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Transcranial direct current stimulation (tDCS) has been proposed as a new treatment in major depressive disorder (MDD). This is a fully remote, multisite, double-blind, placebo-controlled, randomized superiority trial of 10-week home-based tDCS in MDD. Participants were 18 years or older, with MDD in current depressive episode of at least moderate severity as measured using the Hamilton Depression Rating Scale (mean = 19.07 ± 2.73). A total of 174 participants (120 women, 54 men) were randomized to active ( n  = 87, mean age = 37.09 ± 11.14 years) or sham ( n  = 87, mean age = 38.32 ± 10.92 years) treatment. tDCS consisted of five sessions per week for 3 weeks then three sessions per week for 7 weeks in a 10-week trial, followed by a 10-week open-label phase. Each session lasted 30 min; the anode was placed over the left dorsolateral prefrontal cortex and the cathode over the right dorsolateral prefrontal cortex (active tDCS 2 mA and sham tDCS 0 mA, with brief ramp up and down to mimic active stimulation). As the primary outcome, depressive symptoms showed significant improvement when measured using the Hamilton Depression Rating Scale: active 9.41 ± 6.25 point improvement (10-week mean = 9.58 ± 6.02) and sham 7.14 ± 6.10 point improvement (10-week mean = 11.66 ± 5.96) (95% confidence interval = 0.51–4.01, P  = 0.012). There were no differences in discontinuation rates. In summary, a 10-week home-based tDCS treatment with remote supervision in MDD showed high efficacy, acceptability and safety. ClinicalTrials.gov registration: NCT05202119 A randomized, sham-controlled, superiority trial of a 10-week course of home-based transcranial direct current stimulation found greater improvements in depressive symptoms with active compared to sham stimulation in major depressive disorder.

Late-life depression (LLD) is a growing worldwide problem due to demographic changes, with limited treatment options due to high rates of pharmacotherapy adverse effects, accessibility of psychotherapy, and tolerability of electroconvulsive therapy. Novel neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), may overcome these limitations. The objective of this study is to determine the efficacy, tolerability, and cognitive effects of high-dose deep rTMS in LLD. In this study we randomized older adults between 60 and 85 years old with major depressive disorder (MDD) to sham or active deep rTMS (H1 coil, 6012 pulses, 18 Hz, 120% of resting motor threshold) delivered over the dorsolateral and ventrolateral prefrontal cortex 5 days per week over 4 weeks. Our primary outcome was remission of depression in an intention-to-treat analysis. We also assessed change in cognitive functioning with rTMS treatment and tolerability based on adverse effects. Fifty-two participants were randomized to active (n = 25) or sham H1 coil (n = 27). Remission rate was significantly higher with active than sham rTMS (40.0% vs 14.8%) with a number needed to treat of 4.0 (95% CI: 2.1–56.5). There was no change on any measure of executive function and no serious adverse events. Adverse effect profiles were similar between active and sham rTMS, except for reports of pain being significantly more common in the active condition (16.0% vs 0%). High-dose deep rTMS appears to be safe, well tolerated, and efficacious in the treatment of LLD.

Electrical direct-current stimulation applied to the cranium was not shown to be noninferior to escitalopram for major depression. Direct current and escitalopram were superior to placebo, but the electrical treatment was associated with adverse events, including mania. Major depressive disorder is a highly prevalent condition. 1 There is interest in the effectiveness and safety of new and nonpharmacologic treatments for depression. In 2009, transcranial magnetic stimulation was approved by the Food and Drug Administration for the treatment of major depressive disorder. 2 The procedure has had mixed results in various trials, 3 is associated with a small risk of seizure, 4 and is costly. Transcranial direct-current stimulation (tDCS) is a noninvasive brain-stimulation technique that is less costly than transcranial magnetic stimulation and has not been associated with seizures. 5 In this procedure, weak, direct current is applied through electrodes that are placed . . .

