Phase-locked closed-loop ultrasound stimulation of hippocampal slow gamma modulates CA3-CA1 coherence and improves spatial memory in APP/PS1 mice
Zhenyu Xie, Hui Ji, Mürsel Karadas, Yiyao Zhang, Yi Yuan
Journal of Neural Engineering 2026 · 10.1088/1741-2552/aeb075
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.
Abstract via europepmc.
Exposures
Exposure 1: Phase-locked closed-loop ultrasound to CA3 (peak, trough, random phase)
Target: CA3 — “hippocampal CA3 region”
Device: Olympus / Panametrics · Olympus Corporation, USA · V302-SU ✓
| Waveform | other patterned | |
|---|---|---|
| Fundamental frequency (kHz) | 1,000 | ✓✓✓⚑ |
| Pulse duration (ms) | 10 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | not reported | |
| Duty cycle (%) | not reported | |
| Sonication duration (s) | not reported |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
Pulses triggered on detection of a target phase of CA3 slow gamma (30-45 Hz): peak, trough or random phase. Acute experiment: 1, 2, 3 or 4 stimuli per second or all detected events. Chronic (rats and APP/PS1 mice): within each 1 s detection window one 10 ms pulse is triggered, 1 s interval between windows, 15 min per day for two weeks. Acoustic parameters are shown only in a figure.
Flags from extraction
exposures[0].fundamental_frequency_khz— 1 MHz appears only as the rating of the transducer (V302-SU) in the hydrophone sentence; the actual fundamental frequency used is in Figure 3(G), not in text. Reader should verify.exposures[0].device— Sentence is ambiguous whether V302-SU is the stimulating transducer; taken as such.n_subjects— Group sizes by species: 62 SD rats, 15 APP/PS1 mice and 5 wild-type mice; the wild-type mice and some rats were not sonicated.exposures[0].timing.pulse_duration_ms— 10 ms pulse stated for Experiments 2 and 3; Experiment 1 pulses not described in text.exposures[0].free_field— No pressure or intensity values in the text; field mapped by hydrophone but only normalised, in figures.anaesthesia— Experiment 1 anaesthetised rats (isoflurane at surgery; acute stimulation in anaesthetised rats); behaviour in awake animals.