Common causes of hearing loss in humans - exposure to loud noise or ototoxic drugs and aging - often damage sensory hair cells, reflected as elevated thresholds on the clinical audiogram. Recent ...studies in animal models suggest, however, that well before this overt hearing loss can be seen, a more insidious, but likely more common, process is taking place that permanently interrupts synaptic communication between sensory inner hair cells and subsets of cochlear nerve fibers. The silencing of affected neurons alters auditory information processing, whether accompanied by threshold elevations or not, and is a likely contributor to a variety of perceptual abnormalities, including speech-in-noise difficulties, tinnitus and hyperacusis. Work described here will review structural and functional manifestations of this cochlear synaptopathy and will consider possible mechanisms underlying its appearance and progression in ears with and without traditional ‘hearing loss’ arising from several common causes in humans.
•Noise can cause rapid synaptic loss and slow degeneration of cochlear nerve fibers, even if hair cells survive.•Diffuse cochlear synaptopathy does not raise audiometric or ABR thresholds, but does decrease ABR amplitudes.•Ears exposed to ‘synaptopathic’ noise show exaggerated synaptic and neural losses as they age after exposure.
Exposure to intense sound or noise can result in purely temporary threshold shift (TTS), or leave a residual permanent threshold shift (PTS) along with alterations in growth functions of auditory ...nerve output. Recent research has revealed a number of mechanisms that contribute to noise-induced hearing loss (NIHL). The principle cause of NIHL is damage to cochlear hair cells and associated synaptopathy. Contributions to TTS include reversible damage to hair cell (HC) stereocilia or synapses, while moderate TTS reflects protective purinergic hearing adaptation. PTS represents permanent damage to or loss of HCs and synapses. While the substrates of HC damage are complex, they include the accumulation of reactive oxygen species and the active stimulation of intracellular stress pathways, leading to programmed and/or necrotic cell death. Permanent damage to cochlear neurons can also contribute to the effects of NIHL, in addition to HC damage. These mechanisms have translational potential for pharmacological intervention and provide multiple opportunities to prevent HC damage or to rescue HCs and spiral ganglion neurons that have suffered injury. This paper reviews advances in our understanding of cellular mechanisms that contribute to NIHL and their potential for therapeutic manipulation.
•Recent research has identified many cellular mechanisms that contribute to cochlear damage and noise-induced hearing loss.•In addition, protective pathways that oppose cochlear damage mechanisms have been discovered.•Many of these mechanisms can be manipulated pharmacologically, pointing the way to potential new therapies.
Cochlear synaptopathy can result from various insults, including acoustic trauma, aging, ototoxicity, or chronic conductive hearing loss. For example, moderate noise exposure in mice can destroy up ...to ∼50% of synapses between auditory nerve fibers (ANFs) and inner hair cells (IHCs) without affecting outer hair cells (OHCs) or thresholds, because the synaptopathy occurs first in high-threshold ANFs. However, the fiber loss likely impairs temporal processing and hearing-in-noise, a classic complaint of those with sensorineural hearing loss. Non-human primates appear to be less vulnerable to noise-induced hair-cell loss than rodents, but their susceptibility to synaptopathy has not been studied. Because establishing a non-human primate model may be important in the development of diagnostics and therapeutics, we examined cochlear innervation and the damaging effects of acoustic overexposure in young adult rhesus macaques. Anesthetized animals were exposed bilaterally to narrow-band noise centered at 2 kHz at various sound-pressure levels for 4 h. Cochlear function was assayed for up to 8 weeks following exposure via auditory brainstem responses (ABRs) and otoacoustic emissions (OAEs). A moderate loss of synaptic connections (mean of 12–27% in the basal half of the cochlea) followed temporary threshold shifts (TTS), despite minimal hair-cell loss. A dramatic loss of synapses (mean of 50–75% in the basal half of the cochlea) was seen on IHCs surviving noise exposures that produced permanent threshold shifts (PTS) and widespread hair-cell loss. Higher noise levels were required to produce PTS in macaques compared to rodents, suggesting that primates are less vulnerable to hair-cell loss. However, the phenomenon of noise-induced cochlear synaptopathy in primates is similar to that seen in rodents.
•Cochlear synaptopathy is an important component of sensorineural hearing loss.•Cochlear synaptopathy is a primary event following acoustic trauma in primates.•Primates are resilient to noise-induced hair cell loss and threshold shifts.•Primates do not appear to be more resilient to synaptopathy than non-primates.
