Stress priming transcranial direct current stimulation (tDCS) enhances updating of emotional content in working memory.

Transcranial direct current stimulation (tDCS) targeting the prefrontal cortex has emerged as a valuable tool in psychiatric research. Understanding the impact of affective states, such as stress at the time of stimulation, on the efficacy of prefrontal tDCS is crucial for advancing tDCS interventions. Stress-primed tDCS, wherein stress is used as a priming agent, has the potential to modulate neural plasticity and enhance cognitive functions, particularly in emotional working memory. However, prior research using stress-primed tDCS focused solely on non-emotional working memory performance, yielding mixed results. In this sham-controlled study, we addressed this gap by investigating the effects of stress-primed bifrontal tDCS (active versus sham) on both non-emotional and emotional working memory performance. The study was conducted in 146 healthy individuals who were randomly assigned to four experimental groups. The Trier Social Stress Test (TSST) or a control variant of the test was used to induce a stress versus control state. The results showed that stress priming significantly enhanced the effects of tDCS on the updating of emotional content in working memory, as evidenced by improved accuracy. Notably, no significant effects of stress priming were found for non-emotional working memory performance. These findings highlight the importance of an individual's prior affective state in shaping their response to tDCS, especially in the context of emotional working memory.

Dose-dependent response of prefrontal transcranial direct current stimulation on the heart rate variability: An electric field modeling study.

Transcranial direct current stimulation (tDCS) of the prefrontal cortex (PFC) modulates the autonomic nervous system by activating deeper brain areas via top-down pathway. However, effects on the nervous system are heterogeneous and may depend on the amount of current that penetrates. Therefore, we aimed to investigate the variable effects of tDCS on heart rate variability (HRV), a measure of the functional state of the autonomic nervous system. Using three prefrontal tDCS protocols (1.5, 3 mA and sham), we associated the simulated individual electric field (E-field) magnitude in brain regions of interest with the HRV effects. This was a randomized, double-blinded, sham-controlled and within-subject trial, in which healthy young-adult participants received tDCS sessions separated by 2 weeks. The brain regions of interest were the dorsolateral PFC (DLPFC), anterior cingulate cortex, insula and amygdala. Overall, 37 participants were investigated, corresponding to a total of 111 tDCS sessions. The findings suggested that HRV, measured by root mean squared of successive differences (RMSSD) and high-frequency HRV (HF-HRV), were significantly increased by the 3.0 mA tDCS when compared to sham and 1.5 mA. No difference was found between sham and 1.5 mA. E-field analysis showed that all brain regions of interest were associated with the HRV outcomes. However, this significance was associated with the protocol intensity, rather than inter-individual brain structural variability. To conclude, our results suggest a dose-dependent effect of tDCS for HRV. Therefore, further research is warranted to investigate the optimal current dose to modulate HRV.

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.

Incidence of Suicidal Ideation in a Civil Servants Cohort During the COVID-19 Pandemic in Brazil: Insights from the ELSA-Brasil Study.

OBJECTIVE: This study investigated the incidence of suicidal ideation and its associated risk factors in the São Paulo state of ELSA-Brasil cohort during the COVID-19 pandemic. METHODS: During a pre-pandemic ELSA-Brasil onsite assessment in 2016-2018 (wave 3) and a pandemic online assessment in May-July 2020 (wave COVID), we assessed suicidal ideation using the Clinical Interview Scheduled-Revised (CIS-R). Single and multi predictor logistic regressions were performed using sociodemographic characteristics, household finance impact during pandemic, presence of previous chronic diseases, alcohol abuse, adverse childhood experiences (ACE), living alone, and previous CMD as predictors. Suicidal ideation incidence was used as outcome. RESULTS: Out of 4191 participants of wave 3, 2117 (50.5%) answered wave COVID. There was a threefold increase in suicide ideation, from 34 (1.8%) to 104 (5.6%).In multiple predictor models, we found that previous CMD (OR 7.17; 95% CI 4.43 - 11.58) and ACE (OR 1.72; 95% CI 1.09 - 2.72) increased the odds of incident suicidal ideation. The sociodemographic predictors female sex, younger age and low income were significant risk factors only in the single predictor model. Conclusions These findings underscore the importance of monitoring and supporting individuals who suffered ACE and have a history of mental health disorders. This is especially critical in times of heightened societal stress, such as the COVID-19 pandemic. CONCLUSIONS: These findings underscore the importance of monitoring and supporting individuals who suffered ACE and have a history of mental health disorders. This is especially critical in times of heightened societal stress, such as the COVID-19 pandemic.

Vagally-mediated HRV as a marker of trait rumination in healthy individuals? A large cross-sectional analysis.

