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Individual responses to behavioral treatment of anxiety disorders vary considerably, which requires a better understanding of underlying processes. In this study, we examined the violation and change of threat beliefs during exposure. From 8,484 standardized exposure records of 605 patients with different anxiety disorders, learning indicators were derived: expectancy violation as mismatch between threat expectancy before exposure and threat occurrence, expectancy change as difference between original and adjusted expectancy after exposure, and prediction-error learning rate as extent to which expectancy violation transferred into change. Throughout sessions, high threat expectancy but low occurrence and adjusted expectancy indicated successful violation and change of threat beliefs by exposure. Expectancy violation, change, and learning rate substantially varied between patients. Not expectancy violation itself, but higher learning rate and expectancy change predicted better treatment outcome. Successful exposure thus requires expectancy violation to induce actual expectancy change, supporting learning from prediction error as transdiagnostic mechanism underlying successful exposure therapy. Bundesministerium für Bildung und Forschung https://doi.org/10.13039/501100002347

Research on outcome predictors in the field of transcultural treatment for refugees and asylum seekers (RAS) is scarce. We aimed to evaluate predictors of outcome of a group intervention (Empowerment) for RAS with affective disorders which was incorporated at level three of the stratified stepped-care model within the Mental Health in Refugees and Asylum Seekers (MEHIRA) project.A predictor analysis was performed at level three of the MEHIRA project, where 149 refugees with moderate depressive symptoms were treated either with Empowerment or Treatment-as-usual (TAU). Outcome measures were depression severity as assessed by patient-rated Patient Health Questionnaire 9 (PHQ-9) and clinician-rated Montgomery Asberg Depression Rating Scale (MADRS). Regression models with change scores (T1-T0) of PHQ-9 and MADRS as dependent variables were fit. Predictor selection was a mixed-method approach combining testing of literature-based hypotheses and explorative hypothesis-generating analyses of multiple baseline variables.Intention-to-treat (ITT) analyses revealed significant linear relationships between change in PHQ-9 and baseline depression severity (β = -0.35, t = -3.27, p = .002) and perceived self-efficacy (β = -0.24, t = -2.26, p = .027) in the treatment (verum) condition. MADRS change scores were predicted by baseline depression severity (β = -0.71, t = -8.65, p .001) in the treatment (verum) condition.Due to small cell numbers, single predictors could not be evaluated reliably.Severity of depression and self-efficacy at baseline were predictors of symptom improvement at level three (Empowerment) of the MEHIRA project. Comorbidity and trauma indicators did not predict outcomes in the treatment (verum) condition, pointing towards broad applicability of the Empowerment intervention in refugee populations.

Borderline personality disorder (BPD) and persistent depressive disorder (PDD) are related to interpersonal dysfunction which might become particularly apparent in situations of social exclusion (SE). While emotional responses to SE have been widely explored, behavioral data in clinical samples are lacking. In this cross-diagnostic study, we applied a variant of the Cyberball paradigm to investigate the dynamic behavioral response to partial SE in BPD and PDD. BPD patients (n = 36), PDD patients (n = 34) and age and gender matched healthy controls (HC) (total n = 70) played experimental (i.e. partial SE Cyberball) and control (i.e. inclusion only) conditions in randomized order. While all groups tended to increase ball tosses towards the excluder in response to SE, this behavioral turn was significantly lower in PDD (p = .03, d = -.30) and trendwise in BPD patients (p = .06, d = -.28). Thus, an altered immediate response to partial SE was observed in BPD and PDD, in addition to the emotional reactions. This study supports the hypothesis of a behavioral coping with SE in BPD and PDD that might be problematic in the long run and provides an experimental paradigm for future research on interpersonal dysfunction.

Cognitive deficits and negative symptoms in schizophrenia are associated with poor functional outcomes and limited in terms of treatment. The Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) trial has shown efficacy of transcranial direct current stimulation (tDCS) for improving negative symptoms. In this secondary analysis, we investigate its effects on cognitive performance. In STARTS, a double-blinded, sham-controlled, randomized clinical trial, patients were treated with twice-daily, 20-min, 2-mA fronto-temporal tDCS over 5 days or sham-tDCS. In 90 patients, we evaluated the cognitive performance up to 12 weeks post-treatment. We found that active-tDCS showed no beneficial effects over sham-tDCS in any of the tests. Based on a 5-factor cognitive model, improvements of executive functions and delayed memory were observed in favor of sham-tDCS. Overall, the applied active-tDCS protocol, primarily designed to improve negative symptoms, did not promote cognitive improvement. We discuss possible protocol modification potentially required to increase tDCS effects on cognition. ClinicalTrials.gov identifier: NCT02535676

