PROJECT SUMMARY/ABSTRACT The human ability to retrieve information from past experiences is essential for everyday living, shows robust improvement across childhood, and is impaired in many psychiatric and neurological disorders. Yet we know little about the neurophysiological mechanisms subserving this core cognitive ability in the developing brain. Memory retrieval relies on precisely timed dynamic interactions between key brain regions, but noninvasive techniques, commonly used to probe the neural basis of human memory development, are unable to measure both the spatial and temporal properties of memory at high resolution. Intracranial EEG (iEEG) in patients with surgically implanted electrodes for treatment of drug-resistant epilepsy provides the resolution needed to characterize the spatial and temporal dynamics of memory and is thus a powerful tool for examining the neural basis of human memory. During the prior funding period, the investigators established pediatric iEEG as an invaluable tool for elucidating the neurophysiological basis of memory formation in the developing brain. In this project, they will investigate memory retrieval and test the contributions of two complementary processes to successful retrieval: the enactment of strategic control mediated by the prefrontal cortex (PFC) and the representation of mnemonic content in the MTL and visual cortices. Guided by strong preliminary data, the central hypothesis is that the robust improvement in memory ability between childhood and adulthood is largely supported by the enactment of strategic control mediated by the PFC. In contrast, the contribution of the reinstatement of mnemonic content in the MTL and visual cortices to successful retrieval is largely stable across development and is a core component contributing to children’s memory. These hypotheses will be tested with iEEG data collected from 50 pediatric epilepsy patients and fMRI data collected longitudinally from 100 typically developing children, adolescents, and young adults by pursuing these specific aims: Aim 1) Identify strategic control-dependent retrieval mechanisms mediated by PFC and Aim 2) Identify content representation-dependent retrieval mechanisms in MTL and visual cortices. To establish the translational relevance of the mechanisms identified with iEEG and fMRI, the investigators will link measure of retrieval obtained with iEEG or fMRI to individual differences in standardized memory scores (Aim 3). This will pave the way to utilizing these measures in the design of interventions to alleviate memory deficits in children. Moreover, findings from this project will provide crucial insights for the feasibility of mapping of memory networks in children with focal epilepsy which can influence diagnostic and therapeutic surgical approaches, and ultimately improve quality of life in patients with drug-resistant focal epilepsy. At the completion of this project, the investigators will have identified how mechanisms in the developing brain that coordinate memory and bear broad translational relevance for the treatment of memory deficits prominent in many psychiatric and neurological disorders.

PROJECT NARRATIVE The proposed project is relevant to public health because memory deficits occur in many psychiatric and neurological disorders and are common as a result of early life adversity. Identifying the neurophysiological mechanisms of memory retrieval in the developing brain will inform the design of effective interventions for alleviating memory impairment in children and thus have a positive impact on life-long wellbeing. Further, this project will pave the way to designing clinical tools to map memory in the developing brain that will influence diagnostic and therapeutic surgical approaches and ultimately improve quality of life in patients with drug- resistant focal epilepsy.