Effect of cerebellar stimulation on awareness recovery in disorders of consciousness (CARE-DoC): A randomized, sham-controlled, crossover clinical trial

Neurotherapeutics. 2025 Jul 4:e00635. doi: 10.1016/j.neurot.2025.e00635. Online ahead of print.

Abstract

Disorders of consciousness (DoC) are major clinical challenges. We aimed to evaluate the effects of cerebellar intermittent theta-burst stimulation (CRB-iTBS) in the treatment of DoC. We conducted a randomized, sham-controlled, double-blind, cross-over clinical trial. Patients with vegetative state/unresponsive wakefulness syndrome or minimally conscious state within 15 days to 1 year after brain injuries were recruited. The bilateral cerebellum was targeted by iTBS for 5 consecutive days under neuronavigation. The primary outcome was the change in Coma Recovery Scale-Revised (CRS-R) total scores after five sessions. Secondary outcomes included changes in CRS-R scores after the first session, the changes in CRS-R subscales and the alterations in "ABCD" EEG patterns after the first and fifth sessions. Follow-up outcomes included six-month functional outcomes and consciousness recovery. We included 44 patients in the intention-to-treat analysis. No significant difference was observed in the change of CRS-R total scores between active and sham groups after five sessions (difference ​= ​0.428, 95 ​% CI ​= ​-0.202 - 1.057, P ​= ​0.180). However, active stimulation induced greater CRS-R improvements after the first session (difference ​= ​1.048, 95 ​% CI ​= ​0.480-1.615, P ​< ​0.001), especially in auditory, visual, oromotor/verbal, and arousal subscales. Active stimulation increased the prevalence of EEG patterns "C" and "D" after both the first and fifth sessions. Favorable six-month functional outcomes and consciousness recovery were associated with an elevation in "ABCD" EEG patterns during active treatment periods. These findings demonstrate that CRB-iTBS exhibits potential as a neuromodulation strategy to promote consciousness recovery in DoC.

Keywords: Cerebellum; Disorders of consciousness; Intermittent theta burst stimulation; Randomized crossover clinical trial; Transcranial magnetic stimulation.