Synergistic modulation of the dorsolateral prefrontal cortex and precuneus enhances cognitive recovery in mild cognitive impairment: A multimodal neuroimaging study.

Repetitive transcranial magnetic stimulation is a promising intervention for mild cognitive impairment; however, conventional single-site stimulation protocols are often incapable of addressing the complex pathological network alterations underlying the condition. This study investigated the clinical efficacy and neurobiological modulatory mechanisms of multisite versus single-site repetitive transcranial magnetic stimulation in patients with mild cognitive impairment. A total of 101 patients with mild cognitive impairment completed a 10-day repetitive transcranial magnetic stimulation intervention and were analyzed in two cohorts: a single-site group receiving stimulation over the left dorsolateral prefrontal cortex (n = 50) and a multi-site group receiving sequential stimulation over the left dorsolateral prefrontal cortex and precuneus (n = 51). The multi-site group demonstrated significantly greater enhancements in global cognition [Mini-Mental State Examination: group×time interaction F(99) = 25.08, P < 0.001; Montreal Cognitive Assessment: F(99) = 6.17, P = 0.015], memory [Auditory Verbal Learning Test-immediate recall: F(99) = 6.03, P = 0.016], and language (Verbal Fluency Test, Animal Fluency Test: F(99) = 8.13, P = 0.005) compared with the single-site group. Neuroimaging analyses revealed that multi-site repetitive transcranial magnetic stimulation induced robust structural and functional alterations across broader cognitionrelated regions and networks. Specifically, the multi-site protocol significantly increased gray matter volume in the left parahippocampal gyrus and large-scale networks (e.g., default mode network, executive control network), while modulating amplitude of low-frequency fluctuation and regional homogeneity in core memory and executive regions, including the precuneus, hippocampus, parahippocampal gyrus, and middle frontal gyrus. Additionally, multi-site stimulation drove more extensive functional connectivity alterations within the left parahippocampal network. Crucially, these specific neuroimaging alterations significantly correlated with behavioral improvements in memory, language, and global cognitive scores. Multi-site repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex and precuneus yields superior cognitive improvements in mild cognitive impairment compared with conventional single-site stimulation. This enhanced efficacy is underpinned by the robust modulation of structural integrity, spontaneous neural activity, and functional connectivity within core cognitive brain networks. These mechanisms reflect repetitive transcranial magnetic stimulation-induced synaptic plasticity and neurovascular coupling, driving network-level neural repair and providing a mechanistic rationale for optimized, connectivity-based neuromodulation in the early intervention of Alzheimer's disease.