Transcranial Direct Current Stimulation (tDCS) for major depression - Interim analysis of cloud supervised technical data from the DepressionDC trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) of prefrontal cortex regions has been reported to exert antidepressant effects, though large scale multicenter trials in major depressive disorder (MDD) supporting this notion are still lacking. Application of tDCS in multicenter settings, however, requires measurement, storage and evaluation of technical parameters of tDCS sessions not only for safety reasons but also for quality control. To address this issue, we conducted an interim analysis of supervised technical data across study centers in order to monitor technical quality of tDCS in an ongoing multicenter RCT in MDD (DepressionDC trial). METHODS: Technical data of 818 active tDCS sessions were recorded, stored in a data cloud, and analysed without violating study blinding. Impedance, voltage and current were monitored continuously with one data point recorded every second of stimulation. RESULTS: Variability of impedance was considerable (1,42 kΩ, to 8,23 kΩ), inter-individually and even more intra-individually, but did not significantly differ between the study centre in Munich and all other sites. CONCLUSION: Measurement, centralized data storage via data cloud and remote supervision of technical parameters of tDCS are feasible and proposed for future RCTs on therapeutic tDCS in multiple settings.

Beneficial effects of anodal transcranial direct current stimulation (tDCS) on spatial working memory in patients with schizophrenia.

Schizophrenia is a severe and often detrimental psychiatric disorder. The individual patients' level of functioning is essentially determined by cognitive, particularly working memory (WM), deficits that are critically linked to dysfunctional activity of the dorsolateral prefrontal cortex (dlPFC). Transcranial direct current stimulation (tDCS) can transiently modulate activity of the dlPFC and remote areas and has been shown to improve WM functions. It may therefore provide a new, targeted treatment option. For this aim, the present study investigated the effect of anodal tDCS of different intensities on spatial WM in patients with schizophrenia. In two experiments, 32 patients performed a spatial n-back task with increasing WM load (1-, 2-, and 3-back) at baseline and in two sessions with anodal or sham tDCS (EXP I [n = 16]: 1 mA; EXP II [n = 16]: 2 mA) to the right dlPFC (cathode: left m. deltoideus). With 1 mA anodal tDCS, no effect on WM performance could be detected. However, 2 mA anodal tDCS increased accuracy (measured by d') of the task with the highest WM load (3-back). This effect was larger in patients with a lower level of general neurocognitive functioning. These results demonstrate a beneficial effect of 2 mA anodal tDCS on deficient WM accuracy in patients with schizophrenia particularly under challenging conditions and in subjects with higher cognitive impairments. This data will inform future clinical trials on tDCS-enhanced cognitive training to improve treatment of schizophrenia.

Effects of transcranial direct current stimulation on craving, heart-rate variability and prefrontal hemodynamics during smoking cue exposure.

OBJECTIVE: Drug-related cue exposure elicits craving and risk for relapse during recovery. Transcranial direct current stimulation is a promising research tool and possible treatment for relapse prevention. Enhanced functional neuroconnectivity is discussed as a treatment target. The goal of this research was to examine whether transcranial direct current stimulation affected cortical hemodynamic indicators of functional connectivity, craving, and heart rate variability during smoking-related cue exposure in non-treatment-seeking smokers. METHOD: In vivo smoking cue exposure supported by a 2mA transcranial direct current stimulation (anode: dorsolateral prefrontal cortex, cathode: orbitofrontal cortex; placebo-controlled, randomized, double-blind) in 29 (age: M=25, SD=5) German university students (smoking at least once a week). Cue reactivity was assessed on an autonomous (heart rate variability) and a subjective level (craving ratings). Functional near-infrared spectroscopy measured changes in the concentration of deoxygenated hemoglobin, and seed-based correlation analysis was used to quantify prefrontal connectivity of brain regions involved in cue reactivity. RESULTS: Cue exposure elicited increased subjective craving and heart rate variability changes in smokers. Connectivity between the orbitofrontal and dorsolateral prefrontal cortex was increased in subjects receiving verum compared to placebo stimulation (d=0.66). Hemodynamics in the left dorsolateral prefrontal cortex, however, increased in the group receiving sham stimulation (η2=0.140). Transcranial direct current stimulation did not significantly alter craving or heart rate variability during cue exposure. CONCLUSION: Prefrontal connectivity - between regions involved in the processing of reinforcement value and cognitive control - was increased by anodal transcranial direct current stimulation during smoking cue exposure. Possible clinical implications should be considered in future studies.

[Non-invasive brain stimulation for treatment of schizophrenic psychoses]. / Hirnstimulationsverfahren zur Behandlung schizophrener Psychosen.

