The exact neurophysiological basis of chronic tinnitus, which affects 10-15% of the population, remains unknown and is controversial at many levels. It is an open question whether phantom sound perception results from increased central neural gain or not, a crucial question for any future therapeutic intervention strategies for tinnitus.We performed a comprehensive study of mild hearing-impaired participants with and without tinnitus, excluding participants with co-occurrences of hyperacusis. A right-hemisphere correlation between tinnitus loudness and auditory perceptual difficulty was observed in the tinnitus group, independent of differences in hearing thresholds. This correlation was linked to reduced and delayed sound-induced suprathreshold auditory brain responses (ABR wave V) in the tinnitus group, suggesting subsided rather than exaggerated central neural responsiveness. When anatomically predefined auditory regions of interest were analysed for altered sound-evoked BOLD fMRI activity, it became evident that subcortical and cortical auditory regions and regions involved in sound detection (posterior insula, hippocampus), responded with reduced BOLD activity in the tinnitus group, emphasizing reduced, rather than increased, central neural gain. Regarding previous findings of evoked BOLD activity being linked to positive connectivities at rest, we additionally analysed r-fcMRI responses in anatomically predefined auditory regions and regions associated with sound detection. A profound reduction in positive interhemispheric connections of homologous auditory brain regions and a decline in the positive connectivities between lower auditory brainstem regions and regions involved in sound detection (hippocampus, posterior insula) were observed in the tinnitus group. The finding went hand-in-hand with the emotional (amygdala, anterior insula) and temporofrontal/stress-regulating regions (prefrontal cortex, inferior frontal gyrus) that were no longer positively connected with auditory cortex regions in the tinnitus group but were instead positively connected to lower-level auditory brainstem regions. Delayed sound processing, reduced sound-evoked BOLD fMRI activity and altered r-fcMRI in the auditory midbrain correlated in the tinnitus group and showed right hemisphere dominance as did tinnitus loudness and perceptual difficulty. The findings suggest that reduced central neural gain in the auditory stream may lead to phantom perception through a failure to energize attentional/stress-regulating networks for contextualization of auditory-specific information. Reduced auditory-specific information flow in tinnitus has until now escaped detection in humans, as low-level auditory brain regions were previously omitted from neuroimaging studies.Trial registration: German Clinical Trials Register DRKS0006332.

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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.

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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