Hannah Guest

Tinnitus with a normal audiogram: Relation to noise exposure but no evidence for cochlear synaptopathy

&NA; In rodents, exposure to high‐level noise can destroy synapses between inner hair cells and auditory nerve fibers, without causing hair cell loss or permanent threshold elevation. Such “cochlear synaptopathy” is associated with amplitude reductions in wave I of the auditory brainstem response (ABR) at moderate‐to‐high sound levels. Similar ABR results have been reported in humans with tinnitus and normal audiometric thresholds, leading to the suggestion that tinnitus in these cases might be a consequence of synaptopathy. However, the ABR is an indirect measure of synaptopathy and it is unclear whether the results in humans reflect the same mechanisms demonstrated in rodents. Measures of noise exposure were not obtained in the human studies, and high frequency audiometric loss may have impacted ABR amplitudes. To clarify the role of cochlear synaptopathy in tinnitus with a normal audiogram, we recorded ABRs, envelope following responses (EFRs), and noise exposure histories in young adults with tinnitus and matched controls. Tinnitus was associated with significantly greater lifetime noise exposure, despite close matching for age, sex, and audiometric thresholds up to 14 kHz. However, tinnitus was not associated with reduced ABR wave I amplitude, nor with significant effects on EFR measures of synaptopathy. These electrophysiological measures were also uncorrelated with lifetime noise exposure, providing no evidence of noise‐induced synaptopathy in this cohort, despite a wide range of exposures. In young adults with normal audiograms, tinnitus may be related not to cochlear synaptopathy but to other effects of noise exposure. HighlightsTinnitus participants matched with controls for age, sex, & audiogram up to 14 kHz.Tinnitus participants more noise exposed, despite close audiometric matching.No ABR or EFR evidence for cochlear synaptopathy in tinnitus participants.No association between ABR or EFR measures and lifetime noise exposure.

Effects of noise exposure on young adults with normal audiograms I: Electrophysiology

&NA; Noise‐induced cochlear synaptopathy has been demonstrated in numerous rodent studies. In these animal models, the disorder is characterized by a reduction in amplitude of wave I of the auditory brainstem response (ABR) to high‐level stimuli, whereas the response at threshold is unaffected. The aim of the present study was to determine if this disorder is prevalent in young adult humans with normal audiometric hearing. One hundred and twenty six participants (75 females) aged 18–36 were tested. Participants had a wide range of lifetime noise exposures as estimated by a structured interview. Audiometric thresholds did not differ across noise exposures up to 8 kHz, although 16‐kHz audiometric thresholds were elevated with increasing noise exposure for females but not for males. ABRs were measured in response to high‐pass (1.5 kHz) filtered clicks of 80 and 100 dB peSPL. Frequency‐following responses (FFRs) were measured to 80 dB SPL pure tones from 240 to 285 Hz, and to 80 dB SPL 4 kHz pure tones amplitude modulated at frequencies from 240 to 285 Hz (transposed tones). The bandwidth of the ABR stimuli and the carrier frequency of the transposed tones were chosen to target the 3–6 kHz characteristic frequency region which is usually associated with noise damage in humans. The results indicate no relation between noise exposure and the amplitude of the ABR. In particular, wave I of the ABR did not decrease with increasing noise exposure as predicted. ABR wave V latency increased with increasing noise exposure for the 80 dB peSPL click. High carrier‐frequency (envelope) FFR signal‐to‐noise ratios decreased as a function of noise exposure in males but not females. However, these correlations were not significant after the effects of age were controlled. The results suggest either that noise‐induced cochlear synaptopathy is not a significant problem in young, audiometrically normal adults, or that the ABR and FFR are relatively insensitive to this disorder in young humans, although it is possible that the effects become more pronounced with age. HighlightsLarge study on the effects of lifetime noise exposure in normal‐hearing young adults.No clear evidence for noise‐induced cochlear synaptopathy in ABR or FFR measures.Noise exposure associated with elevated 16‐kHz audiometric thresholds in females.

