[Circadian rhythms and depression]. / Störung zirkadianer Rhythmen im Kontext depressiver Erkrankungen.

Depressive disorders are associated with various neurobiological alterations like hyperactivity of the hypothalamic-pituitary-adrenal axis, altered neuroplasticity and altered circadian rhythms. Relating to the circadian symptoms, a process is adopted in which individual genetic factors together with social, psychological and physical stressors may lead to a decompensation of the circadian system. The causal connections between depressive disorders and disturbed circadian rhythms have not been completely clarified. Chronobiological therapy is based on these disturbed processes. For the treatment of the circadian symptoms, various scientifically tested chronotherapeutics are available with however different effectiveness and evidence like light therapy or sleep deprivation. The successful treatment of depression also frequently leads to a improvement in altered circadian rhythm.

Feasibility, safety and efficacy of transcutaneous vagus nerve stimulation in chronic tinnitus: an open pilot study.

OBJECTIVES: Vagus nerve stimulation represents an established treatment strategy for epilepsy and affective disorders. Recently, positive effects were also shown in animals and humans with tinnitus. Here we report the results of an open pilot study exploring feasibility, safety and efficacy of tVNS in the treatment of chronic tinnitus. STUDY DESIGN: Fifty patients with chronic tinnitus underwent tVNS in an open single-armed pilot study which was conducted in two phases applying two different stimulating devices (Cerbomed CM02 and NEMOS). Clinical assessment was based on Tinnitus Questionnaire (TQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), WHO Quality of Life, and various numeric rating scales. Primary outcome was defined as change in TQ (baseline vs. final visit in week 24). The study has been registered with clinicaltrials.gov (NCT01176734). RESULTS: Primary analysis indicated mean TQ reductions of 3.7 points (phase 1) and 2.8 points (phase 2) significant for the first study phase. Secondary analyses indicated a significant BDI reduction for phase 1 (uncorrected for multiple testing), but no further systematic or significant effects. Adverse events included twitching and pressure at electrode placement site. The occurrence of one hospitalization because of palpations and the development of a left bundle branch block were considered as unrelated to the intervention. Cognitive testing revealed no significant changes. CONCLUSION: Our data demonstrate the feasibility of tVNS over a period of 6 months. There was no clinically relevant improvement of tinnitus complaints. Our data suggest tVNS to be considered safe in patients without a history of cardiac disease.

Mindfulness-and body-psychotherapy-based group treatment of chronic tinnitus: a randomized controlled pilot study.

BACKGROUND: Tinnitus, the perception of sound in absence of an external acoustic source, impairs the quality of life in 2% of the population. Since in most cases causal treatment is not possible, the majority of therapeutic attempts aim at developing and strengthening individual coping and habituation strategies. Therapeutic interventions that incorporate training in mindfulness meditation have become increasingly popular in the treatment of stress-related disorders. Here we conducted a randomized, controlled clinical study to investigate the efficacy of a specific mindfulness- and body-psychotherapy based program in patients suffering from chronic tinnitus. METHODS: Thirty-six patients were enrolled in this pilot study. The treatment was specifically developed for tinnitus patients and is based on mindfulness and body psychotherapy. Treatment was performed as group therapy at two training weekends that were separated by an interval of 7 weeks (eleven hours/weekend) and in four further two-hour sessions (week 2, 9, 18 and 22). Patients were randomized to receive treatment either immediately or after waiting time, which served as a control condition. The primary study outcome was the change in tinnitus complaints as measured by the German Version of the Tinnitus Questionnaire (TQ). RESULTS: ANOVA testing for the primary outcome showed a significant interaction effect time by group (F = 7.4; df = 1,33; p = 0.010). Post hoc t-tests indicated an amelioration of TQ scores from baseline to week 9 in both groups (intervention group: t = 6.2; df = 17; p < 0.001; control group: t = 2.5; df = 16; p = 0.023), but the intervention group improved more than the control group. Groups differed at week 7 and 9, but not at week 24 as far as the TQ score was concerned. CONCLUSIONS: Our results suggest that this mindfulness- and body-psychotherapy-based approach is feasible in the treatment of tinnitus and merits further evaluation in clinical studies with larger sample sizes.The study is registered with clinicaltrials.gov (NCT01540357).

Treatment of chronic tinnitus with repeated sessions of prefrontal transcranial direct current stimulation: outcomes from an open-label pilot study.

Tinnitus is the perception of sound in the absence of an environmental sound source. Abnormal activity in central auditory pathways is considered as the neuronal correlate of tinnitus. However, there is increasing evidence from neuroimaging studies for an additional involvement of the frontal cortex in the pathophysiology of tinnitus, especially concerning its attentional and emotional aspects. Recently, in a subgroup of tinnitus patients, temporary reduction of tinnitus intensity and tinnitus-related distress has been reported after bifrontal tDCS with the anode over the right and the cathode over the left dorsolateral prefrontal cortex (DLPFC). The aim of this study was to investigate whether repeated application of bifrontal tDCS results in longer-lasting reduction of tinnitus and may represent a potential treatment approach. Thirty-two patients with chronic and treatment-resistant tinnitus received six sessions of bifrontal tDCS (1.5 mA, 30 min, two sessions per week) with the anode over the right and the cathode over the left DLPFC. Treatment outcome was assessed with several standardized tinnitus questionnaires, numeric rating scales, and a depression scale. In the entire group, beneficial effects of bifrontal tDCS on tinnitus were found for numeric rating scores of loudness, unpleasantness, and discomfort, but not in tinnitus or depression scales. Exploratory analysis revealed an effect of gender on treatment effects with female patients demonstrating a better response in several scores. Our open-label pilot study suggests some beneficial effect of bifrontal tDCS (anode right and cathode left) in the treatment of severe tinnitus, warranting further controlled studies.