The tendency to ruminate (i.e., repetitive, self-referential, negative thoughts) is a maladaptive form of emotional regulation and represents a transdiagnostic vulnerability factor for stress-related psychopathology. Vagally-mediated heart rate variability (vmHRV) provides a non-invasive, surrogate measure of vagal modulation of the heart, and higher HRV is considered an indicator of susceptibility, or ability to respond to stress. Past research has suggested a link between trait rumination and vmHRV; however, inconsistent results exist in healthy individuals. In this study, we investigated the association between the tendency to ruminate, brooding, and reflection (using the Ruminative Response Scale) with vmHRV measured at baseline in a healthy population using a large cross-sectional dataset (N = 1189, 88% female; mean age = 21.55, ranging from 17 to 48 years old), which was obtained by combining samples of healthy individuals from different studies from our laboratory. The results showed no cross-sectional correlation between vmHRV and trait rumination (confirmed by Bayesian analysis), even after controlling for important confounders such as gender, age, and depressive symptoms. Also, a non-linear relationship was rejected. In summary, based on our results in a large sample of healthy individuals, vmHRV is not a marker of trait rumination (as measured by the Ruminative Response Scale).

Investigating the variability of prefrontal tDCS effects on working memory: An individual E-field distribution study.

Transcranial direct current stimulation (tDCS) over the prefrontal cortex has the potential to enhance working memory by means of a weak direct current applied to the scalp. However, its effects are highly variable and possibly dependent on individual variability in cortical architecture and head anatomy. Unveiling sources of heterogeneity might improve fundamental and clinical application of tDCS in the field. Therefore, we investigated sources of tDCS variability of prefrontal 1.5 mA tDCS, 3 mA tDCS and sham tDCS in 40 participants (67.5% women, mean age 24.7 years) by associating simulated electric field (E-field) magnitude in brain regions of interest (dorsolateral prefrontal cortex, anterior cingulate cortex (ACC) and subgenual ACC) and working memory performance. Emotional and non-emotional 3-back paradigms were used. In the tDCS protocol analysis, effects were only significant for the 3 mA group, and only for the emotional tasks. In the individual E-field magnitude analysis, faster responses in non-emotional, but not in the emotional task, were associated with stronger E-fields in all brain regions of interest. Concluding, individual E-field distribution might explain part of the variability of prefrontal tDCS effects on working memory performance and in clinical samples. Our results suggest that tDCS effects might be more consistent or improved by applying personalizing current intensity, although this hypothesis should be confirmed by further studies.

Prefrontal transcranial direct current stimulation over the right prefrontal cortex reduces proactive and reactive control performance towards emotional material in healthy individuals

The prefrontal cortex plays a crucial role in cognitive processes, both during anticipatory and reactive modes of cognitive control. Transcranial Direct Current Stimulation (tDCS) can modulate these cognitive resources. However, there is a lack of research exploring the impact of tDCS on emotional material processing in the prefrontal cortex, particularly in regard to proactive and reactive modes of cognitive control. In this study, 35 healthy volunteers underwent both real and sham tDCS applied to the right prefrontal cortex in a counterbalanced order, and then completed the Cued Emotion Control Task (CECT). Pupil dilation, a measure of cognitive resource allocation, and behavioral outcomes, such as reaction time and accuracy, were collected. The results indicate that, as compared to sham stimulation, active right-sided tDCS reduced performance and resource allocation in both proactive and reactive modes of cognitive control. These findings highlight the importance of further research on the effects of tDCS applied to the right prefrontal cortex on cognitive engagement, particularly for clinical trials utilizing the present electrode montage in combination with cognitive interventions. (AU)

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS)

Objective: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. Methods: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. Results: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. Conclusions: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials. Registration number: PROSPERO CRD42022296246.

An electric field modeling study with meta-analysis to understand the antidepressant effects of transcranial direct current stimulation (tDCS).

OBJECTIVE: Transcranial direct current stimulation (tDCS) has mixed effects for major depressive disorder (MDD) symptoms, partially owing to large inter-experimental variability in tDCS protocols and their correlated induced electric fields (E-fields). We investigated whether the E-field strength of distinct tDCS parameters was associated with antidepressant effect. METHODS: A meta-analysis was performed with placebo-controlled clinical trials of tDCS enrolling MDD patients. PubMed, EMBASE, and Web of Science were searched from inception to March 10, 2023. Effect sizes of tDCS protocols were correlated with E-field simulations (SimNIBS) of brain regions of interest (bilateral dorsolateral prefrontal cortex [DLPFC] and bilateral subgenual anterior cingulate cortex [sgACC]). Moderators of tDCS responses were also investigated. RESULTS: A total of 20 studies were included (21 datasets, 1,008 patients), using 11 distinct tDCS protocols. Results revealed a moderate effect for MDD (g = 0.41, 95%CI 0.18-0.64), while cathode position and treatment strategy were found to be moderators of response. A negative association between effect size and tDCS-induced E-field magnitude was seen, with stronger E-fields in the right frontal and medial parts of the DLPFC (targeted by the cathode) leading to smaller effects. No association was found for the left DLPFC and the bilateral sgACC. An optimized tDCS protocol is proposed. CONCLUSION: Our results highlight the need for a standardized tDCS protocol in MDD clinical trials.