Individual responses to behavioral treatment of anxiety disorders vary considerably, calling for better understanding of underlying processes. This study examined the violation and change of threat beliefs during exposure. From 8484 standardized exposure records of 605 patients with different anxiety disorders, learning indicators were derived: Expectancy violation as mismatch between threat expectancy before exposure and threat occurrence, expectancy change as difference between original and adjusted expectancy after exposure, and prediction-error learning rate as extent to which expectancy violation transferred into change. Throughout sessions, high threat expectancy but low occurrence and adjusted expectancy indicated violation and change of threat beliefs by exposure. Expectancy violation, change, and learning rate substantially varied between patients. Not expectancy violation itself, but higher learning rate and expectancy change predicted better treatment outcome. Successful exposure thus requires expectancy violation to induce actual expectancy change, supporting learning from prediction error as transdiagnostic mechanism underlying successful exposure therapy.

An insecure attachment style (AS), described as being highly anxious and/or avoidant, is often assumed to be stable over time, yet some studies show that AS can change. To the extent that AS may be malleable over shorter time periods, it potentially impacts key therapy processes and outcomes. In the present study, we first investigated the stability of AS in patients with panic disorder (N = 49) treated with short-term cognitive behavioral therapy (CBT) including follow-up. Second, we tested whether time-specific change of AS predicted subsequent symptom severity, interpersonal distress (ID), and alliance, or vice versa. Third, we investigated if anxious attachment and ID average levels impact the alliance-outcome relation. Analyses were conducted at within- and between-patient levels with 5 measurements (baseline, intermediate, end, and follow-up after 4 and 8 months) over the course of CBT (12 sessions/8 weeks, 2 booster sessions) using linear mixed-effects models. A strong decrease in anxious attachment was found that was stable until 8 months after therapy. At the within-patient level, a reciprocal relationship of reduction in anxious attachment with less symptom severity, stronger alliance, and a prediction of less ID was found. ID decrease preceded less avoidance. At the between-patient level, anxious attachment and ID moderated the relation of alliance change and subsequent depressive symptoms. The prolonged improvement in interpersonal patterns suggests that short-term CBT positively modifies attachment working models in panic disorder patients. Effects on therapy process indicate that anxiously attached and interpersonally distressed patients seem to benefit more from alliance increase. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Transcranial electrical stimulation (tES) is considered effective and safe for depression, albeit modestly, and prone to logistical burdens when performed in external facilities. Investigation of portable tES (ptES), and potentiation of ptES with remote psychological interventions have shown positive, but preliminary, results.We report the rationale and design of an ongoing multi-arm, randomized, double-blind, sham-controlled clinical trial with digital features, using ptES and internet-based behavioral therapy (iBT) for major depressive disorder (MDD) (NCT04889976).We will evaluate the efficacy, safety, tolerability and usability of (1) active ptES + active iBT ('double-active'), (2) active ptES + sham iBT ('ptES-only'), and (3) sham ptES + sham iBT ('double-sham'), in adults with MDD, with a Hamilton Depression Rating Scale - 17 item version (HDRS-17) score ≥ 17 at baseline, during 6 weeks. Antidepressants are allowed in stable doses during the trial.We primarily co-hypothesize changes in HDRS-17 will be greater in (1) 'double-active' compared to 'ptES-only,' (2) 'double-active' compared to 'double-sham,' and (3) 'ptES-only' compared to 'double-sham.' We aim to enroll 210 patients (70 per arm).Our results should offer new insights regarding the efficacy and scalability of combined ptES and iBT for MDD, in digital mental health.

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES.Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided.Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity.Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials. (C) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Social exclusion is a critical event for mental health. Patients with interpersonal dysfunction, e.g., with borderline personality disorder (BPD) or persistent depressive disorder (PDD), are particularly vulnerable, often based on their experiences of early adversity in life. The etiological pathways from childhood maltreatment (CM) to current behavior during social exclusion are still underexplored. This cross-diagnostic study investigated the relationship between self-reported CM and behavioral reaction to social exclusion in an experimental paradigm (Cyberball). Data from 140 subjects including patients with BPD and PDD as well as healthy controls were analyzed. The effect of CM (Childhood Trauma Questionnaire, CTQ) on behavior to social exclusion during Cyberball (ball tossing behavior) was analyzed including rejection sensitivity (RS) as a mediator. In the whole sample, the CTQ score (B = -.004, p .05) as well as the emotional neglect subscore (B = -.016, p .01) were associated with a reduced ball tossing behavior towards the excluder. There were no significant indirect effects involving RS. These current findings support the relationship between CM and an altered interpersonal response in critical interpersonal situations. Larger cohorts with multidimensional data in social domains are warranted to further investigate the link between CM and current interpersonal dysfunction.

