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A series of articles discussing advanced diagnostics that can be used to assess noise injury and associated noise-induced hearing disorders (NIHD) was developed under the umbrella of the United States Department of Defense Hearing Center of Excellence Pharmaceutical Interventions for Hearing Loss working group. The overarching goals of the current series were to provide insight into (1) well-established and more recently developed metrics that are sensitive for detection of cochlear pathology or diagnosis of NIHD, and (2) the tools that are available for characterizing individual noise hazard as personal exposure will vary based on distance to the sound source and placement of hearing protection devices. In addition to discussing the utility of advanced diagnostics in patient care settings, the current articles discuss the selection of outcomes and end points that can be considered for use in clinical trials investigating hearing loss prevention and hearing rehabilitation. [ABSTRACT FROM AUTHOR]

Pure-tone thresholds have long served as a gold standard for evaluating hearing sensitivity and documenting hearing changes related to medical treatments, toxic or otherwise hazardous exposures, ear disease, genetic disorders involving the ear, and deficits that develop during aging. Although the use of pure-tone audiometry is basic and standard, interpretation of thresholds obtained at multiple frequencies in both ears over multiple visits can be complex. Significant additional complexity is introduced when audiometric tests are performed within ototoxicity monitoring programs to determine if hearing loss occurs as an adverse reaction to an investigational medication and during the design and conduct of clinical trials for new otoprotective agents for noise and drug-induced hearing loss. Clinical trials using gene therapy or stem cell therapy approaches are emerging as well with audiometric outcome selection further complicated by safety issues associated with biological therapies. This review addresses factors that must be considered, including test-retest variability, significant threshold change definitions, use of ototoxicity grading scales, interpretation of early warning signals, measurement of notching in noise-induced hearing loss, and application of age-based normative data to interpretation of pure-tone thresholds. Specific guidance for clinical trial protocols that will assure rigorous methodological approaches and interpretable audiometric data are provided. [ABSTRACT FROM AUTHOR]

Significance: Noise-induced hearing loss (NIHL) is an important public health issue resulting in decreased quality of life for affected individuals, and significant costs to employers and governmental agencies. Recent Advances: Advances in the mechanistic understanding of NIHL have prompted a growing number of proposed, in-progress, and completed clinical trials for possible protections against NIHL via antioxidants and other drug agents. Thirty-one clinical trials evaluating prevention of either temporary or permanent NIHL were identified and are reviewed. Critical Issues: This review revealed little consistency in the noise-exposed populations in which drugs are evaluated or the primary outcomes used to measure NIHL prevention. Changes in pure-tone thresholds were the most common primary outcomes; specific threshold metrics included both average hearing loss and incidence of significant hearing loss. Changes in otoacoustic emission (OAE) amplitude were relatively common secondary outcomes. Extended high-frequency (EHF) hearing and speech-in-noise perception are commonly adversely affected by noise exposure but are not consistently included in clinical trials assessing prevention of NIHL. Future Directions: Multiple criteria are available for monitoring NIHL, but the specific criterion to be used to define clinically significant otoprotection remains a topic of discussion. Audiogram-based primary outcome measures can be combined with secondary outcomes, including OAE amplitude, EHF hearing, speech-in-noise testing, tinnitus surveys, and patient-reported outcomes. Standardization of test protocols for the above primary and secondary outcomes, and associated reporting criterion for each, would facilitate clinical trial design and comparison of results across investigational drug agents. Antioxid. Redox Signal. 36, 1171–1202. [ABSTRACT FROM AUTHOR]

Background The previous 30 years have provided information on the mechanisms of cell death in the inner ear after noise exposure, ototoxic drug injury, and during aging, and clinical trials have emerged for all of these acquired forms of hearing loss. Sudden hearing loss is less well understood, but restoration of hearing after sudden hearing loss is also a long-standing drug target, typically using steroids as an intervention but with other agents of interest as well. Purpose The purpose of this review was to describe the state of the science regarding clinical testing of investigational medicinal products for the inner ear with respect to treatment or prevention of acquired hearing loss. Data Collection and Analysis Comprehensive search and summary of clinical trials listed in the National Library of Medicine (www.ClinicalTrials.gov) database identified 61 clinical trials. Results Study phase, status, intervention, and primary, secondary, and other outcomes are summarized for studies assessing prevention of noise-induced hearing loss, prevention of drug-induced hearing loss, treatment of stable sensorineural hearing loss, and treatment of sudden sensorineural hearing loss. Conclusion This review provides a comprehensive summary of the state of the science with respect to investigational medicinal products for the inner ear evaluated in human clinical trials, and the current challenges for the field. [ABSTRACT FROM AUTHOR]

Significant variability in noise-induced hearing loss (NIHL) susceptibility suggests there are factors beyond sound level and duration of exposure that contribute to individual susceptibility. External-ear amplification (EEA) from external-ear structures varies significantly due to ear size and shape, potentially influencing NIHL susceptibility. This study tested the hypothesis that EEA can be predicted using non-technical proxy measurements including pinna height (cm), body height (m), and earcanal volume (cm3). 158 participants (4–78 years) completed otoscopy, tympanometry, pinna measurements, body height measurements, and two EEA measurements: (1) total real-ear unaided gain (REUG) of the open ear and (2) real-ear to coupler difference (RECD), representing unaided gain from the earcanal. Participants' individual noise doses were compared in hypothetical exposures. REUG ranged from 5 to 19 dBA and was correlated with pinna height. High-REUG participants were estimated to accrue noise doses at least 5 times higher than low-REUG participants. RECD ranged from 7 to 24 dBA and was correlated with earcanal volume and body height. The results support the hypothesis that EEA measurement could significantly improve estimation of an individual's position along the NIHL risk spectrum. Non-technical proxy measurements of EEA (pinna height, body height, earcanal volume) were statistically significant but yielded high variability in individual EEA prediction. [ABSTRACT FROM AUTHOR]

