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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., (© 2021. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Abstract ., Background: Depression is highly prevalent and marked by a chronic and recurrent course. Despite being a major cause of disability worldwide, little is known regarding the determinants of its heterogeneous course. Machine learning techniques present an opportunity to develop tools to predict diagnosis and prognosis at an individual level., Methods: We examined baseline (2008-2010) and follow-up (2012-2014) data of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), a large occupational cohort study. We implemented an elastic net regularization analysis with a 10-fold cross-validation procedure using socioeconomic and clinical factors as predictors to distinguish at follow-up: (1) depressed from non-depressed participants, (2) participants with incident depression from those who did not develop depression, and (3) participants with chronic (persistent or recurrent) depression from those without depression., Results: We assessed 15 105 and 13 922 participants at waves 1 and 2, respectively. The elastic net regularization model distinguished outcome levels in the test dataset with an area under the curve of 0.79 (95% CI 0.76-0.82), 0.71 (95% CI 0.66-0.77), 0.90 (95% CI 0.86-0.95) for analyses 1, 2, and 3, respectively., Conclusions: Diagnosis and prognosis related to depression can be predicted at an individual subject level by integrating low-cost variables, such as demographic and clinical data. Future studies should assess longer follow-up periods and combine biological predictors, such as genetics and blood biomarkers, to build more accurate tools to predict depression course.

Objective: In 2020, the COVID-19 pandemic brought a work and stress overload to healthcare workers, increasing their vulnerability to mental health impairments. In response, the authors created the COMVC-19 program. The program offered preventive actions and mental health treatment for the 22,000 workers of The Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). This paper aims to describe its implementation and share what we have learned from this experience., Methods: Workers were able to easily access the program through a 24/7 hotline. Additionally, a mobile phone app that screened for signs and symptoms of emotional distress and offered psychoeducation and/or referral to treatment was made available. Data from both these sources as well as any subsequent psychiatric evaluations were collected., Results: The first 20 weeks of our project revealed that most participants were female, and part of the nursing staff working directly with COVID-19 patients. The most frequently reported symptoms were: anxiety, depression and sleep disturbances. The most common diagnoses were Adjustment, Anxiety, and Mood disorders., Conclusions: Implementing a mental health program in a multimodal intervention was feasible in a major quaternary public hospital. Our data also suggests that preventive actions should primarily be aimed at anxiety and depression symptoms, with a particular focus on the nursing staff.

Glaucoma, cataracts, and cognitive decline are most common in older ages. Although cross-sectional studies showed that these disorders are associated, follow-up studies are lacking. To investigate this issue, baseline and follow-up data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) were employed. We evaluated participants ≥ 55 years-old at follow-up without diagnosis of dementia, stroke, and other eye conditions except for glaucoma and cataracts. Cognition was evaluated using delayed word recall, verbal fluency, and trail making (version B) tests. Regression models were employed to investigate associations between glaucoma and cognition, adjusted by several confounders. Out of 3,867 participants, 379 and 118 presented cataracts and glaucoma, respectively. Only glaucoma was apredictor of lower verbal fluency (B = -0.23, 95% CI -035 to -012, p< 0.001). Other associations were not significant (ps>0.57). Our results suggest that glaucoma may be related to declining cognition.

Introduction: Non-invasive brain stimulation (NIBS) as monotherapy has been increasingly used to enhance the activity of brain networks. However, it is unclear whether a combination of distinct NIBS approaches could enhance prefrontal cortical (PFC) activity., Objective: We propose to investigate the combined and standalone effects of two NIBS modalities on the PFC through a working memory task, single photon emission computed tomography (SPECT), and salivary cortisol. We hypothesize that the combined protocol will provoke greater changes in the collected measures compared to the remining protocols., Methods: A randomized, double-blind, sham-controlled, full-factorial design will be conducted. The effects of transcranial direct current stimulation (tDCS) and intermittent theta-burst stimulation (iTBS) will be investigated over four different sessions (sham tDCS + sham iTBS, anodal tDCS + sham iTBS, anodal tDCS + active iTBS and sham tDCS + active iTBS) in 30 healthy adult volunteers. A 99mTc-ethylene cysteine dimer (99mTC-ECD) will be administered during the NIBS session and neuroimaging will be acquired within one hour. Salivary cortisol will be collected before and after each session and an n-back working memory task will be applied after the end of each NIBS session. The outcomes will be cerebral perfusion alterations (99mTC-ECD SPECT), accuracy and reaction time in the n-back task, and changes in salivary cortisol level., Conclusion: The results from this trial can guide future therapeutic protocols for NIBS treatments stimulating the PFC by demonstrating that the combination of NIBS techniques is feasible, tolerable, and can lead to greater enhancement of PFC activity., Competing Interests: ARB is chief medical advisor of Flow™ and has a small equity holding in the company. No other conflicts of interest declared concerning the publication of this article.

An important challenge in mental health research is to translate findings from cognitive neuroscience and neuroimaging research into effective treatments that target the neurobiological alterations involved in psychiatric symptoms. To address this challenge, in this review we propose a heuristic neurocircuit-based taxonomy to guide the treatment of obsessive-compulsive disorder (OCD). We do this by integrating information from several sources. First, we provide case vignettes in which patients with OCD describe their symptoms and discuss different clinical profiles in the phenotypic expression of the condition. Second, we link variations in these clinical profiles to underlying neurocircuit dysfunctions, drawing on findings from neuropsychological and neuroimaging studies in OCD. Third, we consider behavioral, pharmacological, and neuromodulatory treatments that could target those specific neurocircuit dysfunctions. Finally, we suggest methods of testing this neurocircuit-based taxonomy as well as important limitations to this approach that should be considered in future research., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Importance: The placebo effect in depression clinical trials is a substantial factor associated with failure to establish efficacy of novel and repurposed treatments. However, the magnitude of the placebo effect and whether it differs across treatment modalities in treatment-resistant depression (TRD) is unclear., Objective: To examine the magnitude of the placebo effect in patients with TRD across different treatment modalities and its possible moderators., Data Sources: Searches were conducted on MEDLINE, Web of Science, and PsychInfo from inception to June 21, 2021., Study Selection: Randomized clinical trials (RCTs) were included if they recruited patients with TRD and randomized them to a placebo or sham arm and a pharmacotherapy, brain stimulation, or psychotherapy arm., Data Extraction and Synthesis: Independent reviewers used standard forms for data extraction and quality assessment. Random-effects analyses and standard pairwise meta-analyses were performed., Main Outcomes and Measures: The primary outcome was the Hedges g value for the reported depression scales. Secondary outcomes included moderators assessed via meta-regression and response and remission rates. Heterogeneity was assessed with the I2 test, and publication bias was evaluated using the Egger test and a funnel plot. Cochrane Risk of Bias Tool was used to estimate risks., Results: Fifty RCTs were included involving various types of placebo or sham interventions with a total of 3228 participants (mean [SD] age, 45.8 [6.0] years; 1769 [54.8%] female). The pooled placebo effect size for all modalities was large (g = 1.05; 95% CI, 0.91-1.1); the placebo effect size in RCTs of specific treatment modalities did not significantly differ. Similarly, response and remission rates associated with placebo were comparable across modalities. Heterogeneity was large. Three variables were associated with a larger placebo effect size: open-label prospective treatment before double-blind placebo randomization (β = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (β = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (β = 0.34; 95% CI, 0.09 to 0.58; P = .007). The number of failed interventions was associated with the probability a smaller placebo effect size (β = -0.12; 95% CI, -0.23 to -0.01, P = .03). The Egger test result was not significant for small studies' effects., Conclusions and Relevance: This analysis may provide a benchmark for past and future clinical RCTs that recruit patients with TRD standardizing an expected placebo effect size.

