Dissociable effects of β-tACS on spectral power and network organization for proximal versus distal upper-limb recovery in subacute stroke: double-blind, randomized, sham-controlled trial with high-density EEG

BACKGROUND: Upper-limb recovery after stroke is not unitary, and proximal and distal functions may differ in their neural constraints. We tested whether 20-Hz β-tACS paired with rehabilitation differentially affects proximal versus distal recovery in subacute stroke and which EEG changes accompany improvement. METHODS: In this double-blind, randomized, sham-controlled trial, 61 first-ever stroke patients within 1-6 months after onset were enrolled; 56 (28 per group) completed the final analysis. Active stimulation consisted of 20-Hz tACS over ipsilesional M1 (2 mA peak-to-peak, 20 min/session, 10 sessions over 2 weeks) followed by standardized rehabilitation; sham used ramp-up/ramp-down only. FMA-UE total, proximal, and distal scores were assessed at baseline, post-intervention, and 1-month follow-up (F/U). High-density resting-state EEG quantified δ/β-band spectral power, connectivity, and graph metrics. Prespecified moderation analyses examined MEP status, lesion location, and stroke duration. RESULTS: Compared with healthy controls, stroke patients showed higher δ and θ power and lower β power at baseline. Relative to sham, β-tACS reduced whole-brain δ power (F = 4.60, q = 0.037), increased β power (F = 8.29, q = 0.009), and produced a δ-band network downshift, including lower network density (F = 6.73, q = 0.012), mean edge weight (F = 6.16, q = 0.010), clustering coefficient (F = 6.77, q = 0.012), and global efficiency (F = 6.87, q = 0.010). No FDR-significant β-band connectivity main effects were observed. Clinically, within the present 10-session protocol, β-tACS was associated with greater improvement in total FMA-UE at post (F = 7.24, p = 0.007) and F/U (F = 11.33, p = 0.001), with the clearest benefit in proximal FMA-UE at post (F = 11.17, p = 0.002) and F/U (F = 24.37, p < 0.001); distal improvement did not differ significantly between groups. MEP status moderated total and proximal recovery, with larger effects in MEP-negative participants. In the active group, larger total and proximal gains were associated with larger reductions in δ-band network organization; no other EEG-behavior correlations survived FDR correction. CONCLUSIONS: Within the present 10-session protocol, 20-Hz β-tACS over ipsilesional M1 paired with standardized rehabilitation was associated with clearer proximal than distal upper-limb benefits in subacute stroke. Its physiological signature was characterized by β-band target engagement together with reduced δ power and δ-band network organization. Whether longer treatment courses or higher cumulative doses would produce additional distal gains requires further study. Trial registration The study was registered in the Chinese Clinical Trial Registry (ID: ChiCTR2400083526) on April 26, 2024. The registration submitted on March 14, 2024. The first participant enrolled on May 14, 2024.