Transcranial direct current stimulation (tDCS) is a safe, effective treatment for major depressive disorder (MDD). While antidepressant effects are heterogeneous, no studies have investigated trajectories of tDCS response. We characterized distinct improvement trajectories and associated baseline characteristics for patients treated with prefrontal tDCS, an active pharmacotherapy (escitalopram), and placebo. This is a secondary analysis of a randomized, non-inferiority, double-blinded trial (ELECT-TDCS, N = 245). Participants were diagnosed with an acute unipolar, nonpsychotic, depressive episode, and presented Hamilton Depression Rating Scale (17-items, HAM-D) scores ≥17. Latent trajectory modeling was used to identify HAM-D response trajectories over a 10-week treatment. Top-down (hypothesis-driven) and bottom-up (data-driven) methods were employed to explore potential predictive features using, respectively, conservatively corrected regression models and a cross-validated stability ranking procedure combined with elastic net regularization. Three trajectory classes that were distinct in response speed and intensity (rapid, slow, and no/minimal improvement) were identified for escitalopram, tDCS, and placebo. Differences in response and remission rates were significant early for all groups. Depression severity, use of benzodiazepines, and age were associated with no/minimal improvement. No significant differences in trajectory assignment were found in tDCS vs. placebo comparisons (38.3, 34, and 27.6%; vs. 23.3, 43.3, and 33.3% for rapid, slow, and no/minimal trajectories, respectively). Additional features are suggested in bottom-up analyses. Summarily, groups treated with tDCS, escitalopram, and placebo differed in trajectory class distributions and baseline predictors of response. Our results might be relevant for designing further studies.

Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. Device appraisal showed moderate digitalization readiness, with high safety and the possibility of trial implementation, but low connectivity. Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; although they reached no consensus about aspects regarding methodological biases. We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.Graphical Abstract. Consensus Roadmap(A) Recruitment process. The study procedure started with defining the components of the research problem by the core research team. After defining the problems, two different sets of participants (the steering committee (SC) including key leaders of the field identified by the core team and the expert panel (EP) as a more diverse group of experts identified based on the number of publications based on a systematic review) were identified and were invited to participate in a Delphi study. The study facilitators (first and last authors) led the communications with the SC to design the initial questionnaire through an iterative approach. (B) Evidence synthesis: To collect the available evidence, companies producing portable tES (ptES) devices were contacted, based on the companies suggested by the SC and EP to provide details about the available devices. For mapping methodological processes of digitizing tES trials, two distinct strategies were performed and embedded into the questionnaire, namely SIPOC (Suppliers, Inputs, Process, Outputs, and Customer) and SWOT (Strengths, Weaknesses, Opportunities, and Threats) assessment were performed and embedded into the questionnaire. (C) Consensus development: In the next phase, the questionnaire was validated and finalized via collecting and summarizing opinions. Afterward, the SC and EP responded to the final questionnaire, and results were analyzed providing a list of recommendations for running tES digital trials based on a pre-registered consensus threshold.

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.

Functional and structural MRI of prefrontal cortex (PFC) may provide putative biomarkers for predicting the treatment response to transcranial direct current stimulation (tDCS) in depression. A recent MRI study from ELECT-TDCS (Escitalopram versus Electrical Direct-Current Theror Depression Study) showed that depression improvement after tDCS was associated with gray matter volumes of PFC subregions. Based thereon, we investigated whether antidepressant effects of tDCS are similarly associated with baseline resting-state functional connectivity (rsFC). A subgroup of 51 patients underwent baseline rsFC-MRI. All patients of ELECT-TDCS were randomized to three treatment arms for 10 weeks (anodal-left, cathodal-right PFC tDCS plus placebo medication; escitalopram 10 mg/day for 3 weeks and 20 mg/day thereafter plus sham tDCS; and placebo medication plus sham tDCS). RsFC was calculated for various PFC regions and analyzed in relation to the individual antidepressant response. There was no significant association between baseline PFC connectivity of essential structural regions, nor any other PFC regions (after correction for multiple comparisons) and patients’ individual antidepressant response. This study did not reveal an association between antidepressants effects of tDCS and baseline rsFC, unlike the gray matter volume findings. Thus, the antidepressant effects of tDCS may be differentially related to structural and functional MRI measurements.

