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Transcranial random noise stimulation (tRNS) is a non-invasive brain stimulation technique which uses electrical alternating currents applied at random frequencies. Besides the ability to alter cortical excitability, past research demonstrated that high-frequency tRNS over the auditory cortex can modulate both spontaneous and auditory evoked oscillatory brain activity.The aim of the present study was to examine the effects of high- and low-frequency auditory tRNS on EEG power and evoked activity.Low-frequency (0.1-100Hz), high-frequency (100-640Hz) and sham tRNS were administered for a stimulation over the auditory cortex in 22 healthy subjects. Before and after tRNS stimulation auditory steady state responses (ASSR) of 20 and 40Hz stimuli as well as oscillatory brain activity were recorded with electroencephalography (EEG).Stimulation of both verum tRNS protocols revealed no significant changes either in ASSR or in resting state EEG activity. Unexpectedly, sham tRNS resulted in a significant decrease in 20Hz ASSR and an increase in the alpha frequency band (8-12.5Hz).We were not able to replicate previous findings of a modulation of resting state EEG activity and ASSR by tRNS.

Vagus nerve stimulation is a promising new tool in the treatment of chronic tinnitus. Current protocols involve pairing sounds, which exclude the tinnitus frequency, with simultaneous vagus nerve stimulation (VNS). This is based on extensive preclinical animal studies that demonstrate that pairing non-tinnitus sounds with VNS results in a tonotopic map plasticity. It is thought that by expanding the non-tinnitus sound representation, it is possible to overturn the expanded tonotopic map associated with the tinnitus frequency in these animal models. These findings have been translated into a clinical approach, where a clinically significant, but moderate improvement, in tinnitus distress and a modest benefit in tinnitus loudness perception has been shown. Yet, pairing tinnitus matched sound to VNS may produce tinnitus improvement by Pavlovian conditioning, in which the distressful tinnitus sound becomes associated with a relaxing "rest and digest" response from activation of the vagus nerve. If this hypothesis is correct, beneficial effects should be achieved with paired sounds that resemble the tinnitus sounds as much as possible. In conclusion, although the potential to use VNS to drive neural plasticity to reduce or eliminate the neural drivers of ongoing tinnitus is exciting, much work is needed to more completely understand the neural basis of tinnitus and to develop tailored therapies to address the suffering caused by this heterogeneous condition. Whether pairing of the vagus stimulation with non-tinnitus or tinnitus-matched sounds is essential is still to be determined.

Tinnitus, the phantom perception of sound, is a frequent disorder that can lead to severe distress and stress-related comorbidity. The pathophysiological mechanisms involved in the etiology of tinnitus are still under exploration. Electrophysiological and functional neuroimaging studies provide increasing evidence for abnormal functioning in auditory but also in non-auditory, e.g., emotional, brain areas. In order to elucidate alterations of affective processing in patients with chronic tinnitus, we used functional magnetic resonance imaging (fMRI) to measure neural responses to emotionally expressive and neutral faces. Twelve patients with chronic tinnitus and a group of 11 healthy controls, matched for age, sex, hearing loss and depressive symptoms were investigated. While viewing emotionally expressive faces compared to neutral faces brain activations in the tinnitus patients differed from those of the controls in a cluster that encompasses the amygdala, the hippocampus and the parahippocampal gyrus bilaterally. Whereas in controls affective faces induced higher brain activation in these regions than neutral faces, these regions in tinnitus patients were deactivated. Our results (1) provide evidence for alterations of affective processing of facial expressions in tinnitus patients indicating general domain-unspecific dysfunctions in emotion processing and (2) indicate the involvement of medial temporal areas in the pathophysiology of tinnitus.

