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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., 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 © 2024 The Authors. Published by 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: Transcranial direct current stimulation (tDCS) is a promising intervention for major depression. However, its clinical effects are heterogeneous. We investigated, in a subsample of the randomized, clinical trial Escitalopram versus Electrical Direct Current Therapy for Depression Study (ELECT-TDCS), whether the volumes of left and right prefrontal cortex (PFC) and anterior cingulate cortex (ACC) were associated with prefrontal tDCS response., Methods: Baseline structural T1 weighted MRI data were analyzed from 52 patients (15 males). Patients were randomized to the following conditions: escitalopram 20 mg/day, bifrontal tDCS (2 mA, 30min, 22 sessions), or placebo. Antidepressant outcomes were assessed over a treatment period of 10 weeks. Voxel-based gray matter volumes of PFC and ACC were determined using state-of-the-art parcellation approaches., Results: According to our a priori hypothesis, in the left dorsal PFC, larger gray matter volumes were associated with depression improvement in the tDCS group (n = 15) compared to sham (n = 21) (Cohen's d = 0.3, 95% confidence interval [0.01; 0.6], p = 0.04). Neither right PFC nor ACC volumes were associated with depression improvement. Exploratory analyses of distinct PFC subregions were performed, but no area was associated with tDCS response after correction for multiple comparisons., Conclusion: Left PFC baseline gray matter volume was associated with tDCS antidepressant effects. This brain region and its subdivisions should be investigated further as a potential neurobiological predictor for prefrontal tDCS treatment in depression and might be correlated with tDCS antidepressant mechanisms of action., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) has been used to improve exercise performance, though the protocols used, and results found are mixed., Objective: We aimed to analyze the effect of tDCS on improving exercise performance., Methods: A systematic search was performed on the following databases, until December 2017: PubMed/MEDLINE, Embase, Web of Science, SCOPUS, and SportDiscus. Full-text articles that used tDCS for exercise performance improvement in adults were included. We compared the effect of anodal (anode near nominal target) and cathodal (cathode near nominal target) tDCS to a sham/control condition on the outcome measure (performance in isometric, isokinetic or dynamic strength exercise and whole-body exercise)., Results: 22 studies (393 participants) were included in the qualitative synthesis and 11 studies (236 participants) in the meta-analysis. The primary motor cortex (M1) was the main nominal tDCS target (n = 16; 72.5%). A significant effect favoring anodal tDCS (a-tDCS) applied before exercise over M1 was found on cycling time to exhaustion (mean difference = 93.41 s; 95%CI = 27.39 s-159.43 s) but this result was strongly influenced by one study (weight = 84%), no effect was found for cathodal tDCS (c-tDCS). No significant effect was found for a-tDCS applied on M1 before or during exercise on isometric muscle strength of the upper or lower limbs. Studies regarding a-tDCS over M1 on isokinetic muscle strength presented mixed results. Individual results of studies using a-tDCS applied over the prefrontal and motor cortices either before or during dynamic muscle strength testing showed positive results, but performing meta-analysis was not possible., Conclusion: For the protocols tested, a-tDCS but not c-tDCS vs. sham over M1 improved exercise performance in cycling only. However, this result was driven by a single study, which when removed was no longer significant. Further well-controlled studies with larger sample sizes and broader exploration of the tDCS montages and doses are warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique increasingly used to modulate neural activity in the living brain. In order to establish the neurophysiological, cognitive or clinical effects of tDCS, most studies compare the effects of active tDCS to those observed with a sham tDCS intervention. In most cases, sham tDCS consists in delivering an active stimulation for a few seconds to mimic the sensations observed with active tDCS and keep participants blind to the intervention. However, to date, sham-controlled tDCS studies yield inconsistent results, which might arise in part from sham inconsistencies. Indeed, a multiplicity of sham stimulation protocols is being used in the tDCS research field and might have different biological effects beyond the intended transient sensations. Here, we seek to enlighten the scientific community to this possible confounding factor in order to increase reproducibility of neurophysiological, cognitive and clinical tDCS studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique with potential for cost-effective therapeutic neuromodulation. Although positive therapeutic effects were found by stimulating the dorsolateral prefrontal cortex (DLPFC), few studies have investigated physiological effects of DLPFC-tDCS., Objectives: To investigate effects of tDCS with different parameter settings applied to the left DLPFC on cortical responses, measured by resting-state electroencephalography (rs-EEG) and transcranial magnetic stimulation (TMS)-evoked/induced EEG responses., Methods: 22 healthy subjects underwent 5 tDCS sessions with different tDCS parameter settings in a double-blinded randomized crossover design (1: 1.5 mA, anode left-DLPFC, cathode right-DLPFC; 2: 1.5 mA, cathode left-DLPFC, anode right-DLPFC; 3: 0.5 mA, anode left-DLPFC, cathode right-DLPFC; 4: 1.5 mA, anode left-DLPFC, cathode left deltoid muscle; 5: sham stimulation). Rs-EEG and TMS-EEG were recorded before and after tDCS., Results: Rs-EEG power spectrum analysis showed no difference comparing baseline with post stimulation in any of the tDCS conditions. TMS-EEG evoked potential amplitude decreased in parietal cortex after 1.5 mA left-DLPFC anodal tDCS, and TMS-induced gamma and theta oscillations decreased after all conditions using left-DLPFC anodal tDCS. Left-DLPFC cathodal tDCS did not lead to significant change. None of the post-intervention changes was different when comparing the effects across conditions, including sham., Conclusions: Our study does not provide evidence that a single tDCS session results in significant changes in rs-EEG, using the current stimulation parameters. Significant changes in EEG responses to TMS pulses were observed following the anodal 1.5 mA tDCS interventions, although these changes were not statistically significant in a group comparison., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities., Objective: This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment., Methods: The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs., Results: Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them., Conclusions: These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders., (Published by Elsevier Inc.)

