Efficacy of Intermittent Theta-Burst Stimulation for Prolonged Disorders of Consciousness: A Prospective, Randomized, Controlled Trial

Abstract

Background: Emerging evidence suggests that low-frequency neural oscillations are dynamically regulated by consciousness levels, with the recovery of low cortical activity potentially serving as a neurophysiological substrate for conscious emergence. Targeted enhancement of these low-frequency rhythms in patients with disorders of consciousness (DoC) may constitute a promising neuromodulation strategy to facilitate consciousness recovery in severe brain injury. Objective: This study systematically examined the neurophysiological effects of intermittent theta-burst stimulation (iTBS), specifically its potential to enhance low-frequency cortical activity and promote consciousness recovery in patients with DoC. Through multimodal neural assessments, we aimed to elucidate the mechanistic relationship between iTBS-induced neural oscillation modulation and behavioral manifestations of consciousness improvement. Results: This prospective cohort study enrolled 30 patients with DoC, of whom 18 completed the full intervention protocol. Two-way repeated-measures analysis of variance revealed significant group × time interaction effects on the Coma Recovery Scale-Revised (CRS-R) scores, F(1, 16) = 6.543, p = 0.021. Post hoc simple effects analysis demonstrated significant temporal improvement in the active transcranial magnetic stimulation (TMS) group, F(1, 16) = 36.463, p < 0.001, with mean CRS-R scores increased from 9.300 ± 1.320 at baseline to 11.700 ± 1.409 post-intervention (p < 0.001). Conversely, sham stimulation revealed statistically nonsignificant changes (9.845 ± 1.476 versus 10.750 ± 1.575, p = 0.067). Neurophysiological assessments revealed emerging neurophysiological changes in the iTBS group, including enhanced resting-state low-frequency oscillations (delta: 21.642% increase, p = 0.449; theta: 6.800% increase, p = 0.789) and augmented auditory-evoked responses (phrase-level 22.917% increase, p = 0.280; syllable-level: 22.963% increase, p = 0.504), suggesting potential neural plasticity mechanisms that require further validation. Conclusion: Collectively, this study established iTBS targeting the left dorsolateral prefrontal cortex as a clinically effective and well-tolerated neuromodulation approach for consciousness rehabilitation in patients with DoC, with therapeutic effects mediated by iTBS-induced enhancement of thalamocortical low-frequency oscillations. Trial Registration: https://www.clinicaltrials.gov. Unique identifier: NCT03385278. Registered on October 24, 2017.