The current study examines two different protocols of repetitive transcranial magnetic stimulation (rTMS) targeting three key hubs of cortical tinnitus networks. Patients chose whether they preferred to undergo rTMS treatment for 10 or 20 sessions and were randomized to the different rTMS protocols thereafter. Ninety patients were enrolled in the study with a total dropout rate of 10%. Both rTMS protocols were well tolerated by the patients without any serious adverse events. Overall treatment effects were small both for 2 weeks and 4 weeks of treatment. There was no significant interaction effect between measurement time point and treatment group for neither of the outcome measures nor any differences regarding the applied treatment regimens. The effects of this study contradict former observations suggesting multisite rTMS protocols as promising neuromodulatory strategies. This lack of effect could not be enhanced by increasing the number of treatment sessions in our study.

Tinnitus suppression following acoustic stimulation is a well-known phenomenon also termed residual inhibition (RI). Some individuals may experience prolonged RI (PRI), which can last for several hours or even days, after a single short-term acoustic stimulation. Exact mechanisms of this phenomenon are unknown and current evidence anecdotal.The aim of our report is to collect, present, and discuss cases of PRI from our studies on acoustic stimulation in tinnitus with the aim to better understand this phenomenon as well as its implications for individualized treatments.We pooled cases of PRI from four of our studies with a total sample size of n = 130. The criterion was set on a PRI duration which is at least sustained twice as long as the acoustic stimulation duration.We report a total number of about 5% of all participants experiencing some form of PRI, with rates of 3%-7% across the individual studies. PRI lasted from 20 min up to several days and was induced by the first stimulus in four out of six cases. Four out of six individuals experiencing PRI were female and PRI mostly occurred when acoustic stimuli were matched to the frequency or type of the tinnitus.PTS seems to be elicitable in a small subset of tinnitus patients which could inform future individualized treatment options. Future studies should investigate if and how identified factors like stimulus type, position, sex, and chronification grade uphold experimental scrutiny. We propose that the set of methods is furthermore extended with neurophysiology in particular.

Tinnitus is the perception of a phantom sound and the patient's reaction to it. Although much progress has been made, tinnitus remains a scientific and clinical enigma of high prevalence and high economic burden, with an estimated prevalence of 10%-20% among the adult population. The EU is funding a new collaborative project entitled "Unification of Treatments and Interventions for Tinnitus Patients" (UNITI, grant no. 848261) under its Horizon 2020 framework. The main goal of the UNITI project is to set the ground for a predictive computational model based on existing and longitudinal data attempting to address the question of which treatment or combination of treatments is optimal for a specific patient group based on certain parameters. Clinical, epidemiological, genetic and audiological data, including signals reflecting ear-brain communication, as well as patients' medical history, will be analyzed making use of existing databases. Predictive factors for different patient groups will be extracted and their prognostic relevance validated through a Randomized Clinical Trial (RCT) in which different patient groups will undergo a combination of tinnitus therapies targeting both auditory and central nervous systems. From a scientific point of view, the UNITI project can be summarized into the following research goals: (1) Analysis of existing data: Results of existing clinical studies will be analyzed to identify subgroups of patients with specific treatment responses and to identify systematic differences between the patient groups at the participating clinical centers. (2) Genetic and blood biomarker analysis: High throughput Whole Exome Sequencing (WES) will be performed in well-characterized chronic tinnitus cases, together with Proximity Extension Assays (PEA) for the identification of blood biomarkers for tinnitus. (3) RCT: A total of 500 patients will be recruited at five clinical centers across Europe comparing single treatments against combinational treatments. The four main treatments are Cognitive Behavioral Therapy (CBT), hearing aids, sound stimulation, and structured counseling. The consortium will also make use of e/m-health applications for the treatment and assessment of tinnitus. (4) Decision Support System: An innovative Decision Support System will be implemented, integrating all available parameters (epidemiological, clinical, audiometry, genetics, socioeconomic and medical history) to suggest specific examinations and the optimal intervention strategy based on the collected data. (5) Financial estimation analysis: A cost-effectiveness analysis for the respective interventions will be calculated to investigate the economic effects of the interventions based on quality-adjusted life years. In this paper, we will present the UNITI project, the scientific questions that it aims to address, the research consortium, and the organizational structure.