Amplification from natural ear canal resonance has been documented as highly variable across individuals. However, individual variability in total pre-cochlear amplification (i.e., combined external and middle ear mechanisms) remains understudied in relevance to noise-induced hearing loss (NIHL). It is well-known that more noise means more risk of hearing loss, yet the current risk-models do not consider individually variable pre-cochlear amplification, also referred to as the transfer function of the open ear (TFOE). The present study principally documented individual TFOE variability and explored the feasibility and accuracy of simple proxy metrics, which could be used to estimate TFOE. Participants' TFOE values were used to estimate their NIHL risk in hypothetical free-field exposures. Forty-eight adult participants (42 female, 6 male, ages 21–60 years) met inclusion criteria of 2 healthy pinnae and ear canals (<10% cerumen occlusion) and type-A tympanometric examination. Participants underwent otoscopy, tympanometry, pinna size measurement, real-ear-to-coupler-difference, and TFOE measurement. TFOE ranged from 5 to 15 dB-A (mean = 10 dB-A); given that NIHL risk is estimated to double in either 3 or 5 dB-A increments, the observed variability could explain a substantial portion of individual vulnerability to NIHL. A simple regression model with eardrum compliance (ml) was correlated with individual TFOE (p < 0.05). TFOE variability has the potential to substantially explain why two individuals with the same noise-exposure can develop significantly different degrees of NIHL. Eardrum compliance (ml) was a correlated proxy measurement of TFOE in this principally adult, female dataset; additional research is needed to confirm this relationship in a unique, heterogeneous dataset. [ABSTRACT FROM AUTHOR]

Animal models have been used to gain insight into the risk of noise-induced hearing loss (NIHL) and its potential prevention using investigational new drug agents. A number of compounds have yielded benefit in pre-clinical (animal) models. However, the acute traumatic injury models commonly used in pre-clinical testing are fundamentally different from the chronic and repeated exposures experienced by many human populations. Diverse populations that are potentially at risk and could be considered for enrollment in clinical studies include service members, workers exposed to occupational noise, musicians and other performing artists, and children and young adults exposed to non-occupational (including recreational) noise. Both animal models and clinical populations were discussed in this special issue, followed by discussion of individual variation in vulnerability to NIHL. In this final contribution, study design considerations for NIHL otoprotection in pre-clinical and clinical testing are integrated and broadly discussed with evidence-based guidance offered where possible, drawing on the contributions to this special issue as well as other existing literature. The overarching goals of this final paper are to (1) review and summarize key information across contributions and (2) synthesize information to facilitate successful translation of otoprotective drugs from animal models into human application. [ABSTRACT FROM AUTHOR]

The influence of dietary nutrient intake on the onset and trajectory of hearing loss during aging and in mediating protection from challenges such as noise is an important relationship yet to be fully appreciated. Dietary intake provides essential nutrients that support basic cellular processes related to influencing cellular stress response, immune response, cardiometabolic status, neural status, and psychological well-being. Dietary quality has been shown to alter risk for essentially all chronic health conditions including hearing loss and tinnitus. Evidence of nutrients with antioxidant, anti-inflammatory, and anti-ischemic properties, and overall healthy diet quality as otoprotective strategies are slowly accumulating, but many questions remain unanswered. In this article, the authors will discuss (1) animal models in nutritional research, (2) evidence of dietary nutrient-based otoprotection, and (3) consideration of confounds and limitations to nutrient and dietary study in hearing sciences. Given that there are some 60 physiologically essential nutrients, unraveling the intricate biochemistry and multitude of interactions among nutrients may ultimately prove infeasible; however, the wealth of available data suggesting healthy nutrient intake to be associated with improved hearing outcomes suggests the development of evidence-based guidance regarding diets that support healthy hearing may not require precise understanding of all possible interactions among variables. Clinical trials evaluating otoprotective benefits of nutrients should account for dietary quality, noise exposure history, and exercise habits as potential covariates that may influence the efficacy and effectiveness of test agents; pharmacokinetic measures are also encouraged. [ABSTRACT FROM AUTHOR]

With advances in the understanding of mechanisms of noise injury, the past 30 years have brought numerous efforts to identify drugs that prevent noise-induced hearing loss (NIHL). The diverse protocols used across investigations have made comparisons across drugs difficult. A systematic review of the literature by Hammill [(2017). Doctoral thesis, The University of Texas at Austin] identified original reports of chemical interventions to prevent or treat hearing loss caused by noise exposure. An initial search returned 3492 articles. After excluding duplicate articles and articles that did not meet the systematic review inclusion criteria, a total of 213 studies published between 1977 and 2016 remained. Reference information, noise exposure parameters, species, sex, method of NIHL assessment, and pharmaceutical intervention details for these 213 studies were entered into a database. Frequency-specific threshold shifts in control animals (i.e., in the absence of pharmaceutical intervention) are reported here. Specific patterns of hearing loss as a function of species and noise exposure parameters are provided to facilitate the selection of appropriate pre-clinical models. The emphasis of this report is octave band noise exposure, as this is one of the most common exposure protocols across pharmacological otoprotection studies. [ABSTRACT FROM AUTHOR]

