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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]

Some noise exposures resulting in temporary threshold shift (TTS) result in cochlear synaptopathy. The purpose of this retrospective study was to evaluate a human population that might be at risk for noise-induced cochlear synaptopathy (i.e., “hidden hearing loss”). Participants were firearm users who were (1) at-risk for prior audiometric noise-induced threshold shifts, given their history of firearm use, (2) likely to have experienced complete threshold recovery if any prior TTS had occurred, based on this study’s normal-hearing inclusion criteria, and (3) not at-risk for significant agerelated synaptopathic loss, based on this study’s young-adult inclusion criteria. 70 participants (age 18–25 yr) were enrolled, including 33 firearm users experimental (EXP), and 37 non-firearm users control (CNTRL). All participants were required to exhibit audiometric thresholds ≤20 dB HL bilaterally, from 0.25 to 8 kHz. The study was designed to test the hypothesis that EXP participants would exhibit a reduced cochlear nerve response compared to CNTRL participants, despite normal-hearing sensitivity in both groups. No statistically significant group differences in auditory performance were detected between the CNTRL and EXP participants on standard audiom to etry, extended high-frequency audiometry, Words-in-Noise performance, distortion product otoacoustic emission, middle ear muscle reflex, or auditory brainstem response. Importantly, 91% of EXP participants reported that they wore hearing protection either “all the time” or “almost all the time” while using firearms. The data suggest that consistent use of hearing protection during firearm use can effectively protect cochlear and neural measures of auditory function, including suprathreshold responses. The current results do not exclude the possibility that neural pathology may be evident in firearm users with less consistent hearing protection use. However, firearm users with less consistent hearing protection use are also more likely to exhibit threshold elevation, among other cochlear deficits, thereby confounding the isolation of any potentially selective neural deficits. Taken together, it seems most likely that firearm users who consistently and correctly use hearing protection will exhibit preserved measures of cochlear and neural function, while firearm users who inconsistently and incorrectly use hearing protection are most likely to exhibit cochlear injury, rather than evidence of selective neural injury in the absence of cochlear injury. [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]

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]

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]

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]

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]

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]

This study tested hypothesized relationships between noise exposure and auditory deficits. Both retrospective assessment of potential associations between noise exposure history and performance on an audiologic test battery and prospective assessment of potential changes in performance after new recreational noise exposure were completed. Methods: 32 participants (13M, 19F) with normal hearing (25-dB HL or better, 0.25-8 kHz) were asked to participate in 3 pre-and post-exposure sessions including: otoscopy, tympanometry, distortion product otoacoustic emissions (DPOAEs) (f2 frequencies 1-8 kHz), pure-tone audiometry (0.25-8 kHz), Words-in-Noise (WIN) test and electrocochleography (eCochG) measurements at 70, 80 and 90-dB nHL (click and 2-4 kHz tone-bursts). The first session was used to collect baseline data, the second session was collected the day after a loud recreational event and the third session was collected 1-week later. Of the 32 participants, 26 completed all 3 sessions. Results: The retrospective analysis did not reveal statistically significant relationships between noise exposure history and any auditory deficits. The day after new exposure, there was a statistically significant correlation between noise "dose" and WIN performance overall and within the 4-dB signal-to-babble ratio. In contrast, there were no statistically significant correlations between noise dose and changes in threshold, DPOAE amplitude, or AP amplitude the day after new noise exposure. Additional analyses revealed a statistically significant relationship between TTS and DPOAE amplitude at 6 kHz, with temporarily decreased DPOAE amplitude observed with increasing TTS. Conclusions: There was no evidence of auditory deficits as a function of previous noise exposure history and no permanent changes in audiometric, electrophysiologic, or functional measures after new recreational noise exposure. There were very few participants with TTS the day after exposure - a test time selected to be consistent with previous animal studies. The largest observed TTS was approximately 20-dB. The observed pattern of small TTS suggests little risk of synaptopathy from common recreational noise exposure and that we should not expect to observe changes in evoked potentials for this reason. No such changes were observed in this study. These data do not support suggestions that common, recreational noise exposure is likely to result in "hidden hearing loss". [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]