Medial olivocochlear reflex dysfunction in multiple sclerosis: The influence of brainstem lesion localization and its clinical implications

Purpose The medial olivocochlear (MOC) reflex enhances neural encoding of signals in noise, and measurement of its function may hold clinical utility. Previous research on how the reflex aids speech-in-noise perception has been equivocal. Motivated by animal work, we examined associations between MOC reflex activity and formant discrimination in noise in humans to better understand how the MOC reflex contributes to audition. We hypothesised that participants with stronger MOC reflex activity would have better formant discrimination in noise abilities. Method Twenty-six normal-hearing listeners met all inclusion and exclusion criteria (mean age = 21.5 years), with data from 25 participants included in the final analysis. Transient-evoked otoacoustic emissions (TEOAEs) were measured in right ears. MOC reflex activity was assessed using a contralateral inhibition paradigm in which the change in TEOAE amplitude without versus with a contralateral MOC reflex elicitor was computed. Formant discrimination thresholds for a synthetic vowel /ɛ/ were obtained in right ears using a two-alternative forced-choice procedure that adaptively varied the second formant frequency. Discrimination thresholds were obtained at three signal-to-noise ratios (SNRs). Results TEOAE amplitudes were significantly reduced in the presence of the reflex elicitor (p < .05). Discrimination thresholds decreased significantly with increasing SNR (p < .05 in all cases). No significant correlations were found between contralateral inhibition measures and discrimination thresholds at any SNR (p > .05 in all cases). Conclusion Contrary to hypothesis, no significant associations were found between contralateral inhibition and formant discrimination in noise performance. It is possible that the MOC reflex contributes to formant discrimination but not in a monotonic fashion. Future work should consider investigating how the MOC reflex contributes to other perceptual properties to better characterise the functional relevance of the MOC reflex.

Autism spectrum disorder (ASD) is a developmental disability that is poorly understood. ASD can influence communication, social interaction, and behavior. Children with ASD often have sensory hypersensitivities, including auditory hypersensitivity (hyperacusis). In adults with hyperacusis who are otherwise neurotypical, the medial olivocochlear (MOC) efferent reflex is stronger than usual. In children with ASD, the MOC reflex has been measured, but without also assessing hyperacusis. We assessed the MOC reflex in children with ASD by measuring the strength of MOC-induced inhibition of transient-evoked otoacoustic emissions (TEOAEs), a noninvasive physiological measure that reflects cochlear amplification. MOC activity was evoked by contralateral noise. Hyperacusis was assessed subjectively on the basis of the children's symptoms. We found a significant correlation between hyperacusis scores and MOC strength in children with ASD. When children were divided into ASD-with-severe-hyperacusis (ASDs), ASD-with-not-severe-hyperacusis (ASDns), and neurotypical (NT) groups, the last two groups had similar hyperacusis and MOC reflexes, whereas the ASDs group, on average, had hyperacusis and MOC reflexes that were approximately twice as strong. The MOC inhibition of TEOAEs averaged larger at all frequencies in the ASDs compared with ASDns and NT groups. The results suggest that the MOC reflex can be used to estimate hyperacusis in children with ASD and might be used to validate future questionnaires to assess hyperacusis. Our results also provide evidence that strong MOC reflexes in children with ASD are associated with hyperacusis and that hyperacusis is a comorbid condition and is not a necessary, integral part of the abnormal neural processing associated with ASD.NEW & NOTEWORTHY Children with autism spectrum disorder (ASD) are a heterogeneous group, some with hyperacusis and some without. Our research shows that hyperacusis can be estimated in children with ASD by using medial olivocochlear (MOC) reflex measurements. By establishing that an objective measure correlates with attributes of hyperacusis, our results enable future work to enable subtyping of children with ASD to provide improved individualized treatments to at-risk children and those without adequate language to describe their hyperacusis symptoms.