Noise-induced hearing loss (NIHL) is a common injury for service members and civilians. Effective prevention of NIHL with drug agents would reduce the prevalence of NIHL. There are a host of challenges in translation of investigational new drug agents from animals into human clinical testing, however. Initial articles in this special issue describe common pre-clinical (animal) testing paradigms used to assess potential otoprotective drug agents and design-related factors that impact translation of promising agents into human clinical trials. Additional articles describe populations in which NIHL has a high incidence and factors that affect individual vulnerability. While otoprotective drugs will ultimately be developed for use by specific noise-exposed populations, there has been little effort to develop pre-clinical (animal) models that accurately model exposure hazards across diverse human populations. To facilitate advances in the translational framework for NIHL otoprotection in pre-clinical and clinical testing, the overarching goals of the current series are to (1) review the animal models that have been used, highlighting the relevance to the human populations of interest, (2) provide insight into the populations for whom pharmaceutical interventions might, or might not, be appropriate, and (3) highlight the factors that drive the significant individual variability observed in humans. [ABSTRACT FROM AUTHOR]

Objective: Short-term noise exposure that induces transient changes in thresholds has induced permanent cochlear synaptopathy in multiple species. Here, the literature was reviewed to gain translational insight into the relationships between noise exposure, ABR metrics, speech-in-noise performance and TTS in humans. Design: PubMed-based literature search, retrieval and review of full-text articles. Study Sample: Peer-reviewed literature identified using PubMed search. Results: Permanent occupational noise-induced hearing loss (NIHL) is frequently accompanied by abnormal ABR amplitude and latency. In the absence of NIHL, there are mixed results for relationships between noise exposure and ABR metrics. Interpretation of speech-in-noise deficits is difficult as both cochlear synaptopathy and outer hair cell (OHC) loss can drive deficits. Reductions in Wave I amplitude during TTS may reflect temporary OHC pathology rather than cochlear synaptopathy. Use of diverse protocols across studies reduces the ability to compare outcomes across studies. Conclusions: Longitudinal ABR and speech-in-noise data collected using consistent protocols are needed. Although speech-in-noise testing may not reflect cochlear synaptopathy, speech-in-noise testing should be completed as part of a comprehensive test battery to provide the objective measurement of patient difficulty. [ABSTRACT FROM AUTHOR]

Objective: Short-term noise exposure that induces transient changes in thresholds has induced permanent cochlear synaptopathy in multiple species. Here, the literature was reviewed to gain translational insight into the relationships between noise exposure, ABR metrics, speech-in-noise performance and TTS in humans. Design: PubMed-based literature search, retrieval and review of full-text articles. Study Sample: Peer-reviewed literature identified using PubMed search. Results: Permanent occupational noise-induced hearing loss (NIHL) is frequently accompanied by abnormal ABR amplitude and latency. In the absence of NIHL, there are mixed results for relationships between noise exposure and ABR metrics. Interpretation of speech-in-noise deficits is difficult as both cochlear synaptopathy and outer hair cell (OHC) loss can drive deficits. Reductions in Wave I amplitude during TTS may reflect temporary OHC pathology rather than cochlear synaptopathy. Use of diverse protocols across studies reduces the ability to compare outcomes across studies. Conclusions: Longitudinal ABR and speech-in-noise data collected using consistent protocols are needed. Although speech-in-noise testing may not reflect cochlear synaptopathy, speech-in-noise testing should be completed as part of a comprehensive test battery to provide the objective measurement of patient difficulty. [ABSTRACT FROM AUTHOR]

Ototoxicity diagnosis and management has historically been approached using a variety of methods. However, in recent years a consensus on useful and practical approaches has been developed through clinical guidelines of the American Speech Language Hearing Association, the American Academy of Audiology, and multiple clinical trials published in peer-reviewed literature. Some of the guidelines and approaches are used to detect and monitor ototoxicity, while others are used to grade adverse events. Some of the audiologic measures are primary, while others are adjunct measures and may be tailored to the specific needs of the patient or clinical trial. For some types of monitoring, such as drug-induced tinnitus or dizziness, validated paper survey instruments can be both sensitive and easy for fragile patients. This review addresses the characteristics of some of the most common clinical ototoxins and the most common methods for detecting and monitoring ototoxicity in clinical practice and clinical trials. [ABSTRACT FROM AUTHOR]

