Exploring sex-dependent responses to anodal tDCS in subacute stroke rehabilitation: a post-hoc analysis of the randomized sham-controlled NETS Trial
Year: 2026
Type: preprint
Abstract: Background Upper limb dysfunction is among the most disabling consequences of stroke, yet transcranial direct current stimulation (tDCS), an extensively investigated adjunct to motor rehabilitation, has not demonstrated consistent benefit in large randomized trials. Interindividual variability may contribute, and sex is a plausible source given anatomical and neurophysiological differences relevant to tDCS. In this post-hoc, exploratory secondary analysis of the NETS trial, we examined sex as a potential effect modifier of tDCS response across the 90-day follow-up and all three domains of the International Classification of Functioning, Disability and Health (ICF). Methods NETS randomized 119 patients with subacute ischemic stroke to anodal tDCS (1 mA) over the ipsilesional primary motor cortex or sham stimulation alongside standardized rehabilitation. Longitudinal mixed-effects models with autoregressive correlation structures examined treatment-by-sex interactions for the Upper-Extremity-Fugl-Meyer Assessment (UEFMA; body function), Box-and-Block Test (BBT; activity), and Stroke Impact Scale participation domain (SIS; participation). Sensitivity analyses included per-protocol analysis, continuous-time models and three-way sex-by-treatment-by-time interactions. Results Relevant treatment-by-sex interactions were found for the UEFMA and BBT, but not for SIS participation. Women receiving active stimulation improved more than those receiving sham: estimated marginal mean differences: UEFMA 6.0 points (95%-CI 1.2;10.7), BBT 8.4 points (95%-CI 2.4;14.3), whereas no relevant treatment effect was observed in men. Results were similar in intention-to-treat and per-protocol populations. Conclusions This hypothesis-generating analysis suggests that sex may modify the response to tDCS in post-stroke upper limb rehabilitation. Together with similar subgroup signals from other trials, these findings warrant prospective, adequately powered trials with prespecified tests of treatment-by-sex interaction. Highlights Sex may modify response to transcranial direct current stimulation after stroke In this exploratory analysis, women benefited more than men from active stimulation Signals of treatment benefit in women were observed for arm function and activity, not for participation Sex difference in stimulation response appeared to widen over 90-day follow-up
Source: medRxiv
Institution: University Medical Center Hamburg-Eppendorf
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7204102679