this study, we test the hypothesis that the cochleosaccular hydrops of Ménière’s syndrome leads to alterations in saccular motion that change the dynamics of the vestibular evoked myogenic potential. Study Design: Prospective cohort study. Setting: Large specialty hospital, department of otolaryngology. Subjects: Fourteen normal adult volunteers and 34 consecutive consenting adult patients with unilateral Ménière’s disease by American Academy of Otolaryngology–Head and Neck Surgery diagnostic criteria. Interventions: All subjects underwent vestibular evoked myogenic potential testing using ipsilateral broadband click and short tone-burst stimuli at 250, 500, 1,000, 2,000, and 4,000 Hz. Main Outcome Measures: Threshold, amplitude, and latency of vestibular evoked myogenic potential responses in normal and Ménière’s affected and unaffected ears. Results: Vestibular evoked myogenic potential was present in all ears tested. Normal subjects show a frequency-dependent vestibular evoked myogenic potential threshold, with best response (“frequency tuning”) at 500 Hz. Compared with normal subjects and unaffected ears of Ménière’s subjects, affected Ménière’s ears had significantly increased vestibular evoked myogenic potential thresholds. Affected Ménière’s ears showed threshold shifts at all frequencies and there was less tuning apparent at 500 Hz. Unaffected ears of Ménière’s subjects also showed significantly elevated vestibular evoked myogenic potential thresholds compared with normal subjects. Analyses of vestibular evoked myogenic potential thresholds for effects of age, hearing loss, and audiometric configuration showed no significant differences. Conclusions: Ménière’s ears display alterations in vestibular evoked myogenic potential threshold and tuning, supporting our hypothesis of altered saccular motion mechanics arising from hydropic distention. Unaffected ears of unilateral Ménière’s subjects show similar changes, though to a lesser degree. This finding may be because of occult saccular hydrops in the asymptomatic ear or binaural interactions in the vestibular evoked myogenic potential otolith–cervical reflex arc.

Vestibular evoked myogenic potentials (VEMP) can detect asymptomatic saccular hydrops.

Objective: The objective of this study was to explore the useful of vestibular evoked myogenic potential (VEMP) testing for detecting endolymphatic hydrops, especially in the second ear of patients with unilateral Ménière disease (MD).

Mutant β-spectrin 4 causes auditory and motor neuropathies in quivering mice

The autosomal recessive mouse mutation quivering (qv), which arose spontaneously in 1953, produces progressive ataxia with hind limb paralysis, deafness and tremor. Six additional spontaneous alleles, qvJ, qv2J, qv3J, qv4J, qvlnd and qvlnd2J, have been identified. Ear twitch responses (Preyers reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory information, indicating that, in contrast to the many known mutations causing deafness originating in the cochlea, deafness in qv is central in origin. Here we report that quivering mice carry loss-of-function mutations in the mouse β-spectrin 4 gene (Spnb4) that cause alterations in ion channel localization in myelinated nerves; this provides a rationale for the auditory and motor neuropathies of these mice.

Drug delivery for treatment of inner ear disease: current state of knowledge.

Delivery of medications to the inner ear has been an area of considerable growth in both the research and clinical realms during the past several decades. Systemic delivery of medication destined for treatment of the inner ear is the foundation on which newer delivery techniques have been developed. Because of systemic side effects, investigators and clinicians have begun developing and using techniques to deliver therapeutic agents locally. Alongside the now commonplace use of intratympanic gentamicin for Menieres disease and the emerging use of intratympanic steroids for sudden sensorineural hearing loss, novel technologies, such as hydrogels and nanoparticles, are being explored. At the horizon of inner ear drug-delivery techniques, intracochlear devices that leverage recent advances in microsystems technology are being developed to apply medications directly into the inner ear. Potential uses for such devices include neurotrophic factor and steroid delivery with cochlear implantation, RNA interference technologies, and stem-cell therapy. The historical, current, and future delivery techniques and uses of drug delivery for treatment of inner ear disease serve as the basis for this review.

Osteoprotegrin Knockout Mice Demonstrate Abnormal Remodeling of the Otic Capsule and Progressive Hearing Loss

Objectives: The otic capsule, when compared with other bones in the body, is unique in that it undergoes no significant remodeling of bone after development. We previously demonstrated that osteoprotegerin (OPG), which inhibits formation and function of osteoclasts, is produced at high levels in the inner ear of normal mice and secreted into the perilymph from where it diffuses into the surrounding otic capsule bone through a lacunocanalicular system. To test our hypothesis that the high level of OPG may be important in the inhibition of otic capsule remodeling, we studied the light microscopic histology of the otic capsule in OPG knockout mice for evidence of abnormal remodeling of bone. We also tested the hearing in OPG knockout mice to determine whether OPG and its influence on surrounding bone is important for auditory function.

Prospective noise induced changes to hearing among construction industry apprentices

Aims: To characterise the development of noise induced damage to hearing. Methods: Hearing and noise exposure were prospectively monitored among a cohort of newly enrolled construction industry apprentices and a comparison group of graduate students, using standard pure tone audiometry and distortion product otoacoustic emissions (DPOAEs). A total of 328 subjects (632 ears) were monitored annually an average of 3.4 times. In parallel to these measures, noise exposure and hearing protection device (HPD) use were extensively monitored during construction work tasks. Recreational/non-occupational exposures also were queried and monitored in subgroups of subjects. Trade specific mean exposure Leq levels, with and without accounting for the variable use of hearing protection in each trade, were calculated and used to group subjects by trade specific exposure level. Mixed effects models were used to estimate the change in hearing outcomes over time for each exposure group. Results: Small but significant exposure related changes in DPOAEs over time were observed, especially at 4 kHz with stimulus levels (L1) between 50 and 75 dB, with less clear but similar patterns observed at 3 kHz. After controlling for covariates, the high exposure group had annual changes in 4 kHz emissions of about 0.5 dB per year. Pure tone audiometric thresholds displayed only slight trends towards increased threshold levels with increasing exposure groups. Some unexpected results were observed, including an apparent increase in DPOAEs among controls over time, and improvement in behavioural thresholds among controls at 6 kHz only. Conclusions: Results indicate that construction apprentices in their first three years of work, with average noise exposures under 90 dBA, have measurable losses of hearing function. Despite numerous challenges in using DPOAEs for hearing surveillance in an industrial setting, they appear somewhat more sensitive to these early changes than is evident with standard pure tone audiometry.