Tinnitus Network Research Articles

What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a "limbic system," a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain-that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept.

Use of Some Relevant Parameters for Primary Prediction of Brain Activity in Idiopathic Tinnitus Based on a Machine Learning Application

Introduction: Tinnitus is one of the most common complaints, distressing about 15–24% of the adult population. Because of its pathophysiology heterogeneity, no curable treatment has been attained yet. Even though a neuromodulation management technique based on the tinnitus network model is currently being developed, it has not yet worked because the most involved brain areas still remain unpredictable from the patient’s individual clinical and functional profile. A remarkable correlation between tinnitus network activity and the subjective measures of tinnitus like perceived loudness and annoyance and functional handicap is well established. Therefore, this study aimed to develop software for predicting the involved brain areas in the tinnitus network based on the subjective characteristics and clinical profile of patients using a supervised machine-learning method. Methods: The involved brain areas of 30 tinnitus patients ranging from 6 to 80 months in duration were recognized by using QEEG and sLORETA software. There was a correlation between subjective information and those areas of activities in all rhythms by which we wrote our software. Results: For verification and validation of the software, we compared and analyzed the results with SPSS data and the receiver operating characteristic (ROC) curves. Conclusions: The findings of this study confirmed the effectiveness of the software in predicting the brain activity in tinnitus subjects; however, some other important parameters can be added to the model to strengthen its reliability and feasibility in clinical use.

A Protocol to Investigate Deep Brain Stimulation for Refractory Tinnitus: From Rat Model to the Set-Up of a Human Pilot Study

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 suggests that deep brain stimulation (DBS) is a promising treatment to suppress tinnitus. In rats, it has been shown in multiple regions of the auditory pathway that DBS can have an alleviating effect on 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. Here, a protocol is described to evaluate the safety and test the therapeutic effects of DBS in the MGB in severe tinnitus sufferers. Bilateral DBS of the MGB will be applied in a future study in six patients with severe and refractory tinnitus. A double-blinded, randomized 2 × 2 crossover design (stimulation ON and OFF) will be applied, followed by a period of six months of 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. This protocol carefully balances risks and benefits and takes ethical considerations into account. This study will explore the safety and feasibility of DBS in severe refractory tinnitus, through extensive assessment of clinical and neurophysiological outcome measures. Additionally, important insights into the underlying mechanism of tinnitus and hearing function might be revealed. ClinicalTrials.gov NCT03976908 (6 June 2019).

Striatal networks for tinnitus treatment targeting.

Neuromodulation treatment effect size for bothersome tinnitus may be larger and more predictable by adopting a target selection approach guided by personalized striatal networks or functional connectivity maps. Several corticostriatal mechanisms are likely to play a role in tinnitus, including the dorsal/ventral striatum and the putamen. We examined whether significant tinnitus treatment response by deep brain stimulation (DBS) of the caudate nucleus may be related to striatal network increased functional connectivity with tinnitus networks that involve the auditory cortex or ventral cerebellum. The first study was a cross‐sectional 2‐by‐2 factorial design (tinnitus, no tinnitus; hearing loss, normal hearing, n = 68) to define cohort level abnormal functional connectivity maps using high‐field 7.0 T resting‐state fMRI. The second study was a pilot case–control series (n = 2) to examine whether tinnitus modulation response to caudate tail subdivision stimulation would be contingent on individual level striatal connectivity map relationships with tinnitus networks. Resting‐state fMRI identified five caudate subdivisions with abnormal cohort level functional connectivity maps. Of those, two connectivity maps exhibited increased connectivity with tinnitus networks—dorsal caudate head with Heschl's gyrus and caudate tail with the ventral cerebellum. DBS of the caudate tail in the case‐series responder resulted in dramatic reductions in tinnitus severity and loudness, in contrast to the nonresponder who showed no tinnitus modulation. The individual level connectivity map of the responder was in alignment with the cohort expectation connectivity map, where the caudate tail exhibited increased connectivity with tinnitus networks, whereas the nonresponder individual level connectivity map did not.

