Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been proposed as a feasible treatment for major depressive disorder (MDD). However, meta-analytic evidence is heterogenous and data from multicentre trials are scarce. We aimed to assess the efficacy of tDCS versus sham stimulation as an additional treatment to a stable dose of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. METHODS: The DepressionDC trial was triple-blind, randomised, and sham-controlled and conducted at eight hospitals in Germany. Patients being treated at a participating hospital aged 18-65 years were eligible if they had a diagnosis of MDD, a score of at least 15 on the Hamilton Depression Rating Scale (21-item version), no response to at least one antidepressant trial in their current depressive episode, and treatment with an SSRI at a stable dose for at least 4 weeks before inclusion; the SSRI was continued at the same dose during stimulation. Patients were allocated (1:1) by fixed-blocked randomisation to receive either 30 min of 2 mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks, or sham stimulation at the same intervals. Randomisation was stratified by site and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score (ie, <31 or ≥31). Participants, raters, and operators were masked to treatment assignment. The primary outcome was change on the MADRS at week 6, analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one treatment session. The trial was registered with ClinicalTrials.gov (NCT02530164). FINDINGS: Between Jan 19, 2016, and June 15, 2020, 3601 individuals were assessed for eligibility. 160 patients were included and randomly assigned to receive either active tDCS (n=83) or sham tDCS (n=77). Six patients withdrew consent and four patients were found to have been wrongly included, so data from 150 patients were analysed (89 [59%] were female and 61 [41%] were male). No intergroup difference was found in mean improvement on the MADRS at week 6 between the active tDCS group (n=77; -8·2, SD 7·2) and the sham tDCS group (n=73; -8·0, 9·3; difference 0·3 [95% CI -2·4 to 2·9]). Significantly more participants had one or more mild adverse events in the active tDCS group (50 [60%] of 83) than in the sham tDCS group (33 [43%] of 77; p=0·028). INTERPRETATION: Active tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. FUNDING: German Federal Ministry of Education and Research.

Theta burst stimulation add on to dialectical behavioral therapy in borderline-personality-disorder: methods and design of a randomized, single-blind, placebo-controlled pilot trial.

Specialized psychotherapeutic treatments like dialectical behavioral therapy (DBT) are recommended as first treatment for borderline personality disorder (BPD). In recent years, studies have emerged that focus on repetitive transcranial magnetic stimulation (rTMS) in BPD. Both have independently demonstrated efficacy in the treatment of BPD. Intermitted theta burst stimulation (iTBS), a modified design of rTMS, is thought to increase the excitability of neurons and could be a supplement to psychotherapy in addition to being a standalone treatment. However, no studies to date have investigated the combination of DBT and rTMS/iTBS. This study protocol describes the methods and design of a randomized, single-blinded, sham-controlled clinical pilot study in which BPD patients will be randomly assigned to either iTBS or sham during four consecutive weeks (20 sessions in total) in addition to standardized DBT treatment. The stimulation will focus on the unilateral stimulation of the left dorsolateral prefrontal cortex (DLPFC), which plays an important role in the control of impulsivity and risk-taking. Primary outcome is the difference in borderline symptomatology, while secondary target criteria are depressive symptoms, general functional level, impulsivity and self-compassion. Statistical analysis of therapy response will be conducted by Mixed Model Repeated Measurement using a 2 × 2-factorial between-subjects design with the between-subject factor stimulation (TMS vs. Sham) and the within-subject factor time (T0 vs. T1). Furthermore, structural magnetic resonance imaging (MRI) will be conducted and analyzed. The study will provide evidence and insight on whether iTBS has an enhancing effect as add-on to DBT in BPD.Trial registration: drks.de (DRKS00020413) registered 13/01/2020.

Treatment of adult attention-deficit hyperactivity disorder (ADHD) with transcranial direct current stimulation (tDCS): study protocol for a parallel, randomized, double-blinded, sham-controlled, multicenter trial (Stim-ADHD).

