PROJECT SUMMARY Sleep plays a critical role in a vast array of physiological and pathophysiological processes, including executive brain functions, immune and metabolic functions, and neurodegenerative diseases. An improved understanding of sleep mechanisms is important to developing new treatment strategies. Sleep circuits can be manipulated with numerous techniques to infer causal relationships to physiology and behavior. Effects of these manipulations are generally sleep stage or brain state dependent. Thus, closed-loop interrogation provides a powerful paradigm, whereby a temporally precise manipulation (optogenetic, electrical, or sensory stimulation) is delivered in a brain-state dependent manner. This paradigm has been used successfully in mice and humans tethered to data acquisition, state classification, and stimulation hardware. However, tethering can adversely affect natural sleep behavior and prevents use in larger animal models. Here, we propose to develop a fully integrated, wireless, sleep modulation system-on-chip (SoC) with the capability to deliver state-dependent, temporally-precise optical, electrical, and auditory stimulation. In Aims 1 and 2, Co-PI Dr. Liu will iteratively develop an ultra-low-power SoC for polysomnography (PSG) signal acquisition and multi-modal closed-loop stimulation. The final SoC will have five modules: (1) a low-noise, high-precision PSG acquisition module, (2) a programmable mixed-signal data compression module for energy efficiency, (3) a low-power ultra-wideband wireless transmitter, (4) a machine learning-based sleep stage classification module, and (5) a fully programmable multi-modal stimulator. Full integration of the system will result in a small (2 cm3), light (2 g) battery-powered device able to operate continuously for over 10 h on a single charge. In Aim 3, running concurrently with the first two aims, Co-PI Dr. Richardson will validate performance of the SoC with sleep studies in both small (rats) and large (macaques) animal models. Interleaved recordings from the wireless SoC and a tethered commercial system will assess fidelity of compressed PSG acquisition and the impact of tethering on sleep architecture. Real-time 2-stage and all-stage classifiers will be compared to offline ground truth labels. Finally, in-phase closed-loop auditory stimulation will be used to enhance slow wave activity. Our team is uniquely qualified for this proposal since we have extensive experience developing the key modules in the proposed SoC and using wireless electronics for free behavior electrophysiological experiments in both animal models. Once developed, two industry partners, CMC Microsystems and Open Ephys, Inc., will facilitate distribution of the SoC to the worldwide community. The closed-loop SoC will enable unprecedented hypothesis- driven research on sleep-stage specific neural circuits and interventions in models spanning from mice to monkeys, thereby accelerating the mechanistic understanding o...