Cognitive outcomes of the bipolar depression electrical treatment trial (BETTER): a randomized, double-blind, sham-controlled study.

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.

Trial of Electrical Direct-Current Therapy versus Escitalopram for Depression.

BACKGROUND: We compared transcranial direct-current stimulation (tDCS) with a selective serotonin-reuptake inhibitor for the treatment of depression. METHODS: In a single-center, double-blind, noninferiority trial involving adults with unipolar depression, we randomly assigned patients to receive tDCS plus oral placebo, sham tDCS plus escitalopram, or sham tDCS plus oral placebo. The tDCS was administered in 30-minute, 2-mA prefrontal stimulation sessions for 15 consecutive weekdays, followed by 7 weekly treatments. Escitalopram was given at a dose of 10 mg per day for 3 weeks and 20 mg per day thereafter. The primary outcome measure was the change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score (range, 0 to 52, with higher scores indicating more depression). Noninferiority of tDCS versus escitalopram was defined by a lower boundary of the confidence interval for the difference in the decreased score that was at least 50% of the difference in the scores with placebo versus escitalopram. RESULTS: A total of 245 patients underwent randomization, with 91 being assigned to escitalopram, 94 to tDCS, and 60 to placebo. In the intention-to-treat analysis, the mean (±SD) decrease in the score from baseline was 11.3±6.5 points in the escitalopram group, 9.0±7.1 points in the tDCS group, and 5.8±7.9 points in the placebo group. The lower boundary of the confidence interval for the difference in the decrease for tDCS versus escitalopram (difference, -2.3 points; 95% confidence interval [CI], -4.3 to -0.4; P=0.69) was lower than the noninferiority margin of -2.75 (50% of placebo minus escitalopram), so noninferiority could not be claimed. Escitalopram and tDCS were both superior to placebo (difference vs. placebo, 5.5 points [95% CI, 3.1 to 7.8; P<0.001] and 3.2 points [95% CI, 0.7 to 5.5; P=0.01], respectively). Patients receiving tDCS had higher rates of skin redness, tinnitus, and nervousness than did those in the other two groups, and new-onset mania developed in 2 patients in the tDCS group. Patients receiving escitalopram had more frequent sleepiness and obstipation than did those in the other two groups. CONCLUSIONS: In a single-center trial, tDCS for the treatment of depression did not show noninferiority to escitalopram over a 10-week period and was associated with more adverse events. (Funded by Fundação de Amparo à Pesquisa do Estado de São Paulo and others; ELECT-TDCS ClinicalTrials.gov number, NCT01894815 .).

Transcranial direct current stimulation (tDCS) for preventing major depressive disorder relapse: Results of a 6-month follow-up.

BACKGROUND: The efficacy of transcranial direct current stimulation (tDCS) as a continuation therapy for the maintenance phase of the depressive episode is low and insufficiently investigated in literature. We investigated whether it could be enhanced by using a more intensive treatment regimen compared to previous reports. METHODS: Twenty-four patients (16 with unipolar depression and eight with bipolar depression) who presented acute tDCS response (≥50% depression improvement in the Hamilton Depression Rating Scale [HDRS]) after receiving 15 tDCS sessions were followed for up to 6 months or until relapse, defined as clinical worsening and/or HDRS > 15. Sessions were performed twice a week (maximum of 48 sessions) over 24 weeks. The anode and the cathode were positioned over the left and right dorsolateral prefrontal cortex (2 mA current, 30 min sessions were delivered). We performed Kaplan-Meier survival analysis and Cox proportional hazards ratios to evaluate predictors of relapse. RESULTS: Out of 24 patients, 18 completed the follow-up period. tDCS treatment was well tolerated. The mean survival duration was 17.5 weeks (122 days). The survival rate at the end of follow-up was 73.5% (95% confidence interval, 50-87). A trend (P = 0.09) was observed for lower relapse rates in nontreatment- vs. antidepressant treatment-resistant patients (7.7% vs. 45.5%, respectively). No differences in efficacy between unipolar and bipolar depression were observed. CONCLUSION: An intensive tDCS treatment regimen consisting of sessions twice a week achieved relatively low relapse rates after a 6-month follow up of tDCS responders, particularly for nontreatment-resistant patients.