The Pathological Mechanisms and Treatments of Tinnitus.

Tinnitus is defined as the ringing, hissing, clicking or roaring sounds an individual consciously perceives in the absence of an external auditory stimulus. Currently, the literature on the mechanism of tinnitus pathology is multifaceted, ranging from tinnitus generation at the cellular level to its perception at the system level. Cellular level mechanisms include increased neuronal synchrony, neurotransmission changes and maladaptive plasticity. At the system level, the role of auditory structures, non-auditory structures, changes in the functional connectivities in higher regions and tinnitus networks have been investigated. The exploration of all these mechanisms creates a holistic view on understanding the changes the pathophysiology of tinnitus undertakes. Although tinnitus percept may start at the level of cochlear nerve deafferentation, the neuronal changes in the central auditory system to the neuronal and connectivity changes in non-auditory regions, such as the limbic system, become cardinal in chronic tinnitus generation. At the present moment, some tinnitus generation mechanisms are well established (e.g., increased neuronal synchrony) whereas other mechanisms have gained more traction recently (e.g., tinnitus networks, tinnitus-distress networks) and therefore, require additional investigation to solidify their role in tinnitus pathology. The treatments and therapeutics designed for tinnitus are numerous, with varied levels of success. They are generally two-fold: some treatments focus on tinnitus cessation (including cochlear implants, deep brain stimulation, transcranial direct current stimulation and transcranial magnetic stimulation) whereas the other set focuses on tinnitus reduction or masking (including hearing aids, sound therapy, cognitive behavioral therapy, tinnitus retraining therapy, and tailor made notched musical training). Tinnitus management has focused on implementing tinnitus masking/reducing therapies more than tinnitus cessation, since cessation treatments are still lacking in streamlined treatment protocols and long-term sustainability and efficacy of the treatment. This review will focus on concisely exploring the current and most relevant tinnitus pathophysiology mechanisms, treatments and therapeutics.

Behavioral Outcomes and Neural Network Modeling of a Novel, Putative, Recategorization Sound Therapy.

The mechanisms underlying sound’s effect on tinnitus perception are unclear. Tinnitus activity appears to conflict with perceptual expectations of “real” sound, resulting in it being a salient signal. Attention diverted towards tinnitus during the later stages of object processing potentially disrupts high-order auditory streaming, and its uncertain nature results in negative psychological responses. This study investigated the benefits and neurophysiological basis of passive perceptual training and informational counseling to recategorize phantom perception as a more real auditory object. Specifically, it examined underlying psychoacoustic correlates of tinnitus and the neural activities associated with tinnitus auditory streaming and how malleable these are to change with targeted intervention. Eighteen participants (8 females, 10 males, mean age = 61.6 years) completed the study. The study consisted of 2 parts: (1) An acute exposure over 30 min to a sound that matched the person’s tinnitus (Tinnitus Avatar) that was cross-faded to a selected nature sound (Cicadas, Fan, Water Sound/Rain, Birds, Water and Bird). (2) A chronic exposure for 3 months to the same “morphed” sound. A brain-inspired spiking neural network (SNN) architecture was used to model and compare differences between electroencephalography (EEG) patterns recorded prior to morphing sound presentation, during, after (3-month), and post-follow-up. Results showed that the tinnitus avatar generated was a good match to an individual’s tinnitus as rated on likeness scales and was not rated as unpleasant. The five environmental sounds selected for this study were also rated as being appropriate matches to individuals’ tinnitus and largely pleasant to listen to. There was a significant reduction in the Tinnitus Functional Index score and subscales of intrusiveness of the tinnitus signal and ability to concentrate with the tinnitus trial end compared to baseline. There was a significant decrease in how strong the tinnitus signal was rated as well as ratings of how easy it was to ignore the tinnitus signal on severity rating scales. Qualitative analysis found that the environmental sound interacted with the tinnitus in a positive way, but participants did not experience change in severity, however, characteristics of tinnitus, including pitch and uniformity of sound, were reported to change. The results indicate the feasibility of the computational SNN method and preliminary evidence that the sound exposure may change activation of neural tinnitus networks and greater bilateral hemispheric involvement as the sound morphs over time into natural environmental sound; particularly relating to attention and discriminatory judgments (dorsal attention network, precentral gyrus, ventral anterior network). This is the first study that attempts to recategorize tinnitus using passive auditory training to a sound that morphs from resembling the person’s tinnitus to a natural sound. These findings will be used to design future-controlled trials to elucidate whether the approach used differs in effect and mechanism from conventional Broadband Noise (BBN) sound therapy.

