Effectiveness of transcranial direct current stimulation and monoclonal antibodies acting on the CGRP as a combined treatment for migraine (TACTIC): Results of a randomized controlled trial

Background: Migraine pathogenesis involves both central and peripheral mechanisms. Although calcitonin gene-related peptide monoclonal antibodies have shown efficacy over placebo in migraine prevention, a proportion of individuals with migraine may experience a substantial residual burden while on treatment. Transcranial direct current stimulation is a non-invasive neuromodulation technique that can target central migraine mechanisms and may therefore complement calcitonin gene-related peptide monoclonal antibodies. The present study aimed to assess the efficacy of transcranial direct current stimulation as an adjunctive treatment to calcitonin gene-related peptide monoclonal antibodies in migraine prevention and to investigate its neurophysiological effects. Methods: This is a multicenter, randomized double-blind, sham-controlled, parallel-group trial including subjects with migraine on treatment with calcitonin gene-related peptide monoclonal antibodies for ≥90 days and with ≥8 monthly migraine days in the last 30 days. Subjects were randomized to active or sham transcranial direct current stimulation. The transcranial direct current stimulation protocol consisted of five daily 20-minute sessions of bilateral cathodal stimulation on the occipital area and anodal stimulation on the M1 area. High-density electroencephalographic recordings were performed before the first and after the last transcranial direct current stimulation session. The primary endpoint was the number of headache days during the 28-day follow-up period controlling for the 28-days baseline value. Secondary endpoints included the number of migraine days during the follow-up period, disability measures and electroencephalographic spectral power. The active and sham groups were compared using analysis of covariance. For clinical outcomes with significant differences between groups, we also ran paired t-tests comparing baseline and follow-up assessment within groups. Results: Thirty participants were randomized (15 to active and 15 to sham group). Headache days during the 28-day follow-up period did not differ significantly between groups (p = 0.560, ηp2= 0.017). However, participants receiving active transcranial direct current stimulation reported fewer migraine days during follow-up compared to the sham group (p = 0.008, ηp2= 0.241). Paired t-tests indicated that the active tDCS group reported a reduction in migraine days during the follow-up period compared to baseline (t = 2.557, p = 0.023, Cohen's d = 0.660), while no difference was found in the sham group. Referring to neurophysiological endpoints, active transcranial direct current stimulation induced a significant decrease in delta power at frontal regions compared to sham. Conclusions: This randomized-controlled trial suggests that transcranial direct current stimulation is a promising potentially effective treatment that may give additional benefits to subjects with migraine who are already on prevention with calcitonin gene-related peptide monoclonal antibodies but who have a substantial residual migraien burden. Combination treatments need to be better explored to provide strategies to further improve benefits of migraine prevention. Trial Registration: : NCT05161871 (clinicaltrials.gov).