Transcranial Direct Current Stimulation in the Acute Depressive Episode: A Systematic Review of Current Knowledge.

Major depressive disorder is a severe, refractory mental disorder. Only one third of patients treated with antidepressants achieve remission after 3 trials, while subject to adverse effects. Therefore, the investigation of alternative treatments is paramount. The aim of this systematic review was to summarize the most recent evidence of transcranial direct current stimulation (tDCS) intervention for the acute phase of major depressive disorder. A PubMed search was performed including the terms "transcranial direct current stimulation" OR "transcranial direct stimulation" OR "tDCS" AND "major depressive disorder" OR "major depression" OR "depression" AND "trial." The search was conducted from inception until February 2018. Our search yielded initially 165 results, and 14 randomized clinical trials were included according to eligibility criteria. Most studies were pilot studies, with mixed findings. Two large randomized clinical trials recently published also presented primary negative findings. Study protocols usually used anodal left/cathodal right dorsolateral prefrontal cortex stimulation, 1 to 2.5 mA, and 5 to 20 tDCS sessions. We discuss the limitations of the included trials, such as sample and tDCS parameters heterogeneity between studies. To conclude, tDCS seems to be safe and devoid of serious adverse effects, although robust efficacy has not been consistently demonstrated in clinical trials assessing an acute treatment course of up to 4 weeks. Further directions are discussed, such as parameter individualization, investigation of biological markers, and home-use tDCS.

Home-Use Transcranial Direct Current Stimulation for the Treatment of a Major Depressive Episode: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) is moderately effective for depression when applied by trained staff. It is not known whether self-applied tDCS, combined or not with a digital psychological intervention, is also effective. Objective: To determine whether fully unsupervised home-use tDCS, combined with a digital psychological intervention or digital placebo, is effective for a major depressive episode. Design, Setting, and Participants: This was a double-blinded, sham-controlled, randomized clinical trial with 3 arms: (1) home-use tDCS plus a digital psychological intervention (double active); (2) home-use tDCS plus digital placebo (tDCS only), and (3) sham home-use tDCS plus digital placebo (double sham). The study was conducted between April 2021 and October 2022 at participants' homes and at Instituto de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Brazil. Included participants were aged 18 to 59 years with major depression and a Hamilton Depression Rating Scale, 17-item version (HDRS-17), score above 16, a minimum of 8 years of education, and access to a smartphone and internet at home. Exclusion criteria were other psychiatric disorders, except for anxiety; neurologic or clinical disorders; and tDCS contraindications. Interventions: tDCS was administered in 2-mA, 30-minute prefrontal sessions for 15 consecutive weekdays (1-mA, 90-second duration for sham) and twice-weekly sessions for 3 weeks. The digital intervention consisted of 46 sessions based on behavioral therapy. Digital placebo was internet browsing. Main Outcomes and Measures: Change in HDRS-17 score at week 6. Results: Of 837 volunteers screened, 210 participants were enrolled (180 [86%] female; mean [SD] age, 38.9 [9.3] years) and allocated to double active (n = 64), tDCS only (n = 73), or double sham (n = 73). Of the 210 participants enrolled, 199 finished the trial. Linear mixed-effects models did not reveal statistically significant group differences in treatment by time interactions for HDRS-17 scores, and the estimated effect sizes between groups were as follows: double active vs tDCS only (Cohen d, 0.05; 95% CI, -0.48 to 0.58; P = .86), double active vs double sham (Cohen d, -0.20; 95% CI, -0.73 to 0.34; P = .47), and tDCS only vs double sham (Cohen d, -0.25; 95% CI, -0.76 to 0.27; P = .35). Skin redness and heat or burning sensations were more frequent in the double active and tDCS only groups. One nonfatal suicide attempt occurred in the tDCS only group. Conclusions and Relevance: Unsupervised home-use tDCS combined with a digital psychological intervention or digital placebo was not found to be superior to sham for treatment of a major depressive episode in this trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04889976.

