Investigating sensitivity to multi-domain prediction errors in chronic auditory phantom perception.

The perception of a continuous phantom in a sensory domain in the absence of an external stimulus is explained as a maladaptive compensation of aberrant predictive coding, a proposed unified theory of brain functioning. If this were true, these changes would occur not only in the domain of the phantom percept but in other sensory domains as well. We confirm this hypothesis by using tinnitus (continuous phantom sound) as a model and probe the predictive coding mechanism using the established local-global oddball paradigm in both the auditory and visual domains. We observe that tinnitus patients are sensitive to changes in predictive coding not only in the auditory but also in the visual domain. We report changes in well-established components of event-related EEG such as the mismatch negativity. Furthermore, deviations in stimulus characteristics were correlated with the subjective tinnitus distress. These results provide an empirical confirmation that aberrant perceptions are a symptom of a higher-order systemic disorder transcending the domain of the percept.

Phantom perception as a Bayesian Inference problem - a pilot study.

Tinnitus is the perception of a sound in the absence of an external source. Although the role of the auditory system is well investigates, there is a gap in how multisensory signals are integrated to produce a single percept in tinnitus. Here, we train participants to learn a new sensory environment by associating a cue with a target signal that varies in perceptual threshold. In the test phase, we present only the cue to see if the person perceives an illusion of the target signal. We perform two separate experiments to observe the behavioural and electrophysiological responses to the learning and test phases in (i) healthy young adults and (ii) people with continuous subjective tinnitus and matched controls. We observed that in both parts of the study, the percentage of false alarms was negatively correlated with the 75% detection threshold. Additionally, the perception of an illusion goes together with increased evoked response potential in frontal regions of the brain. In patients with tinnitus, we observe no significant difference in behavioural or evoked response in the auditory paradigm, whereas patients with tinnitus were more likely to report false alarms going together with increased evoked activity during the learning and test phases in the visual paradigm. This impresses the importance of integrity of sensory pathways in multisensory integration and how this process may be disrupted in people with tinnitus. Furthermore, the current study also presents preliminary data supporting evidence that tinnitus patients maybe building stronger perceptual models.

The effect of occipital nerve field stimulation on the descending pain pathway in patients with fibromyalgia: a water PET and EEG imaging study.

BACKGROUND: Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain accompanied by fatigue, sleep, memory, and mood problems. Recently, occipital nerve field stimulation (ONS) has been proposed as an effective potential treatment for fibromyalgia-related pain. The aim of this study is to unravel the neural mechanism behind occipital nerve stimulation's ability to suppress pain in fibromyalgia patients. MATERIALS AND METHODS: Seven patients implanted with subcutaneous electrodes in the C2 dermatoma were enrolled for a Positron Emission Tomography (PET) H215O activation study. These seven patients were selected from a cohort of 40 patients who were part of a double blind, placebo-controlled study followed by an open label follow up at six months. The H215O PET scans were taken during both the "ON" (active stimulation) and "OFF" (stimulating device turned off) conditions. Electroencephalogram (EEG) data were also recorded for the implanted fibromyalgia patients during both the "ON" and "OFF" conditions. RESULTS: Relative to the "OFF" condition, ONS stimulation resulted in activation in the dorsal lateral prefrontal cortex, comprising the medial pain pathway, the ventral medial prefrontal cortex, and the bilateral anterior cingulate cortex as well as parahippocampal area, the latter two of which comprise the descending pain pathway. Relative deactivation was observed in the left somatosensory cortex, constituting the lateral pain pathway as well as other sensory areas such as the visual and auditory cortex. The EEG results also showed increased activity in the descending pain pathway. The pregenual anterior cingulate cortex extending into the ventral medial prefrontal cortex displayed this increase in the theta, alpha1, alpha2, beta1, and beta2 frequency bands. CONCLUSION: PET shows that ONS exerts its effect via activation of the descending pain inhibitory pathway and the lateral pain pathway in fibromyalgia, while EEG shows activation of those cortical areas that could be responsible for descending inhibition system recruitment. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT00917176 (June 10, 2009).

Influencing connectivity and cross-frequency coupling by real-time source localized neurofeedback of the posterior cingulate cortex reduces tinnitus related distress.

