Efficacy and safety of transcranial direct current stimulation to the ipsilesional motor cortex in subacute stroke (NETS): a multicenter, randomized, double-blind, placebo-controlled trial

Abstract

Background: Each year, five million people are left disabled after stroke. Upper-extremity (UE) dysfunction is a leading problem. Neuroplasticity can be enhanced by non-invasive brain stimulation (NIBS) but evidence from large, randomized multicenter trials is lacking. We aimed at demonstrating efficacy of NIBS to enhance motor recovery after ischemic stroke.

Methods: We randomly assigned patients to receive anodal transcranial direct current (tDCS, 1 mA, 20 min) or placebo stimulation ('control') over the primary motor cortex of the lesioned hemisphere in addition to standardized rehabilitative training over ten days in the subacute phase after stroke. The original study was planned to enrol 250 but, following a blinded interim analysis, ended with 123 participants. The primary outcome parameter was UE impairment, measured by UE-Fugl-Meyer-Assessment (UEFMA), one to seven days after the end of the treatment intervention (ClinicalTrials.gov, NCT00909714).

Findings: From 2009 to 2019, 123 patients were included, with 119 entering intention-to-treat analysis (ITT). The control group (N = 61) improved 8.9 (SD 7.7) UEFMA points, the tDCS group (N = 58) improved 9.0 (8.8) points. ITT was neutral with respect to the primary efficacy endpoint (p = 0.820). We found no difference in UEFMA change between active tDCS and control. The safety profile of tDCS was favorable. In particular, there were no seizures.

Interpretation: In patients with ischemic stroke, anodal tDCS applied to the motor cortex of the lesioned hemisphere over 10 days in the subacute phase was safe but did not improve the recovery of upper extremity function compared with placebo stimulation.

Funding: Deutsche Forschungsgemeinschaft (GE 844/4-1).

Keywords: Brain stimulation; Clinical trial; Neuroplasticity; Neurorehabilitation; Recovery; Stroke.

Fig. 1

Schematic of the intervention. For both conditions (active tDCS, solid red line, and placebo stimulation, dashed black line, the electrical current was ramped up over 8 s to 1 mA (blue shaded areas indicate ramps). Active tDCS remained at 1 mA for 20 min followed by fade-out over 8 s from 1 mA to 0 mA. Placebo stimulation remained at 1 mA for only 40 s before fading out over 8 s.

Fig. 2

Trial design and assessment flow chart. ARAT = action research arm test; Ashworth = Ashworth spasticity scale; BBT = box-and-block test; BI = Barthel Index; CT = computed tomography scan; MMSE = mini-mental state examination; MRC = Medical Research Council; MRI = magnetic resonance image; NHPT = nine-hole peg test; NIHSS = National Institutes of Health stroke scale; PHQ-9 = patient health questionnaire; SIS = stroke impact scale; tDCS = transcranial direct current stimulation; UEFMA = upper-extremity Fugl-Meyer assessment.

Fig. 3

CONSORT flow diagram. FAS = full analysis set (according to EMA guideline); ITT = intention-to-treat; LOCF = last observation carried forward; NA = not available; PP = per-protocol. ∗The number of patients screened was estimated post-hoc based on the clinical diagnosis lists provided by the principal study center where stroke patients are generally screened for eligibility to participate in mechanistic or clinical studies.

Fig. 4

Individual recovery curves for every patient (light grey) by group as well as the mean together with the 95% CI (black line and error bars). All values shown are based on data imputed by the LOCF approach. P1 = 1–7 days after the end of the treatment intervention (primary outcome); FU1 = follow-up 1, 30 ± 10 days after randomization; FU2 = follow-up 2, 90 ± 20 days after randomization; LOCF = last observation carried forward; UEFMA = upper-extremity Fugl-Meyer assessment.