Objective The medial olivocochlear (MOC) reflex provides efferent feedback from the brainstem to cochlear outer hair cells. Physiologic studies have demonstrated that the MOC reflex is involved in “unmasking” of signals-in-noise at the level of the auditory nerve; however, its functional importance in human hearing remains unclear. Design This study examined relationships between pre-neural measurements of MOC reflex strength (click-evoked otoacoustic emission inhibition; CEOAE) and neural measurements of speech-in-noise encoding (speech frequency following response; sFFR) in four conditions (Quiet, Contralateral Noise, Ipsilateral Noise, and Ipsilateral + Contralateral Noise). Three measures of CEOAE inhibition (amplitude reduction, effective attenuation, and input-output slope inhibition) were used to quantify pre-neural MOC reflex strength. Correlations between pre-neural MOC reflex strength and sFFR “unmasking” (i.e. response recovery from masking effects with activation of the MOC reflex in time and frequency domains) were assessed. Study sample 18 young adults with normal hearing. Results sFFR unmasking effects were insignificant, and there were no correlations between pre-neural MOC reflex strength and sFFR unmasking in the time or frequency domain. Conclusion Our results do not support the hypothesis that the MOC reflex is involved in speech-in-noise neural encoding, at least for features that are represented in the sFFR at the SNR tested.

Otoacoustic emissions serve as a noninvasive probe of the medial olivocochlear (MOC) reflex. Stimulus frequency otoacoustic emissions (SFOAEs) elicited by a low-level probe tone may be the optimal type of emission for studying MOC effects because at low levels, the probe itself does not elicit the MOC reflex [Guinan et al. (2003) J. Assoc. Res. Otolaryngol. 4:521]. Based on anatomical considerations, the MOC reflex activated by ipsilateral acoustic stimulation (mediated by the crossed olivocochlear bundle) is predicted to be stronger than the reflex to contralateral stimulation. Broadband noise is an effective activator of the MOC reflex; however, it is also an effective activator of the middle-ear muscle (MEM) reflex, which can make results difficult to interpret. The MEM reflex may be activated at lower levels than measured clinically, and most previous human studies have not explicitly included measurements to rule out MEM reflex contamination. The current study addressed these issues using a higher-frequency SFOAE probe tone to test for cochlear changes mediated by the MOC reflex, while simultaneously monitoring the MEM reflex using a low-frequency probe tone. Broadband notched noise was presented ipsilaterally at various levels to elicit probe-tone shifts. Measurements are reported for 15 normal-hearing subjects. With the higher-frequency probe near 1.5 kHz, only 20% of subjects showed shifts consistent with an MOC reflex in the absence of an MEM-induced shift. With the higher-frequency probe near 3.5 kHz, up to 40% of subjects showed shifts in the absence of an MEM-induced shift. However, these responses had longer time courses than expected for MOC-induced shifts, and may have been dominated by other cochlear processes, rather than MOC reflex. These results suggest caution in the interpretation of effects observed using ipsilaterally presented acoustic activators intended to excite the MOC reflex.

The medial olivocochlear (MOC) reflex arc is probably a three-neuron pathway consisting of type I spiral ganglion neurons, reflex interneurons in the cochlear nucleus, and MOC neurons that project to the outer hair cells of the cochlea. We investigated the identity of MOC reflex interneurons in the cochlear nucleus by assaying their regional distribution using focal injections of kainic acid. Our reflex metric was the amount of change in the distortion product otoacoustic emission (at 2f(1)-f(2)) just after onset of the primary tones. This metric for MOC reflex strength has been shown to depend on an intact reflex pathway. Lesions involving the posteroventral cochlear nucleus (PVCN), but not the other subdivisions, produced long-term decreases in MOC reflex strength. The degree of cell loss within the dorsal part of the PVCN was a predictor of whether the lesion affected MOC reflex strength. We suggest that multipolar cells within the PVCN have the distribution and response characteristics appropriate to be the MOC reflex interneurons.

