Functional biomarkers that distinguish between tinnitus with and without hyperacusis
2021-05-01

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.1-3 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 questionnaire6 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 Material1) were not different between groups. In contrast, supra-threshold ABR by brainstem-evoked 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 reduced ABR wave V/I ratios (Figure 1I), were found. In contrast, T+H group showed a significantly higher ABR wave III and wave V amplitude at 75 dB compared to controls (Figure 1G,H; Table S3) with no difference in ABR wave V/I ratio (Figure 1I). Questioning if these group differences were reflected in BOLD fMRI responses, stimulus-induced BOLD fMRI signals were recorded from anatomically predefined ROIs in ascending auditory regions (Table S4) in response to binaurally exposed (i) rock music, (ii) LF-chirp, (iii) HF-chirp, and (iv) BB-chirp stimuli (Figure 2). A significant reduction in BOLD fMRI signals in lower auditory brainstem regions (SOC, partly CN) (Figure 2A–C; music, LF stimuli) revealed as a characteristic feature of tinnitus in both groups. From the MGB upwards, BOLD fMRI signals between groups differed, remaining reduced in the T group in the MGB (Figure 2A,C; music, HF), primary auditory cortex (AC-I) (Figure 2D,F; all stimuli), and regions of sound identification (Figure 2G,I; all stimuli), but become elevated in the T+H group in the MGB (Figure 2B,C; music, LF), AC-I (Figure 2E,F; all stimuli), or regions of sound identification in the T+H group (Figure 2G,J; music, LF, BB). Regions active immediately following painful stimulation,7 such as the mammillary body (Mam. Body), the dorsal posterior insula (DpIns), and the postcentral gyrus regions with the parietal operculum (PO1, PO2) responded with reduced BOLD fMRI signals to music stimuli in the T group, but not in the T+H group (Figure 2J,L; music), suggesting more response activity in pain regions to sound in the T+H group. Interested if evoked BOLD fMRI responses were related to BOLD signals at rest, as hypothesized,8 we strikingly observed that the number of correlations of BOLD signals at rest (r-fcMRI) (Figure 3C–L), but not the correlation strength (Figure 3B), when depicted as positive or negative correlations (Figure 3A, Figure 3D-L, lower panel) were related to altered evoked BOLD signals between groups. The number of connectivities between the MGB and subcortical auditory regions such as the CN, SOC, IC (Figure 3D), between MGB and the anterior AC-I regions BA41 and BA42 (Figure 3E), between the AC-I and regions controlling emotional distress, particularly the amygdala (Figure 3G), and between the AC-I and attention-controlling regions such as BA45 and BA46 (Figure 3H) was significantly lower in the T group compared to the T+H group. Few regions with negative correlations that were lower in the T group and T+H group may need further future specification. To summarize, as a most characteristic functional biomarker of the T group, the present study identified (i) delayed and reduced ABR wave V; (ii) reduced evoked BOLD fMRI responses in the MGB, AC-I, and regions of sound identification as the BA13P and hippocampus, particularly specific in response to HF-chirp stimuli; and (iii) reduced number of positive connectivities between subcortical and cortical auditory regions (Figure 4, red). As a characteristic functional biomarker for tinnitus with a co-occurrence of hyperacusis (i) enhanced ABR wave III and ABR wave V for high sound intensities; (ii) elevated evoked BOLD fMRI responses in the MGB, AC-I, BA13P, and hippocampus particularly for LF-chirp stimuli; and (iii) greater number of positive connectivities between subcortical and cortical auditory regions compared to the T group (Figure 4, blue) were found. Group differences were independent of G-H-S group differences (Supporting Material). We conclude that the overall reduced and delayed auditory-specific responsiveness in the T group is best corroborated by previous assumption of a loss of fast (high-SR) auditory fiber processing in tinnitus frequency channels leading to re-emergence of hyperexcitability through loss of tonic parvalbumin interneuron in deprived regions.9 This would lead to diminution of memory-linked contrast amplification and elevated noise, and as a result would promote further alertness and attention to the phantom noise, as reviewed.9 With the co-occurrence of hyperacusis, a more widespread signal amplification process appears to proceed through overactive thalamo-cortical activity that may trigger an excitation spread to limbic and pain regions, and results in overattention to increased loudness at all sound frequencies, as was also previously hypothesized.10 The findings may eventually lead to new differential clinical diagnosis of tinnitus, a prerequisite for achieving a successful, personalized curative therapy for tinnitus with and without hyperacusis, when regarding suggestions for altered strategies to find treatment predictors.9 This work was supported by the Deutsche Forschungsgemeinschaft: KN 316/13-1, RU 713/6-1, KL 1093/12-1. We thank Hyun-Soon Geisler, Karin Rohbock, and Iris Köpschall for excellent technical assistance. English language services were provided by stels-ol.de. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. The ethics committee of Tübingen University (Faculty of Medicine) and University Hospital Tübingen (ethical approval number 264-2016BO1) approved this study. Trial registration: German Clinical Trials Register DRKS0006332. Written informed consent was obtained from all participants at their first visit. Designed research: Marlies Knipper, Lukas Rüttiger, Uwe Klose, and Stephan Wolpert. Conducting experiments: Benedikt Hofmeier, Jakob Wertz, Fatma Refat, and Pauline Hinrichs. Analyzed data: Benedikt Hofmeier, Jakob Wertz, Fatma Refat, Pauline Hinrichs, Jörg Saemisch, Wibke Singer, and Lukas Rüttiger. Wrote the first draft of the paper: Marlies Knipper and Uwe Klose. Edited the paper: Marlies Knipper, Lukas Rüttiger, Uwe Klose, and Stephan Wolpert. Wrote the paper: Benedikt Hofmeier, Jakob Wertz, Lukas Rüttiger, Uwe Klose, Stephan Wolpert, and Marlies Knipper. All the authors have read the manuscript and approved its submission to Clinical and Translational Medicine. The data that support the findings of this study are available from Marlies Knipper upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.