Transcranial Electrical Stimulation for Psychiatric Disorders in Adults: A Primer.

Transcranial electrical stimulation (tES) comprises noninvasive neuromodulation techniques that deliver low-amplitude electrical currents to targeted brain regions with the goal of modifying neural activities. Expanding evidence from the past decade, specifically using transcranial direct current simulation and transcranial alternating current stimulation, presents promising applications of tES as a treatment for psychiatric disorders. In this review, the authors discuss the basic technical aspects and mechanisms of action of tES in the context of clinical research and practice and review available evidence for its clinical use, efficacy, and safety. They also review recent advancements in use of tES for the treatment of depressive disorders, schizophrenia, substance use disorders, and obsessive-compulsive disorder. Findings largely support growing evidence for the safety and efficacy of tES in the treatment of patients with resistance to existing treatment options, particularly demonstrating promising treatment outcomes for depressive disorders. Future directions of tES research for optimal application in clinical settings are discussed, including the growing home-based, patient-friendly methods and the potential pairing with existing pharmacological or psychotherapeutic treatments for enhanced outcomes. Finally, neuroimaging advancements may provide more specific mapping of brain networks, aiming at more precise tES therapeutic targeting in the treatment of psychiatric disorders.

A study protocol for an ongoing multi-arm, randomized, double-blind, sham-controlled clinical trial with digital features, using portable transcranial electrical stimulation and internet-based behavioral therapy for major depression disorders: The PSYLECT study.

BACKGROUND: 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. RESEARCH DESIGN: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: Our results should offer new insights regarding the efficacy and scalability of combined ptES and iBT for MDD, in digital mental health.

Distinct trajectories of response to prefrontal tDCS in major depression: results from a 3-arm randomized controlled trial.

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.

Treatment of mixed depression with theta-burst stimulation (TBS): results from a double-blind, randomized, sham-controlled clinical trial.

Mixed depression is probably different in terms of clinical course and response to treatment. Repetitive transcranial magnetic stimulation (rTMS) is well established in non-mixed depression, and theta-burst stimulation (TBS) protocol is replacing conventional protocols because of noninferiority and reduced delivery time. However, TBS has not been adequately studied in mixed states. This study was a double-blind, six-week, sham-controlled, and randomized clinical trial of bilateral TBS targeting the right and left dorsolateral prefrontal cortex, respectively. Adults with bipolar and major depressive disorder experiencing an acute mixed depression were eligible if they had not benefited from a first- or second-line treatment for acute unipolar or bipolar depression recommended by the Canadian Network for Mood and Anxiety Treatments. Out of 100 patients included, 90 composed modified intention-to-treat sample, which was patients that completed at least one week of the intervention. There were no significant differences in Montgomery-Asberg depression rating scale score changes (least squares mean difference between groups at week 3, -0.06 [95% CI, - 3.39 to 3.51; P = 0.97] in favor of sham TBS). Response and remission rates per MADRS were also not statistically different among active and sham groups (35.7% vs. 43.7%, and 28.5% vs. 37.5% respectively at week 6, ps > 0.51). No other analyses from baseline to weeks 3 or 6 revealed significant time x group interaction or mean differences among groups in the mITT sample. Bilateral TBS targeting the DLPFC is not efficacious as an add-on treatment of acute bipolar and unipolar mixed depression. ClinicalTrials.govIdentifier: NCT04123301.

Appraising the effectiveness of electrical and magnetic brain stimulation techniques in acute major depressive episodes: an umbrella review of meta-analyses of randomized controlled trials.

