Noninvasive neuromodulation for disorders of consciousness: an updated systematic review and meta-analysis.

Background: Despite advances in noninvasive neuromodulation for disorders of consciousness (DoC), the available evidence is inconclusive. We sought to elucidate the efficacy and safety of these interventions for DoC.

Methods: We systematically searched Embase, EBSCO, CINAHL, Medline, PsycINFO, the Cochrane Library, and Web of Science from inception until 15 Mar, 2025, supplemented by manual searches from other sources. Randomised controlled trials (RCTs) comparing any noninvasive neuromodulation (e.g., transcranial direct current stimulation [tDCS], repetitive transcranial magnetic stimulation [rTMS], median nerve stimulation [MNS], trigeminal nerve stimulation [TNS], or transauricular vagus nerve stimulation [tVNS]) with sham control for DoC were selected. Relevant data were extracted. Primary efficacy outcome (change in levels of consciousness post intervention) and safety outcome (adverse events and dropout) were assessed. Effect sizes were pooled for standard pairwise meta-analyses using random-effects model and reported as Hedges' g or risk ratio (RR) with 95% confidence interval (CI). Studies with less than five stimulation sessions were excluded. Methodological quality was assessed by the PEDro scale, risk of bias was evaluated using the RoB 2 tool. Heterogeneity was measured using τ and I statistic. The quality of evidence was performed using the Grade approach.

Results: We included 24 studies and six studies (147 participants) provided data for meta-analysis. The methodological quality was good for all trials according to the PEDro scale, while most studies (18 out of 24 studies, 75%) were rated high risk of bias by the RoB 2 tool. For efficacy, the effect of rTMS (g = 0.49, 95% CI = 0.01, 0.98) and TNS (g = 0.59, 95% CI = 0.08, 1.10) for DoC compared with sham stimulation was medium, while tDCS was not more effective than sham control. No difference was found for dropout in TNS or rTMS compared with sham control.

Conclusions: Our findings provide evidence that rTMS and TNS showed more positive effects for DoC, while tDCS was no better than sham stimulation. While, due to the small number of patients in the different studies, the small number of studies and potential risk of bias in the meta-analysis, robust evidence of noninvasive neuromodulation for patients with DoC is lacking. These findings highlight the importance of precision in targeting noninvasive neuromodulation for patients with DoC, RCTs with high-quality methodological design, conduct and reporting. Trial registration PROSPERO Identifier: CRD42024499177. Registered 20 January 2024.