Project Summary/Abstract Memory is critical for cognitive well-being, and sleep is critical for memory consolidation, yet the underlying mechanisms in the human brain are poorly understood. Research on memory and sleep so far has suffered from a substantial gap between non-invasive cognitive research in humans and detailed electrophysiological research in animals. This proposal seeks a breakthrough by capitalizing on a highly unique opportunity to record and modulate activity of single neurons and neuronal assemblies in the human medial temporal lobe and neocortex during memory tasks and sleep. Recording from depth electrodes in neurosurgical patients, the study will investigate the role of information exchange between hippocampus and neocortex in memory consolidation. To bridge the gap between cognitive human research and mechanistic animal research, two essential approaches will be used. (a) Establish the neural correlates of sleep activities that predict successful memory, using paired-associate learning and object-location association tasks. The leading hypothesis is that coordinated coupling between neocortical slow waves, sleep spindles and hippocampal ripples, co-occurring with reactivation of neuronal ensembles that were selectively engaged in the learning task, will be maximally correlated with successful memory performance after sleep. (b) Test the causal role of these sleep events by modulating them via sensory or direct electrical brain stimulation. This causal approach will involve (1) Auditory Targeted Memory Reactivation. We will examine the neural and behavioral effects of repeating, during slow wave sleep, auditory cues that had been paired with selected stimuli during learning. A widely-held but untested hypothesis is that this will cause reactivation of the neuronal assemblies that encoded those memories. Our ability to record single neurons and hippocampal oscillatory activity during learning and sleep positions us uniquely to test this hypothesis. (2) Locking bursts of intracranial electrical brain stimulation or auditory stimulation to endogenous oscillations. We will achieve well-timed stimulation through the development of a closed-loop system that drives stimulation in the neocortex based on real-time sleep activity in the hippocampus. We will examine the effects of stimulation on memory and electrophysio- logical activity, such as slow waves and ripples. It is anticipated that about 25 patients with depth electrodes will be studied during the 2-year project. This exploratory study builds on the unique capabilities of our center at UCLA to stimulate and record in the human brain, not only intracranial EEG but also well-localized field potentials and single neurons whose response-specificity can be followed before, during, and after sleep. Assembling a group of experts from a wide array of disciplines?including neurobiology of sleep and memory in humans and rodents, neuroengineering, psychology, neurology, and neurosurgery?the proposed study will probe the underlying neuronal mechanisms of memory consolidation in sleep using correlative and causal measures, employing a systematic and reliable approach.