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation treatment used as an alternative or complementary treatment for various neuropsychiatric disorders, and could be an alternative or add-on therapy to psychostimulants in attention-deficit hyperactivity disorder (ADHD). Previous studies provided some evidence for improvements in cognition and clinical symptoms in pediatric and adult ADHD patients. However, data from multi-center randomized controlled trials (RCTs) for this condition are lacking. Thus, our aim is to evaluate short- and mid-term effects of tDCS in this multi-center, randomized, double blind, and sham-controlled, parallel group clinical trial with a 1:1 randomization ratio. Primary endpoint is the total score of DSM-IV scale of the internationally established Conners' Adult ADHD Rating Scales (German self-report screening version, CAARS-S-SR), at day 14 post-intervention (p.i.) to detect short-term lasting effects analyzed via analyses of covariance (ANCOVAs). In case of significant between-groups differences at day 14 p.i., hierarchically ordered hypotheses on mid-term lasting effects will be investigated by linear mixed models with visit (5 time points), treatment, treatment by visit interaction, and covariates as fixed categorical effects plus a patient-specific visit random effect, using an unstructured covariance structure to model the residual within-patient errors. Positive results of this clinical trial will expand the treatment options for adult ADHD patients with tDCS and provide an alternative or add-on therapy to psychostimulants with a low risk for side effects.Trial Registration The trial was registered on July 29, 2022 in the German Clinical Trials Register (DRKS00028148).

Neurocognitive function as outcome and predictor for prefrontal transcranial direct current stimulation in major depressive disorder: an analysis from the DepressionDC trial.

Transcranial direct current stimulation (tDCS) of the prefrontal cortex might beneficially influence neurocognitive dysfunctions associated with major depressive disorder (MDD). However, previous studies of neurocognitive effects of tDCS have been inconclusive. In the current study, we analyzed longitudinal, neurocognitive data from 101 participants of a randomized controlled multicenter trial (DepressionDC), investigating the efficacy of bifrontal tDCS (2 mA, 30 min/d, for 6 weeks) in patients with MDD and insufficient response to selective serotonin reuptake inhibitors (SSRI). We assessed whether active tDCS compared to sham tDCS elicited beneficial effects across the domains of memory span, working memory, selective attention, sustained attention, executive process, and processing speed, assessed with a validated, digital test battery. Additionally, we explored whether baseline cognitive performance, as a proxy of fronto-parietal-network functioning, predicts the antidepressant effects of active tDCS versus sham tDCS. We found no statistically significant group differences in the change of neurocognitive performance between active and sham tDCS. Furthermore, baseline cognitive performance did not predict the clinical response to tDCS. Our findings indicate no advantage in neurocognition due to active tDCS in MDD. Additional research is required to systematically investigate the effects of tDCS protocols on neurocognitive performance in patients with MDD.

Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

Inhibitory Control Training Enhanced by Transcranial Direct Current Stimulation to Reduce Binge Eating Episodes: Findings from the Randomized Phase II ACCElect Trial.

INTRODUCTION: Binge eating disorder (BED) is characterized by recurrent binge eating (BE) episodes with loss of control. Inhibitory control impairments, including alterations in dorsolateral prefrontal cortex (dlPFC) functioning, have been described for BED. A targeted modulation of inhibitory control circuits by the combination of inhibitory control training and transcranial brain stimulation could be promising. OBJECTIVE: The aim of the study was to demonstrate feasibility and clinical effects of a transcranial direct current stimulation (tDCS)-enhanced inhibitory control training to reduce BE episodes and to generate an empirical basis for a confirmatory trial. METHODS: We performed a monocentric clinical phase II double-blind randomized trial with two parallel arms. Forty-one adult outpatients with full-syndrome BED according to DSM-5 received six sessions of food-related inhibitory control training, randomly combined with 2 mA verum or sham tDCS of the right dlPFC. The main outcome was BE frequency within a 4-week interval after treatment termination (T8; primary) and at 12-week follow-up (T9; secondary) as compared to baseline. RESULTS: BE frequency was reduced in the sham group from 15.5 to 5.9 (T8) and to 6.8 (T9); in the verum group, the reduction was 18.6 to 4.4 (T8) resp. 3.8 (T9). Poisson regression with the study arm as the factor and baseline BE frequency as the covariate revealed a p value of 0.34 for T8 and 0.026 for T9. Sham and real tDCS differed at T9 in BE frequency. CONCLUSIONS: Inhibitory control training enhanced by tDCS is safe in patients with BED and results in a substantial and sustainable reduction in BE frequency which unfolds over several weeks post-treatment. These results constitute the empirical basis for a confirmatory trial.