Repetitive transcranial magnetic stimulation (rTMS) is increasingly used clinically in the treatment of patients with major depressive disorder (MDD). However, rTMS treatment response can be slow. Early research suggests that accelerated forms of rTMS may be effective but no research has directly evaluated a schedule of accelerated rTMS compared to standard rTMS. To assess the efficacy of accelerated rTMS compared to standard daily rTMS., 115 outpatients with MDD received either accelerated rTMS (n = 58) (i.e., 63,000 high frequency rTMS pulses delivered as 3 treatments per day over 3 days in week 1, 3 treatments over 2 days in week 2 and 3 treatments on a single day in week 3) or standard rTMS (n = 57) (i.e., 63,000 total high frequency rTMS pulses delivered over 5 days per week for 4 weeks) following randomization. There were no significant differences in remission or response rates (p > 0.05 for all analyses) or reduction in depression scores (Time by group interaction (F (5, 489.452) = 1.711, p = 0.130) between the accelerated and standard rTMS treatment groups. Accelerated treatment was associated with a higher rate of reported treatment discomfort. It is feasible to provide accelerated rTMS treatment for outpatients with depression and this is likely to produce meaningful antidepressant effects.

Major depressive disorder (MDD) is one of the most common psychiatric disorders, but pharmacological treatments are ineffective in a substantial fraction of patients and are accompanied by unwanted side effects. Here we evaluated the feasibility and efficacy of transcranial alternating current stimulation (tACS) at 10 Hz, which we hypothesized would improve clinical symptoms by renormalizing alpha oscillations in the left dorsolateral prefrontal cortex (dlPFC). To this end, 32 participants with MDD were randomized to 1 of 3 arms and received daily 40 min sessions of either 10 Hz-tACS, 40 Hz-tACS, or active sham stimulation for 5 consecutive days. Symptom improvement was assessed using the Montgomery–Åsberg Depression Rating Scale (MADRS) as the primary outcome. High-density electroencephalograms (hdEEGs) were recorded to measure changes in alpha oscillations as the secondary outcome. For the primary outcome, we did not observe a significant interaction between treatment condition (10 Hz-tACS, 40 Hz-tACS, sham) and session (baseline to 4 weeks after completion of treatment); however, exploratory analyses show that 2 weeks after completion of the intervention, the 10 Hz-tACS group had more responders (MADRS and HDRS) compared with 40 Hz-tACS and sham groups (n = 30, p = 0.026). Concurrently, we found a significant reduction in alpha power over the left frontal regions in EEG after completion of the intervention for the group that received per-protocol 10 Hz-tACS (n = 26, p < 0.05). Our data suggest that targeting oscillations with tACS has potential as a therapeutic intervention for treatment of MDD.

Motor impairments contribute substantially to long-term disability following stroke. Studies of transcranial direct current stimulation (tDCS), combined with various rehabilitation therapies, have shown promising results in reducing motor impairment. We aimed to evaluate the safety and efficacy of three doses of tDCS in combination with modified constraint-induced movement therapy (mCIMT) in people who have had their first ischaemic stroke in the preceding 1–6 months. We conducted a phase 2, multicentre, randomised, triple-blind, sham-controlled study with a blinded centrally scored primary outcome. The trial was conducted at 15 medical centres in the USA. Eligible participants were enrolled between 1 month and 6 months after their first ischaemic stroke. Inclusion criteria required participants to have a persistent motor deficit, defined as a Fugl–Meyer Upper-Extremity (FM-UE) score of 54 or lower (out of 66), and two consecutive baseline visits (separated by 7–14 days) with an absolute difference of 2 or fewer points on the FM-UE scale. Participants were randomly assigned to treatment groups by an adaptive randomisation algorithm hosted on the TRANSPORT2 WebDCU study website. Participants received either sham, 2 mA, or 4 mA of bi-hemispheric tDCS for the first 30 min and mCIMT with 120 min of active therapy time per session, administered over ten sessions during a 2-week period. The primary endpoint was the change in FM-UE score from baseline to day 15, which was analysed in all participants who have data both at baseline and post-baseline (modified intention-to-treat group). Safety outcomes were analysed in all participants. TRANSPORT2 is registered at clinicaltrials.gov (NCT03826030) and its status is completed. 129 participants were recruited between Sept 9, 2019, and June 14, 2024, and 43 participants were randomly assigned to each group. 54 (42%) of 129 participants were female, and 69 (53%) were White. Two participants in the sham plus mCIMT group withdrew consent before the day 15 assessment and were excluded from the primary analysis. The median baseline FM-UE score was 39·0 (IQR 30·0–46·0) in the sham plus mCIMT group, 39·0 (27·0–48·0) in the 2 mA plus mCIMT group, and 40·0 (27·0–48·0) in the 4 mA plus mCIMT group. For the primary outcome, the adjusted mean change from baseline to day 15 in FM-UE was 4·91 (3·00–6·82) for sham plus mCIMT, 3·87 (2·00–5·74) for 2 mA plus mCIMT, and 5·53 (3·64–7·42) for 4 mA plus mCIMT (p=0·39). No clinically important adverse events were observed in any group and no deaths were reported. tDCS at doses of 2 mA or 4 mA, in addition to mCIMT, did not lead to further reduction in motor impairment in patients 1–6 months after stroke, but it was safe, well tolerated, and feasible for clinical practice. tDCS at higher doses (ie, >4 mA) might be a consideration for future trials in addition to balancing known covariates affecting stroke recovery during the group allocation. National Institute of Neurological Disorders and Stroke.