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.

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Deficits in episodic memory following traumatic brain injury (TBI) are common and affect independence in activities of daily living. Transcranial direct current stimulation (tDCS) and concurrent cognitive training may contribute to improve episodic memory in patients with TBI. Although previous studies have shown the potential of tDCS to improve cognition, the benefits of the tDCS applied simultaneously to cognitive training in participants with neurological disorders are inconsistent. This study aims to (1) investigate whether active tDCS combined with computer-assisted cognitive training enhances episodic memory compared with sham tDCS; (2) compare the differences between active tDCS applied over the left dorsolateral prefrontal cortex (lDLPFC) and bilateral temporal cortex (BTC) on episodic memory and; (3) investigate inter and intragroup changes on cortical activity measured by quantitative electroencephalogram (qEEG)., Methods and Analysis: A randomised, parallel-group, double-blind placebo-controlled study is conducted. Thirty-six participants with chronic, moderate and severe closed TBI are being recruited and randomised into three groups (1:1:1) based on the placement of tDCS sponges and electrode activation (active or sham). TDCS is applied for 10 consecutive days for 20 min, combined with a computer-based cognitive training. Cognitive scores and qEEG are collected at baseline, on the last day of the stimulation session, and 3 months after the last tDCS session. We hypothesise that (1) the active tDCS group will improve episodic memory scores compared with the sham group; (2) differences on episodic memory scores will be shown between active BTC and lDLPFC and; (3) there will be significant delta reduction and an increase in alpha waves close to the location of the active electrodes compared with the sham group., Ethics and Dissemination: This study was approved by Hospital das Clínicas, University of São Paulo Ethical Institutional Review Border (CAAE: 87954518.0.0000.0068)., Trial Registration Number: NCT04540783., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background/objectives: Obesity has recently been recognized as a neurocognitive disorder involving circuits associated with the reward system and the dorsolateral prefrontal cortex (DLPFC). Noninvasive brain stimulation (NIBS) has been proposed as a strategy for the management of obesity. However, the results have been inconclusive. The aim of the current network meta-analysis (NMA) was to evaluate the efficacy and acceptability of different NIBS modalities for weight reduction in participants with obesity., Methods: Randomized controlled trials (RCTs) examining NIBS interventions in patients with obesity were analyzed using the frequentist model of NMA. The coprimary outcome was change in body mass index (BMI) and acceptability, which was calculated using the dropout rate., Results: Overall, the current NMA, consisting of eight RCTs, revealed that the high-frequency repetitive transcranial magnetic stimulation (TMS) over the left DLPFC was ranked to be associated with the second-largest decrease in BMI and the largest decrease in total energy intake and craving severity, whereas the high-frequency deep TMS over bilateral DLPFC and the insula was ranked to be associated with the largest decrease in BMI., Conclusion: This pilot study provided a "signal" for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on weight reduction in participants with obesity by different NIBS interventions., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Previous evidence supports the notion that the physical activity (PA) domain (leisure-time or transport), and the amount of time spent in PA, influence the association of PA with depressive and anxiety symptoms. However, no study evaluated the associations of different volumes of leisure-time PA (LTPA) and transport PA (TPA) with prevalent depression, anxiety, and co-occurring depression and anxiety (D&A) disorders., Aim: To investigate the associations between different volumes of LTPA and TPA with prevalent depression, anxiety, and D&A., Methods: Cross-sectional study using baseline data of the ELSA-Brasil cohort. The International Physical Activity Questionnaire (IPAQ) long-form was used to assess PA levels in each domain. The Clinical Interview Scheduled Revised (CIS-R) was used to diagnose prevalent depressive, anxiety, and D&A disorders. Logistic regressions, adjusting for confounding factors, were employed. Results are expressed as adjusted odds ratios (aOR) and 95% confidence intervals (CI)., Results: A total of 14,381 adults (54.5% female, 67.5% aged 45-64 years) were assessed. T ime spent in LTPA was associated with a lower prevalence of depression in low, and high volumes ( 60-89min/week aOR = 0.47, 95%CI = 0.29-0.76, p = 0.002, >300min/week aOR = 0.43, 95%CI = 0.31-0.59, p < 0.001). High volumes of LTPA were associated with a lower prevalence D&A ( 270-299min/week aOR = 0.55, 95%CI 0.38-0.79, p = 0.001 ; >300 minutes aOR = 0.63, 95%CI 0.54-0.74, p < 0.001). Low ( 60-89min/week aOR = 0.56, 95%CI = 0.40-0.79, p = 0.001) volumes of TPA were associated with lower prevalence of depression., Limitations: Cross-sectional design and self-reported PA. Lack of assessment of sedentary behaviour or occupational PA., Conclusions: The present study highlights the importance of contextual factors in the association between PA and mental health, particularly at higher levels., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Non-invasive brain stimulation (NIBS) techniques have been suggested as alternative treatments to decrease depression symptoms during the perinatal period. These include brain stimulation techniques that do not require surgery and that are nonpharmacological and non-psychotherapeutic. NIBS with evidence of antidepressant effects include repetitive transcranial magnetic stimulation (rTMS), transcranial electric stimulation (TES) and electroconvulsive therapy (ECT)., Objectives: This systematic review aims to summarize evidence on NIBS efficacy, safety and acceptability in treating peripartum depression (PPD)., Methods: We included randomized, non-randomized and case reports, that used NIBS during pregnancy and the postpartum. The reduction of depressive symptoms and neonatal safety were the primary and co-primary outcomes, respectively., Results: rTMS shows promising results for the treatment of PPD, with clinically significant decreases in depressive symptoms between baseline and end of treatment and overall good acceptability. Although the safety profile for rTMS is adequate in the postpartum, caution is warranted during pregnancy. In TES, evidence on efficacy derives mostly from single-arm studies, compromising the encouraging findings. Further investigation is necessary concerning ECT, as clinical practice relies on clinical experience and is only described in low-quality case-reports., Limitations: The reduced number of controlled studies, the lack of complete datasets and the serious/high risk of bias of the reports warrant cautious interpretations., Conclusions and Implications: Existing evidence is limited across NIBS techniques; comparative studies are lacking, and standard stimulation parameters are yet to be established. Although rTMS benefits from the most robust research, future multicenter randomized clinical trials are needed to determine the position of each NIBS strategy within the pathways of care., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Transcranial Direct Current Stimulation (tDCS) is an effective treatment during the acute phase of a major depressive episode (MDE), although the evidence for its follow-up efficacy is mixed. A systematic review and meta-analysis were performed. MEDLINE/PubMed, Scopus (EMBASE), Web of Science, Cochrane Library and additional sources were searched from inception to April 29, 2021. Studies that followed up adults treated with tDCS during an MDE - using (interventional) and/or not using (observational) tDCS in the follow-up period were included. The primary outcome was the Hedges' g for the follow-up depression scores. Small study effects and sources of heterogeneity were explored. 427 studies were retrieved and 11 trials (13 datasets, n = 311) were included, most presenting moderate bias. Results showed a follow-up depression improvement (k = 13, g = -0.81, 95% confidence interval [CI]: -1.28; -0.34, I² = 84.0%), which was probably driven by the interventional studies (k = 7, g= -1.12, 95% CI: -1.84; -0.40, I² = 87.1%). No predictor of response was associated with the outcome. No risk of publication bias was found. Significant between-study heterogeneity may have influenced the overall results. Our findings suggest that tDCS produces effects beyond the intervention period during MDEs. Maintenance sessions are advised in future research., (Copyright © 2021. Published by Elsevier B.V.)

