Repetitive transcranial magnetic stimulation-driven modulation of unbiased functional connectivity in the supracallosal anterior cingulate cortex causally ameliorates information processing speed in amnestic mild cognitive impairment.

INTRODUCTION: Amnestic mild cognitive impairment (aMCI) exhibits biased functional connectivity (FC) abnormalities impairing neural plasticity modulation. This study aimed to identify unbiased FC deficits using a brain-wide association study (BWAS) and investigate repetitive transcranial magnetic stimulation (rTMS)-driven plasticity restoration. METHODS: BWAS identified unbiased FC-altered voxels (robustness-validated). Region-of-interest (ROI)-wise FC analysis localized disrupted circuits, which were modulated through precuneus-targeted rTMS. Effective connectivity (EC) tested whether the precuneus exerted a causal influence on these disrupted circuits. Correlation analyses linked FC plasticity to cognitive and clinical outcomes. RESULTS: Eleven brain regions with 31 altered unbiased FC circuits were robustly identified, centered on the bilateral anterior cingulate cortex (ACC). rTMS causally restored FC in the right supracallosal ACC and postcentral gyrus, correlating with improved information processing speed (IPS). Remarkably, 80.77% (21/26) of aMCI responded clinically to rTMS. DISCUSSION: This study first maps unbiased FC lesions in aMCI, confirming rTMS-mediated ACC plasticity causally enhances IPS. These findings inform network-targeted therapies to delay Alzheimer's disease (AD) progression. HIGHLIGHTS: This is the first study to robustly map unbiased FC lesions in aMCI patients using a BWAS. rTMS causally restored FC in right supracallosal ACC in aMCI patients. FC and EC recovery demonstrated causal links to improvements in IPS and MoCA scores. Remarkably, 80.77% (21/26) of aMCI patients responded clinically to rTMS modulation.