Bipolar depression is associated with marked cognitive deficits. Pharmacological treatments for this condition are limited and may aggravate depressive and cognitive symptoms. Therefore, therapeutic interventions that preserve adequate cognitive functioning are necessary. Our previous results demonstrated significant clinical efficacy of transcranial direct current stimulation (tDCS) in the Bipolar Depression Electrical Treatment Trial (BETTER). Here, cognitive outcomes of this study are reported. We randomized 59 patients with bipolar disorder I or II in an acute depressive episode to receive active (12 2 mA, 30-min, anodal-left, cathodal-right prefrontal cortex tDCS sessions) or sham tDCS. Patients were on stable pharmacological regimen for at least 2 weeks. A battery of 12 neuropsychological assessments in five cognitive domains (attention and processing speed, memory, language, inhibitory control, and working memory and executive function) was performed at baseline, after two weeks and at endpoint (week 6). No significant differences between groups over 6 weeks of treatment were observed for any cognitive outcomes. Moreover, no decrease in cognitive performance was observed. Our findings warrant further replication in larger studies. Trial Registration: clinicaltrials.gov Identifier: NCT02152878

Patients with borderline personality disorder (BPD) show interpersonal deficits, and altered emotional and oxytocin (OT) responses to social exclusion (Cyberball). In order to extend previous findings, this study applies a novel Cyberball variant. Nineteen BPD patients and 56 healthy controls (HC) played Cyberball for 2 minutes of inclusion, 5 minutes of partial exclusion by one of two co-players, and 2 minutes total exclusion by both. Plasma OT levels at baseline and after 7, 9, 15, and 40 minutes were measured with radioimmunoassay. BPD patients showed a greater aversive reaction and a trend for greater OT reduction after social exclusion than HC. BPD patients also tended to play less frequently with the excluder. Though limited by our sample size, we partially replicate previous findings. Our preliminary behavioral data support the notion of an altered OT regulation and reduced capacity for social cooperation in BPD.

Treatment-refractory auditory hallucinations (TRAH) in schizophrenia often do not improve with pharmacotherapy. We performed a meta-analysis of randomized, double-blind, sham-controlled clinical trials (RCTs) that systematically examined the therapeutic effects and tolerability of adjunctive active versus sham active transcranial direct current stimulation (tDCS) for auditory hallucinations as measured by the Auditory Hallucination Rating Scale (AHRS) in schizophrenia patients with TRAH.Relevant data were extracted, checked and analyzed using the Review Manager, Version 5.3 by three independent investigators.Eight double-blind RCTs covering 329 schizophrenia patients (168 in active tDCS group, 161 in sham tDCS group) were included. Although no advantage of active tDCS on auditory hallucinations [7 RCTs, n = 224; standardized mean difference (SMD): - 0.33 (95% confidence interval (CI): - 0.71, 0.05), P = 0.09; IThis meta-analysis demonstrated that the effects of tDCS for auditory hallucinations symptoms were influenced by the tDCS parameters. Twice-daily stimulation and ≥ 10 stimulation sessions may be needed to improve auditory hallucinations symptoms in schizophrenia with TRAH.

Background Transcranial direct current stimulation (tDCS) is a promising intervention for major depression. However, its clinical effects are heterogeneous. We investigated, in a subsample of the randomized, clinical trial Escitalopram versus Electrical Direct Current Therapy for Depression Study (ELECT-TDCS), whether the volumes of left and right prefrontal cortex (PFC) and anterior cingulate cortex (ACC) were associated with prefrontal tDCS response. Methods Baseline structural T1 weighted MRI data were analyzed from 52 patients (15 males). Patients were randomized to the following conditions: escitalopram 20 mg/day, bifrontal tDCS (2 mA, 30min, 22 sessions), or placebo. Antidepressant outcomes were assessed over a treatment period of 10 weeks. Voxel-based gray matter volumes of PFC and ACC were determined using state-of-the-art parcellation approaches. Results According to our a priori hypothesis, in the left dorsal PFC, larger gray matter volumes were associated with depression improvement in the tDCS group (n = 15) compared to sham (n = 21) (Cohen's d = 0.3, 95% confidence interval [0.01; 0.6], p = 0.04). Neither right PFC nor ACC volumes were associated with depression improvement. Exploratory analyses of distinct PFC subregions were performed, but no area was associated with tDCS response after correction for multiple comparisons. Conclusion Left PFC baseline gray matter volume was associated with tDCS antidepressant effects. This brain region and its subdivisions should be investigated further as a potential neurobiological predictor for prefrontal tDCS treatment in depression and might be correlated with tDCS antidepressant mechanisms of action.

