Acoustic reflexes: should we be paying more attention?

OBJECTIVE: The clinical audiology test battery often involves playing physically simple sounds with questionable ecological value to the listener. In this technical report, we revisit how valid this approach is using an automated, involuntary auditory response; the acoustic reflex threshold (ART). DESIGN: The ART was estimated four times in each individual in a quasi-random ordering of task conditions. The baseline condition (referred to as Neutral) measured the ART following a standard clinical practice. Three experimental conditions were then used in which a secondary task was performed whilst the reflex was measured: auditory attention, auditory distraction and visual distraction tasks. STUDY SAMPLE: Thirty-eight participants (27 males) with a mean age of 23 years were tested. All participants were audiometrically healthy. RESULTS: The ART was elevated when a visual task was performed at the same time as the measurements were taken. Performing an auditory task did not affect the ART. CONCLUSIONS: These data indicate that simple audiometric measures widely used in the clinic, can be affected by central, non-auditory processes even in healthy, normal-hearing volunteers. The role of cognition and attention on auditory responses will become ever more important in the coming years.

Auditory changes in awake guinea pigs exposed to overcompressed music.

Exposure to loud sound during leisure time is identified as a significant risk factor for hearing by health authorities worldwide. The current standard that defines unsafe exposure rests on the equal-energy hypothesis, according to which the maximum recommended exposure is a tradeoff between level and daily exposure duration, a satisfactory recipe except for strongly non-Gaussian intense sounds such as gunshots. Nowadays, sound broadcast by music and videoconference streaming services makes extensive use of numerical dynamic range compression. By filling in millisecond-long valleys in the signal to prevent competing noise from masking, it pulls sound-level statistics away from a Gaussian distribution, the framework where the equal-energy hypothesis emerged. Auditory effects of a single 4 hour exposure to the same music were compared in two samples of guinea pigs exposed either to its original or overcompressed version played at the same average level of 102 dBA allowed by French regulations. Apart from a temporary shift of otoacoustic emissions at the lowest two frequencies 2 and 3 kHz, music exposure had no detectable cochlear effect, as monitored at 1, 2 and 7 days post-exposure. Conversely, middle-ear muscle strength behaved differentially as the group exposed to original music had fully recovered one day after exposure whereas the group exposed to overcompressed music remained stuck to about 50% of baseline even after 7 days. Subsamples were then re-exposed to the same music as the first time and sacrificed for density measurements of inner-hair-cell synapses. No difference in synaptic density was found compared to unexposed controls with either type of music. The present results show that the same music piece, harmless when played in its original version, induces a protracted deficit of one auditory neural pathway when overcompressed at the same level. The induced disorder does not seem to involve inner-hair cell synapses.

Binaural temporal coding and the middle ear muscle reflex in audiometrically normal young adults.

Noise exposure may damage the synapses that connect inner hair cells with auditory nerve fibers, before outer hair cells are lost. In humans, this cochlear synaptopathy (CS) is thought to decrease the fidelity of peripheral auditory temporal coding. In the current study, the primary hypothesis was that higher middle ear muscle reflex (MEMR) thresholds, as a proxy measure of CS, would be associated with smaller values of the binaural intelligibility level difference (BILD). The BILD, which is a measure of binaural temporal coding, is defined here as the difference in thresholds between the diotic and the antiphasic versions of the digits in noise (DIN) test. This DIN BILD may control for factors unrelated to binaural temporal coding such as linguistic, central auditory, and cognitive factors. Fifty-six audiometrically normal adults (34 females) aged 18 - 30 were tested. The test battery included standard pure tone audiometry, tympanometry, MEMR using a 2 kHz elicitor and 226 Hz and 1 kHz probes, the Noise Exposure Structured Interview, forward digit span test, extended high frequency (EHF) audiometry, and diotic and antiphasic DIN tests. The study protocol was pre-registered prior to data collection. MEMR thresholds did not predict the DIN BILD. Secondary analyses showed no association between MEMR thresholds and the individual diotic and antiphasic DIN thresholds. Greater lifetime noise exposure was non-significantly associated with higher MEMR thresholds, larger DIN BILD values, and lower (better) antiphasic DIN thresholds, but not with diotic DIN thresholds, nor with EHF thresholds. EHF thresholds were associated with neither MEMR thresholds nor any of the DIN outcomes, including the DIN BILD. Results provide no evidence that young, audiometrically normal people incur CS with impacts on binaural temporal processing.