The more the merrier? Preliminary results regarding treatment duration and stimulation frequency of multisite repetitive transcranial magnetic stimulation in chronic 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.

Altered effective brain network topology in tinnitus: An EEG source connectivity analysis

Tinnitus is defined as the auditory phantom perception in the absence of any objective external sound source. In this paper, we used the resting-state electroencephalography (EEG) data to reconstruct the neural sources based on the unit-noise-gain linearly constrained minimum-variance (LCMV) beamformer and applied the effective connectivity analysis on the reconstructed sources to examine the directional neuronal interactions between brain regions in tinnitus patients compared to the healthy controls. We found significantly disrupted patterns of effective connectivity in several brain areas including the frontal, temporal, and occipital cortices as well as the caudate nucleus. Particularly, significant aberrant causal couplings were observed in the orbitofrontal cortex, inferior frontal gyrus_triangular, and parahippocampal region that could potentially illustrate the auditory information retrieval, perception, and evaluation of the phantom sound in the brain of tinnitus patients. Furthermore, topological alterations of the brain network were investigated using graph theoretical analysis. Our findings demonstrated significantly decreased both global integration and segregation of the brain network in tinnitus patients accompanied by the topological shift of tinnitus network to a more random structure in the high-frequency bands. These findings were consistent with the hypothesis of the brain network deviation from small-worldness topology accompanied by reduced global integration in brain-related disorders.

Treatment Outcome of Auditory and Frontal Dual-Site rTMS in Tinnitus Patients and Changes in Magnetoencephalographic Functional Connectivity after rTMS: Double-Blind Randomized Controlled Trial

Background: Recently, the role of neural modulation in nonauditory cortices via repetitive transcranial magnetic stimulation (rTMS) for tinnitus control has been emphasized. It is now more compelling to consider these nonauditory cortices and the whole “tinnitus network” as targets for tinnitus treatment to achieve a better outcome. Objective: We aimed to investigate the effects of active dual-site rTMS treatment in tinnitus reduction using a double-blind randomized controlled trial. Method: In study 1, the dual-site rTMS treatment group (n = 17) was treated daily for 4 consecutive days. The sham group (n = 13) also visited the clinic for 4 days; they received sham treatment for the same duration as the dual-site rTMS treatment group. In study 2, the rTMS treatment protocol was exactly the same as in study 1. Magnetoencephalography recordings were performed before and 1 week after the last rTMS treatment. The outcome measure was the Tinnitus Handicap Inventory (THI) score and the visual analog scale score. The effects of treatment were assessed 1, 2, 4, and 8 weeks after rTMS treatment in study 1. Then the mean band power and network changes were compared between pre- and post-treatment values after rTMS in study 2. Result: Patients in the dual-site rTMS treatment group exhibited significantly improved THI scores at 2, 4, and 8 weeks after rTMS treatment compared with the pretreatment scores. However, the sham group did not show any significant reduction in THI scores. When the mean band power changes were compared between pre- and post-treatment assessments, an increased oscillation power was observed in the alpha band after rTMS. Conclusion: A beneficial effect of rTMS on tinnitus suppression was found in the dual-site active rTMS group, but not in the sham rTMS group.

