Repetitive transcranial magnetic stimulation (rTMS): a new therapeutic approach in subjective tinnitus?

Subjective (non-recordable) tinnitus is the conscious perception of a phantom sound, and a very frequent, sometimes disabling, condition. Even if subjective tinnitus is often related to peripheral hearing loss, neurophysiological and functional imaging studies provide increasing evidence for an involvement both auditory and non-auditory central nervous pathways in the generation of tinnitus and related distress. Repetitive transcranial magnetic stimulation (rTMS) has been proposed to relieve tinnitus by reducing auditory cortex hyperexcitability associated with this condition. This paper will review the first clinical results reported in auditory cortex rTMS studies, with special reference to the pathophysiology of tinnitus processing and the mechanisms of action of rTMS. Although rTMS appears to be a very promising tool for the diagnosis and the treatment of tinnitus patients, available knowledge is still very limited at the moment. Further basic research and clinical studies are needed in order to optimize the parameters of stimulation (stimulus frequency, cortical target definition) and to validate the application of this technique in the management of patients with disabling tinnitus.     

The pharmacokinetics of tranylcypromine enantiomers in healthy subjects after oral administration of racemic drug and the single enantiomers

The pharmacokinetics of the two enantiomers of tranylcypromine were evaluated in six healthy subjects after oral dosage of the racemate (20 mg of the sulphate) and the single enantiomers (10 mg of the sulphate) using an enantiospecific assay. Significant differences in AUC, Cmax, lambda(z), and CLR of the two enantiomers were observed both on administration of the racemate and of the individual enantiomers. The plasma concentrations and urinary excretion rates of (-)-tranylcypromine exceeded those of (+)-tranylcypromine. AUCs of the (-)-enantiomer [arithmetical means 197 ng ml(-1) h after the racemate, 130 ng ml(-1) h after the enantiomer] were greater than those of the (+)-enantiomer [26 ng ml(-1) h after the racemate, 28 ng ml(-1) h after the enantiomer] (P = 0.0001). No in vivo racemisation was detected. The power of the study was insufficient to establish any enantiomer-enantiomer interaction except for a possible interaction at the level of renal clearance (P = 0.013 for both enantiomers).     

Multisite rTMS for the Treatment of Chronic Tinnitus: Stimulation of the Cortical Tinnitus Network—A Pilot Study

Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the auditory cortex has been shown to significantly reduce tinnitus severity in some patients. There is growing evidence that a neural network of both auditory and non-auditory cortical areas is involved in the pathophysiology of chronic subjective tinnitus. Targeting several core regions of this network by rTMS might constitute a promising strategy to enhance treatment effects. This study intends to test the effects of a multisite rTMS protocol on tinnitus severity. 45 patients with chronic tinnitus were treated with multisite stimulation (left dorsolateral prefrontal, 2,000 stimuli, 20 Hz; left temporoparietal, 1,000 stimuli, 1 Hz; right temporoparietal, 1,000 stimuli, 1 Hz). Results were compared with a historical control group consisting of 29 patients who received left temporal stimulation (2,000 stimuli, 1 Hz). Both groups were treated on ten consecutive working days. Tinnitus severity was assessed at three time points: at baseline, after the last treatment session (day 12) and after a follow-up period of 90 days. A change of tinnitus severity over time was tested using repeated measures ANOVA with the between-subjects factor treatment group. Both groups improved similarly from baseline to day 12. However, there was a difference on day 90: the multisite stimulation group showed an overall improvement whereas patients receiving temporal stimulation returned to their baseline level of tinnitus severity. These pilot data suggest that multisite rTMS is superior to temporal rTMS and represents a promising strategy for enhancing treatment effects of rTMS in tinnitus. Future studies should explore this new protocol with respect to clinical and neurobiological effects in more detail.     

Neural correlates of tinnitus duration and Distress: A positron emission tomography study

Cerebral ¹⁸F‐deoxyglucose positron emission tomography (FDG‐PET) has shown altered auditory pathway activity in tinnitus. However, the corresponding studies involved only small samples and analyses were restricted to the auditory cortex in most studies. Evidence is growing that also limbic, frontal, and parietal areas are involved in the pathophysiology of chronic tinnitus. These regions are considered to mediate perceptual, attentional, and emotional processes. Thus, the aim of the present study was the systematic evaluation of metabolic brain activity in a large sample of tinnitus patients. Ninety one patients with chronic tinnitus underwent FDG‐PET. The effects of tinnitus severity (assessed by a tinnitus questionnaire score), duration and laterality were evaluated with statistical parametric mapping (SPM) in whole brain analyses. In addition, region of interest analyses were performed for primary auditory areas. Tinnitus duration correlated positively with brain metabolism in right inferior frontal, right ventro‐medial prefrontal, and right posterior cingulate cortex. Tinnitus distress correlated positively with activation of left and right posterior inferior temporal gyrus as well as left and right posterior parahippocampal–hippocampal interface. Region of interest analysis demonstrated an overactivation of left in contrast to right Heschl's gyrus independently from tinnitus laterality and anatomical hemispheric differences. Tinnitus duration and distress were associated with areas involved in attentional and emotional processing. This is in line with recent findings indicating the relevance of higher order areas in the pathophysiology of tinnitus. Earlier results of asymmetric activation of the auditory cortices in tinnitus were confirmed, i.e., left‐sided overactivation was found independently from tinnitus laterality. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

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

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.     

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.     

Effect of alarm therapy on conditioning of central reflex control in nocturnal enuresis: pilot study on changes in prepulse inhibition (PPI)

Background

Alarm therapy is a long-established first-line therapy for nocturnal enuresis (NE). Desamino-arginine vasopressin (dDAVP) as alternative first-line therapy was shown to increase the prepulse inhibition (PPI) of startle reflexes, thus supporting the hypothesis of a maturational delay of reflex inhibition in NE. Effects of alarm therapy on PPI have not yet been investigated.

Methods

The PPI of startle reflexes was measured in 20 children with NE (13 boys, 7 girls, median age 8.5 years, range 5–13) before and after at least 6 weeks of alarm treatment and compared with repeated PPI measurements in 11 healthy controls (7 boys, 4 girls, median age 8 years, range 6–13).

Results

In the NE patients, PPI increased from a median baseline of 20–46 % under alarm therapy (p?=?0.005), with a reduction from a median of 7 to 2 wet nights per week (p?=?0.002). The controls showed no difference in PPI (52 % median at first, 40 % at second measurement, p?=?0.966).

Conclusions

The increase of PPI trough alarm therapy was comparable with that under dDAVP, suggesting an analogous method of action and explaining the alternative or synergistic effect of both therapies. In addition, it further substantiates the hypothesis of a maturational delay of reflex control in NE.