Middle Ear Muscle Reflex in Normal-Hearing Individuals with Occupational Noise Exposure.

Objectives: Noise-induced cochlear synaptopathy is studied extensively in animal models. The diagnosis of synaptopathy in humans is challenging and the roles of many noninvasive measures in identifying synaptopathy are being explored. The acoustic middle ear muscle reflex (MEMR) can be considered as a vital tool since noise exposure affects the low-spontaneous rate fibers that play an important role in elicitation of MEMR. The present study aimed at measuring MEMR threshold and MEMR strength. Design: The study participants were divided into two groups. All the participants had normal-hearing thresholds. The control group consisted of 25 individuals with no occupational noise exposure whereas noise exposure group had 25 individuals who were exposed to occupational noise of 85 dBA for a minimum period of 1 year. MEMR threshold and strength was assessed for pure tones (500 Hz and 1000 Hz) and broadband noise. Results: The results showed that the MEMR threshold was similar in both the groups. MEMR strength was reduced in noise exposure group compared to control group. Conclusions: The results of the study suggest that MEMR strength could be used as a sensitive measure in identifying cochlear synaptopathy with careful consideration of the stimulus characteristics.

Physiological and perceptual auditory consequences of hunting-related recreational firearm noise exposure in young adults with normal hearing sensitivity.

Purpose: The objective of the current study was to describe outcomes on physiological and perceptual measures of auditory function in human listeners with and without a history of recreational firearm noise exposure related to hunting. Design: This study assessed the effects of hunting-related recreational firearm noise exposure on audiometric thresholds, oto-acoustic emissions (OAEs), brainstem neural representation of fundamental frequency (F0) in frequency following responses (FFRs), tonal middle-ear muscle reflex (MEMR) thresholds, and behavioral tests of auditory processing in 20 young adults with normal hearing sensitivity. Results: Performance on both physiological (FFR, MEMR) and perceptual (behavioral auditory processing tests) measures of auditory function were largely similar across participants, regardless of hunting-related recreational noise exposure. On both behavioral and neural measures including different listening conditions, performance degraded as difficulty of listening condition increased for both nonhunter and hunter participants. A right-ear advantage was observed in tests of dichotic listening for both nonhunter and hunter participants. Conclusion: The null results in the current study could reflect an absence of cochlear synaptopathy in the participating cohort, variability related to participant characteristics and/or test protocols, or an insensitivity of the selected physiological and behavioral auditory measures to noise-induced synaptopathy.

Brainstem auditory physiology in children with listening difficulties.

Children who have listening difficulties (LiD) despite having normal audiometry are often diagnosed as having an auditory processing disorder. A lack of evidence regarding involvement of specific auditory mechanisms has limited development of effective treatments for these children. Here, we examined electrophysiologic evidence for brainstem pathway mechanisms in children with and without defined LiD. We undertook a prospective controlled study of 132 children aged 6-14 years with normal pure tone audiometry, grouped into LiD (n = 63) or Typically Developing (TD; n = 69) based on scores on the Evaluation of Children's Listening and Processing Skills (ECLiPS), a validated caregiver report. The groups were matched on age at test, sex, race, and ethnicity. Neither group had diagnoses of major neurologic disorder, intellectual disability, or brain injuries. Both groups received a test battery including a measure of receptive speech perception against distractor speech, Listening in Spatialized Noise - Sentences (LiSN-S), along with multiple neurophysiologic measures that tap afferent and efferent auditory subcortical pathways. Group analysis showed that participants with LiD performed significantly poorer on all subtests of the LiSN-S. The LiD group had significantly greater wideband middle ear muscle reflex (MEMR) growth functions in the left ear, and shorter Wave III and Wave V latencies in auditory brainstem responses (ABR). Across individual participants, shorter latency ABR Wave V correlated significantly with poorer parent report of LiD (ECLiPS composite). Greater MEMR growth functions also correlated with poorer ECLiPS scores and reduced LiSN-S talker advantage. The LiD and TD groups had equivalent summating potentials, compound action potentials, envelope-following responses, and binaurally activated medial olivocochlear reflexes. In conclusion, there was no evidence for auditory synaptopathy for LiD. Evidence for brainstem differences in the LiD group was interpreted as increased central gain, with shorter ABR Wave III and V latencies and steeper MEMR growth curves. These differences were related to poorer parent report and speech perception in competing speech ability.