The non-invasive delivery of electric currents through the scalp (transcranial electrical stimulation) is a popular tool for neuromodulation, mostly due to its highly adaptable nature (waveform, montage) and tolerability at low intensities (< 2 mA). Applied rhythmically, transcranial alternating current stimulation (tACS) may entrain neural oscillations in a frequency- and phase-specific manner, providing a causal perspective on brain–behaviour relationships. While the past decade has seen many behavioural and electrophysiological effects of tACS that suggest entrainment-mediated effects in the brain, it has been difficult to reconcile such reports with the weak intracranial field strengths (< 1 V/m) achievable at conventional intensities. In this review, we first describe the ongoing challenges faced by users of tACS. We outline the biophysics of electrical brain stimulation and the factors that contribute to the weak field intensities achievable in the brain. Since the applied current predominantly shunts through the scalp—stimulating the nerves that innervate it—the plausibility of transcutaneous (rather than transcranial) effects of tACS is also discussed. In examining the effects of tACS on brain activity, the complex problem of salvaging electrophysiological recordings from artefacts of tACS is described. Nevertheless, these challenges by no means mark the rise and fall of tACS: the second part of this review outlines the recent advancements in the field. We describe some ways in which artefacts of tACS may be better managed using high-frequency protocols, and describe innovative methods for current interactions within the brain that offer either dynamic or more focal current distributions while also minimising transcutaneous effects.

Transcranial direct current stimulation (tDCS) uses a weak electric current to modulate neuronal activity. A neurophysiologic outcome measure to demonstrate reliable tDCS modulation at the group level is transcranial magnetic stimulation engendered motor evoked potentials (MEPs). Here, we conduct a study testing the reliability of individual MEP response patterns following a common tDCS protocol. Fourteen participants (7m/7f) each underwent nine randomized sessions of 1 mA, 10 min tDCS (3 anode; 3 cathode; 3 sham) delivered using an M1/orbito-frontal electrode montage (sessions separated by an average of ~5.5 days). Fifteen MEPs were obtained prior to, immediately following and in 5 min intervals for 30 min following tDCS. TMS was delivered at 130 % resting motor threshold using neuronavigation to ensure consistent coil localization. A number of non-experimental variables were collected during each session. At the individual level, considerable variability was seen among different testing sessions. No participant demonstrated an excitatory response ≥20 % to all three anodal sessions, and no participant demonstrated an inhibitory response ≥20 % to all three cathodal sessions. Intra-class correlation revealed poor anodal and cathodal test–retest reliability [anode: ICC (2,1)  = 0.062; cathode: ICC (2,1)  = 0.055] and moderate sham test–retest reliability [ICC (2,1)  = 0.433]. Results also revealed no significant effect of tDCS at the group level. Using this common protocol, we found the effects of tDCS on MEP amplitudes to be highly variable at the individual level. In addition, no significant effects of tDCS on MEP amplitude were found at the group level. Future studies should consider utilizing a more strict experimental protocol to potentially account for intra-individual response variations.