Background: Randomised clinical trials (RCTs) investigating transcranial direct current stimulation (tDCS) efficacy for depression show significant heterogeneity in outcomes., Objective: To investigate the magnitude of the sham tDCS response and its potential moderators in the treatment of depression., Methodology: A systematic review and aggregate meta-analysis (PROSPERO ID CRD42020161254). The systematic review was conducted in the PubMed, Scopus (EMBASE) and Cochrane Library databases. Only RCTs enrolling adult subjects with an acute depressive episode with a sham tDCS group were included., Results: Twenty-three studies (twenty-five datasets, 501 participants) were included. Sham tDCS response was large (Hedges' g = 1.09; 95% CI: 0.8;1.38). Secondary and subgroup analyses showed that sham protocols employing a ramp-up/ramp-down at the beginning and end of stimulation presented a significantly lower sham response compared to other protocols. Univariate meta-regression analyses found that sham response was associated with higher risk of blinding bias, and with thetreatment effect size of the active tDCS group. Subgroup analyses also showed that placement of the cathode over the lateral right frontal area (F8) presented a significantly lower sham response. Other moderators, including treatment resistance, baseline severity of depressive symptoms, and total charge delivered were not associated with the magnitude of the sham response., Conclusion: The sham tDCS response was large. Our findings demonstrate the need for standardization of sham tDCS protocols and bring attention to important considerations that can guide future RCTs employing tDCS for the treatment of MDD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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; CI 95%  = -0.94 to -0.17, p = .009), which was superior to placebo (ES = 0.49; CI 95%  = 0.06 to 0.92, p = .042). TDCS but not escitalopram was superior to placebo in sleep/insomnia symptoms (ES = 0.87; CI 95%  = 0.22 to 1.52, p = .015). Escitalopram but not tDCS was superior to placebo in guilt/anxiety symptoms (ES = 1.66; CI 95%  = 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., Competing Interests: Declaration of competing interest Dr. Padberg reports grants from Federal Ministry of Education and Research, Berlin, Germany, personal fees from Brainsway Inc., Jerusalem, Germany, personal fees, non-financial support from Mag&More GmbH, Munich, Germany, and non-financial support from neuroCare Group GmbH, Munich, Germany outside the submitted work. Dr. Chekroud holds equity in Spring Care Inc, Fitbit Inc, and UnitedHealthcare Inc. He is lead inventor on three patent submissions relating to treatment for major depressive disorder (US Patent and Trademark Office [USPTO] docket no.Y0087.70116US00, USPTO provisional application no. 62/491,660, and USPTO provisional application no. 62/629,041). He has consulted for Fortress Biotech on antidepressant drug development., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although social distancing is necessary to decrease COVID-19 dissemination, it might also be associated with suicidal ideation. Therefore, we analyzed the impact of social distancing and loneliness in suicidal ideation., Methods: We performed two waves of a snowball sample, web-based survey in Brazil (W1: from May 6th to June 6th, 2020; W2: from June 6th to July 6th, 2020). We assessed whether risk factors related to social relationships (loneliness, living alone, not leaving home, and the number of days practicing social distancing) at W1 were associated with suicidal ideation at W1 and W2 using multiple regression models. Analyses were adjusted for sociodemographic, mental health, and lifestyle variables., Results: A total of 1,674 (18-75 years old; 86.5% females) were included in our longitudinal sample. Living alone (OR: 1.16; 95%CI = 1.03 - 1.30; p=0.015), number of days practicing social distancing (OR: 1.002; 95%CI = 1.000 - 1.004; p=0.027), and loneliness (OR: 1.49; 95%CI = 1.32 - 1.68; p<0.001) were associated with suicidal ideation in the cross-sectional analysis of W1. Only loneliness (OR= 2.12; 95%CI = 1.06 - 4.24; p = 0.033) remained significant as a risk factor to suicidal ideation in the longitudinal analysis between both waves., Limitation: Snowball, convenience sample design limits outcome estimates. Assessments were not objectively performed., Conclusion: Loneliness was consistently associated with the incidence of suicidal ideation, while other variables, such as living alone, not leaving home, and the number of days practicing social distancing, were not. Measures to overcome loneliness are therefore necessary to reduce suicidal ideation during pandemics., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Relatively few studies have assessed the prevalence, correlates, and independent impact on quality of life (QoL) of trichotillomania (TTM) in large samples., Methods: Consecutive participants (N = 7639) were recruited from a cross-sectional web-based study. Sociodemographic data were collected and several validated self-reported mental health measures were completed (Minnesota Impulsive Disorders Interview, Hypomania checklist, Fagerström Test for Nicotine Dependence, Alcohol Use Disorders Identification Test, Early Trauma Inventory Self Report-Short Form, and the Symptom Checklist-90-Revised Inventory). Health-related QoL was assessed with the World Health Organization QoL abbreviated scale (WHOQOL-Bref). Multivariable models adjusted associations to potential confounders., Results: The sample was predominantly composed of young females (71.3%; mean age: 27.2 ± 7.9 years). The prevalence of probable TTM was 1.4% (95% confidence intervals [CI]: 1.2-1.7), and was more common among females. Participants with probable TTM had a greater likelihood of having co-occurring probable depression (adjusted odds ratio [ORadj] = 1.744; 95% CI: 1.187-2.560), tobacco (ORadj = 2.250; 95% CI: 1.191-4.250), and alcohol (ORadj = 1.751; 95% CI: 1.169-2.621) use disorders. Probable TTM was also independently associated with suicidal ideation (ORadj = 1.917; 95% CI: 1.224-3.003) and exposure to childhood sexual abuse (ORadj = 1.221; 95% CI: 1.098-1.358). In addition, a positive screen for TTM had more impaired physical and mental QoL., Conclusions: TTM was associated with a positive screen for several psychiatric comorbidities as well as impaired physical and psychological QoL. Efforts towards the recognition and treatment of TTM across psycho-dermatology services are warranted.

