Neuroplasticity underlying prolonged intermittent theta-burst stimulation in the regulation of disorders of consciousness: pilot randomized controlled trial

To investigate the safety, feasibility, and efficacy of prolonged intermittent theta burst stimulation (piTBS) in patients with disorders of consciousness (DOC). In this pilot randomized trial, DOC patients received either piTBS or sham stimulation during 10 sessions alongside conventional treatment. The primary outcome was Coma Recovery Scale-Revised (CRS-R) score changes from baseline (T0) to post-5 sessions (T1), post-10 sessions (T2), and 1-month follow-up (T3). Secondary outcomes included response rates, EEG characteristics, and serum metabolic markers. 20 DOC patients were randomized and were analyzed. The piTBS group showed significantly greater CRS-R improvements vs. sham at T2 (mean improvement, 1.00 (0, 1.25) vs. 0; response rate, 60% vs. 10%) and T3. Within the piTBS group, CRS-R scores at T2 and T3 demonstrated significant improvements compared to T0, with greater enhancement at T3 than at T1. EEG analysis revealed piTBS-specific effects: increased duration and coverage of microstate (MS) B, enhanced transitions between MS D and MS A and B, reduced current source density in delta/theta, and increased alpha activity. PiTBS strengthened frontoparietal functional connectivity across all frequency bands. Serum BDNF increased more prominently with piTBS. No piTBS-related adverse events were observed during the trial. PiTBS demonstrates preliminary feasibility in DOC patients, showing multimodal effects, including: significant CRS-R improvement, reorganization of pathological brain dynamics, and elevated serum BDNF levels. These findings provide preliminary evidence supporting piTBS as a promising adjuvant therapy for awakening interventions. Trial registration: chictr.org.cn, ChiCTR2300069618.