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The thalamic medial geniculate body (MGB) is uniquely positioned within the neural tinnitus networks. Deep brain stimulation (DBS) of the MGB has been proposed as a possible novel treatment for tinnitus, yet mechanisms remain elusive. The aim of this study was to characterize neurophysiologic hallmarks in the MGB after noise exposure and to assess the neurophysiological effects of electrical stimulation of the MGB. Fourteen male Sprague-Dawley rats were included. Nine subjects were unilaterally exposed to a 16-kHz octave-band noise at 115 dB for 90 min, five received sham exposure. Single units were recorded from the contralateral MGB where spontaneous firing, coefficient of variation, response type, rate-level functions, and thresholds were determined. Local field potentials and electroencephalographical (EEG) recordings were performed before and after high-fre-quency DBS of the MGB. Thalamocortical synchronization and power were analyzed. In total, 214 single units were identified (n = 145 in noise-exposed group, n = 69 in control group). After noise exposure, fast-responding neurons become less respon-sive or nonresponsive without change to their spontaneous rate, whereas sustained-and suppressed-type neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activity. MGB DBS suppressed thalamocortical synchroni-zation in the 13 and c bands, supporting suppression of thalamocortical synchronization as an underlying mechanism of tinnitus suppression by high frequency DBS. These findings contribute to our understanding of the neurophysiologic consequences of noise exposure and the mechanism of potential DBS therapy for tinnitus.NEW & NOTEWORTHY Separate functional classes of MGB neurons might have distinct roles in tinnitus pathophysiology. After noise exposure, fast-responding neurons become less responsive or nonresponsive without change to their spontaneous firing, whereas sustained and suppressed neurons exhibit enhanced spontaneous activity without change to their stimulus-driven activ-ity. Furthermore, results suggest desynchronization of thalamocortical 13 and c oscillations as a mechanism of tinnitus suppres-sion by MGB DBS.

Tinnitus is an auditory sensation in the absence of actual external stimulation. Different clinical interventions are used in tinnitus treatment, but only few patients respond to available options. The lack of successful tinnitus treatment is partly due to the limited knowledge about the mechanisms underlying tinnitus. Recently, the auditory part of the thalamus has gained attention as a central structure in the neuropathophysiology of tinnitus. Increased thalamic spontaneous firing rate, bursting activity and oscillations, alongside an increase of GABAergic tonic inhibition have been shown in the auditory thalamus in animal models of tinnitus. In addition, clinical neuroimaging studies have shown structural and functional thalamic changes with tinnitus. This review provides a systematic overview and discussion of these observations that support a central role of the auditory thalamus in tinnitus. Based on this approach, a neuromodulative treatment option for tinnitus is proposed.

Background: Chronic tinnitus can have an immense impact on quality of life. Despite recent treatment advances, many tinnitus patients remain refractory to them. Preclinical and clinical evidence suggest that deep brain stimulation (DBS) is as a promising treatment to suppress tinnitus. The thalamic medial geniculate body (MGB) takes a key position in the tinnitus network, shows pathophysiological hallmarks of tinnitus, and is readily accessible using stereotaxy. This study will evaluate the safety and therapeutic effects of DBS in the MGB in severe tinnitus sufferers.Methods: Bilateral DBS of the MGB will be applied in six patients with severe and refractory tinnitus. A double-blinded, randomized 2x2 crossover design (stimulation ON and OFF) will be applied, followed by a period of six months open label follow-up. The primary focus is to assess safety and feasibility (acceptability). Secondary outcomes assess a potential treatment effect and include tinnitus severity measured by the Tinnitus Functional Index (TFI), tinnitus loudness and distress, hearing, cognitive and psychological functions, quality of life, and neurophysiological characteristics. Discussion: Whilst carefully balancing risks and benefits and taking ethical considerations into account, this study explores the safety and feasibility of DBS in severe refractory tinnitus, by extensive assessment of clinical and neurophysiological outcome measures. Additionally, important insights in the underlying mechanism of tinnitus and hearing function might be revealed. Trial registration: ClinicalTrials.gov NCT03976908 (June 6, 2019)

Tinnitus is the perception of a ‘ringing’ sound without an acoustic source. It is generally accepted that tinnitus develops after peripheral hearing loss and is associated with altered auditory processing. The thalamus is a crucial relay in the underlying pathways that actively shapes processing of auditory signals before the respective information reaches the cerebral cortex. Here, we review animal and human evidence to define thalamic function in tinnitus. Overall increased spontaneous firing patterns and altered coherence between the thalamic medial geniculate body (MGB) and auditory cortices is observed in animal models of tinnitus. It is likely that the functional connectivity between the MGB and primary and secondary auditory cortices is reduced in humans. Conversely, there are indications for increased connectivity between the MGB and several areas in the cingulate cortex and posterior cerebellar regions, as well as variability in connectivity between the MGB and frontal areas regarding laterality and orientation in the inferior, medial and superior frontal gyrus. We suggest that these changes affect adaptive sensory gating of temporal and spectral sound features along the auditory pathway, reflecting dysfunction in an extensive thalamo-cortical network implicated in predictive temporal adaptation to the auditory environment. Modulation of temporal characteristics of input signals might hence factor into a thalamo-cortical dysrhythmia profile of tinnitus, but could ultimately also establish new directions for treatment options for persons with tinnitus.