Toward a Diagnostic Test for Hidden Hearing Loss

Cochlear synaptopathy (or hidden hearing loss), due to noise exposure or aging, has been demonstrated in animal models using histological techniques. However, diagnosis of the condition in individual humans is problematic because of (a) test reliability and (b) lack of a gold standard validation measure. Wave I of the transient-evoked auditory brainstem response is a noninvasive electrophysiological measure of auditory nerve function and has been validated in the animal models. However, in humans, Wave I amplitude shows high variability both between and within individuals. The frequency-following response, a sustained evoked potential reflecting synchronous neural activity in the rostral brainstem, is potentially more robust than auditory brainstem response Wave I. However, the frequency-following response is a measure of central activity and may be dependent on individual differences in central processing. Psychophysical measures are also affected by intersubject variability in central processing. Differential measures may help to reduce intersubject variability due to unrelated factors. A measure can be compared, within an individual, between conditions that are affected differently by cochlear synaptopathy. Validation of the metrics is also an issue. Comparisons with animal models, computational modeling, auditory nerve imaging, and human temporal bone histology are all potential options for validation, but there are technical and practical hurdles and difficulties in interpretation. Despite the obstacles, a diagnostic test for hidden hearing loss is a worthwhile goal, with important implications for clinical practice and health surveillance.

Effects of noise exposure on young adults with normal audiograms II: Behavioral measures

ABSTRACT An estimate of lifetime noise exposure was used as the primary predictor of performance on a range of behavioral tasks: frequency and intensity difference limens, amplitude modulation detection, interaural phase discrimination, the digit triplet speech test, the co‐ordinate response speech measure, an auditory localization task, a musical consonance task and a subjective report of hearing ability. One hundred and thirty‐eight participants (81 females) aged 18–36 years were tested, with a wide range of self‐reported noise exposure. All had normal pure‐tone audiograms up to 8 kHz. It was predicted that increased lifetime noise exposure, which we assume to be concordant with noise‐induced cochlear synaptopathy, would elevate behavioral thresholds, in particular for stimuli with high levels in a high spectral region. However, the results showed little effect of noise exposure on performance. There were a number of weak relations with noise exposure across the test battery, although many of these were in the opposite direction to the predictions, and none were statistically significant after correction for multiple comparisons. There were also no strong correlations between electrophysiological measures of synaptopathy published previously and the behavioral measures reported here. Consistent with our previous electrophysiological results, the present results provide no evidence that noise exposure is related to significant perceptual deficits in young listeners with normal audiometric hearing. It is possible that the effects of noise‐induced cochlear synaptopathy are only measurable in humans with extreme noise exposures, and that these effects always co‐occur with a loss of audiometric sensitivity. HIGHLIGHTSLarge study on the effects of lifetime noise exposure in normal‐hearing young adults.Performance on a range of behavioral tasks unrelated to noise exposure history.Effects of cochlear synaptopathy not evident in young audiometrically normal cohort.

Tinnitus with a normal audiogram : Role of high-frequency sensitivity and reanalysis of brainstem-response measures to avoid audiometric over-matching

Please cite this article in press as: Guest, H., e stem-response measures to avoid audiomet In Guest et al. (2017), we tested for associations between tinnitus and electrophysiological measures of cochlear synaptopathy in young humans with normal hearing sensitivity. Tinnitus and control groups were matched closely for age, sex, and audiometric thresholds up to 14 kHz. The groups did not differ significantly in auditory-brainstem-response (ABR) or envelopefollowing-response (EFR) measures of synaptopathy. The matching of audiograms at extended high frequencies (EHFs) was intended to prevent confounding effects of EHF audiometric loss on brainstem-response measures. Such effects are, in our view, a potential pitfall in synaptopathy research, which tends to employ high stimulus levels that likely elicit contributions from the extreme cochlear base (for example, 120 dB pSPL in Gu et al., 2012; 130 dB peSPL in Liberman et al., 2016). Derived-band responses in humans indicate that ABR wave I is dominated by high-frequency generators, including those above 8 kHz (Don and Eggermont, 1978; Hardy et al., 2017), and increasingly so at high stimulus levels (Eggermont and Don, 1980). Hardy et al. (2017; personal communication, 10/02/17) recently demonstrated that both wave I amplitude and the ratio of wave I amplitude to wave V amplitude are reduced when noise high-pass filtered at 8 kHz is added to remove contributions from EHF regions. Their findings raise questions about apparent evidence for cochlear synaptopathy in humans, since such evidence has often been accompanied by EHF audiometric deficits (Gu et al., 2012; Liberman et al., 2016; Schaette and McAlpine, 2011), or even deficits at standard audiometric frequencies (Bramhall et al., 2017). However, it has come to our attention that control of audiometric factors in our tinnitus study might have come at a cost. Hickox et al. (2017) note that many animal models of synaptopathy additionally produce some degree of basal hair-cell loss. Liberman et al. (2016) posit that “high-frequency threshold elevation will be correlated with mid-frequency cochlear synaptopathy”. If this expectation is justified, then over-matching of audiometric thresholds in our study might have risked obscuring genuine differences in auditory nerve function between groups. Future research might usefully address this issue by allowing variation in EHF audiometric thresholds and preventing their direct influence on proxymeasures of synaptopathy through the application of high-pass masking