BACKGROUND: In this study we are using source localized neurofeedback to moderate tinnitus related distress by influencing neural activity of the target region as well as the connectivity within the default network. HYPOTHESIS: We hypothesize that up-training alpha and down-training beta and gamma activity in the posterior cingulate cortex has a moderating effect on tinnitus related distress by influencing neural activity of the target region as well as the connectivity within the default network and other functionally connected brain areas. METHODS: Fifty-eight patients with chronic tinnitus were included in the study. Twenty-three tinnitus patients received neurofeedback training of the posterior cingulate cortex with the aim of up-training alpha and down-training beta and gamma activity, while 17 patients underwent training of the lingual gyrus as a control situation. A second control group consisted of 18 tinnitus patients on a waiting list for future tinnitus treatment. RESULTS: This study revealed that neurofeedback training of the posterior cingulate cortex results in a significant decrease of tinnitus related distress. No significant effect on neural activity of the target region could be obtained. However, functional and effectivity connectivity changes were demonstrated between remote brain regions or functional networks as well as by altering cross frequency coupling of the posterior cingulate cortex. CONCLUSION: This suggests that neurofeedback could remove the information, processed in beta and gamma, from the carrier wave, alpha, which transports the high frequency information and influences the salience attributed to the tinnitus sound. Based on the observation that much pathology is the result of an abnormal functional connectivity within and between neural networks various pathologies should be considered eligible candidates for the application of source localized EEG based neurofeedback training.

Adding Prefrontal Transcranial Direct Current Stimulation Before Occipital Nerve Stimulation in Fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is a type of chronic musculoskeletal pain without a clear peripheral origin of nociception, often associated with depression. The underlying pathophysiology involves changes in a functional network that is related to pain and emotional processing in the central nervous system. Transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex or the occipital nerve (ON) is a noninvasive neuromodulation technique capable of improving fibromyalgia symptoms. This study aims to test the effect of combining 2 targets of stimulation using tDCS. MATERIALS AND METHODS: We applied ON-tDCS in isolation or coupled with pre-ONS right-anode bifrontal tDCS and assessed its effect on fibromyalgia using the Fibromyalgia Impact Questionnaire, the Beck Depression Inventory, and Numeric Rating Scale for pain scores. These measures were compared with a sham control group using repeated measures analysis of variance. RESULTS: The interaction effect of stimulation trials and the protocols of sham versus ON-tDCS were significant for the impact, distress, and pain caused by fibromyalgia (P<0.05). The interaction effect of trials and protocols of sham versus ON-tDCS with bifrontal tDCS was significant for distress (P<0.01), and it showed a trend of improvement for impact and pain (P<0.1). On the basis of the nonsignificant interaction effect of ON-tDCS versus ON-tDCS with bifrontal tDCS (P>0.1), adding bifrontal tDCS was found not to improve the treatment effect of ON-tDCS in any of the tested clinical outcome measures. DISCUSSION: This study suggests that adding right-anode bifrontal tDCS to ONS has no added benefit in improving fibromyalgia-related symptoms.

Resting state electrical brain activity and connectivity in fibromyalgia.

The exact mechanism underlying fibromyalgia is unknown, but increased facilitatory modulation and/or dysfunctional descending inhibitory pathway activity are posited as possible mechanisms contributing to sensitization of the central nervous system. The primary goal of this study is to identify a fibromyalgia neural circuit that can account for these abnormalities in central pain. The second goal is to gain a better understanding of the functional connectivity between the default and the executive attention network (salience network plus dorsal lateral prefrontal cortex) in fibromyalgia. We examine neural activity associated with fibromyalgia (N = 44) and compare these with healthy controls (N = 44) using resting state source localized EEG. Our data support an important role of the pregenual anterior cingulate cortex but also suggest that the degree of activation and the degree of integration between different brain areas is important. The inhibition of the connectivity between the dorsal lateral prefrontal cortex and the posterior cingulate cortex on the pain inhibitory pathway seems to be limited by decreased functional connectivity with the pregenual anterior cingulate cortex. Our data highlight the functional dynamics of brain regions integrated in brain networks in fibromyalgia patients.

Differential effects of bifrontal and occipital nerve stimulation on pain and fatigue using transcranial direct current stimulation in fibromyalgia patients.

