Abstract / Summary
Background: Response to Comprehensive Behavioral Intervention for Tics (CBIT), the first-line treatment for tic disorders, is suboptimal. We conducted Phase 1 of a two-phase, milestone-driven trial to determine if augmenting CBIT with repetitive transcranial magnetic stimulation (TMS) to supplementary motor area (SMA) could safely engage targeted sensorimotor circuitry and improve tic controllability. Methods: In a 3-arm, double-blind, sham-controlled randomized trial (NCT04578912), 50 youth (ages 12-21) with moderate-to-severe tics received 10 sessions of either 1Hz rTMS, continuous theta burst stimulation (cTBS), or sham stimulation to the SMA, immediately followed by CBIT. Primary outcomes were safety, feasibility, and neural target engagement (fMRI SMA activation and resting-state functional connectivity [RSFC]). Secondary outcomes included change in tic controllability, tic frequency at rest, and urges. Results: The CBIT+TMS intervention was safe and feasible (96% completion). Treatment-related adverse events were mild-to-moderate and occurred more frequently in the 1Hz rTMS group (27% of sessions) vs. cTBS (14.7%) and sham (11.3%). While task-based SMA activation remained unchanged, cTBS demonstrated robust neural target engagement, reducing SMA-primary motor cortex (M1) RSFC and putamen-M1 RSFC. Conversely, 1Hz rTMS blunted the cortico-striatal connectivity reductions observed in the sham group. All groups exhibited significant reductions in tic frequency and improved controllability. Premonitory urges increased in the 1Hz rTMS group but decreased in sham and cTBS. Conclusions: SMA-directed cTBS is a safe, feasible augmentation that may amplify the neural effects of CBIT on sensorimotor circuitry. Findings identify cTBS as the preferred stimulation regimen for future efficacy testing. Clinical Trial Registration: ClinicalTrials.gov; Identifier: NCT04578912.