Background: Transcranial direct current stimulation (tDCS) is a non-invasive electrical stimulation technique, assumed to influence cognition and emotional processing., Objective: However, it is unclear how tDCS influences spontaneous cognitive processes such as momentary self-referential thoughts on the neuronal level., Methods: Forty healthy female volunteers participated in a single session sham-controlled crossover tDCS study while being in the MRI scanner. We measured brain perfusion (arterial spin labeling) just before and just after tDCS. Before and after the stimulation procedure, participants were scored on mood (visual analogue scales) and on the Momentary Ruminative Self-focus Inventory (MRSI). We performed a 1.5 mA, 20-min, anodal left dorsolateral prefrontal cortex, cathodal right supraorbital stimulation., Results: One sham-controlled tDCS session did not result in subjective mood changes. However, as compared to before, MRSI scores significantly decreased only after active tDCS. Regression analysis revealed that this reduction in momentary ruminative self-referential thoughts was related to tDCS-related increases in left prefrontal cortical perfusion. tDCS decreased momentary self-referential thoughts, which was associated with increasing perfusion in the left prefrontal cortex., Conclusion: Our findings are in line with the hypothesis that tDCS of the DLPFC attenuates ruminative processes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Treatment-emergent mania/hypomania (TEM) is a possible adverse effect of pharmacological and non-pharmacological antidepressant treatments., Objective: We performed a systematic review and meta-analysis to evaluate the risk of TEM in depressed patients during randomized, sham-controlled trials (RCTs)., Data Sources: Medline database, from the first date available to August 12, 2016., Results: From 283 references, 10 RCTs were identified. Only 3 of them described TEM. In active and sham groups, respectively, only 8 of 226 (3.5%) and 1 of 190 (0.5%) participants presented TEM. This difference was not statistically significant (OR = 1.79, 95% CI = 0.6 to 5.32). There were also five additional reports of TEM in participants not on RCTs. No risk factors for TEM were identified., Limitations: Low number of studies and TEM reports., Conclusion: Despite previous reports, active vs. sham tDCS was not associated with a significantly greater number of TEM episodes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation investigated as a treatment for several neuropsychiatric disorders. Notwithstanding tDCS-induced adverse events (AEs) are considered to be low and transient, systematic review analyses on safety and tolerability of tDCS derive mostly from single-session studies., Objective: To investigate the tolerability (rate of AEs) and acceptability (rate of dropouts) of tDCS., Methods: Systematic review and meta-analysis of tDCS randomized, sham-controlled trials in healthy or neuropsychiatric adult samples from the first date available to March 9, 2016. We only included parallel studies performing at least 5 tDCS sessions. An adapted version of CONSORT guidelines for reporting harms outcomes was used to evaluate AE reporting., Results: Sixty-four studies (2262 participants) were included. They had a low risk of publication bias and methodological bias for the items assessed. Dropout rates in active and sham tDCS groups were, respectively, 6% and 7.2% (OR = 0.82 [0.59-1.14]). However, almost half of studies reported no dropouts and only 23.4% reported its reasons; when reported, the most frequent reasons were AEs and protocol violation. A tolerability meta-analysis was not performed, as most studies did not report AEs. The quality of AEs reporting was also limited, particularly in smaller studies and stroke studies., Conclusions: Although overall dropout rate was low and similar in active and sham groups, studies did not adequately describe AEs. An updated questionnaire and guidelines for assessment of AEs in tDCS trials are proposed in order to standardize the reporting of AE in the field., (Copyright © 2016 Elsevier Inc. All rights reserved.)