Fibromyalgia is a disorder characterized by widespread musculoskeletal pain frequently accompanied by other symptoms such as fatigue. Moderate improvement from pharmacological and non-pharmacological treatments have proposed non-invasive brain stimulation techniques such as transcranial direct current stimulation (tDCS) to the occipital nerve (more specifically the C2 area) or to the dorsolateral prefrontal cortex (DLPFC) as potential treatments. We aimed to explore the effectiveness of repeated sessions of tDCS (eight sessions) targeting the C2 area and DLPFC in reducing fibromyalgia symptoms, more specifically pain and fatigue. Forty-two fibromyalgia patients received either C2 tDCS, DLPFC tDCS or sham procedure (15 C2 tDCS-11 DLPFC tDCS-16 sham). All groups were treated with eight sessions (two times a week for 4 weeks). Our results show that repeated sessions of C2 tDCS significantly improved pain, but not fatigue, in fibromyalgia patients, whereas repeated sessions of DLPFC tDCS significantly improved pain as well as fatigue. This study shows that eight sessions of tDCS targeting the DLPFC have a more general relief in fibromyalgia patients than when targeting the C2 area, suggesting that stimulating different targets with eight sessions of tDCS can lead to benefits on different symptom dimensions of fibromyalgia.

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 4 weeks). 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.

The Neural Correlates of Chronic Symptoms of Vertigo Proneness in Humans.

Vestibular signals are of significant importance for variable functions including gaze stabilization, spatial perception, navigation, cognition, and bodily self-consciousness. The vestibular network governs functions that might be impaired in patients affected with vestibular dysfunction. It is currently unclear how different brain regions/networks process vestibular information and integrate the information into a unified spatial percept related to somatosensory awareness and whether people with recurrent balance complaints have a neural signature as a trait affecting their development of chronic symptoms of vertigo. Pivotal evidence points to a vestibular-related brain network in humans that is widely distributed in nature. By using resting state source localized electroencephalography in non-vertiginous state, electrophysiological changes in activity and functional connectivity of 23 patients with balance complaints where chronic symptoms of vertigo and dizziness are among the most common reported complaints are analyzed and compared to healthy subjects. The analyses showed increased alpha2 activity within the posterior cingulate cortex and the precuneues/cuneus and reduced beta3 and gamma activity within the pregenual and subgenual anterior cingulate cortex for the subjects with balance complaints. These electrophysiological variations were correlated with reported chronic symptoms of vertigo intensity. A region of interest analysis found reduced functional connectivity for gamma activity within the vestibular cortex, precuneus, frontal eye field, intra-parietal sulcus, orbitofrontal cortex, and the dorsal anterior cingulate cortex. In addition, there was a positive correlation between chronic symptoms of vertigo intensity and increased alpha-gamma nesting in the left frontal eye field. When compared to healthy subjects, there is evidence of electrophysiological changes in the brain of patients with balance complaints even outside chronic symptoms of vertigo episodes. This suggests that these patients have a neural signature or trait that makes them prone to developing chronic balance problems.

A Simple Technique for Surgical Placement of Occipital Nerve Stimulators without Anchoring the Lead.

Introduction Greater occipital nerve stimulation is applied in the treatment of occipital neuralgia, headache, and fibromyalgia. Multiple techniques have been described along with their subsequent complications. The most frequent complications are related to lead migration, infection, and undesired stimulation effects. Revision surgery occurs in up to 60% of the cases. Patients and Methods A total of 92 implantations, 51 trials (6-10 weeks), and 41 permanent implantations (follow-up: 36-72 months) were performed in a single center using a simple technique without an anchoring device. The electrode is tunneled at a 45-degree angle to prevent migration. Complications and additional surgeries were recorded during the follow-up period. Results All patients had bilateral greater occipital nerve stimulation. A total of 16 complications (17.4%) occurred. Seven patients (7.6%) underwent additional surgery. The major complication was infection; lead migration made up only 3.3% of the complications. Conclusions We present a simple technique without the use of an anchoring device that is feasible in achieving bilateral occipital nerve stimulation and decreases the complications, especially lead migration.

Is Transcranial Direct Current Stimulation an Effective Predictor for Invasive Occipital Nerve Stimulation Treatment Success in Fibromyalgia Patients?