Behavioural biases in the interaction with food objects in virtual reality and its clinical implication for binge eating disorder.

Cognitive processes play a central role in the development, maintenance and remission in mental disorders, like in Binge Eating Disorder (BED). Insights into cognitive mechanisms reflected by embodied interaction with food and its connections to clinically relevant psychopathology offer new possibilities for translational diagnostics and interventions. We longitudinally investigated the manual interaction with food in a virtual reality (VR) in 31 patients with BED. Patients were assessed at baseline before participating in a randomized-controlled trial (RCT) investigating a computer-based inhibitory control training programme enhanced by transcranial direct current stimulation (tDCS) and at a 6-week follow-up. At both assessments, an experimental VR paradigm was conducted and patients were characterized concerning eating disorder psychopathology, eating behaviour, general impulsivity and food craving. In the experimental task, one of two simultaneously presented objects (food vs. office tools) had to be collected. Food was recognized faster than office tools and subsequent approach behaviour was initiated faster, whereas thereafter, food was collected slower than office tools. Exploratory, we could not find a modulatory effect of applied tDCS on the interaction with food. No relationship between behavioural biases and sample characterizations could be detected. Two different stages in the manual interaction with food were found: a faster first stage that comprises recognition and movement initiation and a slower second stage that comprises controlled handling and may reflect aversive motivational processes. As the behavioural patterns do not change with an ameliorated BED-psychopathology at the second assessment, the task seems insensitive in detecting translational interconnections between behavioural biases and BED-characteristics.Level of evidence: Level I, experimental study.

Investigating mechanisms of cognitive control training: neural signatures of PASAT performance in depressed patients.

Major depression disorder (MDD) is characterized by cognitive control (CC) dysfunctions associated with increased attention toward negative information. The paced auditory serial addition task (PASAT) has been used as a targeted training of CC and studies show promising effects on depressive symptoms. However, neural mechanisms underlying its efficacy are still unclear. Based on previous findings of feedback-locked event-related potentials in healthy subjects, we investigated neural signatures during PASAT performance in 46 depressed patients. We found significantly larger amplitudes after negative than positive feedback for the P300 and late positive potential (LPP). However, this difference was not significant for the feedback-related negativity (FRN). Moreover, no associations of valence-specific ERPs and PASAT performance nor depressive symptoms were found. This indicates that depressed patients seem unable to use neural activation in late feedback processing stages (P300, LPP) to adapt accordingly. Moreover, lack of valence-specific neural reaction in early feedback processing stages (FRN) might point toward emotional indifference in depressed patients.Trial registration number: NCT03518749 Date of registration: May 8, 2018.

Implicit measures of alcohol approach and drinking identity in alcohol use disorder: A preregistered double-blind randomized trial with cathodal transcranial direct current stimulation (tDCS).

