Five Hz sinusoidal amplitude-modulated focused ultrasound regulates hippocampal oscillations and alleviates cognitive impairment in 5xFAD

Abnormal hippocampal neural oscillations and network dysfunction are early pathophysiological features of Alzheimer's disease (AD), characterized by disrupted theta rhythms, impaired gamma activity, weakened circuit synchrony, and abnormal phase-amplitude coupling. Focused Ultrasound (FUS) can noninvasively target deep hippocampal regions to modulate these abnormalities, however, precisely modulating disease-related oscillatory dynamics remains challenging. A novel 5 Hz sinusoidal amplitude-modulated (AM) FUS paradigm was applied to the hippocampus of 5xFAD mice. Local field potentials were recorded to assess acute and long-term effects on rhythm power, neural circuit connectivity and coordination. Behavioral tests evaluated cognitive function after 14-day stimulation. The 5 Hz sinusoidal AM-FUS rapidly and progressively modulated aberrant hippocampal oscillations. It reduced pathological elevated theta power toward control levels, enhanced suppressed gamma activity, and restored PP–DG circuit synchrony and cross-frequency coupling. The 14-day stimulation significantly improved learning and memory performance. In 5xFAD mice, the 5 Hz sinusoidal AM-FUS achieved bidirectionally normalization aberrant hippocampal oscillations, restored PP–DG network dynamics, and alleviated cognitive impairments, providing preclinical evidence supporting further investigation of temporally patterned AM-FUS as a promising neuromodulatory strategy for AD-related hippocampal network dysfunction.