Electrical and magnetic brain stimulation techniques present distinct mechanisms and efficacy in the acute treatment of depression. This was an umbrella review of meta-analyses of randomized controlled trials of brain stimulation techniques for managing acute major depressive episodes. A systematic review was performed in the PubMed/MEDLINE databases from inception until March 2020. We included the English language meta-analysis with the most randomized controlled trials on the effects of any brain stimulation technique vs. control in adults with an acute depressive episode. Continuous and dichotomous outcomes were assessed. A Measurement Tool to Assess Systematic Reviews-2 was applied and the credibility of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Seven meta-analyses were included (5,615 patients), providing evidence for different modalities of brain stimulation techniques. Three meta-analyses were evaluated as having high methodological quality, three as moderate, and one as low. The highest quality of evidence was found for high frequency-repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, and bilateral rTMS. There is strong clinical research evidence to guide future clinical use of some techniques. Our results confirm the heterogeneity of the effects across these techniques, indicating that different mechanisms of action lead to different efficacy profiles.

The Flow brain stimulation headset for the treatment of depression: overview of its safety, efficacy and portable design.

INTRODUCTION: Major depressive disorder (MDD) is a prevalent and debilitating condition. First-line treatments include antidepressants and cognitive-behavioral psychotherapy (CBT). However, several patients present treatment-resistance and/or adverse effects. Transcranial direct current stimulation (tDCS), a noninvasive neuromodulation technique, is an effective alternative for MDD. AREAS COVERED: We hereby review a portable tDCS device designed to be combined with a cognitive-behavioral intervention. This home-use device was developed by Flow Neuroscience™ and was recently approved in the UK and European Union. We discuss present evidence on tDCS efficacy and safety, both as a monotherapy and as a combined treatment. Moreover, we show a computer modeling tDCS procedure based on Flow parameters and montage. EXPERT OPINION: Electric field simulations revealed that Flow's tDCS device targets prefrontal cortical areas involved in MDD pathophysiology. In addition, the safety and efficacy profile revealed from prior tDCS studies support its use in depression. Finally, combining tDCS with cognitive-behavioral interventions might further enhance overall efficacy, although this aspect should be investigated in upcoming randomized, placebo-controlled trials.

Efficacy, Safety, and Tolerability of Theta-Burst Stimulation in Mixed Depression: Design, Rationale, and Objectives of a Randomized, Double-Blinded, Sham-Controlled Trial.

INTRODUCTION: Mixed-specifier mood disorders are probably a different subgroup in terms of response to treatment, socio-demographic parameters, course, and family history. Here we describe the rationale and design of a clinical trial aimed to test the efficacy, safety, and tolerability of a non-pharmacological treatment known as theta-burst stimulation (TBS) for treating the mixed depressive episodes of both bipolar (I or II), and unipolar depression. METHODS: The study is designed as a randomized, sham-controlled, double-blinded clinical trial evaluating TBS for the treatment of moderate or severe major depressive episodes with mixed features of patients receiving at least one first or second-line pharmacological treatment for depressive episodes without adequate response. Ninety adult (18 to 65 years old) patients will be enrolled and submitted to 6-week (comprising 5 consecutive days a week sessions for the first 3 weeks and then 2 days a week for a further 3 week) of inhibitory followed by excitatory TBS in dorsolateral prefrontal cortex. Participants will be assessed using clinical and neuropsychological tests before and after the intervention. The primary outcome is change in Montgomery-Åsberg Depression Scale (MADRS) score over time and across groups. Cognitive parameters will also be assessed with neuropsychological tests. RESULTS: The clinical results will provide evidence about TBS as an adjunctive treatment for mixed depression treatment and neuropsychological parameters will contribute toward an improved understanding the effects of TBS in cognition. CONCLUSION: Our results could introduce a novel therapeutic technique for mixed depressive episodes of both bipolar and unipolar disorders. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT04123301; date of registration: 10/10/2019; URL: https://clinicaltrials.gov/ct2/show/NCT04123301?term=NCT04123301&rank=1.

Precision non-implantable neuromodulation therapies: a perspective for the depressed brain.