Alcohol use disorder (AUD) is a severe and widespread mental disorder with a huge negative impact on the social, economic and health dimensions. The identification of risk factors for the development of AUD and for relapse in existing AUD are crucial for prevention and treatment approaches. Alcohol-related implicit associations have been shown to contribute to drinking and might partially explain sudden relapses. The aims of this study are to investigate implicit associations in abstinent AUD patients and to test whether cathodal transcranial direct current stimulation (tDCS) modulates implicit associations. We measured performance in two alcohol-related implicit association tests (IATs) and two control tasks (flower-insect IAT, Stroop task) in 27 abstinent AUD patients with 31.5 (SD = 36) days of abstinence on average. During the execution of the tasks, we applied 1 mA cathodal or sham tDCS over the left dorsolateral prefrontal cortex (dlPFC) in a sham-controlled within-subject design. Results show an implicit bias of alcohol avoidance and implicit nondrinking identity for abstinent AUD patients. Cathodal tDCS modulated neither alcohol-related implicit associations nor the control tasks. This study complements knowledge about implicit alcohol-related association in AUD patients and shows no effect of a neuromodulatory intervention to alter implicit associations with the present parameters.

[Non-Invasive Brain Stimulation in Psychiatric Disorders]. / Nichtinvasive Hirnstimulationsverfahren in der Psychiatrie.

Based on neurophysiological findings, non-invasive brain stimulation methods offer an integrative treatment approach for mental disorders. Some of the stimulation methods have already been extensively studied for specific psychiatric indications and have become established as reasonable treatment option. For example, transcranial magnetic stimulation (TMS) for the treatment of refractory depression received approval from the Food and Drug Administration (FDA) in the United States in 2008. However, in Europe and especially in Germany, TMS is not widely offered even in a university setting. The following article describes the available technologies and their biological mechanisms of action, outlines the clinical indication and application of TMS, and summarizes the clinical evidence. The article is based on recently published guidelines for the therapeutic use of non-invasive brain stimulation 1 2 3.

Combined antisaccade task and transcranial direct current stimulation to increase response inhibition in binge eating disorder.

Binge eating disorder (BED) is associated with deficient response inhibition. Malfunctioning response inhibition is linked to hypoactivation of the dorsolateral prefrontal cortex (dlPFC), where excitability could be increased by anodal transcranial direct current stimulation (tDCS). Response inhibition can be assessed using an antisaccade task which requires supressing a dominant response (i.e. saccade) towards a newly appearing picture in the visual field. We performed a double-blind, randomised, placebo-controlled proof-of-concept-study in which we combined a food-modified antisaccade task with tDCS in people with BED. We expected task learning and modulatory tDCS effects. Sixteen people were allocated to a 1 mA condition, 15 people to a 2 mA condition. Each participant underwent the food-modified antisaccade task at three measurement points: baseline without stimulation, anodal verum and sham stimulation at the right dlPFC in a crossover design. The error rate and the latencies of correct antisaccades decreased over time. No tDCS effect on the error rate could be observed. Compared to sham stimulation, 2 mA tDCS decreased the latencies of correct antisaccades, whereas 1 mA tDCS increased it. Self-reported binge eating episodes were reduced in the 2 mA condition, while there was no change in the 1 mA condition. Participants demonstrated increased response inhibition capacities by a task learning effect concerning the error rate and latencies of correct antisaccades over time as well as a nonlinear tDCS effect represented by ameliorated latencies in the 2 mA and impaired latencies in the 1 mA condition. The reduction of binge eating episodes might indicate a transfer effect to everyday life. Given that the reduction in binge eating was observed before tDCS administration, this effect could not be the result of neuromodulation. Randomized clinical trials are needed to fully understand this reduction, and to explore the efficacy of a combined antisaccade and tDCS training for BED.

Treatment of major depressive disorder with bilateral theta burst stimulation: study protocol for a randomized, double-blind, placebo-controlled multicenter trial (TBS-D).

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

Effects of 1 mA and 2 mA transcranial direct current stimulation on working memory performance in healthy participants.

