Project Summary/Abstract Dr. James Gugger is an Assistant Professor of Neurology at the University of Pennsylvania with clinical expertise in both epilepsy and traumatic brain injury (TBI). His long-term goal as a physician-scientist is to use quantitative neuroimaging to define neurobiologically grounded phenotypes of neurological disorders, which will improve our understanding of disorders such as epilepsy and TBI and ultimately improve care. The neurobiological phenotype of TBI involves both focal and diffuse injury mechanisms. Both animal and human data implicate damage to the limbic network in those with epilepsy after head injury. This proposal tests the hypothesis that the effects of focal and diffuse injury mechanisms on the limbic network can be used to distinguish patients with TBI who will develop epilepsy from those who do not. Experiments will utilize neuroimaging data from a large, well-phenotyped cohort of participants with TBI and uninjured controls. The specific aims are (1) to define the relationship between focal post-traumatic lesions and brain networks implicated in post-traumatic epilepsy (PTE) and (2) to determine the profile of diffuse injury in brain networks implicated in PTE. This project will uncover neuroimaging phenotypes present prior to the onset of PTE and advance us towards identification of biomarkers for epilepsy risk stratification. The proposal builds on Dr. Gugger’s prior research on quantitative multimodal neuroimaging in TBI and epilepsy. With the support of a team of mentors at the University of Pennsylvania who are leaders in the field, he will gain expertise in functional neuroimaging, statistical modeling of multimodal neuroimaging data, and the conduct of prospective neuroimaging studies. Dr. Gugger’s team of mentors at the University of Pennsylvania (Drs. Diaz-Arrastia, Davis, Shinohara, and Detre) have strong track records of mentorship and will provide specific expertise in his areas of skill development. He will also leverage his existing relationships with large multicenter consortia focused on PTE research (Transforming Research and Clinical Knowledge in TBI [TRACK-TBI] Network, Military Injuries—Understanding PTE: Bioinformatics with big data to examine multi- modal PTE biomarkers [MINUTE], and the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy [EpiBioS4Rx]) to launch future studies as an independent physician scientist. Dr. Gugger’s clinical background in epilepsy and TBI, with the additional support of this career development award and his unique mentorship opportunities, will position him to succeed as an independent physician-scientist focused on using quantitative neuroimaging to improve the lives of people with epilepsy and TBI.