PROJECT SUMMARY/ABSTRACT Memory is core to human cognition, undergoes protracted developmental maturation and age-related decline, and is disrupted in numerous neurological and neuropsychiatric disorders. Despite the central role of memory in health and disease, remarkably little is known about the neural mechanisms supporting memory in humans. In this K99/R00 project, I propose to combine rare intracranial recordings from neurosurgical patients and advanced electrophysiological data analysis to track memory formation and maintenance in real time, and predict behavior in children, adolescents, and adults. With these spatiotemporally precise measures of memory formation and maintenance, this research will address critical gaps in knowledge about this core neurocognitive function. Comparative analysis between intracranial recordings and scalp electroencephalography (EEG) measures will further identify non-invasive EEG metrics applicable to developmental, lifespan, and disease-related research. Causal links between the medial temporal lobe, prefrontal cortex, and memory are well-established. However, there is a paucity of data on the mechanisms by which medial temporal and prefrontal regions interact to support memory in humans. The proposed research will determine the dynamic, multi-level neural circuit mechanisms that predict memory formation in humans across the lifespan. This research program will follow two complementary, largely unexplored directions. Aim 1 (K99 phase) will map predictors of memory formation and maintenance from the level of single neurons to that of large-scale neural circuits using simultaneous recordings obtained from medial temporal and prefrontal regions in adults. Aim 2 (R00 phase) will define electrophysiological predictors of memory success across the lifespan using intracranial recordings obtained from medial temporal and prefrontal regions in children, adolescents, and adults. The overarching hypothesis is that sub-second interactions in medial temporal, prefrontal, and medial temporal-prefrontal circuits will predict individual memory formation. Completion of these Aims will generate novel mechanistic explanations of human memory formation from childhood into adulthood. This research is directly relevant to Priorities #6 and #7 of the BRAIN 2025 Report and will prepare the Principal Investigator for a successful independent research career. To achieve these Aims, the proposed career development plan will build upon the Principal Investigator’s previous training with four goals to enhance her trajectory toward becoming an independent investigator: (1) analysis of single-unit neuronal data; (2) application of multivariate statistics to time-series data; (2) ethical aspects of conducting scientific research in clinical patients; and (4) research, mentoring, and administrative skills requisite to run a successful laboratory. Training will be accomplished through a balance of direct mentorship from animal and human neurophysiologists and coursework in neurophysiology, statistics, responsible conduct of research, and preparing for a future faculty position.

PROJECT NARRATIVE The ability to maintain relevant information necessary to make decisions and continuously update our autobiographies as we amass experience from childhood into adulthood depends on the medial temporal lobe and prefrontal cortex. By measuring electrical activity directly from the human brain, the proposed research will determine the mechanisms by which these regions interact to form and maintain memories in real time, and identify sources of developmental variability in these mechanisms from childhood into adulthood. The outcomes will increase understanding of how the brain implements normal memory and how brain circuits may go awry in disordered behavior, laying the foundation for translational work aimed at improving memory in populations suffering from disease or injury.