Gamma-band transcranial alternating current stimulation restores motor function in a Parkinson's disease mouse model

Parkinson's disease (PD) is associated with abnormal neural oscillations within the cortico-striatal-thalamo-cortical (CSTC) circuit, and current therapeutic options remain limited in their ability to restore physiological network dynamics. Transcranial alternating current stimulation (tACS) has recently emerged as a promising non-invasive approach. However, its optimal frequency and underlying mechanisms in PD remain incompletely understood. Here, we compared theta (6 Hz), alpha (10 Hz), beta (20 Hz), and gamma (40 Hz) tACS in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice and found that gamma-band tACS most effectively improved motor coordination and locomotion. Resting-state functional magnetic resonance imaging showed that gamma-band tACS increased regional homogeneity and the amplitude of low-frequency fluctuations in the prefrontal cortex, striatum, hippocampus, and thalamus, and strengthened functional connectivity within the CSTC circuit. Electrophysiology revealed enhanced feedforward drive from the primary motor cortex to the striatum and thalamus with reduced thalamo-cortical feedback. Transcriptomic, immunohistochemical, and Western blot analyses indicated activation of glutamatergic N-methyl-D-aspartate receptor (NMDAR)-dependent Ca^2 + /CaMKII-CREB-BDNF signaling, which was partially blocked by the NMDAR antagonist dizocilpine (MK-801). These findings identify gamma-band tACS as a frequency-specific, mechanistically informed intervention for modulating pathological motor network dynamics in PD.