BACKGROUND: Fibromyalgia is a disorder distinguished by pervasive musculoskeletal pain that has pervasive effects on affected individuals magnifying the importance of finding a safe and viable treatment option. OBJECTIVE: The goal of this study is to investigate if transcranial direct current stimulation (tDCS) treatment can predict the outcome of occipital nerve field stimulation (ONFS) via a subcutaneous electrode. METHODS: Nine patients with fibromyalgia were selected fulfilling the American College of Rheumatology-90 criteria. The patients were implanted with a subcutaneous trial-lead in the C2 dermatome innervated by the occipital nerve. After the treatment phase of ONFS using a C2 implant, each patient participated in three sessions of tDCS. Stimulation outcomes for pain suppression were examined between the two methods to determine possible correlations. RESULTS: Positive correlation of stimulation effect was noted between the numeric rating scale changes for pain obtained by tDCS treatments and short-term measures of ONFS, but no correlation was noted between tDCS and long-term ONFS outcomes. A correlation also was noted between short-term ONS C2 implant pain suppression and long-term ONS C2 implant treatment success. CONCLUSIONS: This pilot study suggests that tDCS is a predictive measure for success of OFNS in short-term but cannot be used as a predictive measure for success of long-term OFNS. Our data confirm previous findings that ONFS via an implanted electrode can improve fibromyalgia pain in a placebo-controlled way and exert a long-term pain suppression effect for ONFS via an implanted electrode.

Laser-Evoked Potentials in Fibromyalgia: The Influence of Greater Occipital Nerve Stimulation on Cerebral Pain Processing.

OBJECTIVE: Fibromyalgia causes widespread musculo-skeletal pain in the four quadrants of the body. Greater occipital nerve stimulation has recently shown beneficial effects in fibromyalgia patients on pain, fatigue, and mood disorders. Laser-evoked potentials (LEPs) are used for research to understand the pathophysiological mechanisms of pain and to evaluate the effects of pain treatment. In fibromyalgia patients, LEPs tend to have a higher N2 amplitude, a tendency to shorter latencies, and patients have a lower pain threshold. Greater occipital nerve stimulation might exert a modulation of the medial pain pathways processing the affective motivational components of pain (unpleasantness) as well as the descending pain inhibitory pathways (reducing pain), both of which are contributing to the N2P2 peak. MATERIALS AND METHODS: To test this hypothesis, the authors performed LEPs in a group of fibromyalgia patients with and without greater occipital nerve stimulation. RESULTS: Occipital nerve stimulation does not alter the amplitudes of the LEP recordings, although a significant difference in latencies can be seen. More specifically, latencies of the N2P2 increased in the condition after stimulation, and especially at the Pz electrode. CONCLUSION: Our results suggest Occipital Nerve Stimulation (ONS) induces a modification of the balance between antinociceptive pain inhibitory pathways and pain-provoking pathways.

C2 Nerve Field Stimulation for the Treatment of Fibromyalgia: A Prospective, Double-blind, Randomized, Controlled Cross-over Study.

BACKGROUND: Fibromyalgia is a condition characterized by widespread chronic pain. Due to the high prevalence and high costs, it has a substantial burden on society. Treatment results are diverse and only help a small subset of patients. C2 nerve field stimulation, aka occipital nerve stimulation, is helpful and a minimally invasive treatment for primary headache syndromes. Small C2 pilot studies seem to be beneficial in fibromyalgia. METHODS: Forty patients were implanted with a subcutaneous electrode in the C2 dermatoma as part of a prospective, double-blind, randomized, controlled cross-over study followed by an open label follow up period of 6 months. The patients underwent 2 week periods of different doses of stimulation consisting of minimal (.1 mA), subthreshold, and suprathreshold (for paresthesias) in a randomized order. Twenty seven patients received a permanent implant and 25 completed the 6 month open label follow up period. RESULTS: During the 6 week trial phase of the study, patients had an overall decrease of 36% on the fibromyalgia impact questionnaire (FIQ), a decrease of 33% fibromyalgia pain and improvement of 42% on the impact on daily life activities and quality. These results imply an overall improvement in the disease burden, maintained at 6 months follow up, as well as an improvement in life quality of 50%. Seventy six percent of patients were satisfied or very satisfied with their treatment. There seems to be a dose-response curve, with increasing amplitudes leading to better clinical outcomes. CONCLUSION: Subcutaneous C2 nerve field stimulation seems to offer a safe and effective treatment option for selected medically intractable patients with fibromyalgia.

