Repeated neuromodulation with low-intensity focused ultrasound in patients with Alzheimer's disease

Background: Low-intensity focused ultrasound (LIFU), a non-invasive targeted brain stimulation technology, has shown promise for therapeutic applications in Alzheimer's disease (AD) patients. Despite its potential, the implications of repeated LIFU neuromodulation in AD patients remain to be investigated. Objective: This pilot study evaluated the safety and potential to improve cognition and functional connectivity following repeated LIFU treatment in AD patients. Methods: Ten early-stage AD patients underwent six sessions of neuronavigation-guided LIFU targeting the left dorsolateral prefrontal cortex (DLPFC) within 2–3 weeks, alongside ongoing standard pharmacotherapy. Neuropsychological assessments and resting-state functional magnetic resonance imaging were performed at baseline and eight weeks post-treatment. Results: Memory performance (p = 0.02) and functional connectivity between the left DLPFC and both the left perirhinal cortex and left dorsomedial prefrontal cortex (corrected p < 0.05) significantly improved from baseline. Additionally, enhancements in memory performance were positively correlated with increases in functional connectivity of the left DLPFC with the left perirhinal cortex (Kendall's tau = 0.56, p = 0.03). No adverse events were reported during the LIFU treatments or at the subsequent follow-up. Conclusions: LIFU may have the therapeutic potential to enhance both brain network connectivity and memory functions in AD patients. Our results provide a basis for further research, including randomized sham-controlled trials and optimization of stimulation protocols, on LIFU as a supplementary or alternative treatment option for AD.