White Matter Electric Field Maximization Guided Coil Orientation Optimization for rTMS in Alzheimer's Disease

Background Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising intervention for Alzheimer's disease (AD), yet current protocols lack standardized methodologies for correlating coil orientation with electric field (E-field) characteristics. This study establishes coil orientation optimization protocols for AD-related rTMS targets by analyzing E-field distribution patterns. Methods In a study population of 45 AD patients undergoing targeted stimulation of either the dorsolateral prefrontal cortex (DLPFC, n  = 30, M:F, 11:19) or angular gyrus (AG, n  = 15, M:F, 8:7), we performed E-field simulations across four critical regions: DLPFC, AG, precuneus (PC), and primary motor cortex (M1), determining optimal orientation through region-specific E-field maximization. Post hoc analysis of neuropsychological outcomes validated the proposed optimization strategy. Results Our findings revealed that white matter E-field (E _WM ) and normal E-field component (E _⊥ ) demonstrated higher orientation-dependent variability compared to gray matter E-field (E _GM ), despite larger GM volumes. Orientation optimization achieved more than 85% consistency rates for M1 (45°), AG (-15°) and PC (0°) through E _WM maximization, whereas DLPFC required individualized coil orientation. Clinical validation demonstrated that AG-targeted stimulation maintained significantly lower orientation deviation variance compared to DLPFC protocols, corresponding to reduced coefficient of variation (CV) in the improvement of MoCA scores (55.65% vs. 100.76%, P  = 0.006). Notably, patients aligned with E _WM -optimized orientation in DLPFC group showed superior improvement of auditory verbal learning test (AVLT) scores compared to non-optimized cases ( P  < 0.05). Conclusions These findings establish E _WM as a critical determinant of rTMS efficacy and advocate for region-specific orientation protocols to enhance AD treatment outcomes.