Impaired auditory neural performance, another dimension of hearing loss in type-2 diabetes mellitus.

AIM: To evaluate auditory performance in subjects with poorly controlled type-2 diabetes mellitus, using a simple test battery assessing sensitivity to pure tones and neuronal function. METHODS: Enrolled subjects, aged between 23 and 79 years, reported several auditory dysfunctions. They were tested using pure-tone audiometry, otoacoustic emissions for cochlear-function evaluation, and measurement of middle-ear muscle-reflex thresholds in search of an auditory neuropathy. RESULTS: Compared to the standard established for an age-matched normative population, the distribution of averaged pure-tone thresholds in enrolled subjects shifted by about one standard deviation with respect to the normal distribution, in line with past reports of mild sensorineural hearing impairment in diabetes, even though many diabetic subjects fell well within the normative interval of audiometric thresholds. Otoacoustic emissions showed that pure-tone thresholds correctly predicted the status of cochlear sensory cells that, by amplifying sound, ensure normal hearing sensitivity. Whereas the observed hearing losses should not have affected the acoustic levels above which the protective middle-ear muscle reflex is triggered by intense sounds, this reflex was undetectable in around 40% enrolled subjects, a marker of auditory neuropathy. CONCLUSION: Auditory-neural function should be evaluated to identify diabetic subjects whose hearing is impaired. Simple automatic tests are available for this purpose, for example middle-ear muscle reflex detection, which turns out to be more sensitive than the standard audiogram.

Firing Rate Adaptation of the Human Auditory Nerve Optimizes Neural Signal-to-Noise Ratios.

Several physiological mechanisms act on the response of the auditory nerve (AN) during acoustic stimulation, resulting in an adjustment in auditory gain. These mechanisms include-but are not limited to-firing rate adaptation, dynamic range adaptation, the middle ear muscle reflex, and the medial olivocochlear reflex. A potential role of these mechanisms is to improve the neural signal-to-noise ratio (SNR) at the output of the AN in real time. This study tested the hypothesis that neural SNRs, inferred from non-invasive assessment of the human AN, improve over the duration of acoustic stimulation. Cochlear potentials were measured in response to a series of six high-level clicks embedded in a series of six lower-level broadband noise bursts. This paradigm elicited a compound action potential (CAP) in response to each click and to the onset of each noise burst. The ratio of CAP amplitudes elicited by each click and noise burst pair (i.e., neural SNR) was tracked over the six click/noise bursts. The main finding was a rapid (< 24 ms) increase in neural SNR from the first to the second click/noise burst, consistent with a real-time adjustment in the response of the auditory periphery toward improving the SNR of the signal transmitted to the brainstem. Analysis of cochlear microphonic and ear canal sound pressure recordings, as well as the time course for this improvement in neural SNR, supports the conclusion that firing rate adaptation is likely the primary mechanism responsible for improving neural SNR, while dynamic range adaptation, the middle ear muscle reflex, and the medial olivocochlear reflex played a secondary role on the effects observed in this study. Real-time improvements in neural SNR are significant because they may be essential for robust encoding of speech and other relevant stimuli in the presence of background noise.

The Relative and Combined Effects of Noise Exposure and Aging on Auditory Peripheral Neural Deafferentation: A Narrative Review.

Animal studies have shown that noise exposure and aging cause a reduction in the number of synapses between low and medium spontaneous rate auditory nerve fibers and inner hair cells before outer hair cell deterioration. This noise-induced and age-related cochlear synaptopathy (CS) is hypothesized to compromise speech recognition at moderate-to-high suprathreshold levels in humans. This paper evaluates the evidence on the relative and combined effects of noise exposure and aging on CS, in both animals and humans, using histopathological and proxy measures. In animal studies, noise exposure seems to result in a higher proportion of CS (up to 70% synapse loss) compared to aging (up to 48% synapse loss). Following noise exposure, older animals, depending on their species, seem to either exhibit significant or little further synapse loss compared to their younger counterparts. In humans, temporal bone studies suggest a possible age- and noise-related auditory nerve fiber loss. Based on the animal data obtained from different species, we predict that noise exposure may accelerate age-related CS to at least some extent in humans. In animals, noise-induced and age-related CS in separation have been consistently associated with a decreased amplitude of wave 1 of the auditory brainstem response, reduced middle ear muscle reflex strength, and degraded temporal processing as demonstrated by lower amplitudes of the envelope following response. In humans, the individual effects of noise exposure and aging do not seem to translate clearly into deficits in electrophysiological, middle ear muscle reflex, and behavioral measures of CS. Moreover, the evidence on the combined effects of noise exposure and aging on peripheral neural deafferentation in humans using electrophysiological and behavioral measures is even more sparse and inconclusive. Further research is necessary to establish the individual and combined effects of CS in humans using temporal bone, objective, and behavioral measures.