Conventional hearing aids are commonly recommended for the treatment of tinnitus, though results of studies investigating the efficacy of hearing aid-based tinnitus treatments have been mixed. Recently, it has been suggested that the addition of a notch filter around the tinnitus frequency might enhance lateral inhibitory mechanisms and thereby improve tinnitus severity relative to traditional processing. The primary aim of this study was to compare the effects of conventional versus notch filter amplification strategies on subjective tinnitus severity in adults with mild-to-moderate hearing loss and no previous hearing aid experience.Thirty-nine adults (mean age=53.6 years; SD=9.7 years) with bilateral, mild to moderate sensorineural hearing loss and an established clinical history of stable, tonal tinnitus participated in this double-blinded study. Each participant was randomly assigned to complete a 12-week hearing aid trial using either a conventional amplification strategy or a strategy which applied a notch filter at the given participant's tinnitus pitch match frequency. Tinnitus-related handicap and distress were assessed before and after the hearing aid trial via the Tinnitus Handicap Inventory (Newman et al., 1996) and the Tinnitus Questionnaire (Hallam et al., 1988).Average tinnitus severity did not differ significantly between the conventional and notch filter amplification groups following treatment. Moreover, average pre- to post-intervention change scores were relatively low for both groups, indicating minimal effect of either treatment on tinnitus symptoms. Participant age, high-frequency pure-tone average hearing threshold, average daily hearing aid usage, and pre-intervention tinnitus severity ratings were not predictive of treatment success or failure.Results of the present study suggest no significant effect of either conventional or notch filter amplification on average ratings of tinnitus severity following a 12-week hearing aid trial. However, as clinically meaningful changes in tinnitus severity were identified for some participants, future work is needed to better identify those individuals most likely to benefit, as well as optimal amplification characteristics.

To evaluate efficacy and safety of BGG492 (selurampanel; an orally active, competitive AMPA glutamate receptor antagonist) in patients with moderate-to-catastrophic chronic subjective tinnitus. Study (NCT01302873) enrolled patients with subjective tinnitus based on THI severity grade 3, 4 or 5 (moderate, severe or catastrophic), and those with chronic (6 and36 months) tinnitus. Primary endpoints were clinical status of tinnitus using TBF-12 and tinnitus loudness using VAS after multiple dose 2-week BGG492 treatment. Safety was assessed by recording all adverse events (AEs). After a single dose of BGG492 VAS scores for tinnitus loudness (P=0.012) and tinnitus annoyance (P=0.004) were significantly reduced vs placebo. After 2 weeks treatment a significantly greater proportion of patients showed improvement of ≥4 points from baseline in TBF-12 (stringent responder definition) with BGG492 vs placebo (26.7% [n=23] vs 14% [n=12], respectively; odds ratio [OR] (90% CI):2.30 (1.10, 4.83); P=0.064), fulfilling proof-of-concept achievement criteria. No notable difference in proportion of responders to BGG492 vs placebo was observed as assessed using VAS (26.7% [n=23] vs 27.6% [n=24], respectively; OR (90% CI):0.94 (0.52, 1.67); P=0.848). Dizziness was the most frequently reported AE in 50% [n=21] and 31.5% [n=17] patients on BGG492 100 and 50mg TID, respectively vs 9.6% [n=9] on placebo. In conclusion, BGG492 showed reduction of both tinnitus loudness and annoyance after a single dose and reduction of tinnitus handicap after 2 weeks of treatment in patients with chronic subjective tinnitus, thereby supporting further clinical investigation of AMPA receptor antagonists with an improved benefit/risk ratio. A dose of 100mg TID BGG492 showed higher efficacy but somewhat lower tolerability compared to 50mg TID.