Deep brain stimulation of the central auditory pathway is emerging as a promising treatment modality for tinnitus. Within this pathway, the dorsal cochlear nucleus (DCN) plays a key role in the pathophysiology of tinnitus and is believed to be a tinnitus generator. We hypothesized that high-frequency stimulation (HFS) of the DCN would influence tinnitus-related abnormal neuronal activity within the auditory pathway and hereby suppress tinnitus. To this end, we assessed the effect of HFS of the DCN in a noise-induced rat model of tinnitus. The presence of tinnitus was verified using the gap prepulse inhibition of the acoustic startle response paradigm. Hearing thresholds were determined before and after noise trauma by measuring the auditory brainstem responses. In addition, changes in neuronal activity induced by noise trauma and HFS were assessed using c-Fos immunohistochemistry in related structures. Results showed tinnitus development after noise trauma and hearing loss ipsilateral to the side exposed to noise trauma. During HFS of the DCN, tinnitus was suppressed. There was no change in c-Fos expression within the central auditory pathway after HFS. These findings suggest that DCN-HFS changes patterns of activity and results in information lesioning within the network and hereby blocking the relay of abnormal tinnitus-related neuronal activity.

Background Neuromodulation is a promising treatment modality for tinnitus, especially in chronic and severe cases. The auditory thalamus plays a key role in the pathophysiology of tinnitus, as it integrates and processes auditory and limbic information. Objective The effect of high frequency stimulation and low frequency stimulation of the medial geniculate bodies on tinnitus in a noise-induced tinnitus rat model is assessed. Materials and methods Presence of tinnitus was verified using the gap-induced prepulse inhibition of the acoustic startle response paradigm. Hearing thresholds were determined before and after noise trauma with auditory brainstem responses. Anxiety-related side-effects were evaluated in the elevated zero maze and open field. Results Results show tinnitus development after noise exposure and preserved hearing thresholds of the ear that was protected from noise trauma. We found that high frequency stimulation of the medial geniculate bodies suppressed tinnitus. This effect maintained directly after stimulation when the stimulator was turned off. Low frequency stimulation did not have any effects on the gap:no-gap ratio of the acoustic startle response. Conclusion High frequency stimulation of the MGB has a direct and residual suppressing effect on tinnitus in this animal model. Low frequency stimulation of the MGB did not inhibit tinnitus.

Tinnitus is the perception of a "phantom sound" and has a high prevalence. Although many therapies have been investigated within the last decades, there is still no effective standard therapy. Animal studies and human functional imaging studies revealed that tinnitus perception is associated with many complex changes in multiple brain structures. There is growing evidence that brain stimulation might be able to interrupt the local altered neuronal activity and hereby inhibit tinnitus perception. In this editorial review, an update is given on the most promising targets for brain stimulation. Promising structures for stimulation are the dorsal cochlear nucleus, the inferior colliculus and the medial geniculate body of the thalamus. For cortical stimulation, the auditory cortex is considered as a target. Nevertheless, the field is waiting for evidence from well-designed clinical trials, based on supporting evidence from experimental/mechanistic research, to support or discourage the application of brain stimulation in tinnitus.

Highlights • UHF-fMRI is used to study frequency-specific processing in tinnitus patients. • Control patients are hearing-loss matched to tinnitus patients. • MGB and auditory cortex display reduced frequency selectivity with tinnitus. • Thalamocortical and cortico-cortical connectivity is reduced with tinnitus. • UHF-fMRI is relevant for investigating subcortical auditory regions in tinnitus., Tinnitus is a clinical condition defined by hearing a sound in the absence of an objective source. Early experiments in animal models have suggested that tinnitus stems from an alteration of processing in the auditory system. However, translating these results to humans has proven challenging. One limiting factor has been the insufficient spatial resolution of non-invasive measurement techniques to investigate responses in subcortical auditory nuclei, like the inferior colliculus and the medial geniculate body (MGB). Here we employed ultra-high field functional magnetic resonance imaging (UHF-fMRI) at 7 Tesla to investigate the frequency-specific processing in sub-cortical and cortical regions in a cohort of six tinnitus patients and six hearing loss matched controls. We used task-based fMRI to perform tonotopic mapping and compared the magnitude and tuning of frequency-specific responses between the two groups. Additionally, we used resting-state fMRI to investigate the functional connectivity. Our results indicate frequency-unspecific reductions in the selectivity of frequency tuning that start at the level of the MGB and continue in the auditory cortex, as well as reduced thalamocortical and cortico-cortical connectivity with tinnitus. These findings suggest that tinnitus may be associated with reduced inhibition in the auditory pathway, potentially leading to increased neural noise and reduced functional connectivity. Moreover, these results indicate the relevance of high spatial resolution UHF-fMRI for the investigation of the role of sub-cortical auditory regions in tinnitus.