A Time-Course-Based Estimation of the Human Medial Olivocochlear Reflex Function Using Clicks.

The auditory efferent system, especially the medial olivocochlear reflex (MOCR), is implicated in both typical auditory processing and in auditory disorders in animal models. Despite the significant strides in both basic and translational research on the MOCR, its clinical applicability remains under-utilized in humans due to the lack of a recommended clinical method. Conventional tests employ broadband noise in one ear while monitoring change in otoacoustic emissions (OAEs) in the other ear to index efferent activity. These methods, (1) can only assay the contralateral MOCR pathway and (2) are unable to extract the kinetics of the reflexes. We have developed a method that re-purposes the same OAE-evoking click-train to also concurrently elicit bilateral MOCR activity. Data from click-train presentations at 80 dB peSPL at 62.5 Hz in 13 young normal-hearing adults demonstrate the feasibility of our method. Mean MOCR magnitude (1.7 dB) and activation time-constant (0.2 s) are consistent with prior MOCR reports. The data also suggest several advantages of this method including, (1) the ability to monitor MEMR, (2) obtain both magnitude and kinetics (time constants) of the MOCR, (3) visual and statistical confirmation of MOCR activation.

Auditory Brainstem Changes in Timing may Underlie Hyperacusis in a Salicylate-induced Acute Rat Model.

Hyperacusis, an exaggerated, sometimes painful perception of loudness even for soft sounds, is a poorly understood distressing condition. While the involvement of modified gain of central auditory neurons and the influence of nonauditory brain regions are well-documented, the issue of where in the auditory system these abnormalities arise remains open, particularly when hyperacusis comes without sensorineural hearing loss. Here we used acute intraperitoneal administration of sodium salicylate (150 mg/kg) in rats, enough to produce > 10-dB decrease in acoustic startle threshold with mild hearing loss at low frequencies (<10 kHz). Anesthesia, necessary for middle-ear-reflex (MEMR) threshold measurements, abolished the olivocochlear efferent reflex but not the MEMR acting on frequencies < 10 kHz, and its mean threshold increased from 55 dB SPL in controls to 80 dB SPL in salicylate-treated animals 60-90 minutes after injection, with an about 3-dB increase in acoustic energy reaching the cochlea. The mean latencies of auditory brainstem-evoked responses (ABR) conspicuously decreased after salicylate, by 0.25 millisecond at 6 kHz at every level, a frequency-dependent effect absent above 12 kHz. A generic model of loudness based upon cross-frequency coincidence detection predicts that with such timing changes, a transient sound may seem as loud at <40 dB SPL as it does in controls at >60 dB SPL. Candidate circuits able to act at the same time on the startle reflex, the MEMR and ABRs may be serotoninergic, as salicylate is known to increase brain serotonin and 5-HT neurons participate in MEMR and ABR circuits.

The Role of the Clinically Obtained Acoustic Reflex as a Research Tool for Subclinical Hearing Pathologies.