Despite many different available pharmacological and psychosocial treatment options, an optimal control of symptoms is only partly possible for most schizophrenia patients. Especially, persistent auditory hallucinations, negative symptoms and cognitive impairment are difficult to treat symptoms. Several non-invasive brain stimulation techniques are increasingly being considered as new therapeutic add on options for the management of schizophrenia, targeting these symptom domains. The technique which has been available for the longest time and that is best established in clinical care is electroconvulsive therapy (ECT). New stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) allow a more pathophysiological-based approach. This review article introduces various non-invasive brain stimulation techniques and discusses recent treatment studies on schizophrenia. In total, the novel brain stimulation techniques discussed here can be considered relevant add on therapeutic approaches for schizophrenia. In this context, the best evidence is available for the application of rTMS for the treatment of negative symptoms and persistent auditory hallucinations; however, negative studies have also been published for both indications. Studies using other non-invasive brain stimulation techniques showed promising results but further research is needed to establish the clinical efficacy. Based on a growing pathophysiological knowledge, non-invasive brain stimulation techniques provide new treatment perspectives for patients with schizophrenia.

[Transcranial and invasive brain stimulation for depression]. / Transkranielle und invasive Hirnstimulationsverfahren bei Depression.

Considering the substantial proportion of depressed patients which does not sufficiently benefit from antidepressant pharmacotherapy or psychotherapy, there is increasing interest in non-pharmacological antidepressant strategies. Thus, a whole array of stimulation approaches has been developed as potential new antidepressant interventions. These methods include transcranial convulsive and non-convulsive approaches, e.g. electroconvulsive therapy (ECT), magnetic seizure therapy (MST), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as well as invasive techniques, e.g. deep brain stimulation (DBS), vagus nerve stimulation (VNS) and epidural cortical stimulation (ECS). Each method represents a specific therapeutic approach with distinct targets within neural networks involved in the pathophysiology of depression. The ECT procedure is an established treatment with the highest efficacy of all antidepressant interventions and TMS reaches the highest level of evidence among the novel neurostimulation approaches and may be clinically used. However, the field yields a promising rapid development which may substantially enrich the armamentarium of antidepressant interventions in the near future.

Treatment of chronic tinnitus with θ burst stimulation: a randomized controlled trial.

OBJECTIVE: To test whether 4 weeks of bilateral repetitive transcranial magnetic stimulation (rTMS) to the temporal or temporoparietal cortex is effective and safe in the treatment of chronic tinnitus. METHODS: In this controlled 3-armed trial, 48 patients with chronic tinnitus were treated with 4 weeks (20 sessions) of bilateral continuous theta burst stimulation (cTBS) at the Tübingen University Hospital. They were randomized to stimulation above the temporal cortex, the temporoparietal cortex, or as sham condition behind the mastoid. Patients were masked for the stimulation condition. Tinnitus severity was assessed after 2 and primarily 4 weeks of treatment and at 3 months follow-up with the tinnitus questionnaire and by a tinnitus change score. Audiologic safety was monitored by pure-tone and speech audiometry after 2 and 4 weeks of cTBS. RESULTS: Tinnitus severity was slightly reduced from baseline by a mean (SD) 2.6 (8.2) after sham, 2.4 (8.0) after temporoparietal, 2.2 (8.3) after temporal treatment of 16 patients each, but there was no significant difference between sham treatments and temporal (confidence interval [CI] -5.4 to +6.7) or temporoparietal cTBS (CI -5.9 to +6.3) or real cTBS (CI -7 to +5.1). Patients' global evaluation of tinnitus change after treatment did not indicate any effects. Audiologic measures were unaffected by treatment. CONCLUSIONS: Treating chronic tinnitus for 4 weeks by applying cTBS to the temporal or temporoparietal cortex of both hemispheres appears to be safe but not more effective than sham stimulation. However, these results are not to be generalized to all forms of rTMS treatments for tinnitus.

[Relapse rate within 6 months after successful ECT: a naturalistic prospective peer- and self-assessment analysis]. / Rückfallraten innerhalb von 6 Monaten nach erfolgreicher EKT--Eine naturalistische prospektive Fremd- und Selbstbeurteilungsanalyse.

BACKGROUND: Up to 100% relapse rate after successful electroconvulsive therapy (ECT) poses a challenge for patients and psychiatrists. The aim of the study was to evaluate the outcome of patients affected by major depression after the successful course of acute ECT. METHODS: 84 patients recruited in a randomized double blind multicenter study designed to investigate the optimal stimulation placement in acute ECT had a follow up under naturalistic conditions between the 5th and 7th month. Outcome, maintenance therapy and patients; attitude were evaluated with semi structured questionnaires by patients and the study raters. RESULTS: 82.14% (68/84) questionnaires of the patients and 83.3% (70/84) of the rater were returned. 98% of the patients had at least one antidepressant; only in 23% (20/68) lithium was prescribed. 35% (7/20) of the patients with lithium and 57% (16/28) without lithium had a relapse within the first 6 months (OR 0.6) in a median of 2.5 months. Only one institution offered maintenance ECT in 8.3% (7/84) patients. For 52.2% of the patients ECT was a helpful treatment an 49.3% would recommend the therapy to their relatives. The vast majority (59.4%) wishes a better information about the ECT and 21.4% feel frightening about the therapy. CONCLUSIONS: The results show a high relapse rate and highlight the meaning of maintenance medication especially for a lithium combination therapy, as stated before. In regard to the subjective sensation the patients claim a better education about the ECT and anyway one of four patients feel frightening about the therapy.