Detecting reliable predictors of response to tDCS treatment for mood disorders could potentially facilitate treatment stratification and guide personalized treatment decisions, thereby enhancing treatment efficiency and reducing redundant treatments. Furthermore, hypothesis generation based on predictive information could streamline future research by narrowing the choice of multiple treatment parameters to the most promising targets. While attempts to identify such predictors have been made across multiple domains, these have mostly applied post-hoc exploratory statistics, that likely suffer from poor generalizability. As a result, objective response prediction is currently not feasible. New research strategies relying on artificial intelligence and statistical learning methodology represent promising means to achieve more reliable, clinically translatable predictive models. To be successful, these rely on multisite collaboration to enhance dataset sizes, should include data from naturalistic clinical settings, and embrace an open science framework. At the moment, heuristic clinical decision-making based on RCT results and clinical reasoning should guide tDCS treatment.

Background The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions. Methods This multicenter randomized controlled trial compared two variants of prediction error-based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx-I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx-S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6-months follow-up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression. Results Both treatments resulted in substantial improvements at post (PeEx-I: d\(_{within}\) = 1.50, PeEx-S: d\(_{within}\) = 1.78) and follow-up (PeEx-I: d\(_{within}\) = 2.34; PeEx-S: d\(_{within}\) = 2.03). Both groups showed formally equivalent symptom reduction at post and follow-up. However, time until response during treatment was 32% shorter in PeEx-I (median = 68 days) than PeEx-S (108 days; TR\(_{PeEx-I}\)-I = 0.68). Interestingly, drop-out rates were lower during intensified exposure. PeEx-I was also superior in reducing disability days and improving quality of life at follow-up without increasing relapse. Conclusions Both treatment variants focusing on the transdiagnostic exposure-based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop-out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.

Transcranial direct current stimulation (tDCS) over prefrontal cortex (PFC) regions is currently proposed as therapeutic intervention for major depression and other psychiatric disorders. The in-depth mechanistic understanding of this bipolar and non-focal stimulation technique is still incomplete. In a pilot study, we investigated the effects of bifrontal stimulation on brain metabolite levels and resting state connectivity under the cathode using multiparametric MRI techniques and computational tDCS modeling. Within a double-blind cross-over design, 20 subjects (12 women, 23.7 ± 2 years) were randomized to active tDCS with standard bifrontal montage with the anode over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC. Magnetic resonance spectroscopy (MRS) was acquired before, during, and after prefrontal tDCS to quantify glutamate (Glu), Glu + glutamine (Glx) and gamma aminobutyric acid (GABA) concentration in these areas. Resting-state functional connectivity MRI (rsfcMRI) was acquired before and after the stimulation. The individual distribution of tDCS induced electric fields (efields) within the MRS voxel was computationally modelled using SimNIBS 2.0. There were no significant changes of Glu, Glx and GABA levels across conditions but marked differences in the course of Glu levels between female and male participants were observed. Further investigation yielded a significantly stronger Glu reduction after active compared to sham stimulation in female participants, but not in male participants. For rsfcMRI neither significant changes nor correlations with MRS data were observed. Exploratory analyses of the effect of efield intensity distribution on Glu changes showed distinct effects in different efield groups. Our findings are limited by the small sample size, but correspond to previously published results of cathodal tDCS. Future studies should address gender and efield intensity as moderators of tDCS induced effects. Electronic supplementary material The online version of this article (10.1007/s00406-020-01177-0) contains supplementary material, which is available to authorized users.