The acoustic reflex (AR) shows promise as an objective test for the presence of cochlear synaptopathy in rodents. The AR has also been shown to be reduced in humans with tinnitus compared to those without. The aim of the present study was twofold: (a) to determine if AR strength (quantified as both threshold and growth) varied with lifetime noise exposure, and thus provided an estimate of the degree of synaptopathy and (b) to identify which factors should be considered when using the AR as a quantitative measure rather than just present/absent responses. AR thresholds and growth functions were measured using ipsilateral and contralateral, broadband and tonal elicitors in adults with normal hearing and varying levels of lifetime noise exposure. Only the clinical standard 226 Hz probe tone was used. AR threshold and growth were not related to lifetime noise exposure, suggesting that routine clinical AR measures are not a sensitive measure when investigating the effects of noise exposure in audiometrically normal listeners. Our secondary, exploratory analyses revealed that AR threshold and growth were significantly related to middle-ear compliance. Listeners with higher middle-ear compliance (though still in the clinically normal range) showed lower AR thresholds and steeper AR growth functions. Furthermore, there was a difference in middle-ear compliance between the sexes, with males showing higher middle-ear compliance values than females. Therefore, it may be necessary to factor middle-ear compliance values into any analysis that uses the AR as an estimate of auditory function.

Long-term moderate noise exposure enhances the medial olivocochlear reflex.

OBJECTIVE: To investigate the effects of long-term moderate noise on hearing functions, MOCR, and MEMR. METHODS: Mice were exposed to the moderate noise (11.2 - 22.4 kHz, 80 dB SPL, 6 h/day, 4 weeks). Subsequently, the hearing functions, including threshold and input-output roles of ABR (auditory brainstem response) and cubic (2f1-f2) DPOAEs (distortion product otoacoustic emissions) were evaluated. Also, MEMR and MOCR were assessed shortly after or at four weeks following the termination of exposure to the noise. RESULTS: The mice's acoustic suppression reflex was strengthened, hearing functions and MEMR were unaffected four weeks after the moderate noise. For primary tones of 16, 20 and 24 kHz, the strengths of contralateral and ipsilateral suppression in the noise group were about double those recorded in the control group. In order to further determine whether the functional changes of the afferent or efferent nerves increased the strengths of acoustic suppression, the mouse's left ear was inserted the earplug, and then exposed the moderate noise for four weeks. The strengths of contralateral suppression at 16, 20 and 24 kHz were increased for the noise + earplug than for the control group and were indistinguishable between the noise + earplug and the noise group. While no significant changes were found in the strengths of ipsilateral suppression at all frequencies for the noise + earplug group compared with the control group. Under ketamine/xylazine anesthesia, the broadband suppressor noise did not stimulate the MEMR by 20 min post-induction at all frequencies in three groups. CONCLUSION: Our data demonstrated that the long-term moderate noise-exposure strengthened mice's MOCR by changing its afferent nerves, and unaffected cochlear hair cells and type I spiral ganglion neurons.

Associations between speech recognition at high levels, the middle ear muscle reflex and noise exposure in individuals with normal audiograms.

It has been hypothesized that noise-induced cochlear synaptopathy in humans may result in functional deficits such as a weakened middle ear muscle reflex (MEMR) and degraded speech perception in complex environments. Although relationships between noise-induced synaptic loss and the MEMR have been demonstrated in animals, effects of noise exposure on the MEMR have not been observed in humans. The hypothesized relationship between noise exposure and speech perception has also been difficult to demonstrate conclusively. Given that the MEMR is engaged at high sound levels, relationships between speech recognition in complex listening environments and noise exposure might be more evident at high speech presentation levels. In this exploratory study with 41 audiometrically normal listeners, a combination of behavioral and physiologic measures thought to be sensitive to synaptopathy were used to determine potential links with speech recognition at high presentation levels. We found decreasing speech recognition as a function of presentation level (from 74 to 104 dBA), which was associated with reduced MEMR magnitude. We also found that reduced MEMR magnitude was associated with higher estimated lifetime noise exposure. Together, these results suggest that the MEMR may be sensitive to noise-induced synaptopathy in humans, and this may underlie functional speech recognition deficits at high sound levels.

No Effect of Interstimulus Interval on Acoustic Reflex Thresholds.

