Veronika Vielsmeier

Efficacy of different protocols of transcranial magnetic stimulation for the treatment of tinnitus: Pooled analysis of two randomized controlled studies

Abstract Objectives. Tinnitus is related to alterations in neuronal activity of auditory and nonauditory brain areas. Targeted modulation of these areas by repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new therapeutic approach for chronic tinnitus. Methods. Two randomized, double-blind, parallel-group, controlled clinical trials were performed subsequently and pooled for analysis. A total of 192 tinnitus patients were randomly allocated to receive 10 stimulation sessions of either sham rTMS, PET-based neuronavigated 1 Hz rTMS, 1Hz r TMS over the left auditory cortex, or combined 20 Hz rTMS over the left frontal cortex, followed by 1 Hz rTMS over the left auditory cortex. Results. rTMS treatment was well tolerated and no severe side effects were observed. All active rTMS treatments resulted in significant reduction of the TQ as compared to baseline. The comparison between treatment groups failed to reach significant differences. The number of treatment responders was higher for temporal rTMS(38%) and combined frontal and temporal rTMS (43%), as compared to sham (6%). Conclusions. This large study demonstrates the safety and tolerability of rTMS treatment in patients with chronic tinnitus. While the overall effect did not prove superior to placebo, secondary outcome parameters argue in favour of the active stimulation groups, and specifically the combined frontal and temporal rTMS protocol.

Relationship between Audiometric Slope and Tinnitus Pitch in Tinnitus Patients: Insights into the Mechanisms of Tinnitus Generation

Background Different mechanisms have been proposed to be involved in tinnitus generation, among them reduced lateral inhibition and homeostatic plasticity. On a perceptual level these different mechanisms should be reflected by the relationship between the individual audiometric slope and the perceived tinnitus pitch. Whereas some studies found the tinnitus pitch corresponding to the maximum hearing loss, others stressed the relevance of the edge frequency. This study investigates the relationship between tinnitus pitch and audiometric slope in a large sample. Methodology This retrospective observational study analyzed 286 patients. The matched tinnitus pitch was compared to the frequency of maximum hearing loss and the edge of the audiogram (steepest hearing loss) by t-tests and correlation coefficients. These analyses were performed for the whole group and for sub-groups (uni- vs. bilateral (117 vs. 338 ears), pure-tone vs. narrow-band (340 vs. 115 ears), and low and high audiometric slope (114 vs. 113 ears)). Findings For the right ear, tinnitus pitch was in the same range and correlated significantly with the frequency of maximum hearing loss, but differed from and did not correlate with the edge frequency. For the left ear, similar results were found but the correlation between tinnitus pitch and maximum hearing loss did not reach significance. Sub-group analyses (bi- and unilateral, tinnitus character, slope steepness) revealed identical results except for the sub-group with high audiometric slope which revealed a higher frequency of maximum hearing loss as compared to the tinnitus pitch. Conclusion The study-results confirm a relationship between tinnitus pitch and maximum hearing loss but not to the edge frequency, suggesting that tinnitus is rather a fill-in-phenomenon resulting from homeostatic mechanisms, than the result of deficient lateral inhibition. Sub-group analyses suggest that audiometric steepness and the side of affected ear affect this relationship. Future studies should control for these potential confounding factors.

Can Temporal Repetitive Transcranial Magnetic Stimulation be Enhanced by Targeting Affective Components of Tinnitus with Frontal rTMS? A Randomized Controlled Pilot Trial.

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

Temporomandibular Joint Disorder Complaints in Tinnitus: Further Hints for a Putative Tinnitus Subtype