Pain characteristics in fibromyalgia: understanding the multiple dimensions of pain.

Fibromyalgia is a common disease with a high economic burden. The etiology of this disease remains unclear, as there are no specific abnormalities on clinical or technical examinations. Evidence suggests that central pain sensitization at the brain pain matrix might be involved. Understanding the pain characteristics of this disease is of importance both for diagnosis and treatment. The authors present their findings of pain characteristics in a Belgium population of fibromyalgia patients. Data of 65 patients (57 male and 8 female patients) were analyzed in this study (mean age 46.86, SD = +8.79). Patients filled out the following questionnaires: visual analogue scale, fibromyalgia impact questionnaire, pain-catastrophizing scale, pain vigilance and awareness questionnaire, modified fatigue impact scale, the Beck depression inventory, the short form 36 and the Dutch shortened profile of mood states. Statistical analysis was performed making use of a factor analysis and a hierarchical cluster analysis. We were able to define pain characteristics in this group of patients. The reciprocal effects of mood and fatigue on pain experience could be identified within the data, catastrophizing scores show a high correlation with overall life quality and pain experience. We have performed a cluster analysis on the fibromyalgia patients, based on the four main principal components defining the overall disease burden. Mood explained most of the variance in symptoms, followed by mental health state, fatigue, and catastrophizing. Three clusters of patients could be revealed by these components. Clusters: 1 high scores on mood disorders, pain, and decreased mental health, 2 high scores on fatigue and physical health, and 3 a mixture of these two groups. This data suggest that different subgroups of fibromyalgia patients could be identified and based on that, treatment strategies and results might be adapted.

Neural correlates of high frequency repetitive transcranial magnetic stimulation improvement in post-stroke non-fluent aphasia: a case study.

Damage to the left inferior frontal gyrus (lIFG) affects language and can cause aphasia in stroke. Following left hemisphere damage it has been suggested that the homologue area in the right hemisphere compensates for lost functions. An increasing number of studies have demonstrated that inhibitory 1-Hz repetitive transcranial magnetic stimulation (rTMS) targeting the right IFG can be useful for enhancing recovery in aphasic patients. In the present study we applied activating high frequency (10-Hz) rTMS, which increases cortical excitability, to the damaged lIFG daily for 3 weeks. Pre- and post-TMS EEG are performed, as well as language function assessments with the Aachener Aphasia Test Battery. Results demonstrate a decrease in rIFG activity post rTMS and normalization for the lIFG for beta3 frequency band. Also increased activity was in the right supplementary motor area for beta3 frequency band. In comparison to pre-TMS the aphasic patient improved on repetition tests, for naming and comprehension. After rTMS increased functional connectivity was shown in comparison to before between the lIFG and the rIFG for theta and beta3 frequency band. This case report suggests that 10 Hz rTMS of the lIFG can normalize activity in the lIFG and right IFG possibly mediated via altered functional connectivity.

TMS by double-cone coil prefrontal stimulation for medication resistant chronic depression: a case report.

A double-cone coil with large angled windings has been developed to modulate deeper brain areas such as the anterior cingulate cortex (ACC). Abnormal resting state activity in the pregenual ACC (pgACC), dorsal ACC (dACC) and subgenual ACC (sgACC) has been observed in depression. A patient with medication resistant chronic depression received ten sessions of transcranial magnetic stimulation (TMS) (10 Hz, 2000 stimuli/session) using a double-cone coil placed over the supplementary motor area, targeting the anterior cingulate. Source localized EEG recordings were conducted pre- and post-TMS. The Beck Depression Inventory (BDI-II) improved by 27%, and the two subscales of the Hospital Anxiety Depression Scale (HADS), namely depression (40%) and anxiety (33%) improved as well. Along with the clinical improvement eletrophysiological resting state activity changed in the dACC and sgACC in this patient in comparison to a normative group. The results of this case report further support the involvement of pgACC, dACC and sgACC activity in the pathophysiology of depression and indicate that modulation of neural activity in this area by high frequency TMS with a double-cone coil might represent a new promising approach in the treatment of medication resistant chronic depression.