Noise-induced cochlear synaptopathy has been demonstrated in numerous rodent studies. In these animal models, the disorder is characterized by a reduction in amplitude of wave I of the auditory ...brainstem response (ABR) to high-level stimuli, whereas the response at threshold is unaffected. The aim of the present study was to determine if this disorder is prevalent in young adult humans with normal audiometric hearing. One hundred and twenty six participants (75 females) aged 18–36 were tested. Participants had a wide range of lifetime noise exposures as estimated by a structured interview. Audiometric thresholds did not differ across noise exposures up to 8 kHz, although 16-kHz audiometric thresholds were elevated with increasing noise exposure for females but not for males. ABRs were measured in response to high-pass (1.5 kHz) filtered clicks of 80 and 100 dB peSPL. Frequency-following responses (FFRs) were measured to 80 dB SPL pure tones from 240 to 285 Hz, and to 80 dB SPL 4 kHz pure tones amplitude modulated at frequencies from 240 to 285 Hz (transposed tones). The bandwidth of the ABR stimuli and the carrier frequency of the transposed tones were chosen to target the 3–6 kHz characteristic frequency region which is usually associated with noise damage in humans. The results indicate no relation between noise exposure and the amplitude of the ABR. In particular, wave I of the ABR did not decrease with increasing noise exposure as predicted. ABR wave V latency increased with increasing noise exposure for the 80 dB peSPL click. High carrier-frequency (envelope) FFR signal-to-noise ratios decreased as a function of noise exposure in males but not females. However, these correlations were not significant after the effects of age were controlled. The results suggest either that noise-induced cochlear synaptopathy is not a significant problem in young, audiometrically normal adults, or that the ABR and FFR are relatively insensitive to this disorder in young humans, although it is possible that the effects become more pronounced with age.
•Large study on the effects of lifetime noise exposure in normal-hearing young adults.•No clear evidence for noise-induced cochlear synaptopathy in ABR or FFR measures.•Noise exposure associated with elevated 16-kHz audiometric thresholds in females.
Acquired sensorineural hearing loss is one of the most prevalent chronic diseases, and aging and acoustic overexposure are common contributors. Decades of study in animals and humans have clarified ...the cellular targets and perceptual consequences of these forms of hearing loss, and preclinical studies have led to the development of therapeutics designed to slow, prevent or reverse them. Here, we review the histopathological changes underlying age-related and noise-induced hearing loss and the functional consequences of these pathologies. Based on these relations, we consider the ambiguities that arise in diagnosing underlying pathology from minimally invasive tests of auditory function, and how those ambiguities present challenges in the design and interpretation of clinical trials.
•Noise exposure and aging are major causes of acquired sensorineural hearing loss.•Threshold shifts can be due to hair cell loss, stereocilia or strial damage.•IHC-ANF synapse loss contributes to hearing impairment without elevating thresholds.•Preclinical studies showing cochlear regeneration are spawning clinical trials.•Trial design is complicated by crude non-invasive diagnosis of underlying pathology.
For decades, we have presumed the death of hair cells and spiral ganglion neurons are the main cause of hearing loss and difficulties understanding speech in noise, but new findings suggest synapse ...loss may be the key contributor. Specifically, recent preclinical studies suggest that the synapses between inner hair cells and spiral ganglion neurons with low spontaneous rates and high thresholds are the most vulnerable subcellular structures, with respect to insults during aging and noise exposure. This cochlear synaptopathy can be “hidden” because this synaptic loss can occur without permanent hearing threshold shifts. This new discovery of synaptic loss opens doors to new research directions. Here, we review a number of recent studies and make suggestions in two critical future research directions. First, based on solid evidence of cochlear synaptopathy in animal models, it is time to apply molecular approaches to identify the underlying molecular mechanisms; improved understanding is necessary for developing rational, effective therapies against this cochlear synaptopathy. Second, in human studies, the data supporting cochlear synaptopathy are indirect although rapid progress has been made. To fully identify changes in function that are directly related this hidden synaptic damage, we argue that a battery of tests including both electrophysiological and behavior tests should be combined for diagnosis of “hidden hearing loss” in clinical studies. This new approach may provide a direct link between cochlear synaptopathy and perceptual difficulties.
•Recent animal studies has established the phenomena of cochlear synaptopathy as a consequence of aging, and after acute noise exposure.•Future animal studies are necessary to reveal molecular cascades underlying synaptopathy and inform research on strategies for potential prevention.•Future human studies should develop a combination of electrophysiological and behavior testing for detecting cochlear synaptopathy since it is difficult to model the combination of electrophysiological and immune-histochemical methods in animal studies.
Despite a robust hearing conservation program, military personnel continue to be at high risk for noise induced hearing loss (NIHL). For more than a decade, a number of laboratories have investigated ...the use of antioxidants as a safe and effective adjunct to hearing conservation programs. Of the antioxidants that have been investigated, N-acetylcysteine (NAC) has consistently reduced permanent NIHL in the laboratory, but its clinical efficacy is still controversial. This study provides a prospective, randomized, double-blinded, placebo-controlled clinical trial investigating the safety profile and the efficacy of NAC to prevent hearing loss in a military population after weapons training.