Roughly 10-15% of people suffer from tinnitus (ringing in the ears). Many patients experience various symptoms associated with the continuous ringing sound. Unfortunately, no treatment is currently available for tinnitus. Recent studies have shown that tinnitus is caused by disrupted brain signals. Deep brain stimulation (DBS) sends electrical impulses to the brain to correct these disruptions. Several studies carried out as part of this dissertation found DBS to be a suitable treatment option for tinnitus. However, further research is necessary before this treatment can be applied in practice.

PurposeThe field of neuromodulation is currently seeking to treat a wide range of disorders with various types of invasive devices. In recent years, several preclinical trials and case reports in humans have been published on their potential for chronic tinnitus. However, studies to obtain insight into patients' willingness to undergo these treatments are scarce. The aim of this survey study was to find out whether tinnitus patients are willing to undergo invasive neuromodulation when taking its risks, costs, and potential benefits into account.MethodA Visual Analog Scale (VAS, 0–10) was used to measure the outcome. Spearman's rank-order correlation coefficients were computed to determine the correlation between patient characteristics and acceptance rates.ResultsAround one fifth of the patients were reasonably willing to undergo invasive treatment (VAS 5–7), and around one fifth were fully willing to do so (VAS 8–10). Hearing aids, used as a control, were accepted most, followed by cochlear implantation, deep brain stimulation, and cortical stimulation. Acceptance rates were slightly higher when the chance of cure was higher. Patients with a history of attempted treatments were more eager than others to find a new treatment for tinnitus.ConclusionsA considerable proportion of patients with tinnitus would accept a variety of invasive treatments despite the associated risks or costs. When clinical neuromodulatory studies for tinnitus are to be performed, particular attention should be given to obtaining informed consent, including explaining the potential risks and providing a realistic outcome expectation.

Chronic tinnitus, also known as ringing in the ears, affects up to 15% of the adults and causes a serious socio-economic burden. At present, there is no treatment available which substantially reduces the perception of this phantom sound. In the past few years, preclinical and clinical studies have unraveled central mechanisms involved in the pathophysiology of tinnitus, replacing the classical periphery-based hypothesis. In subcortical auditory and non-auditory regions, increased spontaneous activity, neuronal bursting and synchrony were found. When reaching the auditory cortex, these neuronal alterations become perceptually relevant and consequently are perceived as phantom sound. A therapy with a potential to counteract deeply located pathological activity is deep brain stimulation, which has already been demonstrated to be effective in neurological diseases such as Parkinson's disease. In this review, several brain targets are discussed as possible targets for deep brain stimulation in tinnitus. The potential applicability of this treatment in tinnitus is discussed with examples from the preclinical field and clinical case studies.

BackgroundRecently it has been shown in animal studies that deep brain stimulation (DBS) of auditory structures was able to reduce tinnitus-like behavior. However, the question arises whether hearing might be impaired when interfering in auditory-related network loops with DBS.MethodsThe auditory brainstem response (ABR) was measured in rats during high frequency stimulation (HFS) and low frequency stimulation (LFS) in the central nucleus of the inferior colliculus (CIC,n = 5) or dentate cerebellar nucleus (DCBN,n = 5). Besides hearing thresholds using ABR, relative measures of latency and amplitude can be extracted from the ABR. In this study ABR thresholds, interpeak latencies (I–III, III–V, I–V) and V/I amplitude ratio were measured during off-stimulation state and during LFS and HFS.ResultsIn both the CIC and the CNBN groups, no significant differences were observed for all outcome measures.DiscussionDBS in both the CIC and the CNBN did not have adverse effects on hearing measurements. These findings suggest that DBS does not hamper physiological processing in the auditory circuitry.

Background: Tinnitus is a disorder of the nervous system that cannot be adequately treated with current therapies. The effect of neuromodulation induced by deep brain stimulation (DBS) on tinnitus has not been studied well. This study investigated the effect of DBS on tinnitus by use of a multicenter questionnaire study. Methods: Tinnitus was retrospectively assessed prior to DBS and at the current situation (with DBS). From the 685 questionnaires, 443 were returned. A control group was one-to-one matched to DBS patients who had tinnitus before DBS (n = 61). Tinnitus was assessed by the tinnitus handicap inventory (THI) and visual analog scales (VAS) of loudness and burden. Results: The THI decreased significantly during DBS compared to the situation prior to surgery (from 18.9 to 15.1, P < .001), which was only significant for DBS in the subthalamic nucleus (STN). The THI in the control group (36.9 to 35.5, P = 0.50) and other DBS targets did not change. The VAS loudness increased in the control group (5.4 to 6.0 P < .01). Conclusion: DBS might have a modulatory effect on tinnitus. Our study suggests that DBS of the STN may have a beneficial effect on tinnitus, but most likely other nuclei linked to the tinnitus circuitry might be even more effective.