Bidirectional restoration of sleep homeostasis in neurodegeneration via closed-loop auditory stimulation

Sleep-wake disturbances in Alzheimers (AD) and Parkinsons disease (PD) are linked to disrupted slow-wave activity (SWA) and SW-spindle coupling, critical for memory consolidation and protein clearance. While SWA enhancement shows promise in aging, disease-specific effects on SW synchronization (local, linked to sleep depth vs. global, linked to arousal), spindle dynamics and sleep homeostasis remain unexplored in neurodegeneration. Using mouse closed-loop auditory stimulation (mCLAS), we probed its acute effects on SW subtypes, spindle characteristics, SW-spindle coupling and sleep homeostasis in Tg2576 (AD) and M83 (PD) mice. mCLAS adaptively modulates SW subtypes and SW-spindle coupling depending on baseline impairments. In AD mice, it reduces global synchrony while potentiating local phenomena and network recruitment, restoring SW-spindle coupling strength and normalizing spindle power. In PD mice, mCLAS increases global synchrony, reorganizing 24-hour SW dynamics towards wild-type patterns, while reducing excessive SW-spindle coupling and enhancing spindle power. Critically, mCLAS bidirectionally regulates sleep homeostasis: boosting deficient slow-wave energy in AD and reducing excess in PD to restore physiological sleep. These findings suggest mCLAS acts via complementary mechanisms to rescue sleep homeostasis in neurodegeneration, by modulating cortical synchrony in AD and arousal in PD, offering a noninvasive path to potentially mitigate cognitive decline and pathological progression.