Driving-related cognitive skills during antidepressant transcranial direct current stimulation: results in a subsample from the DepressionDC trial.

Therapeutic transcranial direct current stimulation (tDCS) is a well-tolerated neuromodulatory intervention. However, there are currently no data on its impact on driving skills. Therefore, we conducted a validated assessment of driving-related cognitive skills in participants of the DepressionDC trial, a multicenter, randomized-controlled trial investigating the antidepressant effects of 6-week prefrontal tDCS in patients with major depressive disorder (MDD). Twenty-one patients (12 women, active tDCS, n = 11, sham, n = 10) underwent an assessment of driving-related cognitive skills before and after the intervention. Using a Bayesian analysis approach, we found no group differences between active tDCS and sham tDCS in the pre-post treatment changes for visual perception (estimated median difference: 3.41 [-3.17, 10.55 89%-CI], BF01: 2.1), stress tolerance (estimated median difference: 0.77 [-2.40, 4.15 89%-CI], BF01: 1.6), and reaction time (estimated median difference: 2.06 [-12.33, 16.83 89%-CI], BF01: 6.5). Our results indicate that repeated sessions of a conventional bifrontal tDCS protocol do not negatively impact driving-related cognitive skills in patients with MDD.

Transcranial direct current stimulation as treatment for major depression in a home treatment setting (HomeDC trial): study protocol and methodology of a double-blind, placebo-controlled pilot study.

INTRODUCTION: Transcranial direct current stimulation (tDCS) of prefrontal cortex regions has been reported to exert therapeutic effects in patients with major depressive disorder (MDD). Due to its beneficial safety profile, its easy mode of application, and its cost-effectiveness, tDCS has recently been proposed for treatment at home. This would offer new chances for regionally widespread and long-term application. However, tDCS at home must meet the new methodological challenges of handling and adherence. At the same time, data from randomized controlled trials (RCT) investigating this mode of application are still lacking. In this pilot RCT, we therefore investigate the feasibility, safety, and effectiveness of a new antidepressant tDCS application set-up. METHODS AND ANALYSIS: The HomeDC trial will be conducted as a double-blind, placebo-controlled, parallel-group design trial. Thirty-two study participants with MDD will be randomly assigned to active or sham tDCS groups. Participants will self-administer prefrontal tDCS for 6 weeks. Active tDCS will be conducted with anode over F3, cathode over F4, for 5 sessions/week, with a duration of 30 min/day, and 2 mA stimulation intensity. Sham tDCS, conversely, follows an identical protocol in regard to electrode montage and timing, but with no electric stimulation between the ramp-in and ramp-out periods. Both conditions will be administered either as a monotherapy or an adjunctive treatment to a stable dose of antidepressant medication. Adjunctive magnetic resonance imaging (MRI) and electric field (E-field) modelling will be conducted at baseline. Primary outcome is feasibility based on successfully completed stimulations and drop-out rates. The intervention is considered feasible when 20 out of 30 sessions have been fully conducted by at least 75% of the participants. Effectiveness and safety will be assessed as secondary outcomes. DISCUSSION: In the HomeDC trial, the technical requirements for a placebo-controlled tDCS study in a home-based treatment setting have been established. The trial addresses the crucial points of the home-based tDCS treatment approach: uniform electrode positioning, frequent monitoring of stimulation parameters, adherence, and ensuring an appropriate home treatment environment. This study will further identify constraints and drawbacks of this novel mode of treatment. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . TRIAL REGISTRATION NUMBER: NCT05172505. Registration date: 12/13/2021.

Association between Mood and Sensation Seeking Following rTMS.