Noise exposure that causes a temporary threshold shift but no permanent threshold shift can cause degeneration of synaptic ribbons and afferent nerve fibers, with a corresponding reduction in wave I amplitude of the auditory brainstem response (ABR) inanimals.This formof underlying damage, hypothesized to also occur in humans, has been termed synaptopathy, and it has been hypothesized that there will be a hidden hearing loss consisting of functional deficits at suprathreshold stimulus levels. This study assessed whether recreational noise exposure history was associated with smaller ABR wave I amplitude and poorer performance on suprathreshold auditory test measures.Noise exposure historieswere collected from 26 men and 34women with hearing thresholds ≤ 25 dB hearing loss (HL; 250 Hz to 8 kHz), and a variety of functional suprathreshold hearing tests were performed. Wave I amplitudes of click-evoked ABR were obtained at 70, 80, 90, and 99 dB (nHL) and tone-burst evoked ABR were obtained at 90 dB nHL. Speech recognition performance was measured in quiet and in competing noise, using theWords in Noise test, and the NU-6 word list in broadband noise (BBN). In addition, temporal summation to tonal stimuli was assessed in quiet and in competing BBN. To control for the effects of subclinical conventional hearing loss, distortion product otoacoustic emission amplitude, an indirect measure of outer hair cell integrity, was measured. There was no statistically significant relationship between noise exposure history scores andABRwave I amplitude in eithermen or women for any of the ABR conditions. ABR wave I amplitude and noise exposure history were not reliably correlated with suprathreshold functional hearing tests. Taken together, this study found no evidence of noise-induced decreases inABR wave I amplitude or signal processing in noise in a cohort of subjects with a history of recreational noise exposure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Speech communication often takes place in noisy environments; this is an urgent issue for military personnel who must communicate in high-noise environments. The effects of noise on speech recognition vary significantly according to the sources of noise, the number and types of talkers, and the listener's hearing ability. In this review, speech communication is first described as it relates to current standards of hearing assessment for military and civilian populations. The next section categorizes types of noise (also called maskers) according to their temporal characteristics (steady or fluctuating) and perceptive effects (energetic or informational masking). Next, speech recognition difficulties experienced by listeners with hearing loss and by older listeners are summarized, and questions on the possible causes of speech-in-noise difficulty are discussed, including recent suggestions of “hidden hearing loss”. The final section describes tests used by military and civilian researchers, audiologists, and hearing technicians to assess performance of an individual in recognizing speech in background noise, as well as metrics that predict performance based on a listener and background noise profile. This article provides readers with an overview of the challenges associated with speech communication in noisy backgrounds, as well as its assessment and potential impact on functional performance, and provides guidance for important new research directions relevant not only to military personnel, but also to employees who work in high noise environments. [ABSTRACT FROM AUTHOR]

This study examined potential prevention of music-induced temporary threshold shift (TTS) in normal-hearing participants. A dietary supplement composed of β-carotene, vitamins C and E, and magnesium was assessed using a randomized, placebo-controlled, double-blind study design. Dosing began 3 days prior to the music exposure with the final dose consumed approximately 30-min pre-exposure. Post-exposure TTS was measured, with no significant difference as a function of treatment. Distortion product otoacoustic emission amplitudes were suppressed after music exposure in both groups, with no significant difference as a function of treatment. Tinnitus was more likely to be reported by the treatment group, but there were no group differences in perceived loudness or bothersomeness. Taken together, this supplement had no effect on noise-induced changes in hearing. Recommendations for future clinical trials are discussed. [ABSTRACT FROM AUTHOR]

Neurons of the lateral olivocochlear (LOC) system project from the auditory brainstem to the cochlea, where they synapse on radial dendrites of auditory nerve fibers. Selective LOC disruption depresses sound-evoked auditory nerve activity in the guinea pig, but enhances it in the mouse. Here, LOC disruption depressed spontaneous auditory nerve activity in the guinea pig. Recordings from single auditory nerve fibers revealed a significantly reduced proportion of fibers with the highest spontaneous firing rates (SRs) and an increased proportion of neurons with lower SRs. Ensemble activity, estimated using round window noise, also decreased after LOC disruption. Decreased spontaneous activity after LOC disruption may be a consequence of reduced tonic release of excitatory transmitters from the LOC terminals in guinea pigs. [ABSTRACT FROM AUTHOR]

The article discusses a meeting with theme ‘‘Making Sound Waves'' of the National Hearing Conservation Association (NHCA) that was held in San Diego, California. Topics discussed include improve the success of Hearing Loss Prevention Programmes for preventing the progression of noise-induced hearing loss (NIHL), use of personal protective equipment (PPE) in the form of hearing protection devices (HPDs) such as ear plugs, and predicting noise exposures across workers in the mining industry.

Highlights: [•] The kappa opioid receptor agonist (−)pentazocine was applied to the cochlea. [•] Sound evoked neural potentials were reduced in amplitude after drug treatment. [•] Endogenous dynorphin at biologically plausible levels has an inhibitory effect. [•] Higher (nonbiological) concentrations of drugs excite the auditory nerve. [•] Transmitter effects should be assessed at biologically plausible concentrations. [ABSTRACT FROM AUTHOR]

Purpose: Hearing loss prevention has always been an important issue for audiologists. The importance of hearing loss prevention education for young musicians is now recognized by the National Association for Music Education as well as the National Association of Schools of Music. Adopt-a-Band is a commercial program designed to foster hearing loss prevention behavior in young musicians. Method: This study assessed changes in earplug use, measured using self-report surveys, after Adopt-a-Band training. Participants were members of 2 high school marching bands who viewed an informational DVD and reviewed fact sheets. Flat-attenuation earplugs were distributed, and training was provided. In addition, study participants engaged in discussion of hearing loss with a doctor of audiology student. Results: Before training, 23% of participants reported they had previously used hearing protection. Immediately after training, 94% of participants reported they planned to use hearing protection at least occasionally. In a final end-of-season survey, earplug use had reliably increased; 62% of participants reported they used earplugs at least occasionally. Conclusions: Earplug use increased, but self-reported behavioral change was not as robust as predicted from self-reported participant intentions. Participant comments regarding factors that influenced their earplug use decisions suggest opportunities to improve training. [ABSTRACT FROM AUTHOR]