Current hypotheses on the therapeutic action of non-invasive brain stimulation (NIBS) in psychiatric disorders build on the abundant data from neuroimaging studies. This makes NIBS a very promising tool for developing personalized interventions within a precision medicine framework. NIBS methods fundamentally vary in their neurophysiological properties. They comprise repetitive transcranial magnetic stimulation (rTMS) and its variants (e.g. theta burst stimulation - TBS) as well as different types of transcranial electrical stimulation (tES), with the largest body of evidence for transcranial direct current stimulation (tDCS). In the last two decades, significant conceptual progress has been made in terms of NIBS targets, i.e. from single brain regions to neural circuits and to functional connectivity as well as their states, recently leading to brain state modulating closed-loop approaches. Regarding structural and functional brain anatomy, NIBS meets an individually unique constellation, which varies across normal and pathophysiological states. Thus, individual constitutions and signatures of disorders may be indistinguishable at a given time point, but can theoretically be parsed along course- and treatment-related trajectories. We address precision interventions on three levels: 1) the NIBS intervention, 2) the constitutional factors of a single patient, and 3) the phenotypes and pathophysiology of illness. With examples from research on depressive disorders, we propose solutions and discuss future perspectives, e.g. individual MRI-based electrical field strength as a proxy for NIBS dosage, and also symptoms, their clusters, or biotypes instead of disorder focused NIBS. In conclusion, we propose interleaved research on these three levels along a general track of reverse and forward translation including both clinically directed research in preclinical model systems, and biomarker guided controlled clinical trials. Besides driving the development of safe and efficacious interventions, this framework could also deepen our understanding of psychiatric disorders at their neurophysiological underpinnings.

Background Transcranial direct current stimulation (tDCS) presents small antidepressant efficacy at group level and considerable inter-individual variability of response. Its heterogeneous effects bring the need to investigate whether specific groups of patients submitted to tDCS could present comparable or larger improvement compared to pharmacotherapy. Aggregate measurements might be insufficient to address its effects. Objective /Hypothesis: To determine the efficacy of tDCS, compared to pharmacotherapy and placebo, in depressive symptom clusters. Methods Data from ELECT-TDCS (Escitalopram versus Electrical Direct-Current Therapy for Treating Depression Clinical Study, ClinicalTrials.gov , NCT01894815), in which antidepressant-free, depressed patients were randomized to receive 22 bifrontal tDCS (2 mA, 30 min) sessions (n = 94), escitalopram 20 mg/day (n = 91), or placebo (n = 60) over 10 weeks. Agglomerative hierarchical clustering identified “sleep/insomnia”, “core depressive”, “guilt/anxiety”, and “atypical” clusters that were the dependent measure. Trajectories were estimated using linear mixed regression models. Effect sizes are expressed in raw HAM-D units. P-values were adjusted for multiple comparisons. Results For core depressive symptoms, escitalopram was superior to tDCS (ES = −0.56; CI95% = -0.94 to −0.17, p = .009), which was superior to placebo (ES = 0.49; CI95% = 0.06 to 0.92, p = .042). TDCS but not escitalopram was superior to placebo in sleep/insomnia symptoms (ES = 0.87; CI95% = 0.22 to 1.52, p = .015). Escitalopram but not tDCS was superior to placebo in guilt/anxiety symptoms (ES = 1.66; CI95% = 0.58 to 2.75, p = .006). No active intervention was superior to placebo for atypical symptoms. Conclusions Pharmacotherapy and non-invasive brain stimulation produce distinct effects in depressive symptoms. TDCS or escitalopram could be chosen according to specific clusters of symptoms for a bigger response. Trial registration ClinicalTrials.gov, NCT01894815

Introduction: The Cognitive Behavioral Analysis System of Psychotherapy (CBASP) was developed for the treatment of persistent depressive disorder (PDD), where comorbid personality disorders (PD) are common. In contrast to other PD, comorbid borderline personality disorder (BPD) is often regarded as an exclusion criterion for CBASP. In clinical settings, however, subthreshold BPD symptoms are prevalent in PDD and may not be obvious at an initial assessment prior to therapy. As data on their impact on CBASP outcome are very limited, this naturalistic study investigates BPD features in PDD and their relevance for the therapeutic outcome of a multimodal CBASP inpatient program. Method: Sixty patients (37 female, mean age 38.3, SD 11.9 years) meeting DSM-5 criteria for PDD underwent a 10 weeks CBASP inpatient program. BPD features (i.e., number of fulfilled DSM-5 criteria) together with childhood maltreatment and rejection sensitivity were assessed on admission. Before and after treatment, severity of depressive symptoms was measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Beck Depression Inventory (BDI-II). BPD symptoms were assessed using the Borderline Personality Disorder Severity Index (BPDSI-IV) and the Borderline Symptom List (BSL-23). Intercorrelations of baseline characteristics and symptom change during treatment were analyzed. Results: Patients with PDD met a mean of 1.5 (SD 1.6) BPD criteria with 4 patients fulfilling ≥5 criteria. BPD symptoms and depressive symptoms showed a strong correlation, and BPD symptoms were additionally correlated with emotional abuse and rejection sensitivity. There was no association between BPD features at baseline and improvement on the MADRS, however, BPD features tended to be associated with a lower response according to the BDI-II score after 10 weeks of treatment. Furthermore, BPD symptoms (i.e., abandonment, impulsivity and affective instability) were reduced after 10 weeks of CBASP treatment. Discussion: BPD symptoms are prevalent in patients with PDD and highly intertwined with the experience of depressive symptoms. In this naturalistic study in PDD, BPD features at baseline did not limit the clinical response to CBASP. Future studies may extend the spectrum of PDD to comorbid subsyndromal or even syndromal BPD in order to develop tailored psychotherapeutic treatment for these complex affective disorders.