Previous studies investigating mood changes in healthy subjects after prefrontal repetitive transcranial magnetic stimulation (rTMS) have shown largely inconsistent results. This may be due to methodological issues, considerable inter-individual variation in prefrontal connectivity or other factors, e.g., personality traits. This pilot study investigates whether mood changes after rTMS are affected by personality parameters. In a randomized cross-over design, 17 healthy volunteers received three sessions of 1 Hz rTMS to Fz, F3 and T3 (10/20 system). The T3 electrode site served as the control condition with the coil angled 45° to the scalp. Subjective mood was rated at baseline and after each condition. Personality traits were assessed using the NEO Five-Factor Inventory (NEO-FFI) and the Sensation Seeking Scale (SSS). For all conditions, a significant association between mood changes towards a deterioration in mood and SSS scores was observed. There were no differences between conditions and no correlations between mood changes and NEO-FFI. The data show that sensation-seeking personality has an impact on subjective mood changes following prefrontal rTMS in all conditions. Future studies investigating the effects of rTMS on emotional paradigms should include individual measures of sensation-seeking personality. The pre-selection of subjects according to personality criteria may reduce the variability in results.

Improving mental health care in depression: A call for action.

Depressive disorders have one of the highest disability-adjusted life years (DALYs) of all medical conditions, which led the European Psychiatric Association to propose a policy paper, pinpointing their unmet health care and research needs. The first part focuses on what can be currently done to improve the care of patients with depression, and then discuss future trends for research and healthcare. Through the narration of clinical cases, the different points are illustrated. The necessary political framework is formulated, to implement such changes to fundamentally improve psychiatric care. The group of European Psychiatrist Association (EPA) experts insist on the need for (1) increased awareness of mental illness in primary care settings, (2) the development of novel (biological) markers, (3) the rapid implementation of machine learning (supporting diagnostics, prognostics, and therapeutics), (4) the generalized use of electronic devices and apps into everyday treatment, (5) the development of the new generation of treatment options, such as plasticity-promoting agents, and (6) the importance of comprehensive recovery approach. At a political level, the group also proposed four priorities, the need to (1) increase the use of open science, (2) implement reasonable data protection laws, (3) establish ethical electronic health records, and (4) enable better healthcare research and saving resources.

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.

TDCS at home for depressive disorders: an updated systematic review and lessons learned from a prematurely terminated randomized controlled pilot study.

The application of transcranial direct current stimulation (tDCS) at home for the treatment of major depressive disorder (MDD) is the subject of current clinical trials. This is due to its positive safety profile, cost-effectiveness, and potential scalability for a wide outreach in clinical practice. Here, we provide a systematic review of the available studies and also a report on the results of a randomized controlled trial (RCT) on tDCS at home for the treatment of MDD. This trial had to be prematurely terminated due to safety concerns. The HomeDC trial is a double-blinded, placebo-controlled, parallel-group study. Patients with MDD (DSM-5) were randomized to active or sham tDCS. Patients conducted tDCS at home for 6 weeks with 5 sessions/week (30 min at 2 mA) anode over F3, cathode over F4. Sham tDCS resembled active tDCS, with ramp-in and ramp-out periods, but without intermittent stimulation. The study was prematurely terminated due to an accumulation of adverse events (AEs, skin lesions), so that only 11 patients were included. Feasibility was good. Safety monitoring was not sufficient enough to detect or prevent AEs within an appropriate timeframe. Regarding antidepressant effects, the reduction in depression scales over time was significant. However, active tDCS was not superior to sham tDCS in this regard. Both the conclusions from this review and the HomeDC trial show that there are several critical issues with the use of tDCS at home that need to be addressed. Nevertheless the array of transcranial electric simulation (TES) methods that this mode of application offers, including tDCS, is highly interesting and warrants further investigation in high quality RCTs. TRIAL REGISTRATION: www. CLINICALTRIALS: gov . TRIAL REGISTRATION NUMBER: NCT05172505. Registration date: 12/13/2021, https://clinicaltrials.gov/ct2/show/NCT05172505 . *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers) **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71 . For more information, visit: http://www.prisma-statement.org/.

Examining the synergistic effects of a cognitive control video game and a home-based, self-administered non-invasive brain stimulation on alleviating depression: the DiSCoVeR trial protocol.

