Efficacy and safety of simultaneous rTMS–tDCS over bilateral angular gyrus on neuropsychiatric symptoms in patients with moderate Alzheimer's disease: A prospective, randomized, sham-controlled pilot study

Treating neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) remains highly challenging. Noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) is of considerable interest in this context.To investigate the efficacy and safety of a novel technique involving simultaneous application of rTMS and tDCS (rTMS-tDCS) over bilateral angular gyrus (AG, P5/P6 electrode site) for AD-related NPS.Eighty-four AD patients were randomized to receive rTMS-tDCS, single-rTMS, single-tDCS, or sham stimulation for 4 weeks, with evaluation at week-4 (W4, immediately after treatment) and week-12 (W12, follow-up period) after initial examination. Primary outcome comprising Neuropsychiatric Inventory (NPI) score and secondary outcomes comprising mini-mental state examination (MMSE), AD assessment scale-cognitive subscale (ADAS-cog), and Pittsburgh sleep quality index (PSQI) scores were collected and analyzed by a two-factor (time and treatment), mixed-design ANOVA.rTMS-tDCS produced greater improvement in NPI scores than single-tDCS and sham at W4 and W12 (both P < 0.017) and trended better than single-rTMS (W4: P = 0.058, W12: P = 0.034). rTMS-tDCS improved MMSE scores compared with single-tDCS at W4 (P = 0.011) and sham at W4 and W12 (both P < 0.017). rTMS-tDCS also significantly improved PSQI compared with single-rTMS and sham (both P < 0.017). Interestingly, rTMS-tDCS-induced NPI/PSQI improvement was significantly associated with MMSE/ADAS-cog improvement. tDCS- and/or rTMS-related adverse events appeared slightly and briefly.rTMS-tDCS application to bilateral AG can effectively improve AD-related NPS, cognitive function, and sleep quality with considerable safety.