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      Weak Middle-Ear-Muscle Reflex in Humans with Noise-Induced Tinnitus and Normal Hearing May Reflect Cochlear Synaptopathy

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          Abstract

          Chronic tinnitus is a prevalent hearing disorder, and yet no successful treatments or objective diagnostic tests are currently available. The aim of this study was to investigate the relationship between the presence of tinnitus and the strength of the middle-ear-muscle reflex (MEMR) in humans with normal and near-normal hearing. Clicks were used as test stimuli to obtain a wideband measure of the effect of reflex activation on ear-canal sound pressure. The reflex was elicited using a contralateral broadband noise. The results show that the reflex strength is significantly reduced in individuals with noise-induced continuous tinnitus and normal or near-normal audiometric thresholds compared with no-tinnitus controls. Due to a shallower growth of the reflex strength in the tinnitus group, the difference between the two groups increased with increasing elicitor level. No significant difference in the effect of tinnitus on the strength of the middle-ear muscle reflex was found between males and females. The weaker reflex could not be accounted for by differences in audiometric hearing thresholds between the tinnitus and control groups. Similarity between our findings in humans and the findings of a reduced middle-ear muscle reflex in noise-exposed animals suggests that noise-induced tinnitus in individuals with clinically normal hearing may be a consequence of cochlear synaptopathy, a loss of synaptic connections between inner hair cells (IHCs) in the cochlea and auditory-nerve (AN) fibers that has been termed hidden hearing loss.

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          Tinnitus with a normal audiogram: physiological evidence for hidden hearing loss and computational model.

          Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of "hidden hearing loss" that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.
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            Age-related cochlear synaptopathy: an early-onset contributor to auditory functional decline.

            Aging listeners experience greater difficulty understanding speech in adverse listening conditions and exhibit degraded temporal resolution, even when audiometric thresholds are normal. When threshold evidence for peripheral involvement is lacking, central and cognitive factors are often cited as underlying performance declines. However, previous work has uncovered widespread loss of cochlear afferent synapses and progressive cochlear nerve degeneration in noise-exposed ears with recovered thresholds and no hair cell loss (Kujawa and Liberman 2009). Here, we characterize age-related cochlear synaptic and neural degeneration in CBA/CaJ mice never exposed to high-level noise. Cochlear hair cell and neuronal function was assessed via distortion product otoacoustic emissions and auditory brainstem responses, respectively. Immunostained cochlear whole mounts and plastic-embedded sections were studied by confocal and conventional light microscopy to quantify hair cells, cochlear neurons, and synaptic structures, i.e., presynaptic ribbons and postsynaptic glutamate receptors. Cochlear synaptic loss progresses from youth (4 weeks) to old age (144 weeks) and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts. Cochlear nerve loss parallels the synaptic loss, after a delay of several months. Key functional clues to the synaptopathy are available in the neural response; these can be accessed noninvasively, enhancing the possibilities for translation to human clinical characterization.
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              Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates.

              Acoustic overexposure can cause a permanent loss of auditory nerve fibers without destroying cochlear sensory cells, despite complete recovery of cochlear thresholds (Kujawa and Liberman 2009), as measured by gross neural potentials such as the auditory brainstem response (ABR). To address this nominal paradox, we recorded responses from single auditory nerve fibers in guinea pigs exposed to this type of neuropathic noise (4- to 8-kHz octave band at 106 dB SPL for 2 h). Two weeks postexposure, ABR thresholds had recovered to normal, while suprathreshold ABR amplitudes were reduced. Both thresholds and amplitudes of distortion-product otoacoustic emissions fully recovered, suggesting recovery of hair cell function. Loss of up to 30% of auditory-nerve synapses on inner hair cells was confirmed by confocal analysis of the cochlear sensory epithelium immunostained for pre- and postsynaptic markers. In single fiber recordings, at 2 wk postexposure, frequency tuning, dynamic range, postonset adaptation, first-spike latency and its variance, and other basic properties of auditory nerve response were all completely normal in the remaining fibers. The only physiological abnormality was a change in population statistics suggesting a selective loss of fibers with low- and medium-spontaneous rates. Selective loss of these high-threshold fibers would explain how ABR thresholds can recover despite such significant noise-induced neuropathy. A selective loss of high-threshold fibers may contribute to the problems of hearing in noisy environments that characterize the aging auditory system.
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                Author and article information

                Journal
                eNeuro
                eNeuro
                eneuro
                eneuro
                eNeuro
                eNeuro
                Society for Neuroscience
                2373-2822
                16 November 2017
                27 November 2017
                Nov-Dec 2017
                : 4
                : 6
                : ENEURO.0363-17.2017
                Affiliations
                [1]Department of Psychology, University of Minnesota , Minneapolis, MN 55455
                Author notes

                The authors declare no competing financial interests.

                Author contributions: M.W. designed research; M.W. performed research; M.W. and J.A.B. performed research and analyzed data; M.W. wrote the paper and A.J.O. wrote the paper.

                This work was supported by National Institutes of Health Grants R01 DC015987 (to M.W.) and R01 DC012262 (to A.J.O.).

                Correspondence should be addressed to Magdalena Wojtczak, Department of Psychology, N218 Elliott Hall, 75 East River Road, Minneapolis, MN 55455, E-mail: wojtc001@ 123456umn.edu.
                Author information
                http://orcid.org/0000-0002-1088-4669
                http://orcid.org/0000-0002-9365-1157
                Article
                eN-NWR-0363-17
                10.1523/ENEURO.0363-17.2017
                5702873
                29181442
                d7b534b9-bd73-441b-871a-0d70710b20a5
                Copyright © 2017 Wojtczak et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 23 October 2017
                : 9 November 2017
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 49, Pages: 8, Words: 5977
                Funding
                Funded by: http://doi.org/10.13039/100000002HHS | National Institutes of Health (NIH)
                Award ID: R01 DC015987
                Award ID: R01 DC012262
                Categories
                8
                8.1
                New Research
                Sensory and Motor Systems
                Custom metadata
                November/December 2017

                cochlear synaptopathy,hidden hearing loss,middle-ear-muscle reflex,noise exposure,stapedial reflex,tinnitus

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