Combined effects of 40 Hz ultrasound and light stimulation on neural oscillations and cognition.

Single-modality 40 Hz ultrasound stimulation or 40 Hz light stimulation have demonstrated the efficacy in improving cognitive function in Alzheimer's disease (AD) mice. However, the therapeutic effect of combined 40 Hz ultrasound-light stimulation on AD-related cognitive deficits remain unexplored. To address this gap, we developed a 40 Hz dual-modality stimulation system comprising a dual-targeted holographic ultrasound transducer that enables precise, safe stimulation of the bilateral hippocampal CA1 regions, and a 40 Hz visual stimulation. In wild-type mice, acute 40 Hz ultrasound-light stimulation significantly increased gamma (30-100 Hz) power and cross-regional phase synchronization, revealing a stronger synergistic effect compared to unimodal (ultrasound or light alone) stimulation. In 5XFAD AD model mice, chronic 40 Hz ultrasound-light stimulation robustly improved spatial memory, enhanced gamma phase synchronization and reduced amyloid-β deposition. Our findings demonstrate that this dual-modality strategy serves as a powerful, noninvasive tool to effectively enhance gamma oscillations and mitigate Aβ accumulation, underscoring its promising potential for AD intervention.