This review updates and consolidates evidence on the safety of transcranial Direct Current Stimulation (tDCS). Safety is here operationally defined by, and limited to, the absence of evidence for a Serious Adverse Effect, the criteria for which are rigorously defined. This review adopts an evidence-based approach, based on an aggregation of experience from human trials, taking care not to confuse speculation on potential hazards or lack of data to refute such speculation with evidence for risk. Safety data from animal tests for tissue damage are reviewed with systematic consideration of translation to humans. Arbitrary safety considerations are avoided. Computational models are used to relate dose to brain exposure in humans and animals. We review relevant dose-response curves and dose metrics (e.g. current, duration, current density, charge, charge density) for meaningful safety standards. Special consideration is given to theoretically vulnerable populations including children and the elderly, subjects with mood disorders, epilepsy, stroke, implants, and home users. Evidence from relevant animal models indicates that brain injury by Direct Current Stimulation (DCS) occurs at predicted brain current densities (6.3-13 A/m(2)) that are over an order of magnitude above those produced by conventional tDCS. To date, the use of conventional tDCS protocols in human trials (≤40 min, ≤4 milliamperes, ≤7.2 Coulombs) has not produced any reports of a Serious Adverse Effect or irreversible injury across over 33,200 sessions and 1000 subjects with repeated sessions. This includes a wide variety of subjects, including persons from potentially vulnerable populations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Research into the effects of transcranial direct current stimulation of the dorsolateral prefrontal cortex on cognitive functioning is increasing rapidly. However, methodological heterogeneity in prefrontal tDCS research is also increasing, particularly in technical stimulation parameters that might influence tDCS effects., Objective: To systematically examine the influence of technical stimulation parameters on DLPFC-tDCS effects., Methods: We performed a systematic review and meta-analysis of tDCS studies targeting the DLPFC published from the first data available to February 2016. Only single-session, sham-controlled, within-subject studies reporting the effects of tDCS on cognition in healthy controls and neuropsychiatric patients were included., Results: Evaluation of 61 studies showed that after single-session a-tDCS, but not c-tDCS, participants responded faster and more accurately on cognitive tasks. Sub-analyses specified that following a-tDCS, healthy subjects responded faster, while neuropsychiatric patients responded more accurately. Importantly, different stimulation parameters affected a-tDCS effects, but not c-tDCS effects, on accuracy in healthy samples vs., Patients: increased current density and density charge resulted in improved accuracy in healthy samples, most prominently in females; for neuropsychiatric patients, task performance during a-tDCS resulted in stronger increases in accuracy rates compared to task performance following a-tDCS., Conclusions: Healthy participants respond faster, but not more accurate on cognitive tasks after a-tDCS. However, increasing the current density and/or charge might be able to enhance response accuracy, particularly in females. In contrast, online task performance leads to greater increases in response accuracy than offline task performance in neuropsychiatric patients. Possible implications and practical recommendations are discussed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The dose of transcranial direct current stimulation (tDCS) is defined by electrode montage and current, while the resulting brain current flow is more complex and varies across individuals. The left dorsolateral pre-frontal cortex (lDLPFC) is a common target in neuropsychology and neuropsychiatry applications, with varied approaches used to experimentally position electrodes on subjects., Objective: To predict brain current flow intensity and distribution using conventional symmetrical bicephalic frontal 1 × 1 electrode montages to nominally target lDLPFC in forward modeling studies., Methods: Six high-resolution Finite Element Method (FEM) models were created from five subjects of varied head size and an MNI standard. Seven electrode positioning methods, nominally targeting lDLPFC, were investigated on each head model: the EEG 10-10 including F3-F4, F5-F6, F7-8, F9-F10, the Beam F3-System, the 5-5 cm-Rule and the developed OLE-System were evaluated as electrode positioning methods for 5 × 5 cm(2) rectangular sponge-pad electrodes., Results: Each positioning approach resulted in distinct electrode positions on the scalp and variations in brain current flow. Variability was significant, but trends across montages and between subjects were identified. Factors enhancing electric field intensity and relative targeting in lDLPFC include increased inter-electrode distance and proximity to thinner skull structures., Conclusion: Brain current flow can be shaped, but not focused, across frontal cortex by tDCS montages, including intensity at lDLPFC. The OLE-system balances lDLPFC targeting and reduced electric field variability, along with clinical ease-of-use., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them., Methods: We convened a workgroup of researchers in the field to review, discuss, and provide updates and key challenges of tDCS use in clinical research., Main Findings/discussion: We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (1) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase II, and phase III studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS., (Copyright © 2012 Elsevier Inc. All rights reserved.)