Purpose: Hearing loss prevention has always been an important issue for audiologists. The importance of hearing loss prevention education for young musicians is now recognized by the National Association for Music Education as well as the National Association of Schools of Music. Adopt-a-Band is a commercial program designed to foster hearing loss prevention behavior in young musicians. Method: This study assessed changes in earplug use, measured using self-report surveys, after Adopt-a-Band training. Participants were members of 2 high school marching bands who viewed an informational DVD and reviewed fact sheets. Flat-attenuation earplugs were distributed, and training was provided. In addition, study participants engaged in discussion of hearing loss with a doctor of audiology student. Results: Before training, 23% of participants reported they had previously used hearing protection. Immediately after training, 94% of participants reported they planned to use hearing protection at least occasionally. In a final end-of-season survey, earplug use had reliably increased; 62% of participants reported they used earplugs at least occasionally. Conclusions: Earplug use increased, but self-reported behavioral change was not as robust as predicted from self-reported participant intentions. Participant comments regarding factors that influenced their earplug use decisions suggest opportunities to improve training. [ABSTRACT FROM AUTHOR]

Acquired hearing loss, which can develop after noise insult or ototoxic drug treatment, is a significant clinical, social, and economic issue. A major advance in our understanding came with the discovery that intense metabolic activity in the inner ear drives the formation of free radicals (short-lived, unstable, highly reactive clusters of atoms) in multiple types of cells in the inner ear after both noise and drug insult. Animal studies have now shown that free radicals formed during and after metabolic stress importantly contribute to acquired hearing loss. These new mechanistic insights provided for the first time a rationalefor directly treating the inner ear to prevent hearing impairment. Consequently, use of free radical scavengers, or antioxidants, to prevent acquired hearing loss became a clinically relevant research goal. Many laboratories have now demonstrated that a variety of free radical scavengers reduce the potential for acquired hearing loss in animal subjects. Scientific data, supporting the use of these agents to preventenvironmentally acquired hearing loss, is reviewed. Translational investigations are now essential to confirm the potential utility of these agents in the human inner ear. This article reviews the pharmacological otoprotective agents in or approaching clinical trials to prevent noise-, aminoglycoside-, and cisplatin-induced hearing loss. [ABSTRACT FROM AUTHOR]

Abstract: Free radical formation in the cochlea plays a key role in the development of noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant formation of both reactive oxygen species and reactive nitrogen species 7–10 days after noise exposure. Reduction in cochlear blood flow as a result of free radical formation has also been described. Here we report that the antioxidant agents vitamins A, C, and E act in synergy with magnesium to effectively prevent noise-induced trauma. Neither the antioxidant agents nor the magnesium reliably reduced NIHL or sensory cell death with the doses we used when these agents were delivered alone. In combination, however, they were highly effective in reducing both hearing loss and cell death even with treatment initiated just 1 h before noise exposure. This study supports roles for both free radical formation and noise-induced vasoconstriction in the onset and progression of NIHL. Identification of this safe and effective antioxidant intervention that attenuates NIHL provides a compelling rationale for human trials in which free radical scavengers are used to eliminate this single major cause of acquired hearing loss. [Copyright &y& Elsevier]

Abstract: Recent research has shown the essential role of reduced blood flow and free radical formation in the cochlea in noise-induced hearing loss (NIHL). The amount, distribution, and time course of free radical formation have been defined, including a clinically significant late formation 7–10days following noise exposure, and one mechanism underlying noise-induced reduction in cochlear blood flow has finally been identified. These new insights have led to the formulation of new hypotheses regarding the molecular mechanisms of NIHL; and, from these, we have identified interventions that prevent NIHL, even with treatment onset delayed up to 3days post-noise. It is essential to now assess the additive effects of agents intervening at different points in the cell death pathway to optimize treatment efficacy. Finding safe and effective interventions that attenuate NIHL will provide a compelling scientific rationale to justify human trials to eliminate this single major cause of acquired hearing loss. [Copyright &y& Elsevier]

When sinusoidal electric stimulation is applied to the intact cochlea, a frequency-specific acoustic emission can be recorded in the ear canal. Acoustic emissions are produced by basilar membrane motion, and have been used to suggest a corresponding acoustic sensation termed “electromotile hearing.” Electromotile hearing has been specifically attributed to electric stimulation of outer hair cells in the intact organ of Corti. To determine the nature of the auditory perception produced by electric stimulation of a cochlea with intact outer hair cells, guinea pigs were tested in a psychophysical task. First, subjects were trained to report detection of sinusoidal acoustic stimuli and dynamic range was assessed using response latency. Subjects were then implanted with a ball electrode placed into scala tympani. Following the surgical implant procedure, subjects were transferred to a task in which acoustic signals were replaced by sinusoidal electric stimulation, and dynamic range was assessed again. Finally, the ability of acoustic pure-tone stimuli to mask the detection of the electric signals was assessed. Based on the masking effects, it is concluded that sinusoidal electric stimulation of the intact cochlea results in perception of a tonal (rather than a broadband or noisy) sound at a frequency of 8 kHz or above. [ABSTRACT FROM AUTHOR]

Brief cochlear excitotoxicity produces temporary neural swelling and transient deficits in auditory sensitivity; however, the consequences of long-lasting excitotoxic insult have not been tested. Chronic intra-cochlear infusion of the glutamate agonist AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid! resulted in functional deficits in the sound-evoked auditory brainstem response, as well as in behavioral measures of hearing. The electrophysiological deficits were similar to those observed following acute infusion of AMPA into the cochlea; however, the concentration-response curve was significantly shifted as a consequence of the slower infusion rate used with chronic cochlear administration. As observed following acute excitotoxic insult, complete functional recovery was evident within 7 days of discontinuing the AMPA infusion. Distortion product otoacoustic emissions were not affected by chronic AMPA infusion, suggesting that trauma to outer hair cells did not contribute to AMPA-induced deficits in acoustic sensitivity. Results from the current experiment address the permanence of deficits induced by chronic (14 day) excitotoxic insult as well as deficits in psychophysical detection of longer duration acoustic signals. [ABSTRACT FROM AUTHOR]