Multisite transcranial Random Noise Stimulation (tRNS) modulates the distress network activity and oscillatory powers in subjects with chronic tinnitus

Tinnitus is a common disorder in which auditory and non-auditory areas are involved as a network. Therefore, the multisite protocol of brain stimulation (tRNS) seems effective in relieving tinnitus symptoms. This study aimed to verify the modulatory effects of multisite tRNS on the tinnitus network. Thirty-two tinnitus-suffering patients received two consecutive sessions of tRNS (SHAM+ REAL) applied over the T3, T4 (the auditory cortex group) and F4, FP1 followed by T3, T4 (the multisite group). A 3-min resting-state EEG was recorded before and immediately after each session. After the multisite-tRNS real session, there was a significantly increased power in the alpha-1 band at the auditory and prefrontal cortex accompanied by decreased power in the delta and beta-2 bands in the prefrontal cortex. Standardized low-resolution brain electromagnetic tomography (sLORETA) showed a significant decrease in beta-2 activity in the prefrontal cortex, anterior cingulate cortex, and the parahippocampus and decreased alpha connectivity between the right prefrontal cortex and the left auditory cortex. No significant effects were noticed for the sham session. This study showed that tRNS has modulatory effects on the electrical activity of the brain and that targeting prefrontal and auditory areas in sequence could modulate the distress network and multiple hubs in the tinnitus network.

Recommendations on Collecting and Storing Samples for Genetic Studies in Hearing and Tinnitus Research.

Objectives:Research on the genetic basis of tinnitus is still in its first steps. A group of scientists dedicated to tinnitus genetics within European Tinnitus Network (TINNET) network recognize that further progress requires multicenter collaborative efforts for defining contributing genes. The purpose of the present work is to provide instructions regarding collection, processing, storage, and shipment of samples intended for genetic studies in auditory research.Design:One part of the recommendations has a general character; another part is of particular importance for auditory healthcare practitioners such as otolaryngology physicians, audiologists, and general practitioners.Results:We provide a set of instructions and various options for obtaining samples. We give advice regarding sample processing, storage, and shipment and define the minimal and essential clinical information that should accompany the samples collected for genetic processing.Conclusions:These recommendations offer a basis to standardize and optimize collaborations between geneticists and healthcare practitioners specialized in tinnitus and hearing disorders.

Computer-Aided Tinnitus Detection based on Brain Network Analysis of EEG Functional Connectivity.

Background:Tinnitus known as a central nervous system disorder is correlated with specific oscillatory activities within auditory and non-auditory brain areas. Several studies in the past few years have revealed that in the most tinnitus cases, the response pattern of neurons in auditory system is changed due to auditory deafferentation, which leads to variation and disruption of the brain networks. Objective: In this paper, we introduce an approach to automatically distinguish tinnitus individuals from healthy controls based on whole-brain functional connectivity and network analysis.Material and Methods: The functional connectivity analysis was applied to the resting state electroencephalographic (EEG) data of both groups using Weighted Phase Lag Index (WPLI) for various frequency bands in 2-44 Hz frequency range. In this case- control study, the classification was performed on graph theoretical measures using support vector machine (SVM) as a robust classification method. Results: Experimental results showed promising classification performance with a high accuracy, sensitivity, and specificity in all frequency bands, specifically in the beta2 frequency band.Conclusion: The current study provides substantial evidence that tinnitus network can be successfully detected by consistent measures of the brain networks based on EEG functional connectivity

Tinnitus Identification based on Brain Network Analysis of EEG Functional Connectivity