Ankylosing spondylitis (AS) is achronic systemic inflammatory disease. Via autoimmune mediators, AS can damage the auditory system similar to other systems. Otoacoustic emission studies in AS patients showed that the damage that causes hearing loss was in the outer hair cells. The medial olivocochlear (MOC) reflex is used to evaluate the MOC efferent system (MOES), which includes the outer hair cells. The aim of this study was to evaluate the presence of subclinical damage in the inner ear with the aid of the MOC reflex test in AS patients with no hearing complaints. Thirty-four patients with AS and acontrol group of 30healthy volunteers with similar demographic characteristics were evaluated in the study. Otoacoustic emission responses, MOC reflex results, and frequency-specific and total suppression findings were compared between the groups. The relationship between clinical and laboratory findings for the AS patients, and the MOC reflex data were also investigated. Reduced MOC reflex response (p= 0.04) and suppression (p= 0.019) were detected in AS patients. When the clinical and laboratory findings for the AS patients and the MOC reflex test results were compared, asignificant correlation was found only between the MOC reflex and the erythrocyte sedimentation rate. The results showed that AS can damage the inner ear, especially the MOES, and can reduce the MOC reflex response without clinical hearing loss.

Medial olivocochlear (MOC) neurons project to outer hair cells (OHC), forming the efferent arm of a reflex that affects sound processing and offers protection from acoustic overstimulation. The central pathways that trigger the MOC reflex in response to sound are poorly understood. Insight into these pathways can be obtained by examining the responses of single MOC neurons recorded from anesthetized guinea pigs. Response latencies of MOC neurons are as short as 5 ms. This latency is consistent with the idea that type I, but not type II, auditory-nerve fibers provide the major inputs to the reflex interneurons in the cochlear nucleus. This short latency also implies that the cochlear-nucleus interneurons have rapidly conducting axons. In the cochlear nucleus, lesions of the posteroventral subdivision (PVCN), but not the anteroventral (AVCN) or dorsal (DCN) subdivisions, produce permanent disruption of the MOC reflex, based on a metric of adaptation of the distortion-product otoacoustic emission (DPOAE). This finding supports earlier anatomical results demonstrating that some PVCN neurons project to MOC neurons. Within the PVCN, there are two general types of units when classified according to poststimulus time histograms: onset units and chopper units. The MOC response is sustained and cannot be produced solely by inputs having an onset pattern. The MOC reflex interneurons are thus likely to be chopper units of PVCN. Also supporting this conclusion, chopper units and MOC neurons both have sharp frequency tuning. Thus, the most likely pathway for the sound-evoked MOC reflex begins with the responses of hair cells, proceeds with type I auditory-nerve fibers, PVCN chopper units, and MOC neurons, and ends with the MOC terminations on OHC.

The auditory system is regulated by various adaptive mechanisms that modify sound as it passes upstream to the cortex. Studying these adaptive mechanisms, such as the middle ear muscle (MEM) reflex and the medial olivocochlear (MOC) reflex, reveals how the normal auditory system adjusts to challenging listening tasks and how abnormal reflexes may contribute to perceptual difficulties experienced by patients with sensorineural hearing loss. Studies in laboratory animals reveal that MOC and MEM reflexes result in neural antimasking at the output of the auditory nerve. Antimasking effects at the level of the middle ear and at the level of the cochlear hair cells should carry over to effects observed at the output of the auditory nerve. Antimasking due to MEM and MOC reflexes has been difficult to study in humans since measurement approaches are limited to non-invasive techniques with only a single output variable (e.g., ear canal pressure). In these studies, we assess MEM and MOC function by simultaneous measurements of ear canal pressure and electrocochleography, including the cochlear microphonic potential and compound action potential. Simultaneous measurements are expected to reveal the antimasking effects of MEM and MOC reflexes to middle ear, hair cell, and auditory nerve responses.