Enhanced behavioral interventions are gaining increasing interest as innovative treatment strategies for major depressive disorder (MDD). In this study protocol, we propose to examine the synergistic effects of a self-administered home-treatment, encompassing transcranial direct current stimulation (tDCS) along with a video game based training of attentional control. The study is designed as a two-arm, double-blind, randomized and placebo-controlled multi-center trial (ClinicalTrials.gov: NCT04953208). At three study sites (Israel, Latvia, and Germany), 114 patients with a primary diagnosis of MDD undergo 6 weeks of intervention (30 × 30 min sessions). Patients assigned to the intervention group receive active tDCS (anode F3 and cathode F4; 2 mA intensity) and an action-like video game, while those assigned to the control group receive sham tDCS along with a control video game. An electrode-positioning algorithm is used to standardize tDCS electrode positioning. Participants perform their designated treatment at the clinical center (sessions 1-5) and continue treatment at home under remote supervision (sessions 6-30). The endpoints are feasibility (primary) and safety, treatment efficacy (secondary, i.e., change of Montgomery-Åsberg Depression Rating Scale (MADRS) scores at week six from baseline, clinical response and remission, measures of social, occupational, and psychological functioning, quality of life, and cognitive control (tertiary). Demonstrating the feasibility, safety, and efficacy of this novel combined intervention could expand the range of available treatments for MDD to neuromodulation enhanced interventions providing cost-effective, easily accessible, and low-risk treatment options.ClinicalTrials.gov: NCT04953208.

Cognitive and functional deficits are associated with white matter abnormalities in two independent cohorts of patients with schizophrenia.

BACKGROUND: Significant evidence links white matter (WM) microstructural abnormalities to cognitive impairment in schizophrenia (SZ), but the relationship of these abnormalities with functional outcome remains unclear. METHODS: In two independent cohorts (C1, C2), patients with SZ were divided into two subgroups: patients with higher cognitive performance (SZ-HCP-C1, n = 25; SZ-HCP-C2, n = 24) and patients with lower cognitive performance (SZ-LCP-C1, n = 25; SZ-LCP-C2, n = 24). Healthy controls (HC) were included in both cohorts (HC-C1, n = 52; HC-C2, n = 27). We compared fractional anisotropy (FA) of the whole-brain WM skeleton between the three groups (SZ-LCP, SZ-HCP, HC) by a whole-brain exploratory approach and an atlas-defined WM regions-of-interest approach via tract-based spatial statistics. In addition, we explored whether FA values were associated with Global Assessment of Functioning (GAF) scores in the SZ groups. RESULTS: In both cohorts, mean FA values of whole-brain WM skeleton were significantly lower in the SCZ-LCP group than in the SCZ-HCP group. Whereas in C1 the FA of the frontal part of the left inferior fronto-occipital fasciculus (IFOF) was positively correlated with GAF score, in C2 the FA of the temporal part of the left IFOF was positively correlated with GAF score. CONCLUSIONS: We provide robust evidence for WM microstructural abnormalities in SZ. These abnormalities are more prominent in patients with low cognitive performance and are associated with the level of functioning.

Transcranial Direct Current Stimulation (tDCS) for Depression during Pregnancy: Results from an Open-Label Pilot Study.

INTRODUCTION: Depression is the most common morbidity during pregnancy. Available first-line therapy options are limited and depressive disorders in pregnant women are often untreated, leading to negative effects on maternal and fetal health. OBJECTIVES: The aim of this open-label pilot study is to extend evidence on the use of transcranial direct current stimulation (tDCS) as a treatment of antenatal depression and to point out options for the use of tDCS in this population. METHODS: Six drug-free female patients with major depressive disorder during pregnancy (later than 10th gestational week) were included in this pilot study. Patients were treated with twice-daily tDCS (2 mA, 30 min, anode: F3, cathode: F4) over ten days during inpatient stay (Phase 1) and with once-daily tDCS over 10 days during an optional outpatient stay (Phase 2). Clinical (HAMD-21, BDI) and neuropsychological ratings (Trail Making Test A/B) were performed at baseline, after two and four weeks as well as an obstetric examination. RESULTS: Six right-handed females (23-43 years, 12-33. gestational week) completed Phase 1; four patients additionally joined in Phase 2. tDCS was well tolerated and no adverse effects occurred. Clinical ratings showed an improvement of mean baseline HAMD-21 from 22.50 ± 7.56 to 13.67 ± 3.93 after week 2, and to 8.75 ± 4.99 after week 4. The mean baseline BDI was 26.00 ± 13.90 and declined to 11.17 ± 5.46 after week 2, and to 9.25 ± 3.30 after week 4. CONCLUSIONS: Statistically significant changes in HAMD-21 and BDI were observed after Phase 1. One patient achieved remission in terms of HAMD in Phase 1. Although this small-scale study lacks sham control, it shows clinical improvement and absence of adverse events in this critical population.