Paired associative stimulation of the auditory system: a proof-of-principle study.

BACKGROUND: Paired associative stimulation (PAS) consisting of repeated application of transcranial magnetic stimulation (TMS) pulses and contingent exteroceptive stimuli has been shown to induce neuroplastic effects in the motor and somatosensory system. The objective was to investigate whether the auditory system can be modulated by PAS. METHODS: Acoustic stimuli (4 kHz) were paired with TMS of the auditory cortex with intervals of either 45 ms (PAS(45 ms)) or 10 ms (PAS(10 ms)). Two-hundred paired stimuli were applied at 0.1 Hz and effects were compared with low frequency repetitive TMS (rTMS) at 0.1 Hz (200 stimuli) and 1 Hz (1000 stimuli) in eleven healthy students. Auditory cortex excitability was measured before and after the interventions by long latency auditory evoked potentials (AEPs) for the tone (4 kHz) used in the pairing, and a control tone (1 kHz) in a within subjects design. RESULTS: Amplitudes of the N1-P2 complex were reduced for the 4 kHz tone after both PAS(45 ms) and PAS(10 ms), but not after the 0.1 Hz and 1 Hz rTMS protocols with more pronounced effects for PAS(45 ms). Similar, but less pronounced effects were observed for the 1 kHz control tone. CONCLUSION: These findings indicate that paired associative stimulation may induce tonotopically specific and also tone unspecific human auditory cortex plasticity.

Modulation of human motor cortex excitability by valproate.

RATIONALE: Valproate is widely used in the treatment of epilepsy, bipolar disorder, and chronic pain disorders, but its exact mechanisms of action is still incompletely understood. OBJECTIVES: Here we used transcranial magnetic stimulation to explore effects of a single dose of 800 mg valproate on motor cortex excitability in healthy volunteers. METHODS: Motor threshold, peripheral maximum M-wave, cortical silent period short intracortical inhibition, intracortical facilitation, and motor evoked potential recruitment were assessed before and 1.5 h after the administration of valproate in 15 (eight male, seven female) healthy volunteers. RESULTS: None of the measures of cortical excitability were found to be altered significantly after valproate. CONCLUSION: These results are in line with previous findings of unaffected intracortical excitability after a single dose of valproate, suggesting that valproate's immediate in vivo actions do not resemble the effects of classic GABAergic compounds.

Controversy: Does repetitive transcranial magnetic stimulation/ transcranial direct current stimulation show efficacy in treating tinnitus patients?

BACKGROUND: Tinnitus affects 10% of the population, its pathophysiology remains incompletely understood, and treatment is elusive. Functional imaging has demonstrated a relationship between the intensity of tinnitus and the degree of reorganization in the auditory cortex. Experimental studies have further shown that tinnitus is associated with synchronized hyperactivity in the auditory cortex. Therefore, targeted modulation of auditory cortex has been proposed as a new therapeutic approach for chronic tinnitus. METHODS: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive methods that can modulate cortical activity. These techniques have been applied in different ways in patients with chronic tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been successful in reducing the intensity of tinnitus during the time of stimulation and could be predictive for treatment outcome of chronic epidural stimulation using implanted electrodes. RESULTS: Another approach that uses rTMS as a treatment for tinnitus is application of low-frequency rTMS in repeated sessions, to induce a lasting change of neuronal activity in the auditory cortex beyond the duration of stimulation. Beneficial effects of this treatment have been consistently demonstrated in several small controlled studies. However, results are characterized by high interindividual variability and only a moderate decrease of the tinnitus. The role of patient-related (for example, hearing loss, tinnitus duration, age) and stimulation-related (for example, stimulation site, stimulation protocols) factors still remains to be elucidated. CONCLUSIONS: Even in this early stage of investigation, there is a convincing body of evidence that rTMS represents a promising tool for pathophysiological assessment and therapeutic management of tinnitus. Further development of this technique will depend on a more detailed understanding of the neurobiological effects mediating the benefit of TMS on tinnitus perception. Moreover clinical studies with larger sample sizes and longer follow-up periods are needed.

Cerebellar and thalamic metabolic changes visualized by [18]-FDG-PET in olanzapine-induced acute akathisia.

OBJECTIVES: Akathisia is a clinical important symptom, frequently induced by neuroleptic treatment. Despite its clinical importance, less is known about its pathophysiology. METHODS: Using [18]-FDG-PET, imaging patterns of cortical metabolic activity were obtained in a patient during olanzapine-induced akathisia and after recovery. RESULTS: Akathisia was characterized by a reduced metabolic activity in thalamus and cerebellum. After discontinuing medication akathisia disappeared, reflected by a recovery of metabolic activity in these brain areas. CONCLUSION: [18]-FDG-PET may be useful to identify cortical regions mediating clinical aspects of drug-induced akathisia, thereby offering a deeper insight into the pathophysiology of this serious side effect.