Current first-line treatments for major depressive disorder (MDD) include pharmacotherapy and cognitive-behavioral therapy. However, one-third of depressed patients do not achieve remission after multiple medication trials, and psychotherapy can be costly and time-consuming. Although non-implantable neuromodulation (NIN) techniques such as transcranial magnetic stimulation, transcranial direct current stimulation, electroconvulsive therapy, and magnetic seizure therapy are gaining momentum for treating MDD, the efficacy of non-convulsive techniques is still modest, whereas use of convulsive modalities is limited by their cognitive side effects. In this context, we propose that NIN techniques could benefit from a precision-oriented approach. In this review, we discuss the challenges and opportunities in implementing such a framework, focusing on enhancing NIN effects via a combination of individualized cognitive interventions, using closed-loop approaches, identifying multimodal biomarkers, using computer electric field modeling to guide targeting and quantify dosage, and using machine learning algorithms to integrate data collected at multiple biological levels and identify clinical responders. Though promising, this framework is currently limited, as previous studies have employed small samples and did not sufficiently explore pathophysiological mechanisms associated with NIN response and side effects. Moreover, cost-effectiveness analyses have not been performed. Nevertheless, further advancements in clinical trials of NIN could shift the field toward a more "precision-oriented" practice.

Associations between symptoms of depression and heart rate variability: An exploratory study.

Major depressive disorder (MDD) is associated with decreased heart rate variability (HRV), a predictor of cardiovascular morbidity by many, but not all studies. This inconsistency could be due to the association of HRV with specific depressive symptoms. Here, we investigated the association of HRV parameters with components of depressive symptoms from 120 MDD patients, at baseline of a published trial comparing the effect of sertraline to transcranial direct current stimulation. We used Principal Component Analysis to extract components of the Hamilton Rating Scale for Depression (HAM-D-17), the Montgomery Asberg Depression Rating Scale (MADRS) and the Beck Inventory for Depressive Symptomatology (BDI). We constructed one equation of multiple linear regression for each HRV parameter as the dependent variable, and the components of depressive symptoms of the three scales as the independent ones, adjusted for age and gender. A component of HAM-D-17 predicted LF/HF (low frequency/high frequency) and a component of MADRS predicted LF (low frequency). "Guilt" and "loss of interest/pleasure in activities" were present in the components of both scales, and the MADRS component also included "psychomotor retardation". These results suggest that melancholic features might be relevant for the association between MDD and HRV. Considering multiple comparisons, these results are preliminary.

Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression: A Randomized Clinical Trial.

Importance: More effective, tolerable interventions for bipolar depression treatment are needed. Transcranial direct current stimulation (tDCS) is a novel therapeutic modality with few severe adverse events that showed promising results for unipolar depression. Objective: To determine the efficacy and safety of tDCS as an add-on treatment for bipolar depression. Design, Setting, and Participants: A randomized, sham-controlled, double-blind trial (the Bipolar Depression Electrical Treatment Trial [BETTER]) was conducted from July 1, 2014, to March 30, 2016, at an outpatient, single-center academic setting. Participants included 59 adults with type I or II bipolar disorder in a major depressive episode and receiving a stable pharmacologic regimen with 17-item Hamilton Depression Rating Scale (HDRS-17) scores higher than 17. Data were analyzed in the intention-to-treat sample. Interventions: Ten daily 30-minute, 2-mA, anodal-left and cathodal-right prefrontal sessions of active or sham tDCS on weekdays and then 1 session every fortnight until week 6. Main Outcomes and Measures: Change in HDRS-17 scores at week 6. Results: Fifty-nine patients (40 [68%] women), with a mean (SD) age of 45.9 (12) years participated; 36 (61%) with bipolar I and 23 (39%) with bipolar II disorder were randomized and 52 finished the trial. In the intention-to-treat analysis, patients in the active tDCS condition showed significantly superior improvement compared with those receiving sham (ßint = -1.68; number needed to treat, 5.8; 95% CI, 3.3-25.8; P = .01). Cumulative response rates were higher in the active vs sham groups (67.6% vs 30.4%; number needed to treat, 2.69; 95% CI, 1.84-4.99; P = .01), but not remission rates (37.4% vs 19.1%; number needed to treat, 5.46; 95% CI, 3.38-14.2; P = .18). Adverse events, including treatment-emergent affective switches, were similar between groups, except for localized skin redness that was higher in the active group (54% vs 19%; P = .01). Conclusions and Relevance: In this trial, tDCS was an effective, safe, and tolerable add-on intervention for this small bipolar depression sample. Further trials should examine tDCS efficacy in a larger sample. Trial Registration: clinicaltrials.gov Identifier: NCT02152878.