Objective Tinnitus is considered to be highly heterogeneous with respect to its etiology, its comorbidities and the response to specific interventions. Subtyping is recommended, but it remains to be determined which criteria are useful, since it has not yet been clearly demonstrated whether and to which extent etiologic factors, comorbid states and interventional response are related to each other and are thus applicable for subtyping tinnitus. Analyzing the Tinnitus Research Initiative Database we differentiated patients according to presence or absence of comorbid temporomandibular joint (TMJ) disorder complaints and compared the two groups with respect to etiologic factors. Methods 1204 Tinnitus patients from the Tinnitus Research Initiative (TRI) Database with and without subjective TMJ complaints were compared with respect to demographic, tinnitus and audiological characteristics, questionnaires, and numeric ratings. Data were analysed according to a predefined statistical analysis plan. Results Tinnitus patients with TMJ complaints (22% of the whole group) were significantly younger, had a lower age at tinnitus onset, and were more frequently female. They could modulate or mask their tinnitus more frequently by somatic maneuvers and by music or sound stimulation. Groups did not significantly differ for tinnitus duration, type of onset (gradual/abrupt), onset related events (whiplash etc.), character (pulsatile or not), hyperacusis, hearing impairment, tinnitus distress, depression, quality of life and subjective ratings (loudness etc.). Conclusion Replicating previous work in tinnitus patients with TMJ complaints, classical risk factors for tinnitus like older age and male gender are less relevant in tinnitus patients with TMJ complaints. By demonstrating group differences for modulation of tinnitus by movements and sounds our data further support the notion that tinnitus with TMJ complaints represents a subgroup of tinnitus with clinical features that are highly relevant for specific therapeutic management.

Left temporal low-frequency rTMS for the treatment of tinnitus: clinical predictors of treatment outcome--a retrospective study.

Background:  There is increasing evidence that repetitive transcranial magnetic stimulation (rTMS) can reduce chronic tinnitus. However, treatment results are characterized by high interindividual variability. Therefore, the identification of predictors for treatment response is of high clinical relevance.

Transcranial magnetic stimulation for the treatment of tinnitus: 4-year follow-up in treatment responders--a retrospective analysis.

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) over the temporal cortex has been proposed as a new approach for the treatment of tinnitus. Even if most studies have shown beneficial effects, there is only limited knowledge about clinical predictors for treatment response and about the duration of treatment effects. OBJECTIVE In this study, we compared clinical characteristics of rTMS responders and nonresponders and assessed long-term outcome in the responder group. METHOD Results from 235 patients, who were treated with rTMS because of chronic tinnitus were analysed. Patients received either a standard protocol of low-frequency rTMS (n = 188; 110% motor threshold, 1 Hz, 2000 stimuli/day) over the left temporal cortex or combined frontal and temporal rTMS (n = 47; 110% motor threshold, 1000 stimuli at 20 Hz, left dorsolateral prefrontal cortex plus 1000 stimuli at 1 Hz left temporal cortex). Response criterion was defined as an improvement of at least 10 points in the tinnitus questionnaire (TQ) score between baseline and the follow-up assessment 90 days after treatment. RESULTS For the entire study group there was a highly significant effect of treatment on the TQ score. Fifty patients (21.3%) were responders according to the above mentioned definition. The response criterion was fulfilled by 19.7% of the patients receiving left temporal rTMS and by 26% of the patients receiving combined rTMS. The only significant difference between responders and nonresponders was a higher baseline score of the TQ in the responder group. There were no significant differences in all other assessed patient parameters (gender, age, tinnitus duration, tinnitus laterality, motor threshold, handedness). Ninety days after treatment the average TQ reduction in the responder group was 18.2 points as compared with baseline. At the two long-term follow-up assessments (2.12 ± 1.17 years and 3.9 ± 1.17 years after treatment) the improvement in the responder group was still 14.2, respective 14.4 points. CONCLUSIONS These data underscore the clinical relevance of rTMS in the treatment of tinnitus. A potential explanation for the observed long-lasting clinical effects is that rTMS interferes with tinnitus related neuronal activity and thus facilitates the intrinsic ability of the brain to restore normal function.

Predictors for rTMS response in chronic tinnitus

Background: Repetitive transcranial magnetic stimulation (rTMS) has been studied as a treatment option for chronic tinnitus for almost 10 years now. Although most of these studies have demonstrated beneficial effects, treatment results show high interindividual variability and yet, little is known about predictors for treatment response. Methods: Data from 538 patients with chronic tinnitus were analyzed. Patients received either low-frequency rTMS over the left temporal cortex (n = 345, 1 Hz, 110% motor threshold, 2000 stimuli/day) or combined temporal and frontal stimulation (n = 193, 110% motor threshold, 2000 stimuli at 20 Hz over left dorsolateral prefrontal cortex plus 2000 stimuli at 1 Hz over temporal cortex). Numerous demographic, clinical, and audiological variables as well as different tinnitus characteristics were analyzed as potential predictors for treatment outcome, which was defined as change in the tinnitus questionnaire (TQ) score. Results: Both stimulation protocols resulted in a significant decrease of TQ scores. Effect sizes were small, however. In the group receiving combined treatment, patients with comorbid temporomandibular complaints benefited more from rTMS than patients without those complaints. In addition, patients with higher TQ scores at baseline had more pronounced TQ reductions than patients with low TQ baseline scores. Also, patients who had already improved from screening to baseline benefited less than patients without initial improvement. Conclusions: The results from this large sample demonstrate that rTMS shows only small but clinically significant effects in the treatment of chronic tinnitus. There are no good demographic or clinical predictors for treatment outcome.