Of the 566 total study subjects, 277 received NAC while 289 were given placebo. The null hypothesis for the rate of STS was not rejected based on the measured results. While no significant differences were found for the primary outcome, rate of threshold shifts, the right ear threshold shift rate difference did approach significance (p = 0.0562). No significant difference was found in the second primary outcome, percentage of subjects experiencing an adverse event between placebo and NAC groups (26.7% and 27.4%, respectively, p = 0.4465). Results for the secondary outcome, STS rate in the trigger hand ear, did show a significant difference (34.98% for placebo-treated, 27.14% for NAC-treated, p-value = 0.0288). Additionally, post-hoc analysis showed significant differences in threshold shift rates when handedness was taken into account.
While the secondary outcomes and post-hoc analysis suggest that NAC treatment is superior to the placebo, the present study design failed to confirm this. The lack of significant differences in overall hearing loss between the treatment and placebo groups may be due to a number of factors, including suboptimal dosing, premature post-exposure audiograms, or differences in risk between ears or subjects. Based on secondary outcomes and post hoc analyses however, further studies seem warranted and are needed to clarify dose response and the factors that may have played a role in the observed results.
•A Phase II-like study assessed the efficacy and safety of orally-administered NAC.•Despite use of ear plugs, 37% of subjects exhibited significant threshold shift.•NAC was safe and well tolerated compared to placebo.•Based on limited preliminary data, groups did not show significance differences.•Post hoc and Sign tests suggested that there may be a treatment effect.
Summary Noise is pervasive in everyday life and can cause both auditory and non-auditory health effects. Noise-induced hearing loss remains highly prevalent in occupational settings, and is ...increasingly caused by social noise exposure (eg, through personal music players). Our understanding of molecular mechanisms involved in noise-induced hair-cell and nerve damage has substantially increased, and preventive and therapeutic drugs will probably become available within 10 years. Evidence of the non-auditory effects of environmental noise exposure on public health is growing. Observational and experimental studies have shown that noise exposure leads to annoyance, disturbs sleep and causes daytime sleepiness, affects patient outcomes and staff performance in hospitals, increases the occurrence of hypertension and cardiovascular disease, and impairs cognitive performance in schoolchildren. In this Review, we stress the importance of adequate noise prevention and mitigation strategies for public health.
Hearing loss caused by exposure to recreational and occupational noise remains a worldwide disabling condition and dysregulation of redox homeostasis is the hallmark of cochlear damage induced by ...noise exposure. In this review we discuss the dual function of ROS to both promote cell damage (oxidative stress) and cell adaptive responses (ROS signaling) in the cochlea undergoing a stressful condition such as noise exposure. We focus on animal models of noise-induced hearing loss (NIHL) and on the function of exogenous antioxidants to maintaining a physiological role of ROS signaling by distinguishing the effect of exogenous "direct" antioxidants (i.e. CoQ10, NAC), that react with ROS to decrease oxidative stress, from the exogenous "indirect" antioxidants (i.e. nutraceutics and phenolic compounds) that can activate cellular redox enzymes through the Keap1-Nrf2-ARE pathway. The anti-inflammatory properties of Nrf2 signaling are discussed in relation to the ROS/inflammation interplay in noise exposure. Unveiling the mechanisms of ROS regulating redox-associated signaling pathways is essential in providing relevant targets for innovative and effective therapeutic strategies against NIHL.
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•NIHL causes cochlear metabolic damage centered on the formation of free radicals.•ROS promote both cell damage and cell adaptation in the cochlea after noise exposure.•ROS can be counteracted by indirect antioxidants activating redox signaling pathway.•ROS signaling/inflammation interplay has a key role in noise-induced cochlear damage.
Noise-induced hearing loss is one of the most common forms of sensorineural hearing loss, is a major health problem, is largely preventable and is probably more widespread than revealed by ...conventional pure tone threshold testing. Noise-induced damage to the cochlea is traditionally considered to be associated with symmetrical mild to moderate hearing loss with associated tinnitus; however, there is a significant number of patients with asymmetrical thresholds and, depending on the exposure, severe to profound hearing loss as well.
Recent epidemiology and animal studies have provided further insight into the pathophysiology, clinical findings, social and economic impacts of noise-induced hearing loss. Furthermore, it is recently shown that acoustic trauma is associated with vestibular dysfunction, with associated dizziness that is not always measurable with current techniques. Deliberation of the prevalence, treatment and prevention of noise-induced hearing loss is important and timely. Currently, prevention and protection are the first lines of defence, although promising protective effects are emerging from multiple different pharmaceutical agents, such as steroids, antioxidants and neurotrophins.
This review provides a comprehensive update on the pathophysiology, investigations, prevalence of asymmetry, associated symptoms, and current strategies on the prevention and treatment of noise-induced hearing loss.
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