The acoustic reflex (AR), a longstanding component of the audiological test battery, has received renewed attention in the context of noise-induced cochlear synaptopathy-the destruction of synapses between inner hair cells and auditory nerve fibers. Noninvasive proxy measures of synaptopathy are widely sought, and AR thresholds (ARTs) correlate closely with synaptic survival in rodents. However, measurement in humans at high stimulus frequencies-likely important when testing for noise-induced pathology-can be challenging; reflexes at 4 kHz are frequently absent or occur only at high stimulus levels, even in young people with clinically normal audiograms. This phenomenon may partly reflect differences across stimulus frequency in the temporal characteristics of the response; later onset of the response, earlier onset of adaptation, and higher rate of adaptation have been observed at 4 kHz than at 1 kHz. One temporal aspect of the response that has received little attention is the interstimulus interval (ISI); inadequate duration of ISI might lead to incomplete recovery of the response between successive presentations and consequent response fatigue. This research aimed to test for effects of ISI on ARTs in normally hearing young humans, measured at 1 and 4 kHz. Contrary to our hypotheses, increasing ISIs from 2.5 to 8.5 s did not reduce ART level, nor raise ART reliability. Results confirm that clinically measured ARTs-including those at 4 kHz-can exhibit excellent reliability and that relatively short (2.5 s) ISIs are adequate for the measurement of sensitive and reliable ARTs.

Non-Invasive Assays of Cochlear Synaptopathy - Candidates and Considerations.

Studies in multiple species, including in post-mortem human tissue, have shown that normal aging and/or acoustic overexposure can lead to a significant loss of afferent synapses innervating the cochlea. Hypothetically, this cochlear synaptopathy can lead to perceptual deficits in challenging environments and can contribute to central neural effects such as tinnitus. However, because cochlear synaptopathy can occur without any measurable changes in audiometric thresholds, synaptopathy can remain hidden from standard clinical diagnostics. To understand the perceptual sequelae of synaptopathy and to evaluate the efficacy of emerging therapies, sensitive and specific non-invasive measures at the individual patient level need to be established. Pioneering experiments in specific mice strains have helped identify many candidate assays. These include auditory brainstem responses, the middle-ear muscle reflex, envelope-following responses, and extended high-frequency audiograms. Unfortunately, because these non-invasive measures can be also affected by extraneous factors other than synaptopathy, their application and interpretation in humans is not straightforward. Here, we systematically examine six extraneous factors through a series of interrelated human experiments aimed at understanding their effects. Using strategies that may help mitigate the effects of such extraneous factors, we then show that these suprathreshold physiological assays exhibit across-individual correlations with each other indicative of contributions from a common physiological source consistent with cochlear synaptopathy. Finally, we discuss the application of these assays to two key outstanding questions, and discuss some barriers that still remain. This article is part of a Special Issue entitled: Hearing Loss, Tinnitus, Hyperacusis, Central Gain.

Acoustic Middle-Ear-Muscle-Reflex Thresholds in Humans with Normal Audiograms: No Relations to Tinnitus, Speech Perception in Noise, or Noise Exposure.

The acoustic middle-ear-muscle reflex (MEMR) has been suggested as a sensitive non-invasive measure of cochlear synaptopathy, the loss of synapses between inner hair cells and auditory nerve fibers. In the present study, clinical MEMR thresholds were measured for 1-, 2-, and 4-kHz tonal elicitors, using a procedure shown to produce thresholds with excellent reliability. MEMR thresholds of 19 participants with tinnitus and normal audiograms were compared to those of 19 age- and sex-matched controls. MEMR thresholds did not differ significantly between the two groups at any frequency. These 38 participants were included in a larger sample of 70 participants with normal audiograms. For this larger group, MEMR thresholds were compared to a measure of spatial speech perception in noise (SPiN) and a detailed self-report estimate of lifetime noise exposure. MEMR thresholds were unrelated to either SPiN or noise exposure, despite a wide range in both measures. It is possible that thresholds measured using a clinical paradigm are less sensitive to synaptopathy than those obtained using more sophisticated measurement techniques; however, we had good sensitivity at the group level, and even trends in the hypothesized direction were not observed. To the extent that MEMR thresholds are sensitive to cochlear synaptopathy, the present results provide no evidence that tinnitus, SPiN, or noise exposure are related to synaptopathy in the population studied.

Reliability and interrelations of seven proxy measures of cochlear synaptopathy.

