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Multimodal evidence associated with 20Hz rTMS in AD: neuroaxonal injury reduction, neural oscillatory rebalancing,
Tian Wang1, Yong Ji2, Shuai Liu2
1State Key Laboratory of Intelligent Power Distribution Equipment and System, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300130, China; Tianjin Key Laboratory of Bioelectromagnetic Technology and Intelligent Health, School of Health Sciences and Biomedical Engineering, Hebei University of Technology, Tianjin 300130, China.
Abstract:
High-frequency repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to enhance cognitive function in patients with Alzheimer's disease (AD), but the neurobiological mechanisms associated with neuroaxonal injury, neural oscillatory dynamics, and large-scale network reorganization remain unclear. In this study, we first conducted a randomized, sham-controlled trial with 16 patients with AD to evaluate the efficacy of DLPFC-targeted rTMS, followed by a single-arm multimodal cohort study of 30 patients to explore potential neurobiological mechanisms through cognitive assessments, blood biomarkers, EEG oscillatory activity, and multiplex brain network analysis. In Stage 1, the sham group showed no significant pre-post changes in MMSE or MoCA scores (MMSE: Z = -0.738, Cohen's r = 0.26; MoCA: Z =-0.853, Cohen's r = 0.30). The active rTMS group showed improvements in MMSE (Z = -2.124, Cohen's r = 0.75) and MoCA (Z = -2.108, Cohen's r = 0.75). In stage 2, rTMS was associated with improvements in MMSE (Z = -2.863, Cohen's r = 0.523) and MoCA (t = -6.137, Cohen's r = 0.752) scores. Biomarker analyses indicated a significant decrease in NfL concentrations (Z=-2.371, Cohen's r=0.484). EEG recordings revealed a decrease in delta power in the left temporal lobe (t=2.158, Cohen's r=0.372) and increases in beta power in the right parietal lobe and gamma power in the temporal lobe (beta: Z=-2.088, Cohen's r=0.381; gamma: Z=-2.129, Cohen's r=0.389). Network analysis showed reduced modularity and enhanced global efficiency across theta, alpha, and beta bands, accompanied by increased degree of overlap in frontal, parietal, and occipital regions. Importantly, MoCA improvement correlated with gamma-band global efficiency (R=0.389, P=0.034) and multilayer clustering coefficients in the left frontal and right occipital regions (R=0.478, P=0.008; R=0.398, P=0.029). Overall, rTMS exposure was associated with cognitive improvements in patients with AD, together with changes in neurodegeneration-related biomarkers and EEG network organization. These findings suggest that cognitive changes following rTMS may be associated with oscillatory modulation and large-scale network remodeling. TRIAL REGISTRATION: Registration number: ChiCTR2500095949; Registration Date: 2025-01-15.