Bifrontal and bioccipital transcranial direct current stimulation (tDCS) does not induce mood changes in healthy volunteers: a placebo controlled study.

Transcranial direct current stimulation (tDCS) is the application of a weak electrical direct current (1.5 mA), which has the ability to modulate spontaneous firing rates of the cortical neurons by depolarizing or hyperpolarizing the neural resting membrane potential. tDCS in patients with depressive disorders has been proven to be an interesting therapeutic method potentially influencing pathologic mood states. Except one study, no alterations in mood could be confirmed applying tDCS in healthy participants. In this study, bifrontal or bioccipital stimulation was applied in 17 healthy subjects during 20 minutes with 1.5 mA in a placebo-controlled manner. Bifrontal stimulation consisted of both anodal and cathodal placement on right and left dorsolateral prefrontal cortex (DLPFC) in two separate sessions. Using a set of self-reported moodscales (SUDS, POMS-32, PANAS, BISBAS) no significant mood changes could be observed, neither with bifrontal nor bioccipital tDCS. As already demonstrated by previous studies, we confirmed the minimal side effects and the safety of this neuromodulation technique.

Bilateral dorsolateral prefrontal cortex modulation for tinnitus by transcranial direct current stimulation: a preliminary clinical study.

Tinnitus is considered as an auditory phantom percept. Preliminary evidence indicates that transcranial direct current stimulation (tDCS) of the temporo-parietal area might reduce tinnitus. tDCS studies of the prefrontal cortex have been successful in reducing depression, impulsiveness and pain. Recently, it was shown that the prefrontal cortex is important for the integration of sensory and emotional aspects of tinnitus. As such, frontal tDCS might suppress tinnitus as well. In an open label study, a total of 478 tinnitus patients received bilateral tDCS on dorsolateral prefrontal cortex (448 patients anode right, cathode left and 30 anode left, cathode right) for 20 min. Treatment effects were assessed with visual analogue scale for tinnitus intensity and distress. No tinnitus-suppressing effect was found for tDCS with left anode and right cathode. Analyses show that tDCS with right anode and left cathode modulates tinnitus perception in 29.9% of the tinnitus patients. For these responders a significant reduction was found for both tinnitus-related distress and tinnitus intensity. In addition, the amount of suppression for tinnitus-related distress is moderated by an interaction between tinnitus type and tinnitus laterality. This was, however, not the case for tinnitus intensity. Our study supports the involvement of the prefrontal cortex in the pathophysiology of tinnitus.

Influence of tonic and burst transcranial magnetic stimulation characteristics on acute inhibition of subjective tinnitus.

OBJECTIVE: Transcranial magnetic stimulation (TMS) is already broadly used in different areas of neuroscience research. In the last years, special attention was drawn to TMS in tinnitus. The aim of our study is to investigate the stimulation characteristics of TMS in tinnitus patients, in particular the effect of tonic and burst stimulation of the superior temporal lobe. STUDY DESIGN: Prospective sham-controlled study. SETTING: Tertiary referral center. PATIENTS: Fifty tinnitus patients were included in the study. Thirty-one patients had pure-tone tinnitus, and 19 patients had noise-like tinnitus. STUDY DESIGN: Transcranial magnetic stimulation was performed in 1 session of 200 pulses at different frequencies. Stimuli were delivered to the auditory cortex region contralateral to the tinnitus side. Tonic and burst stimulations were delivered at different frequencies. Patients were asked to rate the acute tinnitus reduction after TMS on a visual analog scale. MAIN OUTCOME MEASURE: Acutely perceived tinnitus reduction immediately after TMS, scored by the patient on a visual analogue scale ranging from 0 to 100%. RESULTS: Tinnitus reduction increased when stimulation intensity was higher relative to the patient's motor threshold. Nevertheless, this stimulation intensity was shown only to account for 10% of this increased tinnitus reduction, meaning that up to 90% of this effect should be ascribed to other factors than stimulation intensity alone. Different reactions on TMS were found in bilateral tinnitus patients compared with unilateral tinnitus patients. CONCLUSION: Several parameters determine the amount of tinnitus reduction after TMS. An increased stimulation intensity relative to the patient's motor threshold only accounts for 10% of this effect. Our data also suggest different pathophysiologic mechanisms for unilateral and bilateral tinnitus.