Obsessive-compulsive disorder (OCD) is a frequent, disabling disorder with high rates of treatment resistance. Transcranial direct current stimulation (tDCS) is a safe, tolerable noninvasive neuromodulation therapy with scarce evidence for OCD. This double-blind, randomized, and sham-controlled study investigates the efficacy of tDCS as add-on treatment for treatment-resistant OCD (failure to respond to at least one previous pharmacological treatment). On 20 consecutive weekdays (4 weeks), 43 patients with treatment-resistant OCD underwent 30 min active or sham tDCS sessions, followed by a 8 week follow-up. The cathode was positioned over the supplementary motor area (SMA) and the anode over the left deltoid. The primary outcome was the change in baseline Y-BOCS score at week 12. Secondary outcomes were changes in mood and anxiety and the occurrence of adverse events. Response was evaluated considering percent decrease of baseline Y-BOCS scores and the Improvement subscale of the Clinical Global Impression (CGI-I) between baseline and week 12. Patients that received active tDCS achieved a significant reduction of OCD symptoms than sham, with mean (SD) Y-BOCS score changes of 6.68 (5.83) and 2.84 (6.3) points, respectively (Cohen's d: 0.62 (0.06-1.18), p = 0.03). We found no between-group differences in responders (four patients in the active tDCS and one in the sham group). Active tDCS of the SMA was not superior to sham in reducing symptoms of depression or anxiety. Patients in both groups reported mild adverse events. Our results suggest that cathodal tDCS over the SMA is an effective add-on strategy in treatment-resistant OCD.

Functional and structural MRI of prefrontal cortex (PFC) may provide putative biomarkers for predicting the treatment response to transcranial direct current stimulation (tDCS) in depression. A recent MRI study from ELECT-TDCS (Escitalopram versus Electrical Direct-Current Theror Depression Study) showed that depression improvement after tDCS was associated with gray matter volumes of PFC subregions. Based thereon, we investigated whether antidepressant effects of tDCS are similarly associated with baseline resting-state functional connectivity (rsFC). A subgroup of 51 patients underwent baseline rsFC-MRI. All patients of ELECT-TDCS were randomized to three treatment arms for 10 weeks (anodal-left, cathodal-right PFC tDCS plus placebo medication; escitalopram 10 mg/day for 3 weeks and 20 mg/day thereafter plus sham tDCS; and placebo medication plus sham tDCS). RsFC was calculated for various PFC regions and analyzed in relation to the individual antidepressant response. There was no significant association between baseline PFC connectivity of essential structural regions, nor any other PFC regions (after correction for multiple comparisons) and patients' individual antidepressant response. This study did not reveal an association between antidepressants effects of tDCS and baseline rsFC, unlike the gray matter volume findings. Thus, the antidepressant effects of tDCS may be differentially related to structural and functional MRI measurements.

Bipolar depression is associated with marked cognitive deficits. Pharmacological treatments for this condition are limited and may aggravate depressive and cognitive symptoms. Therefore, therapeutic interventions that preserve adequate cognitive functioning are necessary. Our previous results demonstrated significant clinical efficacy of transcranial direct current stimulation (tDCS) in the Bipolar Depression Electrical Treatment Trial (BETTER). Here, cognitive outcomes of this study are reported. We randomized 59 patients with bipolar disorder I or II in an acute depressive episode to receive active (12 2 mA, 30-min, anodal-left, cathodal-right prefrontal cortex tDCS sessions) or sham tDCS. Patients were on stable pharmacological regimen for at least 2 weeks. A battery of 12 neuropsychological assessments in five cognitive domains (attention and processing speed, memory, language, inhibitory control, and working memory and executive function) was performed at baseline, after two weeks and at endpoint (week 6). No significant differences between groups over 6 weeks of treatment were observed for any cognitive outcomes. Moreover, no decrease in cognitive performance was observed. Our findings warrant further replication in larger studies. Trial Registration: clinicaltrials.gov Identifier: NCT02152878.