Objective: Research suggests that the combination of different non-invasive brain stimulation techniques, such as intermittent theta-burst stimulation (iTBS) and transcranial direct current stimulation (tDCS), could enhance the effects of stimulation. Studies investigating the combination of tDCS and iTBS over the dorsolateral prefrontal cortex (DLPFC) are lacking. In this within-subjects study, we evaluated the additive effects of iTBS with tDCS on psychophysiological measures of stress., Method: Sixty-eight healthy individuals were submitted to a bifrontal tDCS + iTBS and sham tDCS + iTBS protocol targeting the DLPFC with a one-week interval. The Maastricht Acute Stress Test was used to activate the stress system after stimulation. Stress reactivity and recovery were assessed using physiological and self-report measures., Results: The stressor evoked significant psychophysiological changes in both stimulation conditions. However, no evidence was found for differences between them in stress reactivity and recovery. Participants reported more pain and feelings of discomfort to the bifrontal tDCS + iTBS protocol., Conclusion: In this study set-up, iTBS plus tDCS was not superior to iTBS in downregulating stress in healthy subjects., Significance: There is no evidence for an effect of combined tDCS-iTBS of the DLPFC on stress according to the parameters employed in our study. Future studies should explore other stimulation parameters, additive approaches and/or neurobiological markers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: This study aimed to prospectively evaluate whether TSH levels at baseline were associated with incident depression after four years of follow-up in a cohort of middle-aged adults, the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)., Methods: TSH and free-thyroxine (FT4) levels were evaluated at baseline. Depression diagnoses were performed using the Clinical Interview Schedule-Revised (CIS-R) at baseline and after a 4-year follow-up. Poisson regression models (95% Confidence Intervals) were built to evaluate the association between TSH quintiles at baseline and incident depression. All analyses were stratified by sex. Models were presented crude, adjusted for age and sex; and further adjusted for race, education, BMI, smoking, alcohol consumption, use of antidepressants/benzodiazepines, kidney function and comorbidities., Results: Mean age was 51.5 years, and 51.2% were women. Overall, low TSH levels (1 st quintile) were associated with incident depression (adjusted RR = 1.36, 95% CI 1.02-1.81), remaining significant for women (adjusted RR = 1.64, 95% CI 1.15-2.33), but not for men. The same results were found when restricting analysis to euthyroid participants (adjusted RR = 1.46, 95% CI 1.08-1.99), also significant for women only (adjusted RR = 1.63, 95% CI 1.12-2.38)., Conclusions: Our results showed that low TSH levels were positively associated with incident depression, particularly among women. Similar results were found when restricting the analysis to euthyroid participants. In contrast, high TSH levels were inversely associated with incident depression, also among women., (© 2021 John Wiley & Sons Ltd.)

Introduction: The associations of anxiety and depression with metabolic syndrome (MetS) are not consistent across studies. Anxiety and depression are highly correlated and traditional methods don't take the structure of this correlation into account. Our aim is to disentangle the relationship of these emotional conditions with MetS, using bifactor models, modelling both general and specific aspects between anxiety and depression., Methods: Bifactor models were tested using the baseline data from the Brazilian Longitudinal Study of Adult Health (n = 13,584). Anxiety and depression were accessed with the Clinical Interview Schedule - Revised. MetS was measured through assessment of its continuous components., Results: A bifactor S-1 model better represent the 14 CIS-R indicators, composed by an internalizing factor corresponding to depressive symptoms, anxiety, worry and the shared variance of all remaining CIS-R indicators, and also by residual variance explained by a somatic (e.g., fatigue and pain) and fear (e.g., panic and phobias) specific factors. Internalizing spectrum (β = 0.116; p < 0.001) and the fear specific factor (β = 0.060; p = 0.008) were associated with MetS after adjusting for confounders, whereas somatic specific factor was unlikely to be associated with MetS (β = 0.002; p = 0.934)., Conclusions: Anxiety and depression indicators were associated with MetS via a shared internalizing factor and also by a residual fear factor, but not by somatic residual factor. This finding has potential implications about shared biological and behavioral mechanisms that may link emotional conditions with MetS in adults., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Transcranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects., Objective: We convened a team of transcranial direct current stimulation experts to conduct a systematic review of clinical trials with more than 1 session of stimulation testing: pain, Parkinson's disease motor function and cognition, stroke motor function and language, epilepsy, major depressive disorder, obsessive compulsive disorder, Tourette syndrome, schizophrenia, and drug addiction., Methods: Experts were asked to conduct this systematic review according to the search methodology from PRISMA guidelines. Recommendations on efficacy were categorized into Levels A (definitely effective), B (probably effective), C (possibly effective), or no recommendation. We assessed risk of bias for all included studies to confirm whether results were driven by potentially biased studies., Results: Although most of the clinical trials have been designed as proof-of-concept trials, some of the indications analyzed in this review can be considered as definitely effective (Level A), such as depression, and probably effective (Level B), such as neuropathic pain, fibromyalgia, migraine, post-operative patient-controlled analgesia and pain, Parkinson's disease (motor and cognition), stroke (motor), epilepsy, schizophrenia, and alcohol addiction. Assessment of bias showed that most of the studies had low risk of biases, and sensitivity analysis for bias did not change these results. Effect sizes vary from 0.01 to 0.70 and were significant in about 8 conditions, with the largest effect size being in postoperative acute pain and smaller in stroke motor recovery (nonsignificant when combined with robotic therapy)., Conclusion: All recommendations listed here are based on current published PubMed-indexed data. Despite high levels of evidence in some conditions, it must be underscored that effect sizes and duration of effects are often limited; thus, real clinical impact needs to be further determined with different study designs., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

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.

