Phase-locked closed-loop ultrasound stimulation of hippocampal slow gamma modulates CA3-CA1 coherence and improves spatial memory in APP/PS1 mice

Abstract Objective. Impaired hippocampal slow gamma oscillations and CA3-CA1 dysfunction may contribute to spatial memory deficits in early Alzheimer’s disease (AD). This study examined whether phase-locked closed-loop transcranial ultrasound stimulation (TUS) could modulate CA3-CA1 activity and improve memory. Approach. A closed-loop TUS system was developed that uses the phase of endogenous slow gamma (30–45 Hz) rhythms in CA3 local field potentials as a trigger. Acute experiments were performed to assess phase-dependent neural responses. Normal rats received 14 d of stimulation to examine circuit connectivity and behavior. APP/PS1 mice received 14 d of peak-phase stimulation to test behavioral and electrophysiological effects. Main results. Acute experiments showed that both stimulation phase and stimulation number jointly modulated neural responses. Peak-phase and random-phase stimulation increased slow gamma power and cross-frequency coupling, while peak-phase stimulation also decreased sample entropy and increased CA3-CA1 coherence. In normal rats, behavioral performance did not differ among groups after 14 d, but task-related CA3-CA1 slow gamma coherence was higher in the peak-phase group. In APP/PS1 mice, peak-phase stimulation improved Y-maze spontaneous alternation and novel object location discrimination, alongside increased CA1 power, CA3-CA1 coherence, cross-frequency coupling, and spike-field coherence, all of which were positively correlated with behavioral scores. Significance. These findings indicate that phase-locked closed-loop ultrasound stimulation modulates hippocampal slow gamma activity and CA3-CA1 connectivity in a phase-dependent manner and improves spatial memory in an AD mouse model, supporting oscillation-guided noninvasive neuromodulation as a potential intervention strategy.