There is evidence that Japanese macaques (Macaca fuscata) are extremely sensitive to dynamic changes in the relative amplitudes of coo call harmonics during discrimination tests. To verify this evidence using more controlled stimulus configurations, the authors examined threshold sensitivity of macaque monkeys to amplitude increments added to the standard level of coo call harmonics. Psychophysical threshold determination methods paralleled those used previously to determine macaque sensitivity to amplitude increments added to vowel-like stimuli. Variation was detectable although thresholds were elevated relative to those obtained with vowel-like stimuli in another investigation (C. G. Le Prell, A. J. Niemiec, & D. B. Moody, 2001). This elevation was probably a function of natural amplitude modulation in the standard stimuli. [ABSTRACT FROM AUTHOR]

Investigates the factors affecting the salience of temporal cues in the discrimination of Japanese macaque smooth early and smooth late high coo calls. Difference between original calls and calls temporally reversed in the frequency domain; Reaction of macaques to amplitude increments; Response of macaques to different amount of frequency modulation.

Guinea pigs have been used in diverse studies to better understand acquired hearing loss induced by noise and ototoxic drugs. The guinea pig has its best hearing at slightly higher frequencies relative to humans, but its hearing is more similar to humans than the rat or mouse. Like other rodents, it is more vulnerable to noise injury than the human or nonhuman primate models. There is a wealth of information on auditory function and vulnerability of the inner ear to diverse insults in the guinea pig. With respect to the assessment of potential otoprotective agents, guinea pigs are also docile animals that are relatively easy to dose via systemic injections or gavage. Of interest, the cochlea and the round window are easily accessible, notably for direct cochlear therapy, as in the chinchilla, making the guinea pig a most relevant and suitable model for hearing. This article reviews the use of the guinea pig in basic auditory research, provides detailed discussion of its use in studies on noise injury and other injuries leading to acquired sensorineural hearing loss, and lists some therapeutics assessed in these laboratory animal models to prevent acquired sensorineural hearing loss. [ABSTRACT FROM AUTHOR]

Objectives: This study had two objectives. First, baseline audiometric data was assessed for associations with noise exposure history. Seconds, subjects were followed prospectively to assess potential auditory effects of new loud recreational activities. Material and methods: Testing included tympanometry, pure-tone and speech reception thresholds, word-in-noise tests, and ABR and DPOAE measurements. All tests were completed at baseline, and repeated the day after a "loud" recreational event and one week later. Results: There was no reliable relationship between recreational noise history and auditory test metrics. After acute event exposures, a variety of dose-dependent temporary changes were observed across metrics. Final tests one week later showed recovery. Conclusions: Recreational noise was not correlated with chronic or acute changes in function or evoked potential amplitude. However, two subjects with 16-hr exposures had changes in function, indicating hazardous exposures for which hearing protection was needed. [ABSTRACT FROM AUTHOR]

An introduction is presented in which the editors discuss various reports within the issue on topics including the auditory risk of impulse noise generated by firearms, hearing protection enhancement devices (HPEDs), and the effects of background noise on speech production and understanding.

In animals, noise exposures that produce robust temporary threshold shifts (TTS) can produce immediate damage to afferent synapses and long-term degeneration of low spontaneous rate auditory nerve fibers. This synaptopathic damage has been shown to correlate with reduced auditory brainstem response (ABR) wave-I amplitudes at suprathreshold levels. The perceptual consequences of this “synaptopathy” remain unknown but have been suggested to include compromised hearing performance in competing background noise. Here, we used a modified startle inhibition paradigm to evaluate whether noise exposures that produce robust TTS and ABR wave-I reduction but not permanent threshold shift (PTS) reduced hearing-in-noise performance. Animals exposed to 109 dB SPL octave band noise showed TTS >30 dB 24-h post noise and modest but persistent ABR wave-I reduction 2 weeks post noise despite full recovery of ABR thresholds. Hearing-in-noise performance was negatively affected by the noise exposure. However, the effect was observed only at the poorest signal to noise ratio and was frequency specific. Although TTS >30 dB 24-h post noise was a predictor of functional deficits, there was no relationship between the degree of ABR wave-I reduction and degree of functional impairment. [ABSTRACT FROM AUTHOR]

Many recreational activities are accompanied by loud concurrent sounds and decisions regarding the hearing hazards associated with these activities depend on accurate sound measurements. Sound level meters (SLMs) are designed for this purpose, but these are technical instruments that are not typically available in recreational settings and require training to use properly. Mobile technology has made such sound level measurements more feasible for even inexperienced users. Here, we assessed the accuracy of sound level measurements made using five mobile phone applications or "apps" on an Apple iPhone 4S, one of the most widely used mobile phones. Accuracy was assessed by comparing application-based measurements to measurements made using a calibrated SLM. Whereas most apps erred by reporting higher sound levels, one application measured levels within 5 dB of a calibrated SLM across all frequencies tested. [ABSTRACT FROM AUTHOR]