Introduction: Tinnitus known as a central nervous system disorder is correlated with specific oscillatory activities within auditory and non-auditory brain areas. Several studies in the past few years have revealed that in the most tinnitus cases, the response pattern of neurons in auditory system is changed due to auditory deafferentation, which leads to variation of the brain networks. According to neuroimaging studies, the human brain is assumed as an organization with the different degree of small-worldness, which is a concept in graph theory. Such organization is able to optimize the functional integration and segregation and therefore efficiently transfer the information among its different pairs of nodes. Materials and Methods: In this paper, we introduce an approach to automatically distinguish tinnitus individuals from healthy controls based on whole-brain functional connectivity and network analysis. Eight participants with tinnitus and eight healthy individuals were included in the study. Resting state electroencephalographic (EEG) data were recorded using a 64-channel recorder. The functional connectivity analysis was applied to the EEG data using Weighted Phase Lag Index (WPLI) for various frequency bands in 2-44 Hz frequency range. The classification was performed on graph theoretical measures using support vector machine (SVM) as a robust classification method. Results: Experimental results showed that the variations of connectivity patterns in tinnitus group were observed within the frontal, temporal and parietal regions. Further, promising classification performance was achieved with a high accuracy, sensitivity, and specificity in all frequency bands. The best classification performance was observed in the beta2 frequency band with accuracy, sensitivity, and specificity of 100%. The results demonstrate that four graph theory based network measures i.e. node strength, clustering coefficient, local efficiency and characteristic path length could successfully discriminate tinnitus from healthy group. Conclusion: The results would be interpreted that the tinnitus network is more segregated but has weaker global efficiency compared to healthy group in high frequencies. In addition, tinnitus individuls presented lower segregation and greater integration relative to the healthy group in the theta frequency domain. As a conclusion, the tinnitus group shows a reduction of small-worldness as well as network integration in high-frequency bands. In general, our study provides substantial evidence that the tinnitus network can be successfully detected by consistent measures of the brain networks based on EEG functional connectivity.

Effective connectivity analysis of inter- and intramodular hubs in phantom sound perception - identifying the core distress network.

Tinnitus, the perception of a phantom sound, is accompanied by loudness and distress components. Distress however accompanies not just tinnitus, but several disorders. Several functional connectivity studies show that distress is characterized by disconnectivity of fronto-limbic circuits or hyperconnectivity of default mode/salience networks. The drawback, however, is that it considers only the magnitude of connectivity, not the direction. Thus, the current study aims to identify the core network of the domain-general distress component in tinnitus by comparing whole brain directed functional networks calculated from 5min of resting state EEG data collected from 310 tinnitus patients and 256 non-tinnitus controls. We observe a reorganization of the overall tinnitus network, reflected by a decrease in strength and efficiency of information transfer between fronto-limbic and medial temporal regions, forming the main hubs of the tinnitus network. Further, a disconnection amongst a subset of these connections was observed to correlate with distress, forming a core distress network. The core distress network showed a decrease in strength of connections specifically going from the left hippocampus/parahippocampus to the subgenual anterior cingulate cortex. Such a disconnection suggests that the parahippocampal contextual memory has little influence on the (paradoxical) value that is attached to the phantom sound and that distress is the consequence of the absence of modulation of the phantom sound.

An overview of the tinnitus network activity and its clinical implications

Background and Aim: Tinnitus, the phantom perception of sound, in which many cortical and subcortical areas are involved has become one of the popular subjects of neuroscience research. Neuroimaging studies have introduced the tinnitus network model to explain the involvement of auditory and non-auditory areas in this perception. In such a model, the cognitive and emotional aspects of tinnitus can be interpreted conveniently. Therefore, this paper aimed to review the neural basis of tinnitus networks, including data from neuroimaging studies, and discuss the clinical implication of this concept, as well.Recent Findings: The data from neuroimaging studies were reviewed and discussed in order to complete the overall image of tinnitus network and its correlates such as the distress network, attentional network and other cognitive mechanisms. In addition to the auditory system, the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) were considered to be important hubs in tinnitus distress network, especially for having important connectivity with the other networks like attention and salience networks. Moreover, the top-down control of DLPFC over the other brain areas was regarded as the most important brain area to be targeted using the non-invasive interventions and the results were compelling.Conclusion: Understanding the network model has helped in optimizing the neuromodulation protocols like electrical stimulation techniques. Thus, the clinical implications of this model can be generalized to the other types of treatments and the outcomes might be satisfying.

Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in Chronic Tinnitus.

Chronic tinnitus is characterized by neuroplastic changes of the auditory cortex. A promising method for therapy of chronic tinnitus is vagus nerve stimulation (VNS) combined with auditory stimulation. The principle of VNS is reversal of pathological neuroplastic changes of the auditory cortex toward physiological neural activity and synchronicity. The VNS mechanism of action in chronic tinnitus patients is prevailingly through the muscarinic neuromodulation of the auditory cortex by the activation of nc. basalis Meynerti. The aim of this study is to propose potential pharmaceutics which may improve the neuromodulatory effects of VNS. The working hypothesis is that M1 receptors have a dominant role in the neural plasticity of the auditory cortex. We propose that allosteric agonists of the muscarinic receptor type 1 (M1) receptor could improve specificity and selectivity of the neuromodulatory effect of VNS on the auditory cortex of chronic tinnitus patients even in the circumstances of lower acetylcholine brain concentration. This intervention would also reinforce the re-learning process of tinnitus (sub)networks by acting on cholinergic memory and learning mechanisms. We performed in silico screening of drug space using the EIIP/AQVN filter and selected 50 drugs as candidates for allosteric modulators of muscarinic receptors. Further filtering of these compounds by means of 3D QSAR and docking revealed 3 approved drugs—bromazepam, estazolam and flumazenil as the most promising candidates for combined chronic tinnitus therapy. These drugs should be further evaluated by biological tests and clinical trials.

P055 Combined repetitive transcranial magnetic stimulation and peripheral muscle magnetic stimulation in chronic tinnitus

Question Chronic tinnitus is characterized by several comorbid disorders. One of them is neck and back pain. Here, we investigate the feasibility, safety and clinical efficacy of the combination of repetitive transcranial magnetic stimulation (rTMS) and peripheral muscle stimulation (rPMS) in chronic tinnitus in a pilot study. rTMS is considered to interact with neural tinnitus networks. rPMS is suggested to bring relief to muscle tension. This is a one arm study where explorative analyses will be done with special consideration on patients suffering from neck pain in the analysis. Methods In this one-arm study, thirty patients receive rPMS and rTMS consisting of ten daily sessions. rPMS is done in five medial–lateral movements starting from the neck: left and right trapezius and deltoid muscle, trapezius and latissimus dorsi muscle, and over the backbone using 20 stimuli per movement with 2 s inter-train interval. Stimulation is done with four repetitions for each of the five movements - the first 20 trains with a frequency of 5 Hz and the second 20 trains at 20 Hz. Stimulation is done at individual comfortable level (20–30% stimulator output) using a round coil. rTMS is done at 20 Hz with 2000 stimuli over the left dorso-lateral prefrontal cortex at 110% motor threshold followed by 1 Hz stimulation with 2000 stimuli over the left temporo-parietal cortex with an stimulation intensity if 110% motor threshold using a figure-of-eight coil. Results The trial is registered (ClinicalTrials.gov identifier: NCT02306447). The last visit will be done in April 2016 – just after the abstract deadline. First clinical impressions show good tolerability and clinical efficacy in a proportion of patients. For the conference we will present the completed statistical analyses for the whole group and for a subgroup with neck pain. Further analyses will include contrasts with an historical control sample. Conclusions We will discuss putative mechanisms of action of rPMS and rTMS for the treatment of chronic tinnitus.

Acoustic Coordinated Reset Neuromodulation: A Systematic Review of a Novel Therapy for Tinnitus.

