The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants

Knipper, Marlies; Dijk, Pim van; Schulze, Holger; Mazurek, Birgit; Krauß, Patrick; Scheper, Verena; Warnecke, Athanasia; Schlee, Winfried; Schwabe, Kerstin; Singer, Wibke; Braun, Christoph; Délano, Paul H.; Fallgatter, Andreas J.; Ehlis, Ann‐Christine; Searchfield, Grant D.; Munk, Matthias H. J.; Baguley, David; Rüttiger, Lukas

doi:10.1523/jneurosci.1314-19.2020

Cited by 86 publications

(118 citation statements)

References 178 publications

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“…As a consequence, excessive MOC efferent activity would diminish OHC baseline motile responses and inner hair cell output ( 58 ). In the view of previous ( 47 , 51 ) and present findings, this might further accelerate a critical reduction of fast auditory processing in possibly deafferented cochlear regions in the non-tinnitus side and thereby contribute that over time uni-lateral tinnitus becomes bilateral in the T-group ( Figure 5 ). On the other side the same event of diminished OHCs baseline motile response following excessive MOC efferent activity could trigger in other frequency regions compensating enhanced sound-induced brainstem activity ( 58 ).…”

Section: Discussionsupporting

confidence: 77%

“…Other studies, including the present findings, proposed that tinnitus is not related to increased central gain ( 24 , 27 , 48 ), but instead occurs when auditory input falls short of the critical firing rate of auditory fibers for increasing neural gain, so that stimulus-evoked responses are diminished in the ascending auditory pathway ( 23 , 24 , 48 – 50 ). A critical reduction of fast (high spontaneous rate, high-SR) auditory processing has been suggested to be linked to the reduced and delayed late ABR wave V in tinnitus, as diminished fast (high-SR) auditory fiber activity might reduce contrast-amplification circuits that are essential to amplify relevant, and ignore irrelevant, stimuli ( 47 ). This implies that tinnitus is brain noise that is ‘heard’ at frequencies of diminished fast (high-SR) auditory processing ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

“…A critical reduction of fast (high spontaneous rate, high-SR) auditory processing has been suggested to be linked to the reduced and delayed late ABR wave V in tinnitus, as diminished fast (high-SR) auditory fiber activity might reduce contrast-amplification circuits that are essential to amplify relevant, and ignore irrelevant, stimuli ( 47 ). This implies that tinnitus is brain noise that is ‘heard’ at frequencies of diminished fast (high-SR) auditory processing ( 47 ). Disrupted fast (high-SR) auditory processing as a correlate of tinnitus ( 23 , 24 , 51 ) was also suggested to impair fast communication between auditory-specific and fronto-striatal regions and would, therefore, diminish memory-dependent adjustment of stimulus-evoked responses following, for example, acoustic trauma.…”

Section: Discussionmentioning

confidence: 99%

“…This suggests that objective markers for either tinnitus or hyperacusis may have indeed been identified. Keeping this in mind, numerous previously controversial findings of either reduced or enhanced central auditory responses in tinnitus (27,47,67) may find a rational explanation. Also, previous studies that included tinnitus patients with unilateral and bilateral tinnitus and only found tinnitus characteristics in the sub-chronical group (28) may reconsider the findings in the context of the present study.…”

Section: Differences In Neural Correlates Behind T-group and Th-groupmentioning

confidence: 99%

“…What underlies the reduced and delayed ABR wave V responses in the T-group and enhanced and shortened ABR wave III and wave V response in the TH-group? Here, we may reconsider an ongoing discussion as to whether neural gain (ABR wave V/I ratio) is a marker of tinnitus or not (27,47). To date, numerous studies have suggested that tinnitus is the result of homeostatic increases in central neural gain [see reviews: (12,13,15,17,(19)(20)(21)(22)].…”

Section: Differences In Neural Correlates Behind T-group and Th-groupmentioning

confidence: 99%

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Co-occurrence of Hyperacusis Accelerates With Tinnitus Burden Over Time and Requires Medical Care

et al. 2021

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Although tinnitus represents a major global burden, no causal therapy has yet been established. Ongoing controversies about the neuronal pathophysiology of tinnitus hamper efforts in developing advanced therapies. Hypothesizing that the unnoticed co-occurrence of hyperacusis and differences in the duration of tinnitus may possibly differentially influence the neural correlate of tinnitus, we analyzed 33 tinnitus patients without (T-group) and 20 tinnitus patients with hyperacusis (TH-group). We found crucial differences between the T-group and the TH-group in the increase of annoyance, complaints, tinnitus loudness, and central neural gain as a function of tinnitus duration. Hearing thresholds did not differ between T-group and TH-group. In the TH-group, the tinnitus complaints (total tinnitus score) were significantly greater from early on and the tinnitus intensity distinctly increased over time from ca. 12 to 17 dB when tinnitus persisted more than 5 years, while annoyance responses to normal sound remained nearly constant. In contrast, in the T-group tinnitus complaints remained constant, although the tinnitus intensity declined over time from ca. 27 down to 15 dB beyond 5 years of tinnitus persistence. This was explained through a gradually increased annoyance to normal sound over time, shown by a hyperacusis questionnaire. Parallel a shift from a mainly unilateral (only 17% bilateral) to a completely bilateral (100%) tinnitus percept occurred in the T-group, while bilateral tinnitus dominated in the TH-group from the start (75%). Over time in the T-group, ABR wave V amplitudes (and V/I ratios) remained reduced and delayed. By contrast, in the TH-group especially the ABR wave III and V (and III/I ratio) continued to be enhanced and shortened in response to high-level sound stimuli. Interestingly, in line with signs of an increased co-occurrence of hyperacusis in the T-group over time, ABR wave III also slightly increased in the T-group. The findings disclose an undiagnosed co-occurrence of hyperacusis in tinnitus patients as a main cause of distress and the cause of complaints about tinnitus over time. To achieve urgently needed and personalized therapies, possibly using the objective tools offered here, a systematic sub-classification of tinnitus and the co-occurrence of hyperacusis is recommended.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Differences In Neural Correlates Behind T-group and Th-groupmentioning