Firearms produce peak sound pressure levels (peak SPL) between ∼130 and 175 dB peak SPL, creating significant risk of noise-induced hearing loss (NIHL) in those exposed to firearm noise during occupational, recreational, and/or military operations. Noise-induced tinnitus and hearing loss are common in military service members, public safety officers, and hunters/shooters. Given the significant risk of NIHL due to firearm and other noise sources, there is an interest in, and demand for, interventions to prevent and/or treat NIHL in high-risk populations. However, research and clinical trial designs assessing NIHL prevention have varied due to inconsistent data from the literature, specifically with end point definitions, study protocols, and assessment methodologies. This article presents a scoping review of the literature pertaining to auditory changes following firearm noise exposure. Meta-analysis was not possible due to heterogeneity of the study designs. Recommendations regarding audiologic test approach and monitoring of populations at risk for NIHL are presented based on critical review of the existing literature. [ABSTRACT FROM AUTHOR]

Animal studies demonstrate that noise exposure can permanently damage the synapses between inner hair cells and auditory nerve fibers, even when outer hair cells are intact and there is no clinically relevant permanent threshold shift. Synaptopathy disrupts the afferent connection between the cochlea and the central auditory system and is predicted to impair speech understanding in noisy environments and potentially result in tinnitus and/or hyperacusis. While cochlear synaptopathy has been demonstrated in numerous experimental animal models, synaptopathy can only be confirmed through post-mortem temporal bone analysis, making it difficult to study in living humans. A variety of non-invasive measures have been used to determine whether noise-induced synaptopathy occurs in humans, but the results are conflicting. The overall objective of this article is to synthesize the existing data on the functional impact of noise-induced synaptopathy in the human auditory system. The first section of the article summarizes the studies that provide evidence for and against noise-induced synaptopathy in humans. The second section offers potential explanations for the differing results between studies. The final section outlines suggested methodologies for diagnosing synaptopathy in humans with the aim of improving consistency across studies. • There is evidence for and against noise-induced cochlear synaptopathy. • Inconsistencies between studies are identified and discussed. • Recommended methods to minimize inconsistencies are suggested. [ABSTRACT FROM AUTHOR]

Objective: To examine the relationship between the healthy eating index (HEI), a measure of dietary quality based on United States Department of Agriculture recommendations and report of tinnitus. Design: This cross-sectional analysis was based on HEI data and report of tinnitus. Study sample: Data for adults between 20 and 69 years of age were drawn from the National Health and Nutrition Examination Survey (NHANES), 1999-2002. The NHANES is a programme of studies, to assess the health and nutritional status of adults and children in the United States. Two thousand one hundred and seventy-six participants were included in the analytic sample. Results: Of the sample, 21.1% reported tinnitus within the past year and 11.7% reported persistent tinnitus, defined as tinnitus experienced at least monthly or greater. Controlling for age, sex, race/ethnicity, diabetes, noise exposure and smoking status, we found that with healthier diet (poorer vs. better HEI) there was decreased odds of reported persistent tinnitus [odds ratio (OR); 0.67; 95% confidence interval (CI) 0.45-0.98; p = 0.03].Conclusions: The current findings support a possible relationship between healthier diet quality and reported persistent tinnitus. [ABSTRACT FROM AUTHOR]

Background: Noise-induced hearing loss is a leading cause of occupational and recreational injury and disease, and a major determinant of age-related hearing loss. No therapeutic agent has been approved for the prevention or treatment of this disorder. In animal models, glutathione peroxidase 1 (GPx1) activity is reduced after acute noise exposure. Ebselen, a novel GPx1 mimic, has been shown to reduce both temporary and permanent noise-induced hearing loss in preclinical studies. We assessed the safety and efficacy of ebselen for the prevention of noise-induced hearing loss in young adults in a phase 2 clinical trial.Methods: In this single-centre, randomised, double-blind, placebo-controlled phase 2 trial, healthy adults aged 18-31 years were randomly assigned (1:1:1:1) at the University of Florida (Gainsville, FL, USA) to receive ebselen 200 mg, 400 mg, or 600 mg, or placebo orally twice daily for 4 days, beginning 2 days before a calibrated sound challenge (4 h of pre-recorded music delivered by insert earphones). Randomisation was done with an allocation sequence generated by an independent third party. The primary outcome was mean temporary threshold shift (TTS) at 4 kHz measured 15 min after the calibrated sound challenge by pure tone audiometry; a reduction of 50% in an ebselen dose group compared with the placebo group was judged to be clinically relevant. All participants who received the calibrated sound challenge and at least one dose of study drug were included in the efficacy analysis. All randomly assigned patients were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT01444846.Findings: Between Jan 11, 2013, and March 24, 2014, 83 participants were enrolled and randomly assigned to receive ebselen 200 mg (n=22), 400 mg (n=20), or 600 mg (n=21), or placebo (n=20). Two participants in the 200 mg ebselen group were discontinued from the study before the calibrated sound challenge because they no longer met the inclusion criteria; these participants were excluded from the efficacy analysis. Mean TTS at 4 kHz was 1·32 dB (SE 0·91) in the 400 mg ebselen group compared with 4·07 dB (0·90) in the placebo group, representing a significant reduction of 68% (difference -2·75 dB, 95% CI -4·54 to -0·97; p=0·0025). Compared with placebo, TTS at 4 kHz was non-significantly reduced by 21% in the 200 mg ebselen group (3·23 dB [SE 0·91] vs 4·07 dB [0·90] in the placebo group; difference -0·84 dB, 95% CI -2·63 to 0·94; p=0·3542) and by 7% in the 600 mg ebselen group (3·81 dB [0·90] vs 4·07 dB [0·90] in the placebo group; difference -0·27, 95% CI -2·03 to 1·50; p=0·7659). Ebselen treatment was well tolerated across all doses and no significant differences were seen in any haematological, serum chemistry, or radiological assessments between the ebselen groups and the placebo group.Interpretation: Treatment with ebselen was safe and effective at a dose of 400 mg twice daily in preventing a noise-induced TTS. These data lend support to a role of GPx1 activity in acute noise-induced hearing loss.Funding: Sound Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: There has been significant discussion in the literature regarding music player use by adolescents and young adults, including whether device use is driving an increase in hearing loss in these populations. While many studies report relatively safe preferred listening levels, some studies with college student participants have reported listening habits that may put individuals at risk for noise-induced hearing loss (NIHL) if those listening habits continue over the long term. Purpose: The goal of the current investigation was to extend listening level data collection sites from urban city settings studied by others to a more rural campus setting. Research Design: This was a prospective study. Study Sample: Participants were 138 students on the University of Florida campus (94 males, 44 females), 18 years or older (mean = 21 years; range: 18-33 years). Data Collection and Analysis: In this investigation, the current output level (listening level) was measured from personal listening devices used by students as they passed by a recruiting table located in one of three areas of the University of Florida campus. One location was in an open-air campus square; the other two locations were outside the campus recreation building ("gym") and outside the undergraduate library, with participants recruited as they exited the gym or library buildings. After providing written informed consent, participants completed a survey that included questions about demographics and typical listening habits (hours per day, days per week). The output level on their device was then measured using a "Jolene" mannequin. Results: Average listening levels for participants at the three locations were as follows: gym: 85.9 ± 1.4 dBA; campus square: 83.3 ± 2.0 dBA; library: 76.9 ± 1.3 dBA. After adjusting to free-field equivalent level, average listening levels were gym: 79.7 ± 1.4 dBA; campus square: 76.9 ± 2.1 dBA; library: 70.4 ± 1.4 dBA. There were no statistically significant differences between male and female listeners, and there were no reliable differences as a function of race. After accounting for daily and weekly use patterns, 5% were deemed at risk based on the criteria put forward by the Occupational Safety and Health Administration, and 9% were deemed at risk based on the guidance provided by the National Institute for Occupational Safety and Health. Conclusions: Some 5-10% of the participants were deemed at risk; this finding is consistent with other studies using similar methods. It is possible that the same listeners would have selected different listening levels in other noise backgrounds, however. This unknown variable makes it difficult to estimate risk with a single listening level measurement. [ABSTRACT FROM AUTHOR]