Home Use, Remotely Supervised, and Remotely Controlled Transcranial Direct Current Stimulation: A Systematic Review of the Available Evidence.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is gaining growing importance in the treatment of neurological and psychiatric disorders and is currently investigated for home-based and remotely supervised applications. METHODS: Here, we systematically review the available evidence from a database search (PubMed, ICTRP, clinicaltrials.gov) from January 2000 to May 2017. RESULTS: We detected 22 original research papers, trial protocols or trial registrations dealing with tDCS as an add-on intervention to cognitive or physiotherapeutic intervention. Overall, study samples are small; many studies are single-blinded and focus on feasibility and safety. There are two guideline papers setting basic requirements for clinical trials. CONCLUSIONS: Further research needs to focus on home-based treatment from different viewpoints, that is, safety, technical monitoring, reproducibility of repeated applications, feasibility of combined interventions and systematic assessment of efficacy, and safety in large randomized controlled clinical trials (RCTs). However, remotely controlled and supervised tDCS for home use represents a promising approach for widespread use of noninvasive brain stimulation (NIBS) in clinical care.

Prefrontal tDCS and sertraline in obsessive compulsive disorder: a case report and review of the literature.

Obsessive-compulsive (OC) disorder is a disabling disorder resulting in tremendous individual and social burden. It has a large overlap with depression and anxiety disorders and shows treatment resistance in a relevant proportion of patients. Since a couple of years, different noninvasive brain stimulation methods have been investigated to improve OC symptoms. The application of transcranial direct current stimulation (tDCS) has shown inconsistent results which can probably be attributed to a lack in randomized controlled trials with adequate sample size. Anodal stimulation of pre-supplementary motor areas has shown promising results, and there is also sparse data on orbitofrontal and prefrontal stimulation. Here, we provide the first report on a patient with treatment-refractory OC disorder treated with sertraline and an enhanced prefrontal tDCS protocol (twice per day, 10 days) with a classic left-anodal/right cathodal montage, experiencing a 22% reduction of OC symptoms as well as reduction in depression (-10%) and anxiety symptoms (-21%). Due to multifactorial origin of OC disorder and the variety of brain circuits involved, there are probably multiple approaches for brain stimulation regarding site, polarity, and frequency to be assessed in future studies.

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.

Imaging transcranial direct current stimulation (tDCS) of the prefrontal cortex-correlation or causality in stimulation-mediated effects?

Transcranial current stimulation approaches include neurophysiologically distinct non-invasive brain stimulation techniques widely applied in basic, translational and clinical research: transcranial direct current stimulation (tDCS), oscillating transcranial direct current stimulation (otDCS), transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS). Prefrontal tDCS seems to be an especially promising tool for clinical practice. In order to effectively modulate relevant neural circuits, systematic research on prefrontal tDCS is needed that uses neuroimaging and neurophysiology measures to specifically target and adjust this method to physiological requirements. This review therefore analyses the various neuroimaging methods used in combination with prefrontal tDCS in healthy and psychiatric populations. First, we provide a systematic overview on applications, computational models and studies combining neuroimaging or neurophysiological measures with tDCS. Second, we categorise these studies in terms of their experimental designs and show that many studies do not vary the experimental conditions to the extent required to demonstrate specific relations between tDCS and its behavioural or neurophysiological effects. Finally, to support best-practice tDCS research we provide a methodological framework for orientation among experimental designs.