Tinnitus is defined as the perception of noise without an external acoustic stimulus. Due to the heterogeneity of tinnitus, no treatment has proven equally beneficial to every single of these patients. Previous studies have shown that trigeminal input can interfere with the perception of tinnitus. Therefore, we aimed to explore the therapeutic potential of lidocaine injections in trigeminal structures. We conducted a pilot study with 19 participants to explore feasibility and tolerability of this approach. The intervention consisted of three injections of lidocaine in the anatomical area of the trigeminal ganglion and the ganglion oticum via an oral approach corresponding to the affected side of tinnitus. We performed an assessment that included the Mini-TQ, CGII, and numeric rating scales of tinnitus loudness and severity at different time points over a follow-up period of 12 weeks. In addition to changes of subjective tinnitus complaints, potential adverse events were documented. Patients were treated at the Centre of Otorhinolaryngology in Traunstein, Germany, and data were analyzed at the University of Regensburg, Germany. We did not observe any relevant side effects. There was a significant reduction of tinnitus distress (Mini-TQ, Tinnitus severity) and loudness (measured subjectively) over time. Our pilot data suggests that lidocaine injections targeting trigeminal structures may be able to reduce tinnitus complaints. Future studies should investigate the effects of lidocaine injections in placebo-controlled trials in an extended sample size to further explore the potential benefits of this therapeutic approach on tinnitus.

Acoustic stimulation was shown to be effective in short-term suppression of tinnitus. However, tinnitus cannot be suppressed in all patients. Recent insights from mental health research suggests that personality traits may be important factors in prediction of treatment outcomes or improvement of tinnitus over time. No previous acoustic stimulation study investigated the effects of personality traits on tinnitus suppression and rating of sound stimuli.The aim of this study was therefore to examine whether personality is capable to predict tinnitus suppression in chronic tinnitus patients as well as related emotional stimulus evaluation.Personality data (Big Five Index 2; BFI-2) of two acoustic stimulation experiments were pooled for this analysis. Both experiments were conducted at the University of Regensburg, Germany in the time period between April 2018 and October 2019 and consisted of individual designed noise and amplitude modulated tones matched to the participants' tinnitus pitch. Logistic regressions or linear mixed effect models were performed with tinnitus suppression as well as valence and arousal data as dependent variables and BFI-2 personality dimensions as predictors.28% of the participants showed pronounced short-term tinnitus suppression after acoustic stimulation (50% reduction in subjective tinnitus loudness). Analyzing BFI-2 data, no significant impact of the big five personality traits (neuroticism, agreeableness, extraversion, conscientiousness, openness) were found, neither on acoustic tinnitus suppression, nor on emotional stimulus evaluation, namely arousal.Personality was not shown to be a predictive factor, neither for acoustic stimulation, nor for emotional reaction to stimuli sounds in our studies. However, since tinnitus cannot be suppressed by acoustic stimulation in all patients, future studies should investigate other explaining factors such as patient-related or (neuro)physiological characteristics.

Sleep problems are common in individuals with tinnitus but it is not known if they can be seen as a reaction to the acoustic percept of tinnitus disturbing normal sleep, or if there are common causes. Sleep problems further impair the quality of life of individuals with tinnitus and the impairment correlates with the severity of the tinnitus. However the nature of the relationship between tinnitus and disturbed sleep in individuals with tinnitus is not clearly understood. Preliminary studies suggest that chronically disturbed sleep (insomnia) in individuals with tinnitus that is not caused by organic disorders exists unrelated to the tinnitus. We studied the relationship between tinnitus and insomnia in a retrospective sleep study of 13 hospitalized patients with insomnia and tinnitus. Patients with sleep apnea, periodic leg movements, or a severe psychiatric disorder were excluded. We collected physiologic sleep measures (EEG, EOG, EMG, and respiration) and subjective sleep information from a morning protocol during two nights. We also obtained information about performance in sustained attention tasks and the scores of self-rated depression scale and self-rated daytime-tiredness scale. Thirteen age- and sex-matched inpatients with primary insomnia who did not have tinnitus served as controls. There were no significant differences between the physiologic data obtained in patients with tinnitus and in the controls. Both groups had low sleep efficiency but the patients with both insomnia and tinnitus had longer subjective sleep latencies than insomnia patients without tinnitus (controls). No differences were found in sustained attention tasks, subjective daytime tiredness, and depression rating scores between the two groups. Similarities between the results from these two groups suggest that sleep specific psychotherapeutic methods, which are established for treating insomnia, should be further developed for the use in patients with insomnia and tinnitus.