Inflammation is associated with poor cognitive performance. GlycA is a novel marker of systemic inflammation, but information on GlycA and cognition is scarce. We aimed to evaluate the association between GlycA and cognitive performance in a large sample from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). In this cross-sectional study, participants with GlycA measured at baseline were included. Cognitive function was evaluated using the word list test, the trail-making test, and the semantic and phonemic verbal fluency tests. The association of GlycA with cognitive performance was investigated using linear regression models adjusted for sociodemographic and clinical variables. A total of 4327 participants were analyzed (mean age=51.5±9.0 y old, 54% were female, 60% white). The mean GlycA was 414.9±69.8 µmol/L. Higher GlycA levels were associated with lower global cognitive performance, even after adjustments for confounders and C-reactive protein. Higher GlycA levels were associated with lower performance in language and executive function domains (language: β=-0.005, 95% confidence interval CI=-0.010, -0.001, P=0.01; and executive function: β=-0.005, 95% confidence interval=0.009, -0.001, P=0.02]. GlycA was associated with worse cognitive performance in the ELSA-Brasil study, independent of C-reactive protein levels. GlycA may be a potential biomarker for cognitive impairment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: We investigated the role of peripheral biomarkers associated with neuroplasticity and immune-inflammatory processes on the effects of transcranial direct current stimulation (tDCS), a safe, affordable, and portable non-invasive neuromodulatory treatment, in bipolar depression., Methods: This is an exploratory analysis using a dataset from the sham-controlled study the Bipolar Depression Electrical Treatment Trial (BETTER)(clinicaltrials.govNCT02152878). Participants were 52 adults with type I or II bipolar disorder in a moderate-to-severe depressive episode, randomized to 12 bifrontal active or sham tDCS sessions over a 6-week treatment course. Plasma levels of brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), interleukins (IL) 2, 4, 6, 8, 10, 18, 33, 1β, 12p70, 17a, interferon gamma (IFN), tumor necrosis factor alpha (TNF) and its soluble receptors 1 and 2, ST2, and KLOTHO were investigated at baseline and endpoint. We performed analyses unadjusted for multiple testing to evaluate whether baseline biomarkers were predictive for depression improvement and changed during treatment using linear regression models., Results: A time x group interaction (Cohen's d: -1.16, 95% CI = -1.96 to -0.3, p = .005) was found for IL-8, with greater reductions after active tDCS. Higher baseline IL-6 plasma levels was associated with symptomatic improvement after tDCS (F (1,43)  = 5.43; p = .025). Other associations were not significant., Conclusions: Our exploratory findings suggested that IL-6 is a potential predictor of tDCS response and IL-8 might decrease after tDCS; although confirmatory studies are warranted due to the multiplicity of comparisons., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of the current study was to assess the associations between dynapenia and the onset and persistence of depression and anxiety among older adults., Methods: This prospective cohort study enrolled community-living older adults ( N  = 5271; 51.1% females) aged ≥ 50 years (mean age = 63.2, standard deviation = 9.0) from The Irish Longitudinal Study on Aging (TILDA), Ireland. At baseline, participants completed a handgrip assessment. Depression was defined by a score ≥ 16 in the Center of Epidemiology Studies Depression (CES-D) tool and anxiety was considered when participants scored ≥ 8 on the anxiety section of the Hospital Anxiety and Depression Scale (HADS). Outcomes were incident and persistent depression and anxiety at two years follow-up. Multivariable logistic regression models were built for each outcome., Results: After controlling for age, sex, education, marital status, employment status, smoking, body mass index, number of chronic conditions, physical activity, and cognitive function, low handgrip strength indicative of dyapenia (< 30 Kg for men and < 20 Kg for women) was associated with a greater likelihood for incident depressive (OR = 1.44; 95%CI: 1.08-1.92) as well as for persistent depressive (OR = 1.61; 95% CI: 1.01-2.58) and anxiety (OR = 1.61; 95% CI: 1.20-2.14) symptoms., Conclusions: Dynapenia was associated with a higher odds of developing depressive symptoms as well as a greater likelihood to persistent depressive and anxiety symptoms among older adults. Our data suggest that interventions targeting muscle strength may prevent the onset of late-life depression and also may hold promise as novel therapeutic opportunities for depression and anxiety in later life.

Objectives: Normative data should consider sociodemographic diversity for the accurate diagnosis of cognitive impairment. This study aims to provide normative data for a brief neuropsychological battery and present diagnostic criteria for cognitive impairment that could be used in primary care settings., Methods: We selected 9618 Brazilian middle-aged and older adults after detailed exclusion criteria to avoid subtle cognitive impairment. We analyzed age, sex, and education influence on cognitive performance. To verify the evidence of criterion validity, we compared the cognitive performance of subjects with and without a depressive episode. Additionally, we verified the percentage of spurious scores under three different cutoffs., Results: Age and education had the greatest impact on cognition. Normative scores were provided according to age and education groups. Participants with a depressive episode performed poorer than control subjects. The clinical cutoff of at least two scores below the 7th percentile revealed the adequate percentage of spurious and possible clinical performance., Conclusions: The Longitudinal Study on Adult Health (ELSA-Brasil) provided normative data based on a unique selected set of cognitively normal subjects. Normative groups were selected based on age and education, and the battery was sensitive to the presence of a depressive episode. We suggested clinical cutoffs for the tests in this battery that could be used in primary care settings to improve the accurate diagnosis of cognitive impairment.

Purpose: Current therapies for the management of epilepsy are still suboptimal for several patients due to inefficacy, major adverse events, and unavailability. Transcranial direct current stimulation (tDCS), an emergent non-invasive neuromodulation technique, has been tested in epilepsy samples over the past two decades to reduce either seizure frequency or electroencephalogram (EEG) epileptiform discharges., Methods: A systematic review was performed in accordance with PRISMA guidelines (PROSPERO record CRD42020160292). A thorough electronic search was completed in MEDLINE, EMBASE, CENTRAL and Scopus databases for trials that applied tDCS interventions to children and adults with epilepsy of any cause, from inception to April 30, 2020., Results: Twenty-seven studies fulfilled eligibility criteria, including nine sham-controlled and 18 uncontrolled trials or case reports/series. Samples consisted mainly of drug-resistant focal epilepsy patients that received cathodal tDCS stimulation targeted at the site with maximal EEG abnormalities. At follow-up, 84 % (21/25) of the included studies reported a reduction in seizure frequency and in 43 % (6/14) a decline in EEG epileptiform discharge rate was observed. No serious adverse events were reported., Conclusions: Cathodal tDCS is both a safe and probably effective technique for seizure control in patients with drug-resistant focal epilepsy. However, published trials are heterogeneous regarding samples and methodology. More and larger sham-controlled randomized trials are needed, preferably with mechanistic informed stimulation protocols, to further advance tDCS therapy in the management of epilepsy., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

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.