Systemic and local changes in body temperature can have a profound effect on traumatic injuries including those to the inner ear. Therefore, we investigated the effects of acutely increasing or decreasing the temperature of the external ear canal on cisplatin-induced hearing loss. The external auditory canals of male guinea pigs were acutely irrigated with warm (44 °C), euthermic (37 °C), or cool (30 °C) water and subsequently injected with cisplatin (12 mg/kg, i.p.). Hearing was assessed by the auditory brainstem response and cochleograms were prepared to determine loss of hair cells. Ear canal irrigation with warm water potentiated cisplatin-induced hearing loss and outer hair cell loss whereas cool ear canal irrigation showed significant protection from cisplatin-induced hearing loss and outer hair cell loss. These results suggest that non-invasive cool water ear canal irrigation may be highly effective clinical procedure for protecting against cisplatin-induced hearing loss. [ABSTRACT FROM AUTHOR]

Objectives: Noise exposures that produce robust temporary threshold shift (TTS) reduce auditory brainstem response (ABR) wave-I amplitude. This study evaluated whether these ABR reductions were associated with functional hearing-in-noise deficits. Material and methods: ABR threshold and amplitude, otoacoustic emissions, and hearing-in-noise were assessed in rats before and after noise exposure (106 or 109 dB SPL octave band noise, 8-16 kHz, 2 h). Hearing-in-noise was assessed at various signal-to-noise ratios (SNR). Results: The 106 dB SPL exposure had no effect on ABR or hearing-in-noise after 2 weeks. In contrast, the 109-dB SPL noise reduced ABR wave-1 amplitude at 16-24 kHz and showed hearing-in-noise deficits in the poorest SNR condition, despite threshold recovery. Conclusions: Reduced wave-I amplitude and poorer hearing- in-noise were observed after noise exposure producing robust (>30 dB) TTS at 24 hrs post exposure. Future studies should assess effects of lower level, repeated, exposures that model occupational noise. [ABSTRACT FROM AUTHOR]

Objective: Firearm discharges produce hazardous levels of impulse noise that can lead to permanent hearing loss. In the present study, we evaluated the effects of suppression, ammunition, and barrel length on AR-15 rifles.Design: Sound levels were measured left/right of a user’s head, and 1-m left of the muzzle, per MIL-STD-1474-D, under both unsuppressed and suppressed conditions.Study sample: Nine commercially available AR-15 rifles and 14 suppressors were used.Results: Suppressors significantly decreased peak dB SPL at the 1-m location and the left ear location. However, under most rifle/ammunition conditions, levels remained above 140 dB peak SPL near a user’s right ear. In a subset of conditions, subsonic ammunition produced values near or below 140 dB peak SPL. Overall suppression ranged from 7–32 dB across conditions.Conclusions: These data indicate that (1) suppressors reduce discharge levels to 140 dB peak SPL or below in only a subset of AR-15 conditions, (2) shorter barrel length and use of muzzle brake devices can substantially increase exposure level for the user, and (3) there are significant left/right ear sound pressure differences under suppressed conditions as a function of the AR-15 direct impingement design that must be considered during sound measurements to fully evaluate overall efficacy. [ABSTRACT FROM PUBLISHER]