AB0702 Medial Olivocochlear Reflex in Patients with Ankylosing Spondylitis

The relationship between MOC reflex and masked threshold

Previous work demonstrates the importance of a high signal to noise ratio (SNR) when using transient evoked otoacoustic emissions (TEOAEs) to assay the medial olivocochlear reflex (MOCR). Increasing stimulus level provides one means to increase TEOAE SNR. However, this may come at the expense of a smaller MOCR effect. It is not clear whether the gain in SNR associated with the use of higher stimulus levels outweighs the disadvantage of a potentially smaller MOCR effect. The present study investigated the strength and detectability of the MOCR when assayed using TEOAEs at different stimulus levels. The hypothesis was that although the strength of the MOCR decreases with increasing stimulus level, the occurrence of statistically significant MOCR effects increases due to an increase in TEOAE SNR. Twenty-five young adult females with normal hearing participated in the study. TEOAEs were measured in the right ear with and without broadband noise presented in the left ear. The strength of the MOCR was quantified as the percent difference in the TEOAE between the contralateral noise and quiet conditions. Statistical bootstrapping was used to detect significant MOCR effects in individual subjects across different frequency bands and stimulus levels. The relationship between a detectable MOCR (response variable) and frequency, stimulus level, TEOAE SNR, MOCR strength, and subject (predictor variables) was evaluated using generalized linear mixed-effect models. The number of statistically significant MOCR effects increased with stimulus level at all frequencies. Occurrence was highest for the 2-kHz TEOAE frequency band and lowest for the 4-kHz frequency band. The strength of the MOCR decreased with increasing click level. TEOAE SNR, MOCR strength, and stimulus level were significant predictors of a detectable MOCR: The likelihood of a detectable MOCR increased with TEOAE SNR, MOCR strength, and stimulus level. Despite a reduction in the strength of the MOCR with increasing stimulus level, the detectability of the MOCR increased. This is due, in part, to an increase in TEOAE SNR with stimulus level. For clinical implementation of TEOAE-based MOCR assays, achieving a high SNR is necessary to permit the detection of the MOCR in individual patients.

Past work applying otoacoustic emissions to gauge maturational status of the medial olivocochlear (MOC) reflex in human newborns has produced mixed results. The present study revisits the question while considering the dual nature of the 2f(1) - f(2) distortion product otoacoustic emission (DPOAE) and expanding measures of medial efferent function. Subjects included premature and term-born neonates, 6-month-old infants and young adults. The MOC reflex was elicited with contralateral acoustic stimulation (CAS) while shifts in amplitude and phase of the DPOAE, and its distortion and reflection components, were monitored. Overall, CAS-elicited reductions in DPOAE level did not differ among age groups. For all ages, the MOC reflex was strongest at frequencies below 1.5 kHz, and the reflection component of the DPOAE was most affected, showing maximally reduced amplitude and shallower phase slope when contralateral noise was presented. Results suggest that the MOC reflex likely reaches maturation prior to full-term birth. However, prematurely born neonates show markedly more episodes of CAS-induced DPOAE level enhancement. This may be due to more intrusive component mixing in this age group or disruptions in the formation of the MOC pathway or synapse in the most premature neonates.

Otoacoustic emissions-based efferent assays are evolving to become a part of auditory diagnostics. The wide range of clinical applications, such as assessment of auditory neuropathy, auditory processing disorders, learning disability, monitoring success in auditory intervention and others illustrate the significance of this measurement. Defining the procedure's test-retest repeatability is of critical importance, to allow for distinction between measurement deviations and true physiological or pathological changes. The purpose of this study was to assess the repeatability of a click-evoked otoacoustic emission-based (CEOAE) test of the medial olivocochlear (MOC) reflex in normal-hearing (NH) adults. Test-retest data were collected from 35 NH young adults in two distinct test sessions separated by 1 to 4 days. CEOAEs were recorded without and with contralateral acoustic stimulation (CAS; 35 dB SL). Three indices of the MOC reflex were computed: CAS-induced (a) absolute changes in CEOAE amplitude, (b) normalized changes in CEOAE amplitude, and (c) changes in CEOAE input-output functions. Repeatability of these indices was assessed by a three-layered approach, which consisted of Bland-Altman plots, coefficient of reliability (Cronbach's α), and analysis of variance. Analyses indicated good repeatability of three CEOAE-based MOC reflex indices. A two-way analysis of variance of the indices demonstrated no significant difference between test and retest. Normalized index showed similar repeatability as other indices. CEOAE signal to noise ratio did not seem to vary between test sessions. Notably, CAS caused a decrease in CEOAE input-output functions slope in a majority of participants (n = 29). The present study is the first to elucidate the intrasubject variability of absolute and normalized indices of the MOC inhibitory effect. Although the measurements were conducted under realistic conditions resembling the clinical setting, repeatability was generally good in NH adults. For MOC reflex test, the signal to noise ratio of 6 dB for recording CEOAEs seems to be a recommendable criterion when considering practicability and measurement quality in clinical conditions. The present findings exemplify the suitability of CEOAE-based MOC assay as a monitoring tool of medial efferent status over time. The data are intended to assist clinicians and scientists alike in the accurate interpretation of CAS-induced CEOAE changes in the test-retest situation.