Introduction: The high placebo response in depression treatment trials is a major contributing factor for randomised control trial failure to establish efficacy of novel or repurposed treatments in treatment-resistant depression (TRD) and major depressive disorder in general. Though there have been a number of meta-analyses and primary research studies evaluating the placebo response in non-TRD, placebo response in TRD is poorly understood. It is important to understand the placebo response of TRD as treatments are only moderately effective and up to 1/3 of patients will experience TRD., Methods and Analysis: We will conduct a search of electronic databases (MEDLINE and PsychINFO) from inception to 24th January 2020 including randomised, placebo-controlled trials of pharmacological, somatic and psychological interventions for adults with TRD. TRD will be defined as a failure to respond to at least two interventions of adequate dose or duration. We will also search reference lists from review articles. We will perform several meta-analyses to quantify the placebo response for each treatment modality. Regression analysis will explore potential contributing demographic and clinical variables to the placebo response. We will use Cochrane risk of bias tool., Ethics and Dissemination: There is no research ethics board approval required. The dissemination plan is to publish results in a peer-reviewed academic journal., Prospero Registration Number: 190 465., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Alzheimer's disease (AD) is a leading cause of years lived with disability in older age, and several cerebrospinal fluid (CSF) markers have been proposed in individual meta-analyses to be associated with AD but field-wide evaluation and scrutiny of the literature is not available., Materials and Methods: We performed an umbrella review for the reported associations between CSF biomarkers and AD. Data from available meta-analyses were reanalyzed using both random and fixed effects models. We also estimated between-study heterogeneity, small-study effects, excess significance, and prediction interval., Results: A total of 38 meta-analyses on CSF markers from 11 eligible articles were identified and reanalyzed. In 14 (36%) of the meta-analyses, the summary estimate and the results of the largest study showed non-concordant results in terms of statistical significance. Large heterogeneity (I2≥75%) was observed in 73% and small-study effects under Egger's test were shown in 28% of CSF biomarkers., Conclusions: Our results suggest that there is an excess of statistically significant results and significant biases in the literature of CSF biomarkers for AD. Therefore, the results of CSF biomarkers should be interpreted with caution.

Objectives: To compare cognitive effects and acceptability of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) in patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI), and to determine whether cognitive training (CT) during rTMS or tDCS provides additional benefits., Methods: Electronic search of PubMed, Medline, Embase, the Cochrane Library and PsycINFO up to 5 March 2020. We enrolled double-blind, randomised controlled trials (RCTs). The primary outcomes were acceptability and pre-post treatment changes in general cognition measured by Mini-Mental State Examination, and the secondary outcomes were memory function, verbal fluency, working memory and executive function. Durability of cognitive benefits (1, 2 and ≥3 months) after brain stimulation was examined., Results: We included 27 RCTs (n=1070), and the treatment components included high-frequency rTMS (HFrTMS) and low-frequency rTMS, anodal tDCS (atDCS) and cathodal tDCS (ctDCS), CT, sham CT and sham brain stimulation. Risk of bias of evidence in each domain was low (range: 0%-11.1%). HFrTMS (1.08, 9, 0.35-1.80) and atDCS (0.56, 0.03-1.09) had short-term positive effects on general cognition. CT might be associated with negative effects on general cognition (-0.79, -2.06 to 0.48) during rTMS or tDCS. At 1-month follow-up, HFrTMS (1.65, 0.77-2.54) and ctDCS (2.57, 0.20-4.95) exhibited larger therapeutic responses. Separate analysis of populations with pure AD and MCI revealed positive effects only in individuals with AD. rTMS and tDCS were well tolerated., Conclusions: HFrTMS is more effective than atDCS for improving global cognition, and patients with AD may have better responses to rTMS and tDCS than MCI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention investigated for the treatment of depression. Clinical results have been heterogeneous, partly due to the variability of electric field (EF) strength in the brain owing to interindividual differences in head anatomy. Therefore, we investigated whether EF strength was correlated with behavioral changes in 16 depressed patients using simulated electric fields in real patient data from a controlled clinical trial. We hypothesized that EF strength in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC), brain regions implicated in depression pathophysiology, would be associated with changes in depression, mood and anxiety scores. SimNIBS were used to simulate individual electric fields based on the MRI structural T1-weighted brain scans of depressed subjects. Linear regression models showed, at the end of the acute treatment phase, that simulated EF strength was inversely associated with negative affect in the bilateral ACC (left: β = - 160.463, CI [- 291.541, - 29.385], p = 0.021; right: β = - 189.194, CI [- 289.479, - 88.910], p = 0.001) and DLPFC (left: β = - 93.210, CI [- 154.960, - 31.461], p = 0.006; right: β = - 82.564, CI [- 142.867, - 22.262], p = 0.011) and with depression scores in the left ACC (β = - 156.91, CI [- 298.51, - 15.30], p = 0.033). No association between positive affect or anxiety scores, and simulated EF strength in the investigated brain regions was found. To conclude, our findings show preliminary evidence that EF strength simulations might be associated with further behavioral changes in depressed patients, unveiling a potential mechanism of action for tDCS. Further studies should investigate whether individualization of EF strength in key brain regions impact clinical response.

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.

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.

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.

Background: This prospective study aimed to evaluate the cortical excitability (CE) of patients with brain tumors surrounding or directly involving the corticospinal tract (CST) using navigated transcranial magnetic stimulation (nTMS). Methods: We recruited 40 patients with a single brain tumor surrounding or directly involving the CST as well as 82 age- and sex-matched healthy controls. The patients underwent standard nTMS and CE evaluations. Single and paired pulses were applied to the primary motor area (M1) of both affected and unaffected cerebral hemispheres 1 week before surgery. The CE parameters included resting motor threshold (RMT), motor evoked potential (MEP) ratio for 140 and 120% stimulus (MEP 140/120 ratio), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Motor outcome was evaluated on hospital discharge and on 30-day and 90-day postoperative follow-up. Results: In the affected hemispheres of patients, SICI and ICF were significantly higher than in the unaffected hemispheres ( p =0.002 and p =0.009, respectively). The 140/120 MEP ratio of patients' unaffected hemispheres was lower than that in controls ( p =0.001). Patients with glioblastomas (GBM) had a higher interhemispheric RMT ratio than patients with grade II and III gliomas ( p = 0.018). A weak correlation was observed among the RMT ratio and the preoperative motor score ( R 2 = 0.118, p = 0.017) and the 90-day follow-up ( R 2 = 0.227, p = 0.016). Conclusion: Using preoperative nTMS, we found that brain hemispheres affected by tumors had abnormal CE and that patients with GBM had a distinct pattern of CE. These findings suggest that tumor biological behavior might play a role in CE changes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Neville, Gomes dos Santos, Almeida, Hayashi, Solla, Galhardoni, de Andrade, Brunoni, Teixeira and Paiva.)