Primum non nocere or primum facere meliorem? Hacking the brain in the 21st century.

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique that modulates cortical excitability. It is devoid of serious adverse events and exerts variable effects on cognition, with several research findings suggesting that it can improve memory, verbal and mathematical skills. Because tDCS devices are low-cost, portable and relatively easy to assemble, they have become available outside of the medical setting and used for non-medical ("cosmetic") purposes by laypersons. In this sense, tDCS has become a popular technique aiming to improve cognition and the achievement of a better performance not only at work, but also in other fields such as sports, leisure activities (video games) and even the military. In spite of these unforeseen developments, there has been a general paralysis of the medical and regulatory agencies to develop guidelines for the use of tDCS for cosmetic purposes. Several challenges are present, most importantly, how to restrict tDCS use outside of the medical setting in face of variable and sometimes conflicting results from scientific research. This article aims to describe the popular use of tDCS, in light of the pillars of neuroethics, a branch of bioethics relative to brain research. Between two possible but extreme solutions - total release or total restriction of tDCS - it is paramount to develop a spectrum of alternatives, which may vary over time and in different cultural backgrounds.

Nonverbal behaviors are associated with increased vagal activity in major depressive disorder: Implications for the polyvagal theory.

BACKGROUND: Major depressive disorder (MDD) is associated with impairments in nonverbal behaviors (NVBs) and vagal activity. The polyvagal theory proposes that vagal activity regulates heart rate and NVBs by modulating a common anatomically and neurophysiologically discrete social engagement system. However, the association between these putative endophenotypes has not yet been explored. We hypothesize that in MDD, NVBs indicating positive affects and social interest and those indicating negative feelings and social disinterest could be associated with different patterns of vagal activity. METHODS: For this cross-sectional study we recruited 50 antidepressant-free participants with moderate-to-severe MDD. Vagal activity was indexed by heart rate variability (HRV) measures, and positive and negative nonverbal behaviors (NVBs) by a validated ethogram. Associations between NVBs and HRV were explored by bivariate analyses and multivariable models were adjusted by age, gender, depression severity, and self-reported positive and negative affects. RESULTS: HRV measures indicative of higher vagal activity were positively correlated with positive NVBs exhibited during the clinical interview. Conversely, NVBs related to negative affects, low energy and social disinterest were not associated with HRV. LIMITATIONS: Absence of a control group. CONCLUSIONS: The findings highlight that the examined depression endophenotypes (nonverbal behaviors and vagal activity) are related, shedding light on MDD pathophysiology in the context of the polyvagal theory.

Appraising the effectiveness of electrical and magnetic brain stimulation techniques in acute major depressive episodes: an umbrella review of meta-analyses of randomized controlled trials

Electrical and magnetic brain stimulation techniques present distinct mechanisms and efficacy in the acute treatment of depression. This was an umbrella review of meta-analyses of randomized controlled trials of brain stimulation techniques for managing acute major depressive episodes. A systematic review was performed in the PubMed/MEDLINE databases from inception until March 2020. We included the English language meta-analysis with the most randomized controlled trials on the effects of any brain stimulation technique vs. control in adults with an acute depressive episode. Continuous and dichotomous outcomes were assessed. A Measurement Tool to Assess Systematic Reviews-2 was applied and the credibility of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation framework. Seven meta-analyses were included (5,615 patients), providing evidence for different modalities of brain stimulation techniques. Three meta-analyses were evaluated as having high methodological quality, three as moderate, and one as low. The highest quality of evidence was found for high frequency-repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation, and bilateral rTMS. There is strong clinical research evidence to guide future clinical use of some techniques. Our results confirm the heterogeneity of the effects across these techniques, indicating that different mechanisms of action lead to different efficacy profiles.