Background Transcranial alternating current stimulation (tACS) has proven to be an effective treatment for improving cognition, a crucial factor in motor learning. However, current studies are predominantly focused on the motor cortex, and the potential brain mechanisms responsible for the therapeutic effects are still unclear. Given the interconnected nature of motor learning within the brain network, we have proposed a novel approach known as multi-target tACS. This study aims to ascertain whether multi-target tACS is more effective than single-target stimulation in stroke patients and to further explore the potential underlying brain mechanisms by using techniques such as transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI). Methods This study employs a double-blind, sham-controlled, randomized controlled trial design with a 2-week intervention period. Both participants and outcome assessors will remain unaware of treatment allocation throughout the study. Thirty-nine stroke patients will be recruited and randomized into three distinct groups, including the sham tACS group (SS group), the single-target tACS group (ST group), and the multi-target tACS group (MT group), at a 1:1:1 ratio. The primary outcomes are series reaction time tests (SRTTs) combined with electroencephalograms (EEGs). The secondary outcomes include motor evoked potential (MEP), central motor conduction time (CMCT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), magnetic resonance imaging (MRI), Box and Block Test (BBT), and blood sample RNA sequencing. The tACS interventions for all three groups will be administered over a 2-week period, with outcome assessments conducted at baseline (T0) and 1 day (T1), 7 days (T2), and 14 days (T3) of the intervention phase. Discussion The study’s findings will determine the potential of 40-Hz tACS to improve motor learning in stroke patients. Additionally, it will compare the effectiveness of multi-target and single-target approaches, shedding light on their respective improvement effects. Through the utilization of techniques such as TMS and MRI, the study aims to uncover the underlying brain mechanisms responsible for the therapeutic impact. Furthermore, the intervention has the potential to facilitate motor learning efficiency, thereby contributing to the advancement of future stroke rehabilitation treatment. Trial registration Chinese Clinical Trial Registry ChiCTR2300073465. Registered on 11 July 2023.

tDCS studies typically find that: lowest levels of comfort occur at stimulation-onset; young adult participants experience less comfort than older participants; and participants' blinding seems effective at low current strengths. At 2 mA conflicting results have been reported, questioning the effectiveness of blinding in sham-controlled paradigms using higher current strengths. Investigator blinding is rarely reported. Using a protocol with 30 min of 2 mA stimulation we sought to: (a) investigate the level of perceived comfort in young and older adults, ranging in age from 19 to 29 years and 63 to 76 years, respectively; (b) test investigator and participant blinding; (c) assess comfort over a longer stimulation duration; (d) add to the literature on protocols using 2 mA current strength. A two-session experiment was conducted where sham and active stimulation were administered to the frontal cortex at the F8/FP1 sites in a within-subjects manner. Levels of perceived comfort were measured, using a visual analogue scale, at the start and end of stimulation in young and older adults. Post-stimulation, participants and investigators judged whether or not active stimulation was used. Comfort scores were lower at stimulation onset in both age groups. Older adults reported: (i) more comfort than young participants overall; (ii) comparable levels of comfort in sham and active stimulation; (iii) significantly more comfort than the young participants during active stimulation. Stimulation mode was correctly identified above chance in the second of the two sessions; 65% of all participants correctly identified the stimulation mode, resulting in a statistical trend. Similarly, the experimenter correctly identified stimulation mode significantly above chance, with 62% of all investigator judgements correct across 120 judgements. Using 2 mA current strength over 30 minutes, tDCS stimulation comfort is lower at stimulation onset in young and older adults and, overall, lower for young participants. Investigators and participants may be able to identify active stimulation at above chance levels, although accuracy never exceeded 65% for either participants or the experimenter. Further research into blinding efficacy is recommended.