Anodal transcranial current stimulation (tDCS) to the left dorsolateral prefrontal cortex (DLPFC) has been shown to enhance working memory (WM) in neuropsychiatric patients. In healthy populations, however, tDCS obtains inconclusive results, mostly due to heterogeneous study and stimulation protocols. Here, we approached these issues by investigating effects of tDCS intensity on simultaneous WM performance with three cognitive loads by directly comparing findings of two double-blind, cross-over, sham-controlled experiments. TDCS was administrated to the left DLPFC at intensity of 1 mA (Experiment 1) or 2 mA (Experiment 2), while participants completed a verbal n-back paradigm (1-, 2-, 3-back). Analysis showed no overall effects of tDCS on WM, but a significant interaction with cognitive load. The present study suggests that cognitive load rather than tDCS intensity could be a decisive factor for effects on WM. Moreover, it emphasizes the need of thorough investigation on study parameters to develop more efficient stimulation protocols.

[Non-Invasive Brain Stimulation in the Treatment of Eating Disorders - A Narrative Review]. / Nicht-invasive Hirnstimulation als Behandlungsverfahren bei Essstörungen ­ ein narrativer Überblick.

OBJECTIVE: Treatment success in many patients with eating disorders (ED) is not substantial and sustainable. Therefore, there is an urgent need for the advancement of existing treatment approaches and novel innovative interventions. Non-invasive brain stimulation (NIBS) is such an innovative approach which has recently been introduced to the treatment of ED patients. This article is a narrative review concerning the most frequently used brain stimulation techniques in ED and the current evidence concerning the efficacy of treatment. METHODS: We conducted a literature search in the PubMed database concerning the topic NIBS in ED and identified 32 relevant articles. Only 9 of these articles described empirical studies in patients with ED. RESULTS: The studies were conducted in patients with different ED diagnoses, regarding different treatment targets, used different stimulation techniques and showed differences in frequency, duration and intensity of the stimulation. Some, but not all of these studies suggest ameliorations of ED symptoms, e. g. reduction of food craving, restrictive eating and ED-related cognitions. DISCUSSION: Evidence is scarce and heterogeneous, but overall, the evidence suggests that NIBS is a promising treatment approach in ED.

Forgiveness and cognitive control - Provoking revenge via theta-burst-stimulation of the DLPFC.

In order to act in a socially acceptable way, the ability to forgive is indispensable. It has been suggested that forgiveness relies on cognitive control, more specifically inhibition. In this study, we combined an ultimatum game (UG) and a dictator game (DG) with inhibitory, continuous theta-burst stimulation (cTBS; verum vs. placebo, within-subjects design) of the right dorsolateral prefrontal cortex (DLPFC) to investigate the effect of reduced cognitive control on forgiveness. To this end, participants played an UG against fair and unfair opponents, where they had to accept or reject (fair and unfair) monetary offers, and then received a cTBS prior to playing a DG against the same opponents with reversed roles. The participants now had the possibility to forgive the unfair opponents (allocation of a fair amount of money) or to take revenge whereby the cTBS effects were assessed with functional near-infrared spectroscopy. Following verum cTBS, participants allocated significantly less money to their unfair opponents than in the placebo cTBS condition. Also, reaction times (RTs) differed significantly between verum and placebo cTBS for unfair opponents (higher RTs following verum stimulation) but not for fair opponents. These results strongly indicate that cognitive control is a fundamental requirement for overcoming unwanted emotional responses.

Reduction of implicit cognitive bias with cathodal tDCS to the left prefrontal cortex.

Implicit associations can interfere with cognitive operations and behavioral decisions without direct intention. Enhancement of neural activity with anodal transcranial direct current stimulation (tDCS) was proposed to reduce implicit associations by means of improved cognitive control. However, a targeted reduction of distractive implicit associations by inhibitory cathodal tDCS, recently shown in spatial-numerical associations, provides an interesting alternative approach to support goal-directed behavior with transcranial brain stimulation. To test this rationale with a sham-controlled cross-over design, a standardized Implicit Association Test (IAT) was performed by 24 healthy participants parallel to 1 mA cathodal or sham tDCS to the left prefrontal cortex. In this double-classification task, insect versus flower pictures and negative versus positive words are mapped together onto two shared response keys with crossed response assignments in separate blocks. Responses were faster when insect + negative and flower + positive stimuli required the same answer (IAT effect). Most critically, the IAT effect was reduced during cathodal tDCS as compared to sham stimulation. Thus, results are consistent with the proposed stimulation rationale, with previous observations, and complementary to previous studies using different tDCS configurations.