Human medial olivocochlear reflex: Contralateral activation effect on low and high frequency cochlear response

The contralateral medial olivocochlear reflex (MOCR) strength may indicate various auditory conditions in humans, but a clinically viable assay and equipment are needed for quick, accurate, and reliable measurements. The first experiment compared an earlier version of the assay, which used a nonlinear-mode chirp stimulus, with a new assay using a linear-mode click stimulus, designed to give reliable MOCR measurements in most normal-hearing ears. The second experiment extended the improved assay on a purpose-built binaural hardware platform that used forward-pressure level (FPL) calibration for both the stimulus and the contralateral MOCR elicitor. Transient-evoked otoacoustic emission (TEOAE) tests were measured with and without a 60-dB SPL MOCR-evoking contralateral broadband noise. The normalized MOCR strength (MOCR%) was derived from the TEOAE responses for each trial pair using the complex pressure difference weighted by the TEOAE magnitude. Experiment 1 compared MOCR% within-subject and across-day using two TEOAE stimuli: nonlinear-mode chirps (50 dB SPL, bandpass 1-5 kHz, 14 ms window delayed by 2 ms) and linear-mode clicks (50 dB SPL, bandpass 0.5-2.5 kHz, 13 ms window delayed by 5 ms). TEOAE responses were analyzed in the 0.5 to 2.5 kHz band. Thirty adult participants with normal hearing (30 ears) completed the study. The TEOAE stimulus was calibrated in situ using spectral flattening, and the contralateral noise was calibrated in a coupler. Twelve TEOAE trial pairs were collected for each participant and condition. Experiment 2 used a purpose-built binaural system. The TEOAE stimuli were linear-mode clicks (50 dB SPL, bandpass 1-3 kHz, 13 ms window delayed by 5 ms), analyzed in the 1 to 3 kHz band over ~12 trial pairs. After a probe refit, an additional trial pair was collected for the two early-stopping signal-to-noise ratio criteria (15 and 20 dB). They were evaluated for single-trial reliability and test time. Nineteen adult participants with normal hearing (38 ears) completed the study. The TEOAE clicks and contralateral elicitor noise were calibrated in situ using FPL and delivered with automated timing. MOCR% for linear-mode clicks was distinguishable from measurement variability in 98% to 100% of participants' ears (both experiments), compared with only 73% for the nonlinear-mode chirp (experiment 1). MOCR detectability was assessed using the MOCR% across-subject/within-subject variance ratio. The ratio in experiment 1 for linear-mode clicks was higher (8.0) than for nonlinear-mode chirps (6.4). The ratio for linear-mode clicks (8.9) in experiment 2 was slightly higher than for the comparable linear-mode stimulus (8.0) in experiment 1. TEOAEs showed excellent reliability with high signal-to-noise ratios in both experiments, but reliability was higher for linear-mode clicks than nonlinear-mode chirps. MOCR reliability for the two stimuli was comparable. The FPL pressure response retest reliability derived from the SPL at the microphone was higher than the SPL retest reliability across 0.4 to 8 kHz. Stable results required 2 to 3 trial pairs for the linear-mode click (experiments 1 and 2) and three for the nonlinear-mode chirp (experiment 1), taking around 2 min on average. The linear-mode click assay produced measurable, reliable, and stable TEOAE and MOCR results on both hardware platforms in around 2 min per ear. The stimulus design and response window ensured that any stimulus artifact in linear mode was unlikely to confound the results. The refined assay is ready to produce high-quality data quickly for clinical and field studies to develop population norms, recognize diagnostic patterns, and determine risk profiles.