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      Too Blind to See the Elephant? Why Neuroscientists Ought to Be Interested in Tinnitus

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          Abstract

          A curative therapy for tinnitus currently does not exist. One may actually exist but cannot currently be causally linked to tinnitus due to the lack of consistency of concepts about the neural correlate of tinnitus. Depending on predictions, these concepts would require either a suppression or enhancement of brain activity or an increase in inhibition or disinhibition. Although procedures with a potential to silence tinnitus may exist, the lack of rationale for their curative success hampers an optimization of therapeutic protocols. We discuss here six candidate contributors to tinnitus that have been suggested by a variety of scientific experts in the field and that were addressed in a virtual panel discussion at the ARO round table in February 2021. In this discussion, several potential tinnitus contributors were considered: (i) inhibitory circuits, (ii) attention, (iii) stress, (iv) unidentified sub-entities, (v) maladaptive information transmission, and (vi) minor cochlear deafferentation. Finally, (vii) some potential therapeutic approaches were discussed. The results of this discussion is reflected here in view of potential blind spots that may still remain and that have been ignored in most tinnitus literature. We strongly suggest to consider the high impact of connecting the controversial findings to unravel the whole complexity of the tinnitus phenomenon; an essential prerequisite for establishing suitable therapeutic approaches.

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          Most cited references140

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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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            Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms.

            Common causes of hearing loss in humans - exposure to loud noise or ototoxic drugs and aging - often damage sensory hair cells, reflected as elevated thresholds on the clinical audiogram. Recent studies in animal models suggest, however, that well before this overt hearing loss can be seen, a more insidious, but likely more common, process is taking place that permanently interrupts synaptic communication between sensory inner hair cells and subsets of cochlear nerve fibers. The silencing of affected neurons alters auditory information processing, whether accompanied by threshold elevations or not, and is a likely contributor to a variety of perceptual abnormalities, including speech-in-noise difficulties, tinnitus and hyperacusis. Work described here will review structural and functional manifestations of this cochlear synaptopathy and will consider possible mechanisms underlying its appearance and progression in ears with and without traditional 'hearing loss' arising from several common causes in humans.
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              Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons.

              Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in the bdnf gene, resulting in a valine to methionine substitution in the prodomain (BDNF(Met)), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders in humans heterozygous for the variant BDNF. When expressed by itself in hippocampal neurons, less BDNF(Met) is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNF(Met) and wild-type BDNF (BDNF(Val)) are present in the same cell is not known. Given that this is the predominant expression profile in humans, we examined the effect of coexpressed BDNF(Met) on BDNF(Val) intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNF(Met) occurred only in neuronal and neurosecretory cells and that BDNF(Met) could alter the intracellular distribution and activity-dependent secretion of BDNF(Val). We determined that, when coexpressed in the same cell, approximately 70% of the variant BDNF forms BDNF(Val).BDNF(Met) heterodimers, which are inefficiently sorted into secretory granules resulting in a quantitative decreased secretion. Finally, we determined the form of BDNF secreted in an activity-dependent manner and observed no differences in the forms of BDNF(Met) or the BDNF(Val).BDNF(Met) heterodimer compared with BDNF(Val). Together, these findings indicate that components of the regulated secretory machinery interacts specifically with a signal in the BDNF prodomain and that perturbations in BDNF trafficking may lead to selective impairment in CNS function.
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                Author and article information

                Contributors
                marlies.knipper@uni-tuebingen.de
                Journal
                J Assoc Res Otolaryngol
                J Assoc Res Otolaryngol
                JARO: Journal of the Association for Research in Otolaryngology
                Springer US (New York )
                1525-3961
                1438-7573
                22 October 2021
                22 October 2021
                December 2021
                : 22
                : 6
                : 609-621
                Affiliations
                [1 ]GRID grid.10392.39, ISNI 0000 0001 2190 1447, Molecular Physiology of Hearing, Tübingen Hearing Research Centre (THRC), Department of Otolaryngology, Head & Neck Surgery, , University of Tübingen, ; Elfriede-Aulhorn-Straße 5, 72076 Tübingen, Germany
                [2 ]GRID grid.6363.0, ISNI 0000 0001 2218 4662, Tinnitus Center Charité, , Universitätsmedizin Berlin, ; Berlin, Germany
                [3 ]GRID grid.4494.d, ISNI 0000 0000 9558 4598, Department of Otorhinolaryngology/Head and Neck Surgery, , University of Groningen, University Medical Center Groningen, ; Groningen, The Netherlands
                [4 ]GRID grid.4830.f, ISNI 0000 0004 0407 1981, Graduate School of Medical Sciences (Research School of Behavioural and Cognitive Neurosciences), , University of Groningen, ; Groningen, The Netherlands
                [5 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Experimental Otolaryngology, , Friedrich-Alexander Universität Erlangen-Nürnberg, ; Waldstrasse 1, 91054 Erlangen, Germany
                Author information
                http://orcid.org/0000-0002-6181-5735
                Article
                815
                10.1007/s10162-021-00815-1
                8599745
                34686939
                ac213070-6619-4da0-a7d1-1f4f8dc8266d
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 June 2021
                : 30 August 2021
                Funding
                Funded by: deutsche forschungsgemeinschaft
                Award ID: DFG-Kni-316/13-1
                Award Recipient :
                Funded by: era-net neuron
                Award ID: Neuron-023 CoSy Speech (BMBF 01EW2102)
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007601, horizon 2020;
                Award ID: 764604 TIN-ACT
                Award ID: 764604 TIN-ACT
                Award ID: 764604 TIN-ACT
                Award Recipient :
                Funded by: heinsius houbolt foundation
                Funded by: Eberhard Karls Universität Tübingen (1020)
                Categories
                Symposia
                Custom metadata
                © The Author(s) under exclusive licence to Association for Research in Otolaryngology 2021

                Otolaryngology
                tinnitus,hyperacusis,parvalbumin positive interneuron,fast auditory processing,stress,attention

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