There are growing technological advances in the development of sound-based methods for the treatment of tinnitus. Most of these methods intend to affect the speculated underlying neurological causes of tinnitus. Acoustic coordinated reset (CR) neuromodulation is one of them. A novel method that as of yet seems inadequately reviewed. To evaluate the current evidence on acoustic CR neuromodulation as a method for the treatment of tinnitus and to assess whether the method can be implemented in daily clinical practice. A systematic literature search was performed in 13 databases in the period from February 1, 2015 to May 1, 2016. Studies regarding acoustic CR neuromodulation as a treatment method for tinnitus were included in the present review. A total of 8 studies were eligible for being reviewed comprising a total of 329 patients. Overall, the evidence level of the published literature was low. The main findings in the included studies were that acoustic CR neuromodulation was safe and well tolerated and most patients reported reduction of tinnitus symptoms. The neurophysiological basis of the method was claimed to be desynchronization, anti-kindling, and change of abnormal frequency couplings in a widespread tinnitus network comprising both auditory and non/auditory brain areas based on EEG analyses. The available evidence is insufficient for clinical implementation of acoustic CR neuromodulation. The limited level of evidence suggests that acoustic CR neuromodulation may have positive effects on tinnitus symptoms. Preliminary electroencephalographic data are compatible with the claim that tinnitus reduction after CR treatment is mediated by a desynchronizing effect. However, a proof for this claim is still lacking.

The added value of auditory cortex transcranial random noise stimulation (tRNS) after bifrontal transcranial direct current stimulation (tDCS) for tinnitus.

Tinnitus is the perception of a sound in the absence of a corresponding external sound source. Research has suggested that functional abnormalities in tinnitus patients involve auditory as well as non-auditory brain areas. Transcranial electrical stimulation (tES), such as transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex and transcranial random noise stimulation (tRNS) to the auditory cortex, has demonstrated modulation of brain activity to transiently suppress tinnitus symptoms. Targeting two core regions of the tinnitus network by tES might establish a promising strategy to enhance treatment effects. This proof-of-concept study aims to investigate the effect of a multisite tES treatment protocol on tinnitus intensity and distress. A total of 40 tinnitus patients were enrolled in this study and received either bifrontal tDCS or the multisite treatment of bifrontal tDCS before bilateral auditory cortex tRNS. Both groups were treated on eight sessions (two times a week for 4weeks). Our results show that a multisite treatment protocol resulted in more pronounced effects when compared with the bifrontal tDCS protocol or the waiting list group, suggesting an added value of auditory cortex tRNS to the bifrontal tDCS protocol for tinnitus patients. These findings support the involvement of the auditory as well as non-auditory brain areas in the pathophysiology of tinnitus and demonstrate the idea of the efficacy of network stimulation in the treatment of neurological disorders. This multisite tES treatment protocol proved to be save and feasible for clinical routine in tinnitus patients.

Top-down and bottom-up neurodynamic evidence in patients with tinnitus

Although a peripheral auditory (bottom-up) deficit is an essential prerequisite for the generation of tinnitus, central cognitive (top-down) impairment has also been shown to be an inherent neuropathological mechanism. Using an auditory oddball paradigm (for top-down analyses) and a passive listening paradigm (for bottom-up analyses) while recording electroencephalograms (EEGs), we investigated whether top-down or bottom-up components were more critical in the neuropathology of tinnitus, independent of peripheral hearing loss. We observed significantly reduced P300 amplitudes (reflecting fundamental cognitive processes such as attention) and evoked theta power (reflecting top-down regulation in memory systems) for target stimuli at the tinnitus frequency of patients with tinnitus but without hearing loss. The contingent negative variation (reflecting top-down expectation of a subsequent event prior to stimulation) and N100 (reflecting auditory bottom-up selective attention) were different between the healthy and patient groups. Interestingly, when tinnitus patients were divided into two subgroups based on their P300 amplitudes, their P170 and N200 components, and annoyance and distress indices to their tinnitus sound were different. EEG theta-band power and its Granger causal neurodynamic results consistently support a double dissociation of these two groups in both top-down and bottom-up tasks. Directed cortical connectivity corroborates that the tinnitus network involves the anterior cingulate and the parahippocampal areas, where higher-order top-down control is generated. Together, our observations provide neurophysiological and neurodynamic evidence revealing a differential engagement of top-down impairment along with deficits in bottom-up processing in patients with tinnitus but without hearing loss.