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Background Transcranial direct current stimulation (tDCS) of the prefrontal cortex (PFC) has been widely applied in cognitive neurosciences and advocated as a therapeutic intervention, e.g. in major depressive disorder. Although several targets and protocols have been suggested, comparative studies of tDCS parameters, particularly electrode montages and their cortical targets, are still lacking. Objective This study investigated a priori hypotheses on specific effects of prefrontal-tDCS montages by using multimodal functional magnetic resonance imaging (fMRI) in healthy participants. Methods 28 healthy male participants underwent three common active-tDCS montages and sham tDCS in a pseudo-randomized order, comprising a total of 112 tDCS-fMRI sessions. Active tDCS was applied at 2 mA for 20 min. Before and after tDCS, a resting-state fMRI (RS fMRI) was recorded, followed by a task fMRI with a delayed-response working-memory (DWM) task for assessing cognitive control over emotionally negative or neutral distractors. Results After tDCS with a cathode-F3/anode-F4 montage, RS-fMRI connectivity decreased in a medial part of the left PFC. Also, after the same stimulation condition, regional brain activity during DWM retrieval decreased more in this area after negative than after neutral distraction, and responses to the DWM task were faster, independent of distractor type. Conclusion The current study does not confirm our a priori hypotheses on direction and localization of polarity-dependent tDCS effects using common bipolar electrode montages over PFC regions, but it provides evidence for montage-specific effects on multimodal neurophysiological and behavioral outcome measures. Systematic research on the actual targets and the respective dose-response relationships of prefrontal tDCS is warranted.

Background: Based on the vulnerability model, several studies indicate that low self-esteem seems to contribute to depressive symptoms. Aims: The aim of this study was to treat depressive symptoms in a cognitive behavioural group therapy, focusing on the enhancement of self-esteem, and to explore co-variation in depressive symptoms and the level of self-esteem. Method: The Multidimensional Self-esteem Scale (MSWS) and the Beck Depression Inventory (BDI) were administered to 147 psychiatric in-patients with current depressive symptoms due to an affective disorder (major depression, bipolar I, dysthymia). Self-esteem was measured pre-treatment (t0) and post-treatment (t4, after 5 weeks of eight group sessions); the BDI was applied weekly. A linear mixed growth analysis was conducted to estimate the change in depressive symptoms including interactions with self-esteem. Results: Within the 5 weeks of group therapy, depressive symptoms showed a linear decline, which was stronger for patients with higher gains in self-esteem between t0 and t4. Self-esteem at t0 was unrelated to the change in depression but predicted self-esteem at t4. Conclusions: Treating depressive symptoms in a cognitive behavioural group therapy in a naturalistic setting might have a positive effect on the process of recovery. Moreover, depressive symptoms and level of self-esteem seemed to co-vary.

Background Loneliness is a distressing and prevalent symptom in patients with persistent depressive disorder (PDD) that is associated with depression severity, a history of childhood maltreatment and rejection sensitivity. As loneliness is no primary focus of psychotherapy to date and the Cognitive Behavioral Analysis System of Psychotherapy (CBASP) particularly addresses interpersonal relationships, we investigate the effects of CBASP on loneliness in an open study in inpatients with PDD. Methods Sixty patients with PDD (DSM-5) underwent a comprehensive 10-weeks inpatient program of CBASP. Loneliness, social network characteristics, and depressive symptoms were assessed before and after treatment. Further, history of childhood maltreatment, peer victimization, and rejection sensitivity were measured at baseline. Results Loneliness and depressive symptoms significantly and independently decreased, whereas social network characteristics showed no change after 10 weeks of CBASP. Higher levels of loneliness, larger social network size at baseline, and a history of emotional neglect predicted a larger reduction of loneliness, whereas higher levels of rejection sensitivity and depressive symptoms at baseline were associated with an inferior outcome. Limitations Unspecific factors of the inpatient setting cannot be ruled out and a control group is lacking. Conclusions After 10 weeks of CBASP, PDD patients reported a reduced burden of loneliness. The study provides first evidence that CBASP, which addresses dysfunctional interpersonal patterns and their origin in childhood maltreatment and peer victimization, could provide valuable techniques for developing mechanism based psychotherapeutic intervention for loneliness.