Different modulation patterns of theta and gamma dual-site HD-tACS on cognitive impairment

Alzheimer's disease (AD) is characterized by impaired local network integration and long-range connections. Theta and gamma oscillations are critical for cognitive function, so this study used dual-site fronto-temporoparietal junction (TPJ) high-density transcranial alternating current stimulation (HD-tACS) to explore its frequency-specific effects on brain networks and cognition. Thirty-six AD patients were randomized 1:1:1 to 6Hz-tACS, 40Hz-tACS and sham stimulation targeting bilateral fronto-TPJ cortex for four weeks. Cognitive functions were assessed at baseline, post-treatment and 8-week follow-up. TMS-EEG and voxel-based distance-related functional connectivity analysis evaluated network changes. Both active stimulation groups showed sustained cognitive improvements for eight weeks compared to the sham stimulation group (all p < 0.017). 40Hz-tACS also enhanced language function (p < 0.025). 6Hz-tACS increased anterior functional connections and anterior-to-posterior information flow, while 40Hz-tACS increased posterior connections and posterior-to-anterior flow, closely linked to cognitive improvements. These effects are oscillation frequency-dependent, supporting cognitive improvement in AD.