Antidepressant effects of augmentative transcranial magnetic stimulation: randomised multicentre trial.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new treatment option for depression. Previous studies were performed with low sample sizes in single centres and reported heterogeneous results. AIMS: To investigate the efficacy of rTMS as augmentative treatment in depression. METHOD: In a randomised, double-blind, sham-controlled multicentre trial 127 patients with moderate to severe depressive episodes were randomly assigned to real or sham stimulation for 3 weeks in addition to simultaneously initiated antidepressant medication. RESULTS: We found no difference in the responder rates of the real and the sham treatment groups (31% in each) or in the decrease of the scores on the depression rating scales. CONCLUSIONS: The data do not support previous reports from smaller samples indicating an augmenting or accelerating antidepressant effect of rTMS. Further exploration of the possible efficacy of other stimulation protocols or within selected sub-populations of patients is necessary.

Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study.

BACKGROUND: Tinnitus has been shown to respond to modulations of cortical activity by high-frequency and low-frequency repetitive transcranial magnetic stimulation (rTMS). OBJECTIVE: To determine the tinnitus-attenuating effects of a 2-week daily regimen of rTMS, navigated to the maximum of tinnitus-related increase in regional cerebral blood flow. METHODS: Six patients with chronic tinnitus were enrolled in this sham-controlled crossover study and treated with 2x2 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus-related increase in regional cerebral blood flow delineated by functional imaging with [15O]H2O positron emission tomography and a control area. Tinnitus-related distress was assessed before and after each treatment and 2 weeks after the end of the 4-week course of stimulation using a validated tinnitus questionnaire. Additional self-assessment scores of tinnitus change, loudness and annoyance were obtained. RESULTS: In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus-associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one. CONCLUSION: Tinnitus can be attenuated by low-frequency rTMS navigated to each person's maximum tinnitus-related cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus-related anterior cingulate cortex activation seems to predict the response to rTMS treatment.

[Which patients with major depression benefit from prefrontal repetitive magnetic stimulation]. / Welche depressiven Patienten profitieren von präfrontaler repetitiver transkranieller Magnetstimulation (RTMS)?

Antidepressive benefit of prefrontal repetitive magnetic stimulation (RTMS) for one or two weeks varies between 6 % and 60 % (mean 37 %) improvement of the Hamilton depression scale vs. 12 % improvement following sham RTMS. This variance is probably caused by study specific stimulus parameters but also by genetic, psychopathological and neuropsychological characteristics of the patients as well as by the functional state of the cortex area below the stimulation coil. Data from 10 open and 7 sham controlled studies including two own studies comprising more than 300 patients with major depression have been published to date. In synopsis several positive predictors for antidepressive response of prefrontal RTMS become apparent: 1) younger age, 2) somatic signs of anxiety, 3) lack of cortical hyperactivity below the magnetic coil pulsed by 10 Hz stimuli, 4) cortical hypermetabolism below the 1 Hz pulsed coil. Negative predictors of response to prefrontal RTMS were: 1) Advanced age, 2) prefrontal atrophy, 3) cognitive impairment in neuropsychological tasks assigned to the prefrontal cortex, 4) psychotic symptoms, 5) cortical hyperactivity below 10 Hz pulsed coil 6) non-response to electroconvulsive therapy (ECT). While prefrontal RTMS will probably not replace ECT in severe major depression with psychotic symptoms it could be beneficial especially in younger anxious patients without cognitive impairment.

Noradrenergic modulation of human cortex excitability by the presynaptic alpha(2)-antagonist yohimbine.

The objective of this study was to determine if yohimbine, a central norepinephrine enhancing drug, increases cortico-motoneuronal excitability in intact humans. Transcranial magnetic stimulation was used to assess excitability of the motor system reflected in the parameters motor threshold, recruitment curve, intracortical inhibition and intracortical facilitation before and after oral administration of 20 and 40 mg yohimbine. Oral intake of 40 but not 20 mg yohimbine increased slope and plateau of the recruitment curve and intracortical facilitation. Motor threshold and intracortical inhibition remained unchanged. The data show that pharmacological enhancement of central norepinephrine in humans is effective to increase the cortico-motoneuronal excitability. Since cortical excitability is closely linked to neuroplasticity, this observation might be of possible relevance for strategies to enhance rehabilitative processes after cortical lesions by pairing noradrenergic drugs with motor training.