Non-invasive brain stimulation in amyotrophic lateral sclerosis: a systematic review and meta-analysis of transcranial direct current stimulation and transcranial magnetic stimulation

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with limited disease-modifying treatments. Noninvasive brain stimulation techniques have been investigated as potential neuromodulatory interventions targeting cortical hyperexcitability in ALS. OBJECTIVE: To systematically evaluate the clinical efficacy, neurophysiological effects, and safety of tDCS and TMS-based interventions in ALS. METHODS: A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Scopus, Web of Science, and Cochrane Library were searched from inception to March 2026. RESULTS: Thirty studies involving ALS patients were included. Pooled analyses showed no significant difference between active stimulation and sham in ALSFRS-R at 6 months (MD = 0.58, 95% CI - 0.16 to 1.31) or at end of follow-up (MD = 0.20, 95% CI - 0.49 to 0.89). No significant effect was observed for manual muscle testing. Considerable heterogeneity was noted across studies. However, several studies demonstrated modulation of cortical excitability and intracortical inhibitory circuits, particularly with repeated stimulation protocols. Both tDCS and TMS were consistently safe and well tolerated, with no serious adverse events reported. CONCLUSION: Noninvasive brain stimulation in ALS does not significantly improve functional outcomes, but induces measurable neurophysiological changes with a strong safety profile. Further studies should optimize protocols and identify responsive subgroups.