Investigations of cochlear synaptopathy in living humans rely on proxy measures of auditory nerve function. Numerous procedures have been developed, typically based on the auditory brainstem response (ABR), envelope-following response (EFR), or middle-ear-muscle reflex (MEMR). Validation is challenging, due to the absence of a gold-standard measure in humans. Some metrics correlate with synaptic survival in animal models, but translation between species is not straightforward; measurements in humans are likely to reflect greater error and greater variability from non-synaptopathic sources. The present study assessed the reliability of seven measures, as well as testing for correlations between them. Thirty-one young women with normal audiograms underwent repeated measurements of ABR wave I amplitude, ABR wave I growth, ABR wave V latency shift in noise, EFR amplitude, EFR growth with stimulus modulation depth, MEMR threshold, and an MEMR across-frequency difference measure. Intraclass correlation coefficients for ABR wave I amplitude, EFR amplitude, and MEMR threshold ranged from 0.85 to 0.93, suggesting that such tests can yield highly reliable results, given careful measurement techniques. The ABR and EFR difference measures exhibited only poor-to-moderate reliability. No significant correlations, nor any consistent trends, were observed between the various measures, providing no indication that these metrics reflect the same underlying physiological processes. Findings suggest that many proxy measures of cochlear synaptopathy should be regarded with caution, at least when employed in young adults with normal audiograms.

Click-Evoked Auditory Efferent Activity: Rate and Level Effects.

There currently are no standardized protocols to evaluate auditory efferent function in humans. Typical tests use broadband noise to activate the efferents, but only test the contralateral efferent pathway, risk activating the middle ear muscle reflex (MEMR), and are laborious for clinical use. In an attempt to develop a clinical test of bilateral auditory efferent function, we have designed a method that uses clicks to evoke efferent activity, obtain click-evoked otoacoustic emissions (CEOAEs), and monitor MEMR. This allows for near-simultaneous estimation of cochlear and efferent function. In the present study, we manipulated click level (60, 70, and 80 dB peak-equivalent sound pressure level [peSPL]) and rate (40, 50, and 62.5 Hz) to identify an optimal rate-level combination that evokes measurable efferent modulation of CEOAEs. Our findings (n = 58) demonstrate that almost all click levels and rates used caused significant inhibition of CEOAEs, with a significant interaction between level and rate effects. Predictably, bilateral activation produced greater inhibition compared to stimulating the efferents only in the ipsilateral or contralateral ear. In examining the click rate-level effects during bilateral activation in greater detail, we observed a 1-dB inhibition of CEOAE level for each 10-dB increase in click level, with rate held constant at 62.5 Hz. Similarly, a 10-Hz increase in rate produced a 0.74-dB reduction in CEOAE level, with click level held constant at 80 dB peSPL. The effect size (Cohen's d) was small for either monaural condition and medium for bilateral, faster-rate, and higher-level conditions. We were also able to reliably extract CEOAEs from efferent eliciting clicks. We conclude that clicks can indeed be profitably employed to simultaneously evaluate cochlear health using CEOAEs as well as their efferent modulation. Furthermore, using bilateral clicks allows the evaluation of both the crossed and uncrossed elements of the auditory efferent nervous system, while yielding larger, more discernible, inhibition of the CEOAEs relative to either ipsilateral or contralateral condition.

Effects of cochlear synaptopathy on middle-ear muscle reflexes in unanesthetized mice.

Cochlear synaptopathy, i.e. the loss of auditory-nerve connections with cochlear hair cells, is seen in aging, noise damage, and other types of acquired sensorineural hearing loss. Because the subset of auditory-nerve fibers with high thresholds and low spontaneous rates (SRs) is disproportionately affected, audiometric thresholds are relatively insensitive to this primary neural degeneration. Although suprathreshold amplitudes of wave I of the auditory brainstem response (ABR) are attenuated in synaptopathic mice, there is not yet a robust diagnostic in humans. The middle-ear muscle reflex (MEMR) might be a sensitive metric (Valero et al., 2016), because low-SR fibers may be important drivers of the MEMR (Liberman and Kiang, 1984; Kobler et al., 1992). Here, to test the hypothesis that narrowband reflex elicitors can identify synaptopathic cochlear regions, we measured reflex growth functions in unanesthetized mice with varying degrees of noise-induced synaptopathy and in unexposed controls. To separate effects of the MEMR from those of the medial olivocochlear reflex, the other sound-evoked cochlear feedback loop, we used a mutant mouse strain with deletion of the acetylcholine receptor required for olivocochlear function. We demonstrate that the MEMR is normal when activated from non-synaptopathic cochlear regions, is greatly weakened in synaptopathic regions, and is a more sensitive indicator of moderate synaptopathy than the suprathreshold amplitude of ABR wave I.