Treatment of auditory hallucinations with bilateral theta burst stimulation (cTBS): protocol of a randomized, double-blind, placebo-controlled, multicenter trial.

Auditory verbal hallucinations (AH) are core symptoms of schizophrenia. They are often severely distressing and refractory to therapy. Their perception is associated with increased activity in temporoparietal areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) can reduce focal brain hyperactivity and has been shown to ameliorate AH. However, controlled multicenter clinical trials are still missing, effect sizes are moderate, and the treatment with rTMS is time consuming. Continuous theta burst stimulation (cTBS) is a quicker and potentially more effective technique to reduce cortical hyperactivity. First case and pilot studies indicate effectiveness in the treatment of AH. In this randomized, sham-controlled, double-blind multicenter clinical trial, 86 patients with schizophrenia spectrum disorder will be randomized to either cTBS or sham to the left and right temporoparietal cortex during three consecutive weeks (15 sessions totally). In each session, both hemispheres will be stimulated sequentially. The order in the first session (left-right or right-left, respectively) will be determined by randomization and alternated in all following sessions. Primary outcome is the reduction of mean PSYRATS-AH score after cTBS as compared to sham treatment. Follow-up measurements will be performed 1, 3 and 6 months after the end of the treatment. Statistical analysis will be based on the intention-to-treat population including all randomized patients using an analysis of covariance. This multicenter-controlled clinical trial will be able to provide decisive evidence for the efficacy of cTBS in the treatment of AH. The results will be suitable to clarify the role of this innovative, pathophysiology-based therapeutic approach in treatment guidelines for AH. TRIAL REGISTRY: ClinicalTrials.gov identifier: NCT02670291.

PsychotherapyPlus: augmentation of cognitive behavioral therapy (CBT) with prefrontal transcranial direct current stimulation (tDCS) in major depressive disorder-study design and methodology of a multicenter double-blind randomized placebo-controlled trial.

Major Depressive Disorder (MDD) is one of the most prevalent psychiatric disorders worldwide. About 20-30% of patients do not respond to the standard psychopharmacological and/or psychotherapeutic interventions. Mounting evidence from neuroimaging studies in MDD patients reveal altered activation patterns in lateral prefrontal brain areas. Successful cognitive behavioral therapy (CBT) is associated with a recovery of these neural alterations. Moreover, it has been demonstrated that transcranial direct current stimulation (tDCS) is capable of influencing prefrontal cortex activity and cognitive functions such as working memory and emotion regulation. Thus, a clinical trial investigating the effects of an antidepressant intervention combining CBT with tDCS seems promising. The present study investigates the antidepressant efficacy of a combined CBT-tDCS intervention as compared to CBT with sham-tDCS or CBT alone. A total of 192 patients (age range 20-65 years) with MDD (Hamilton Depression Rating Scale Score ≥ 15, 21-item version) will be recruited at four study sites across Germany (Berlin, Munich, Tuebingen, and Freiburg) and randomly assigned to one of the following three treatment arms: (1) CBT + active tDCS; (2) CBT + sham-tDCS; and (3) CBT alone. All participants will attend a 6-week psychotherapeutic intervention comprising 12 sessions of CBT each lasting 100 min in a closed group setting. tDCS will be applied simultaneously with CBT. Active tDCS includes stimulation with an intensity of 2 mA for 30 min with the anode placed over F3 and the cathode over F4 according to the EEG 10-20 system, if assigned. The primary outcome measure is the change in Montgomery-Åsberg Depression Rating Scale scores from baseline to 6, 18, and 30 weeks after the first session. Participants also undergo pre- and post-treatment neuropsychological testing and functional magnetic resonance imaging (fMRI) to assess changes in prefrontal functioning and connectivity. The study investigates whether CBT can be augmented by non-invasive brain stimulation techniques such as tDCS in the treatment of MDD. It is designed as a proof-of-principle trial for the combined tDCS-CBT treatment, but also allows the investigation of the neurobiological underpinnings of the interaction between both interventions in MDD. Trial registration ClinicalTrials.gov Identifier NCT02633449.