Tinnitus with Temporomandibular Joint Disorders A Specific Entity of Tinnitus Patients

Objective. Tinnitus is frequently associated with temporomandibular joint (TMJ) dysfunction. However, the nature of the relationship is not fully understood. Here the authors compared 30 patients with a confirmed diagnosis of temporomandibular joint dysfunction and tinnitus to a group of 61 patients with tinnitus but without any subjective complaints of TMJ dysfunction with respect to clinical and demographic characteristics. Study Design. Case-control study. Setting. Tertiary referral center. Subjects. Tinnitus patients with and without TMJ dysfunction presenting at the Department of Prosthetic Dentistry and the Tinnitus Clinic at the University of Regensburg. Results. Tinnitus patients with TMJ disorder had better hearing function (P < .0005), lower age (P = .001), and lower age at tinnitus onset (P = .002) and were more frequently female (P = .003). Their subjectively perceived tinnitus loudness was lower (P = .01), and more of them could modulate their tinnitus by jaw or neck movements (P = .001). Conclusion. Classical risk factors for tinnitus (age, male gender, hearing loss) are less relevant in tinnitus patients with TMJ disorder, suggesting a causal role of TMJ pathology in the generation and maintenance of tinnitus. Based on this finding, treatment of TMJ disorder may represent a causally oriented treatment strategy for tinnitus.

Levodopa does not enhance the effect of low-frequency repetitive transcranial magnetic stimulation in tinnitus treatment

OBJECTIVE: Low-frequency repetitive transcranial magnetic stimulation (rTMS) has shown promise for the treatment of tinnitus. Experimental data from motor cortex stimulation in healthy subjects indicate that the suppressing effect of low-frequency rTMS can be enhanced by dopaminergic receptor activation. Here we investigated whether administration of the dopamine precursor levodopa before low-frequency rTMS enhances its efficacy in tinnitus treatment. STUDY DESIGN: Sixteen patients with chronic tinnitus received 100 mg of levodopa before each session of low-frequency rTMS. Results were compared with a matched control group of 16 patients who received the same treatment, but without levodopa. Treatment outcome was assessed with a standardized tinnitus questionnaire. RESULTS: Both stimulation protocols resulted in a significant reduction of tinnitus scores after 10 days of stimulation; however, there was no significant difference between the two groups. CONCLUSION: Our data suggest that 100 mg of levodopa does not enhance the effect of rTMS in the treatment of tinnitus.

Chronic tinnitus: an interdisciplinary challenge.

BACKGROUND Tinnitus is defined as the perception of sound in the absence of a corresponding external acoustic stimulus. It is a common problem that markedly impairs the quality of life of about 1% of the general population. METHODS We selectively reviewed the pertinent literature to provide an overview of the current treatment options for chronic tinnitus. RESULTS Cognitive behavioral therapy is effective and is the best studied of all currently available treatments. All patients should have a therapeutic interview for counseling. Auditory stimulation can also lessen tinnitus: It is used in tinnitus maskers and hearing aids, as well as in tinnitus retraining therapy. An improved understanding of the neural mechanisms of tinnitus has led to the development of innovative techniques of neuromodulation and neurostimulation, but these are still experimental. Drugs are indicated only for the treatment of tinnitus-associated symptoms such as depression, sleep disturbances, and anxiety. CONCLUSION There are many ways to treat chronic tinnitus, and new treatments are now being developed. As tinnitus has many causes and can be associated with many different comorbid disturbances, multidisciplinary diagnostic evaluation and treatment are important. For many tinnitus patients, long-term therapeutic success depends on the maintenance of a therapeutic relationship with the treating physician, so that the physician and the patient can work together to give careful consideration to each newly proposed diagnostic test or treatment step.