The Physiological Bases of Hidden Noise-Induced Hearing Loss: Protocol for a Functional Neuroimaging Study

Background Rodent studies indicate that noise exposure can cause permanent damage to synapses between inner hair cells and high-threshold auditory nerve fibers, without permanently altering threshold sensitivity. These demonstrations of what is commonly known as hidden hearing loss have been confirmed in several rodent species, but the implications for human hearing are unclear. Objective Our Medical Research Council–funded program aims to address this unanswered question, by investigating functional consequences of the damage to the human peripheral and central auditory nervous system that results from cumulative lifetime noise exposure. Behavioral and neuroimaging techniques are being used in a series of parallel studies aimed at detecting hidden hearing loss in humans. The planned neuroimaging study aims to (1) identify central auditory biomarkers associated with hidden hearing loss; (2) investigate whether there are any additive contributions from tinnitus or diminished sound tolerance, which are often comorbid with hearing problems; and (3) explore the relation between subcortical functional magnetic resonance imaging (fMRI) measures and the auditory brainstem response (ABR). Methods Individuals aged 25 to 40 years with pure tone hearing thresholds ≤20 dB hearing level over the range 500 Hz to 8 kHz and no contraindications for MRI or signs of ear disease will be recruited into the study. Lifetime noise exposure will be estimated using an in-depth structured interview. Auditory responses throughout the central auditory system will be recorded using ABR and fMRI. Analyses will focus predominantly on correlations between lifetime noise exposure and auditory response characteristics. Results This paper reports the study protocol. The funding was awarded in July 2013. Enrollment for the study described in this protocol commenced in February 2017 and was completed in December 2017. Results are expected in 2018. Conclusions This challenging and comprehensive study will have the potential to impact diagnostic procedures for hidden hearing loss, enabling early identification of noise-induced auditory damage via the detection of changes in central auditory processing. Consequently, this will generate the opportunity to give personalized advice regarding provision of ear defense and monitoring of further damage, thus reducing the incidence of noise-induced hearing loss.

Supra-threshold auditory brainstem response amplitudes in humans: Test-retest reliability, electrode montage and noise exposure

&NA; The auditory brainstem response (ABR) is a sub‐cortical evoked potential in which a series of well‐defined waves occur in the first 10 ms after the onset of an auditory stimulus. Wave V of the ABR, particularly wave V latency, has been shown to be remarkably stable over time in individual listeners. However, little attention has been paid to the reliability of wave I, which reflects auditory nerve activity. This ABR component has attracted interest recently, as wave I amplitude has been identified as a possible non‐invasive measure of noise‐induced cochlear synaptopathy. The current study aimed to determine whether ABR wave I amplitude has sufficient test‐retest reliability to detect impaired auditory nerve function in an otherwise normal‐hearing listener. Thirty normal‐hearing females were tested, divided equally into low‐ and high‐noise exposure groups. The stimulus was an 80 dB nHL click. ABR recordings were made from the ipsilateral mastoid and from the ear canal (using a tiptrode). Although there was some variability between listeners, wave I amplitude had high test‐retest reliability, with an intraclass correlation coefficient (ICC) comparable to that for wave V amplitude. There were slight gains in reliability for wave I amplitude when recording from the ear canal (ICC of 0.88) compared to the mastoid (ICC of 0.85). The summating potential (SP) and ratio of SP to wave I were also quantified and found to be much less reliable than measures of wave I and V amplitude. Finally, we found no significant differences in the amplitude of any wave components between low‐ and high‐noise exposure groups. We conclude that, if the other sources of between‐subject variability can be controlled, wave I amplitude is sufficiently reliable to accurately characterize individual differences in auditory nerve function. HighlightsABR wave I and V amplitudes have excellent test‐retest reliability in humans.SP amplitude and SP/AP ratio have poor test‐retest reliability.Canal tiptrodes result in only slightly increased reliability re. mastoid electrodes.No significant differences in amplitudes between low‐ and high‐noise exposed females.

