Bilateral Angular Gyrus 810-nm Transcranial Near-Infrared Stimulation Reshapes Brain Network: Ameliorate Alzheimer's Disease Cognitive Deficits.

Objective: To investigate the clinical efficacy and neural mechanisms of targeted 810-nm transcranial near-infrared stimulation (tNIRS) over the bilateral angular gyrus in Alzheimer's disease (AD). Impact Statement: We provide the first clinical evidence that targeted tNIRS ameliorates AD cognitive deficits by dynamically reconfiguring large-scale brain networks, establishing a precise, mechanistic neuromodulation strategy. Introduction: While tNIRS shows potential for AD, conventional whole-brain irradiation lacks anatomical precision and yields inconsistent outcomes. Resolving these elusive network-level mechanisms requires targeted stimulation paradigms. Methods: In a randomized, sham-controlled trial, 36 biomarker-confirmed AD patients received 810-nm tNIRS targeted at the bilateral angular gyrus or sham stimulation (20 min/side daily, 15 d). Baseline and post-intervention neuropsychological assessments, resting-state functional magnetic resonance imaging (fMRI), and transcranial magnetic stimulation-electroencephalography (TMS-EEG) were utilized to decode cognitive improvements and network dynamics. Results: Targeted tNIRS obviously improved cognition, memory, language, attention, and executive functions while reducing neuropsychiatric symptoms. fMRI revealed enhanced intra-network connectivity within the default mode network (DMN) and promoted functional synergy between the DMN, dorsal attention, frontoparietal, and limbic networks. TMS-EEG demonstrated enhanced information flow and dynamic nodal reconfiguration, specifically boosting prefrontal and temporo-occipital activation. Conclusion: Bilateral angular gyrus targeted tNIRS may effectively mitigate AD cognitive impairment potentially through modulation of functional connectivity and adaptively reconfiguring higher-order cognitive networks, serving as a highly promising clinical neuromodulation therapy.