The brain is a dynamic organ whose growth and organization varies according to each subject's life experiences. Through adaptations in gene expression and the release of neurotrophins and neurotransmitters, these experiences induce a process of cellular realignment and neural network reorganization, which consolidate what is called neuroplasticity. However, despite the brain's resilience and dynamism, neuroplasticity is maximized during the first years of life, when the developing brain is more sensitive to structural reorganization and the repair of damaged neurons. This review presents an overview of non-invasive brain stimulation (NIBS) techniques that have increasingly been a focus for experimental research and the development of therapeutic methods involving neuroplasticity, especially Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS). Due to its safety risk profile and extensive tolerability, several trials have demonstrated the benefits of NIBS as a feasible experimental alternative for the treatment of brain and mind disorders in children and adolescents. However, little is known about the late impact of neuroplasticity-inducing tools on the developing brain, and there are concerns about aberrant plasticity. There are also ethical considerations when performing interventions in the pediatric population. This article will therefore review these aspects and also obstacles related to the premature application of NIBS, given the limited evidence available concerning the extent to which these methods interfere with the developing brain., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Posterior segment eye diseases, such as glaucoma and retinal diseases (such as diabetic retinopathy, age-related macular degeneration, and retinal detachment), are chronic diseases that are among the major causes of visual impairment., Objective: We investigated the prevalence of anxiety disorders, depressive disorders, and common mental disorders in these patients and also the incidence of depression., Methods: We examined baseline (2008-2010) and follow-up (2012-2014) data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). We used the Clinical Interview Schedule-Revised (CIS-R) to perform International Classification of Diseases-10-based diagnoses of anxiety and depressive disorders. Common mental disorder was defined as a Clinical Interview Schedule-Revised >11. We used multinomial logistic regression models to investigate associations between eye diseases and mental disorders, adjusted by age, gender, educational level, self-reported ethnicity, cardiovascular conditions, and self-reported quality of vision., Results: Out of 10,775 subjects, 249 (2.3%), 303 (2.8%), and 30 (0.3%) reported having retinal diseases, glaucoma, or both, respectively. Patients with retinal diseases and those with glaucoma and retinal diseases presented a higher prevalence of common mental disorders (relative-risk ratios of 1.7 and 3.7, respectively, P < 0.001). These patients also presented a higher incidence of depression at follow-up (relative-risk ratios of 3.0 and 5.9, respectively, P < 0.001). Patients with glaucoma presented neither a higher prevalence nor a higher incidence of mental disorders or depression., Conclusions: Retinal diseases but not glaucoma were associated with mental disorders, indicating that patients with posterior segment eye diseases require distinct management of psychiatric morbidity according to the underlying pathology., (Copyright © 2020 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Most evidence for the association between ideal vascular health (IVH) and cognitive performance comes from high income countries. The aim was to investigate this association in the Brazilian Longitudinal Study of Adult Health., Methods: Cognition was assessed using the word list, verbal fluency and trail making tests. The IVH score included ideal metrics for body mass index, smoking, physical activity, diet, blood pressure, fasting glucose and total cholesterol. Poor, intermediate and optimal health were characterized in those presenting 0-2, 3-4, 5-7 ideal metrics, respectively. To determine the association between IVH score and cognitive performance, linear regression models adjusted for age, sex, education, race, alcohol use, depression and thyroid function were used., Results: In 12 271 participants, the mean age was 51.3 ± 8.9 years, 54% were women, 57% White and 53% had poor vascular health. Participants with intermediate (β = 0.064, 95% confidence interval 0.033; 0.096) and optimal health (β = 0.108, 95% confidence interval 0.052; 0.164) had better global cognitive Z-scores. In addition, interactions of IVH score with age, education and race were found, suggesting a better cognitive performance with higher IVH in older adults, Black/Brown participants and those with lower levels of education., Conclusion: Ideal vascular health was associated with better cognitive performance. Older, Black/Brown and low-educated participants had better cognition in the presence of higher IVH scores., (© 2020 European Academy of Neurology.)

Transcranial direct current stimulation (tDCS) is a re-emerging non-invasive brain stimulation technique that has been used in animal models and human trials aimed to elucidate neurophysiology and behavior interactions. It delivers subthreshold electrical currents to neuronal populations that shift resting membrane potential either toward depolarization or hyperpolarization, depending on stimulation parameters and neuronal orientation in relation to the induced electric field (EF). Although the resulting cerebral EFs are not strong enough to induce action potentials, spontaneous neuronal firing in response to inputs from other brain areas is influenced by tDCS. Additionally, tDCS induces plastic synaptic changes resembling long-term potentiation (LTP) or long-term depression (LTD) that outlast the period of stimulation. Such properties place tDCS as an appealing intervention for the treatment of diverse neuropsychiatric disorders. Although findings of clinical trials are preliminary for most studied conditions, there is already convincing evidence regarding its efficacy for unipolar depression. The main advantages of tDCS are the absence of serious or intolerable side effects and the portability of the devices, which might lead in the future to home-use applications and improved patient care. This chapter provides an up-to-date overview of a number tDCS relevant topics such as mechanisms of action, contemporary applications and safety. Furthermore, we propose ways to further develop tDCS research., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Psychogenic nonepileptic seizures (PNES) are a common and debilitating problem in patients with epilepsy. They can be virtually indistinguishable from epileptic seizures, demanding video-electroencaphalogram monitoring, which is costly and not widely available, for differential diagnosis. Specific functional brain correlates of PNES have not been demonstrated so far. We hypothesized that PNES and epileptic seizures have distinct brain activation patterns, assessed by functional neuroimaging during ictal events of both conditions., Objective: Compare ictal brain activation patterns of PNES and epileptic seizures using single-photon emission computerized tomography., Methods: We prospectively assessed brain functional activation using single-photon emission computerized tomography 99mTc-ethyl cysteinate dimer in 26 patients with PNES, confirmed by trained psychiatrists in epileptology, who had their seizures induced by provocative tests compared with 22 age- and sex-matched subjects with temporal lobe epilepsy who underwent prolonged intensive video-electroencaphalogram monitoring., Results: In PNES patients compared with temporal lobe epilepsy group, we found a consistent increase in regional cerebral blood flow in the right precuneus (Brodmann area 7; P = 0.003) and right posterior cingulate cortex (Brodmann area 31; P = 0.001), as well as a decrease in regional cerebral blood flow in the right amygdala (P = 0.027)., Conclusions: Activation of default mode network brain areas and temporoparietal junction may be a distinct feature of ictal PNES and could be explained by a disruption between movement prediction input and sensory outcome. Such information mismatch might be the neurobiological underpinning of dissociative episodes., (Copyright © 2020 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to analyze the longitudinal course of depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms in patients with cardiac disease after heart surgery (HS)., Methods: We conducted a systematic review and random-effects meta-analysis of cohort studies in patients undergoing HS, measuring anxiety, depressive, and PTSD symptoms before and at least 30 days thereafter. Subgroup and meta-regression analyses, investigation of publication bias, and quality assessment were undertaken., Results: We included 94 studies relating to 15,561 patients. HS included coronary artery bypass graft surgery, valve replacement, implantable cardioverter-defibrillator placement, left ventricular assist device placement, heart transplantation, and other types of HS. Across studies, symptoms of depression (g = 0.32; 95% confidence interval [CI] = 0.25 to 0.39; p < .001) and anxiety improved after HS (g = 0.52; 95% CI = 0.43 to 0.62; p < .001), whereas PTSD symptoms worsened (g = -0.42; 95% CI = -0.80 to -0.04; p = .032). The reduction of depression and anxiety levels was more pronounced for patients with underlying coronary artery disease and heart failure and persisted for 1 year after HS, whereas the increase in PTSD symptoms returned to baseline after 6 months. Depression improvement was inversely associated with older age, diabetes, hypertension, and dyslipidemia and positively with baseline heart failure. No additional clinical or demographic variables were associated with the course of anxiety symptoms. Quality of included studies was low overall. Publication bias was nonsignificant., Conclusions: Depressive and anxiety symptoms improve for 1 year after HS, whereas PTSD symptoms might worsen. Older patients and those with metabolic comorbidities, valve disease, or ventricular arrhythmias are at higher risk for continued depressive and anxiety symptoms and should be monitored closely., (Copyright © 2020 by the American Psychosomatic Society.)

