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Abstract BACKGROUND: Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas. OBJECTIVES: Here we report effects of tVNS on cardiac function from a pilot study, which was conducted to evaluate the feasibility and safety of tVNS for the treatment of chronic tinnitus. METHODS: Twenty-four patients with chronic tinnitus underwent treatment with tVNS over 3 to 10 weeks in an open single-armed pilot study. Safety criteria and practical usability of the neurostimulating device were to investigate by clinical examination and electrocardiography at baseline and at several visits during and after tVNS treatment (week 2, 4, 8, 16 and 24). RESULTS: Two adverse cardiac events (one classified as a severe adverse event) were registered but considered very unlikely to have been caused by the tVNS device. Retrospective analyses of electrocardiographic parameters revealed a trend towards shortening of the QRS complex after tVNS. CONCLUSION: To our knowledge this is one of the first studies investigating feasibility and safety of tVNS in a clinical sample. In those subjects with no known pre-existing cardiac pathology, preliminary data do not indicate arrhythmic effects of tVNS.

An inherent limitation of functional imaging studies is their correlational approach. More information about critical contributions of specific brain regions can be gained by focal transient perturbation of neural activity in specific regions with noninvasive focal brain stimulation methods.Functional imaging studies have revealed that tinnitus is related to alterations in neuronal activity of central auditory pathways. Modulation of neuronal activity in auditory cortical areas by repetitive transcranial stimulation (rTMS) can reduce tinnitus loudness and, if applied repeatedly, exerts therapeutic effects, confirming the relevance of auditory cortex activation for tinnitus generation and persistence. Measurements of oscillatory brain activity before and after rTMS demonstrate that the same stimulation protocol has different effects on brain activity in different patients, presumably related to interindividual differences in baseline activity in the clinically heterogeneous study cohort.In addition to alterations in auditory pathways, imaging techniques also indicate the involvement of non-auditory brain areas, such as the fronto-parietal ‘awareness’ network and the non-tinnitus-specific distress network consisting of the anterior cingulate cortex, anterior insula and amygdale. Involvement of the hippocampus and the parahippocampal region putatively reflects the relevance of memory mechanisms in the persistence of the phantom percept and the associated distress. Preliminary studies targeting the dorsolateral prefrontal cortex, the dorsal anterior cingulate cortex and the parietal cortex with rTMS and with transcranial direct current stimulation confirm the relevance of the mentioned non-auditory networks. Available data indicate the important value added by brain stimulation as a complementary approach to neuroimaging for identifying the neuronal correlates of the various clinical aspects of tinnitus.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been studied as a treatment option for chronic tinnitus for almost ten years now. Although most of these studies have demonstrated beneficial effects, treatment results show high interindividual variability and yet, little is known about predictors for treatment response. Methods: Data from 538 patients with chronic tinnitus were analysed. Patients received either low-frequency rTMS over the left temporal cortex (n= 345, 1 Hz, 110% motor threshold, 2000 stimuli/day) or combined temporal and frontal stimulation (n = 193, 110% motor threshold, 2000 stimuli at 20 Hz, left dorsolateral prefrontal cortex plus 2000 stimuli at 1 Hz, temporal cortex). Numerous demographic, clinical and audiological variables as well as different tinnitus characteristics were analysed as potential predictors for treatment outcome, which was defined as change in the tinnitus questionnaire (TQ) score. Results: Both stimulation protocols resulted in a significant improvement in TQ scores. In the group receiving combined treatment, patients with comorbid temporomandibular complaints benefited more from rTMS than patients without those complaints. In addition, for both stimulation protocols the TQ score at baseline as well as the change in TQ score from screening to baseline correlated significantly with treatment response. Patients with higher TQ scores at baseline had more pronounced TQ reductions than patients with low TQ baseline scores. Also, patients who had already improved from screening to baseline benefited less than patients without initial improvement. Conclusions: The results from this large sample confirm the effectiveness of rTMS for the treatment of chronic tinnitus. Nonetheless, the high interindividual variability in treatment response can only be partly explained by the investigated clinical variables.

Objectives: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been investigated as a new treatment tool for chronic tinnitus during the last years and has shown moderate efficacy. However, there is growing evidence that tinnitus is not a pathology of a specific brain region, but rather the result of network dysfunction involving both auditory and non-auditory brain regions. In functional imaging studies the right dorsolateral prefrontal cortex has been identified as an important hub in tinnitus related networks and has been shown to particularly reflect the affective components of tinnitus. Based on these findings we aimed to investigate whether the effects of left low frequency rTMS can be enhanced by antecedent right prefrontal low-frequency rTMS. Study Design: Fifty-six patients were randomized to receive either low-frequency left temporal rTMS or a combination of low-frequency right prefrontal followed by low-frequency left temporal rTMS. The change of the tinnitus questionnaire (TQ) score was the primary outcome, secondary outcome parameters included the Tinnitus Handicap Inventory, numeric rating scales and the Beck Depression Inventory. The study is registered in clinicaltrials.gov (NCT01261949).Results: Directly after therapy there was a significant improvement of the TQ-score in both groups. Comparison of both groups revealed a trend towards more pronounced effects for the combined group (effect size: Cohen’s d=0.176), but this effect did not reach significance. A persistent trend towards better efficacy was also observed in all other outcome criteria. Conclusion: Additional stimulation of the right prefrontal cortex seems to be a promising strategy for enhancing TMS effects over the temporal cortex. These results further support the involvement of the right DLPFC in the pathophysiology of tinnitus. The small effect size might be due to the study design comparing the protocol to an active control condition.