confidence: 99%

Section: Differences In Neural Correlates Behind T-group and Th-groupmentioning

confidence: 99%

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Co-occurrence of Hyperacusis Accelerates With Tinnitus Burden Over Time and Requires Medical Care

et al. 2021

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Preclinical Efficacy And Safety Evaluation of AAV‐OTOF in DFNB9 Mouse Model And Nonhuman Primate

Qi,

Zhang,

Tan

et al. 2023

Advanced Science

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OTOF mutations are the principal causes of auditory neuropathy. There are reports on Otof‐related gene therapy in mice, but there is no preclinical research on the drug evaluations. Here, Anc80L65 and the mouse hair cell‐specific Myo15 promoter (mMyo15) are used to selectively and effectively deliver human OTOF to hair cells in mice and nonhuman primates to evaluate the efficacy and safety of OTOF gene therapy drugs. A new dual‐AAV‐OTOF‐hybrid strategy to transfer full‐length OTOF is generated, which can stably restore hearing in adult OTOFp.Q939*/Q939* mice with profound deafness, with the longest duration being at least 150 days, and the best therapeutic effect without difference in hearing from wild‐type mice. An AAV microinjection method into the cochlea of cynomolgus monkeys without hearing impairment is further established and found the OTOF can be safely and effectively driven by the mMyo15 promoter in hair cells. In addition, the therapeutic dose of AAV drugs has no impact on normal hearing and does not cause significant systemic toxicity both in mouse and nonhuman primates. In summary, this study develops a potential gene therapy strategy for DFNB9 patients in the clinic and provides complete, standardized, and systematic research data for clinical research and application.

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Functional biomarkers that distinguish between tinnitus with and without hyperacusis

Hofmeier

Wertz

Refat

et al. 2021

Clinical & Translational Med

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To the Editor:We recently observed that tinnitus is associated with reduced auditory input that fails to increase neural gain due to diminished stimulus-evoked responses. [1][2][3] This was in contrast to views that suggested a homeostatic increase in neural gain to generate central hyper-excitability leading to tinnitus. 4 A curative therapy for tinnitus currently does not exist. Its progress is mostly impeded by the existing controversial views about the neural correlate of tinnitus that, depending on predictions, either would require the suppression or the enhancement of brain activity. We hypothesized that different neural correlates of tinnitus, whether with or without the co-occurrence of hyperacusis, contributed to this dilemma. To test this hypothesis, we recruited 43 controls and 50 audiologically examined tinnitus patients with and without a co-occurrence of hyperacusis (Tables S1 and S2) and performed brainstem audiometry (ABR) and functional imaging of brain activity (fMRI).Among the group of 50 tinnitus patients, 20 could be identified with the co-occurrence of hyperacusis (T+H group) from the HKI hyperacusis questionnaire (Figure 1A). 5 The overall score of the Goebel and Hiller Score (G-H-S) tinnitus questionnaire 6 was significantly higher for the T+H group than the tinnitus-only patients (T group) (Figure 1B, p < .001***) for nearly all subscores (Figure S1, p < .002***). In the T+H group (Figure 1D) but not the T group (Figure 1C), auditory perceptional difficulty became worse for patients with self-rated tinnitus loudness ≤15 dB HL (Figure 1E, Figure S2). The T and T+H group differences in annoyance and distress were not linked to differences in hearing sensitivity (Figure S3A-C, p > .5), since pure tone audiometry (PTA) thresholds (Supporting Material 1 ) were not different between groups. In contrast, supra-threshold ABR by brainstemevoked response audiometry (BERA) 1,2 revealed group differences: In T group, significantly reduced ABR wave V amplitude together with significantly prolonged interpeak latency (IPL) I-V (Figure 1F,H,J; Table S3) and reducedThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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The Neural Bases of Tinnitus: Lessons from Deafness and Cochlear Implants

Cited by 86 publications

References 178 publications

Co-occurrence of Hyperacusis Accelerates With Tinnitus Burden Over Time and Requires Medical Care

Co-occurrence of Hyperacusis Accelerates With Tinnitus Burden Over Time and Requires Medical Care

Preclinical Efficacy And Safety Evaluation of AAV‐OTOF in DFNB9 Mouse Model And Nonhuman Primate

Functional biomarkers that distinguish between tinnitus with and without hyperacusis

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