Background: Traumatic brain injury (TBI) is one of the leading causes of neuropsychiatric disorders in young adults. Repetitive Transcranial Magnetic Stimulation (rTMS) has been shown to improve psychiatric symptoms in other neurologic disorders, such as focal epilepsy, Parkinson's disease, and fibromyalgia. However, the efficacy of rTMS as a treatment for anxiety in persons with TBI has never been investigated. This exploratory post-hoc analyzes the effects of rTMS on anxiety, depression and executive function in participants with moderate to severe chronic TBI. Methods: Thirty-six participants with moderate to severe TBI and anxiety symptoms were randomly assigned to an active or sham rTMS condition in a 1:1 ratio. A 10-session protocol was used with 10-Hz rTMS stimulation over the left dorsolateral prefrontal cortex (DLPFC) for 20 min each session, a total of 2,000 pulses were applied at each daily session (40 stimuli/train, 50 trains). Anxiety symptoms; depression and executive function were analyzed at baseline, after the last rTMS session, and 90 days post intervention. Results: Twenty-seven participants completed the entire protocol and were included in the post - hoc analysis. Statistical analysis showed no interaction of group and time ( p > 0.05) on anxiety scores. Both groups improved depressive and executive functions over time, without time and group interaction ( p s < 0.05). No adverse effects were reported in either intervention group. Conclusion: rTMS did not improve anxiety symptoms following high frequency rTMS in persons with moderate to severe TBI. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02167971., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Rodrigues, Zaninotto, Ventresca, Neville, Hayashi, Brunoni, de Paula Guirado, Teixeira and Paiva.)

Background: Novel coronavirus disease (COVID-19) morbidity is not restricted to the respiratory system, but also affects the nervous system. Non-invasive neuromodulation may be useful in the treatment of the disorders associated with COVID-19. Objective: To describe the rationale and empirical basis of the use of non-invasive neuromodulation in the management of patients with COVID-10 and related disorders. Methods: We summarize COVID-19 pathophysiology with emphasis of direct neuroinvasiveness, neuroimmune response and inflammation, autonomic balance and neurological, musculoskeletal and neuropsychiatric sequela. This supports the development of a framework for advancing applications of non-invasive neuromodulation in the management COVID-19 and related disorders. Results: Non-invasive neuromodulation may manage disorders associated with COVID-19 through four pathways: (1) Direct infection mitigation through the stimulation of regions involved in the regulation of systemic anti-inflammatory responses and/or autonomic responses and prevention of neuroinflammation and recovery of respiration; (2) Amelioration of COVID-19 symptoms of musculoskeletal pain and systemic fatigue; (3) Augmenting cognitive and physical rehabilitation following critical illness; and (4) Treating outbreak-related mental distress including neurological and psychiatric disorders exacerbated by surrounding psychosocial stressors related to COVID-19. The selection of the appropriate techniques will depend on the identified target treatment pathway. Conclusion: COVID-19 infection results in a myriad of acute and chronic symptoms, both directly associated with respiratory distress (e.g., rehabilitation) or of yet-to-be-determined etiology (e.g., fatigue). Non-invasive neuromodulation is a toolbox of techniques that based on targeted pathways and empirical evidence (largely in non-COVID-19 patients) can be investigated in the management of patients with COVID-19., (Copyright © 2020 Baptista, Baltar, Okano, Moreira, Campos, Fernandes, Brunoni, Badran, Tanaka, de Andrade, da Silva Machado, Morya, Trujillo, Swami, Camprodon, Monte-Silva, Sá, Nunes, Goulardins, Bikson, Sudbrack-Oliveira, de Carvalho, Duarte-Moreira, Pagano, Shinjo and Zana.)

Background: Major Depressive Disorder (MDD) affects more than 264 million people worldwide. Current treatments include the use of psychotherapy and/or drugs, however ~30% of patients either do not respond to these treatments, or do not tolerate the side effects associated to the use of pharmacological interventions. Thus, it is important to study non-pharmacological interventions targeting mechanisms not directly involved with the regulation of neurotransmitters. Several studies demonstrated that transcranial Direct Current Stimulation (tDCS) can be effective for symptoms relief in MDD. However, tDCS seems to have a better effect when used as an add-on treatment to other interventions. Methods/Design: This is a study protocol for a parallel, randomized, triple-blind, sham-controlled clinical trial in which a total of 90 drug-naïve, first-episode MDD patients (45 per arm) will be randomized to one of two groups to receive a 6-weeks of CBT combined with either active or sham tDCS to the dorsolateral prefrontal cortex (DLPFC). The primary outcome will depressive symptoms improvement as assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) at 6-weeks. The secondary aim is to test whether CBT combined with tDCS can engage the proposed mechanistic target of restoring the prefrontal imbalance and connectivity through the bilateral modulation of the DLPFC, as assessed by changes over resting-state and emotional task eliciting EEG. Discussion: This study evaluates the synergetic clinical effects of CBT and tDCS in the first episode, drug-naïve, patients with MDD. First episode MDD patients provide an interesting opportunity, as their brains were not changed by the pharmacological treatments, by the time course, or by the recurrence of MDD episodes (and other comorbidities). Trial Registration: This study is registered with the United States National Library of Medicine Clinical Trials Registry (NCT03548545). Registered June 7, 2018, clinicaltrials.gov/ct2/show/NCT03548545. Protocol Version 1., (Copyright © 2020 Carvalho, Gonçalves, Brunoni, Fernandes-Gonçalves, Fregni and Leite.)