Efficacy and safety of bilateral continuous theta burst stimulation (cTBS) for the treatment of chronic tinnitus: design of a three-armed randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Tinnitus, the perception of sound and noise in absence of an auditory stimulus, has been shown to be associated with maladaptive neuronal reorganization and increased activity of the temporoparietal cortex. Transient modulation of tinnitus by repetitive transcranial magnetic stimulation (rTMS) indicated that these areas are critically involved in the pathophysiology of tinnitus and suggested new treatment strategies. However, the therapeutic efficacy of rTMS in tinnitus is still unclear, individual response is variable, and the optimal stimulation area disputable. Recently, continuous theta burst stimulation (cTBS) has been put forward as an effective rTMS protocol for the reduction of pathologically enhanced cortical excitability.</p> <p>Methods</p> <p>48 patients with chronic subjective tinnitus will be included in this randomized, placebo controlled, three-arm trial. The treatment consists of two trains of cTBS applied bilaterally to the secondary auditory cortex, the temporoparietal associaction cortex, or to the lower occiput (sham condition) every working day for four weeks. Primary outcome measure is the change of tinnitus distress as quantified by the Tinnitus Questionnaire (TQ). Secondary outcome measures are tinnitus loudness and annoyance as well as tinnitus change during and after treatment. Audiologic and speech audiometric measurements will be performed to assess potential side effects. The aim of the present trail is to investigate effectiveness and safety of a four weeks cTBS treatment on chronic tinnitus and to compare two areas of stimulation. The results will contribute to clarify the therapeutic capacity of rTMS in tinnitus.</p> <p>Trial registration</p> <p>The trial was registered with the clinical trials register of <url>http://www.clinicaltrials.gov</url> (NCT00518024).</p

Meta-Review of Metanalytic Studies with Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Major Depression

BACKGROUND: Major Depression (MD) and treatment-resistant depression (TRD) are worldwide leading causes of disability and therapeutic strategies for these impairing and prevalent conditions include pharmacological augmentation strategies and brain stimulation techniques. In this perspective, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique with a favorable profile of tolerability which, despite being recently approved by the Food and Drug Administration (FDA) for the treatment of patients with medication-refractory unipolar depression, still raises some doubts about most effective parameters of stimulation.METHODS: A literature search was performed using PubMed for the years 2001 through February 2011 in order to review meta-analytic studies assessing efficacy and safety issues for rTMS in depressive disorders. Fifteen meta-analyses were identified and critically discussed in order to provide an updated and comprehensive overview of the topic with specific emphasis on potentially optimal parameters of stimulation.RESULTS: First meta-analyses on the efficacy of rTMS for the treatment of MD and TRD have shown mixed results. On the other hand, more recent meta-analytic studies seem to support the antidepressant efficacy of the technique to a greater extent, also in light of longer periods of stimulation (e.g. > 2 weeks).CONCLUSION: rTMS seems to be an effective and safe brain stimulation technique for the treatment of medication refractory depression. Nevertheless, further studies are needed to better define specific stimulation-related issues, such as duration of treatment as well as durability of effects and predictors of response

rTMS of the Left Dorsolateral Prefrontal Cortex Modulates Dopamine Release in the Ipsilateral Anterior Cingulate Cortex and Orbitofrontal Cortex

Background: Brain dopamine is implicated in the regulation of movement, attention, reward and learning and plays an important role in Parkinson’s disease, schizophrenia and drug addiction. Animal experiments have demonstrated that brain stimulation is able to induce significant dopaminergic changes in extrastriatal areas. Given the up-growing interest of noninvasive brain stimulation as potential tool for treatment of neurological and psychiatric disorders, it would be critical to investigate dopaminergic functional interactions in the prefrontal cortex and more in particular the effect of dorsolateral prefrontal cortex (DLPFC) (areas 9/46) stimulation on prefrontal dopamine (DA). Methodology/Principal Findings: Healthy volunteers were studied with a high-affinity DA D2-receptor radioligand, [ 11 C]FLB 457-PET following 10 Hz repetitive transcranial magnetic stimulation (rTMS) of the left and right DLPFC. rTMS on the left DLPFC induced a significant reduction in [ 11 C]FLB 457 binding potential (BP) in the ipsilateral subgenual anterior cingulate cortex (ACC) (BA 25/12), pregenual ACC (BA 32) and medial orbitofrontal cortex (BA 11). There were no significant changes in [ 11 C]FLB 457 BP following right DLPFC rTMS. Conclusions/Significance: To our knowledge, this is the first study to provide evidence of extrastriatal DA modulation following acute rTMS of DLPFC with its effect limited to the specific areas of medial prefrontal cortex. [ 11 C]FLB 457-PET combined with rTMS may allow to explore the neurochemical functions of specific cortical neural networks and help t

The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker

Temporal restriction of feeding can phase-shift behavioral and physiological circadian rhythms in mammals. These changes in biological rhythms are postulated to be brought about by a food-entrainable oscillator (FEO) that is independent of the suprachiasmatic nucleus. However, the neural substrates of FEO have remained elusive. Here, we carried out an unbiased search for mouse brain region(s) that exhibit a rhythmic expression of the Period genes in a feeding-entrainable manner. We found that the compact part of the dorsomedial hypothalamic nucleus (DMH) demonstrates a robust oscillation of mPer expression only under restricted feeding. The oscillation persisted for at least 2 days even when mice were given no food during the expected feeding period after the establishment of food-entrained behavioral rhythms. Moreover, refeeding after fasting rapidly induced a transient mPer expression in the same area of DMH. Taken in conjunction with recent findings (i) that behavioral expression of food-entrainable circadian rhythms is blocked by cell-specific lesions of DMH in rats and (ii) that DMH neurons directly project to orexin neurons in the lateral hypothalamus, which are essential for proper expression of food-entrained behavioral rhythms, the present study suggests that DMH plays a key role as a central FEO in the feeding-mediated regulation of circadian behaviors

A robust automated system elucidates mouse home cage behavioral structure

Patterns of behavior exhibited by mice in their home cages reflect the function and interaction of numerous behavioral and physiological systems. Detailed assessment of these patterns thus has the potential to provide a powerful tool for understanding basic aspects of behavioral regulation and their perturbation by disease processes. However, the capacity to identify and examine these patterns in terms of their discrete levels of organization across diverse behaviors has been difficult to achieve and automate. Here, we describe an automated approach for the quantitative characterization of fundamental behavioral elements and their patterns in the freely behaving mouse. We demonstrate the utility of this approach by identifying unique features of home cage behavioral structure and changes in distinct levels of behavioral organization in mice with single gene mutations altering energy balance. The robust, automated, reproducible quantification of mouse home cage behavioral structure detailed here should have wide applicability for the study of mammalian physiology, behavior, and disease