Prefrontal transcranial direct current stimulation over the right prefrontal cortex reduces proactive and reactive control performance towards emotional material in healthy individuals.

The prefrontal cortex plays a crucial role in cognitive processes, both during anticipatory and reactive modes of cognitive control. Transcranial Direct Current Stimulation (tDCS) can modulate these cognitive resources. However, there is a lack of research exploring the impact of tDCS on emotional material processing in the prefrontal cortex, particularly in regard to proactive and reactive modes of cognitive control. In this study, 35 healthy volunteers underwent both real and sham tDCS applied to the right prefrontal cortex in a counterbalanced order, and then completed the Cued Emotion Control Task (CECT). Pupil dilation, a measure of cognitive resource allocation, and behavioral outcomes, such as reaction time and accuracy, were collected. The results indicate that, as compared to sham stimulation, active right-sided tDCS reduced performance and resource allocation in both proactive and reactive modes of cognitive control. These findings highlight the importance of further research on the effects of tDCS applied to the right prefrontal cortex on cognitive engagement, particularly for clinical trials utilizing the present electrode montage in combination with cognitive interventions.

Transcranial direct current stimulation versus intermittent theta-burst stimulation for the improvement of working memory performance

Non-invasive brain stimulation (NIBS) techniques have been increasingly used over the dorsolateral prefrontal cortex (DLPFC) to enhance working memory (WM) performance. Notwithstanding, NIBS protocols have shown either small or inconclusive cognitive effects on healthy and neuropsychiatric samples. Therefore, we assessed working memory performance and safety of transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), and both therapies combined vs placebo over the neuronavigated left DLPFC of healthy participants. Twenty-four subjects were included to randomly undergo four sessions of NIBS, once a week: tDCS alone, iTBS alone, combined interventions and placebo. The 2-back task and an adverse effect scale were applied after each NIBS session. Results revealed a significantly faster response for iTBS (b= -21.49, p= 0.04), but not for tDCS and for the interaction tDCS vs. iTBS (b= 13.67, p= 0.26 and b= 40.5, p= 0.20, respectively). No changes were observed for accuracy and no serious adverse effects were found among protocols. Although tolerable, an absence of synergistic effects for the combined protocol was seen. Nonetheless, future trials accessing different outcomes for the combined protocols, as well as studies investigating iTBS over the left DLPFC for cognition and exploring sources of variability for tDCS are encouraged. (AU)

Transcranial direct current stimulation versus intermittent theta-burst stimulation for the improvement of working memory performance.

Non-invasive brain stimulation (NIBS) techniques have been increasingly used over the dorsolateral prefrontal cortex (DLPFC) to enhance working memory (WM) performance. Notwithstanding, NIBS protocols have shown either small or inconclusive cognitive effects on healthy and neuropsychiatric samples. Therefore, we assessed working memory performance and safety of transcranial direct current stimulation (tDCS), intermittent theta-burst stimulation (iTBS), and both therapies combined vs placebo over the neuronavigated left DLPFC of healthy participants. Twenty-four subjects were included to randomly undergo four sessions of NIBS, once a week: tDCS alone, iTBS alone, combined protocol and placebo. The 2-back task and an adverse effect scale were applied after each NIBS session. Results revealed a significantly faster response for iTBS (b= -21.49, p= 0.04), but not for tDCS and for the interaction tDCS vs. iTBS (b= 13.67, p= 0.26 and b= 40.5, p= 0.20, respectively). No changes were observed for accuracy and no serious adverse effects were found among protocols. Although tolerable, an absence of synergistic effects for the combined protocol was seen. Nonetheless, future trials accessing different outcomes for the combined protocols, as well as studies investigating iTBS over the left DLPFC for cognition and exploring sources of variability for tDCS are encouraged.

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.

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.

Magnitude of the Placebo Response Across Treatment Modalities Used for Treatment-Resistant Depression in Adults: A Systematic Review and Meta-analysis.

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 (ß = 0.35; 95% CI, 0.11 to 0.59; P = .004), later year of publication (ß = 0.03; 95% CI, 0.003 to 0.05; P = .03), and industry-sponsored trials (ß = 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 (ß = -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.

Non-invasive cortical stimulation: Transcranial direct current stimulation (tDCS).

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.

Follow-up effects of transcranial direct current stimulation (tDCS) for the major depressive episode: A systematic review and meta-analysis.

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.

Effects of combined theta burst stimulation and transcranial direct current stimulation of the dorsolateral prefrontal cortex on stress.

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 bifrontaltDCS + iTBS and shamtDCS + 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 bifrontaltDCS + 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.

Protocol for a systematic review and meta-analysis of the placebo response in treatment-resistant depression: comparison of multiple treatment modalities.

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.