Prefrontal transcranial direct current stimulation (tDCS) as treatment for major depression: study design and methodology of a multicenter triple blind randomized placebo controlled trial (DepressionDC).

Transcranial direct current stimulation (tDCS) has been proposed as novel treatment for major depressive disorder (MDD) based on clinical pilot studies as well as randomized controlled monocentric trials. The DepressionDC trial is a triple-blind (blinding of rater, operator and patient), randomized, placebo controlled multicenter trial investigating the efficacy and safety of prefrontal tDCS used as additive treatment in MDD patients who have not responded to selective serotonin reuptake inhibitors (SSRI). At 5 study sites, 152 patients with MDD receive a 6-weeks treatment with active tDCS (anode F3 and cathode F4, 2 mA intensity, 30 min/day) or sham tDCS add-on to a stable antidepressant medication with an SSRI. Follow-up visits are at 3 and 6 months after the last tDCS session. The primary outcome measure is the change of the Montgomery-Asberg Depression Rating Scale (MADRS) scores at week 6 post-randomisation compared to baseline. Secondary endpoints also cover other psychopathological domains, and a comprehensive safety assessment includes measures of cognition. Patients undergo optional investigations comprising genetic testing and functional magnetic resonance imaging (fMRI) of structural and functional connectivity. The study uses also an advanced tDCS technology including standard electrode positioning and recording of technical parameters (current, impedance, voltage) in every tDCS session. Aside reporting the study protocol here, we present a novel approach for monitoring technical parameters of tDCS which will allow quality control of stimulation and further analysis of the interaction between technical parameters and clinical outcome. The DepressionDC trial will hopefully answer the important clinical question whether prefrontal tDCS is a safe and effective antidepressant intervention in patients who have not sufficiently responded to SSRIs. TRIAL REGISTRY: ClinicalTrials.gov Identifier NCT0253016.

Counteracting Implicit Conflicts by Electrical Inhibition of the Prefrontal Cortex.

Cognitive conflicts and distractions by task-irrelevant information often counteract effective and goal-directed behaviors. In some cases, conflicting information can even emerge implicitly, without an overt distractor, by the automatic activation of mental representations. For instance, during number processing, magnitude information automatically elicits spatial associations resembling a mental number line. This spatial-numerical association of response codes (SNARC) effect can modulate cognitive-behavioral performance but is also highly flexible and context-dependent, which points toward a critical involvement of working memory functions. Transcranial direct current stimulation to the PFC, in turn, has been effective in modulating working memory-related cognitive performance. In a series of experiments, we here demonstrate that decreasing activity of the left PFC by cathodal transcranial direct current stimulation consistently and specifically eliminates implicit cognitive conflicts based on the SNARC effect, but explicit conflicts based on visuospatial distraction remain unaffected. This dissociation is polarity-specific and appears unrelated to functional magnitude processing as classified by regular numerical distance effects. These data demonstrate a causal involvement of the left PFC in implicit cognitive conflicts based on the automatic activation of spatial-numerical processing. Corroborating the critical interaction of brain stimulation and neurocognitive functions, our findings suggest that distraction from goal-directed behavior by automatic activation of implicit, task-irrelevant information can be blocked by the inhibition of prefrontal activity.