Evidence that hidden hearing loss does not vary systematically as a function of noise exposure in young adults with normal audiometric hearing

Cochlear synaptopathy, or “hidden hearing loss,” refers to a loss of synapses between inner hair cells and auditory nerve fibers, and is observed in rodent models as a consequence of noise exposure and/or aging. In humans, cochlear synaptopathy is not thought to be detectable by pure tone audiometry, as thresholds to soft sounds in the rodent models are not permanently elevated. One hundred and forty audiometrically normal participants below the age of 35 and with a range of lifetime noise exposures performed an extensive battery of tests, including electrophysiological measures, psychophysical tests, and speech-in-noise tests. Inter-aural phase discrimination, amplitude modulation detection, and spatial release from masking on a speech task were found to be sensitive to noise exposure; however, these trends are weak and only the phase discrimination task followed the predicted direction (i.e., high noise exposed individuals showing elevated thresholds). None of the electrophysiological measures, includin...

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). Some metrics correlate with synaptic survival in animal models, but translation between species is not straightforward; measurements in humans likely 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 normally hearing young women underwent repeated measurements of ABR wave I amplitude, ABR wave I growth with level, ABR wave V latency shift in noise, EFR amplitude, EFR growth with stimulus modulation depth, MEMR threshold, and an MEMR difference measure. Intraclass correlation coefficients indicated good-to-excellent reliability for the raw ABR and EFR amplitudes, and for both MEMR measures. The ABR and EFR difference measures exhibited poor-to-moderate reliability. No significant correlations, nor any consistent trends, were observed between measures, providing no indication that the between-subject variability in responses are due to the same underlying physiological processes. Findings suggest that proxy measures of cochlear synaptopathy should be regarded with caution, at least when employed in young, normally hearing adults.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). Some metrics correlate with synaptic survival in animal models, but translation between species is not straightforward; measurements in humans likely 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 normally hearing young women underwent repeated measurements of ABR wave I amplitude, ABR wave I growth with level, ABR wave V latency shift in noise, EFR amplitude, EFR growth with stimulus modulation depth, MEMR threshold, and an MEMR difference measure. Intraclass correlation coefficients indicated good-to-excellent reliability for the raw ABR and EFR amplitudes, and for both MEMR meas...

Relations between speech perception in noise, high-frequency audiometry, and physiological measures of cochlear synaptopathy

Cochlear synaptopathy, a loss of synapses between inner hair cells and auditory nerve fibers, is associated with age and noise exposure in animal models. However, the functional consequences of synaptopathy for humans are unclear. We pooled data from two recent studies to answer the question: are the common physiological measures of cochlear synaptopathy related to speech-perception-in-noise (SPiN) performance? Eighty-three audiometrically normal participants (ages 18–39) took part. Measures of synaptopathy were as follows: auditory brainstem response (ABR) wave I amplitude (102 dB peSPL click); ABR wave I:V amplitude ratio; envelope following response (EFR) amplitude (4 kHz carrier, 105 Hz modulation frequency); EFR amplitude growth with stimulus modulation depth; and middle ear muscle reflex threshold (1–4 kHz elicitors). We also conducted extended high-frequency (EHF) audiometry (10 and 14 kHz), suggested as a marker for synaptopathy in lower frequency regions. SPiN performance was assessed using the coordinate response measure with spatial maskers. None of the physiological measures of synaptopathy correlated significantly with SPiN. There was a significant correlation between EHF thresholds and SPiN, although it is unclear whether this is due to a direct relation between EHF hearing and SPiN, or whether elevated EHF thresholds are a marker for hidden damage at lower frequencies.Cochlear synaptopathy, a loss of synapses between inner hair cells and auditory nerve fibers, is associated with age and noise exposure in animal models. However, the functional consequences of synaptopathy for humans are unclear. We pooled data from two recent studies to answer the question: are the common physiological measures of cochlear synaptopathy related to speech-perception-in-noise (SPiN) performance? Eighty-three audiometrically normal participants (ages 18–39) took part. Measures of synaptopathy were as follows: auditory brainstem response (ABR) wave I amplitude (102 dB peSPL click); ABR wave I:V amplitude ratio; envelope following response (EFR) amplitude (4 kHz carrier, 105 Hz modulation frequency); EFR amplitude growth with stimulus modulation depth; and middle ear muscle reflex threshold (1–4 kHz elicitors). We also conducted extended high-frequency (EHF) audiometry (10 and 14 kHz), suggested as a marker for synaptopathy in lower frequency regions. SPiN performance was assessed using the c...