Determining network signatures of pharmacoresistance in focal cortical dysplasia-related epilepsy - Focal cortical dysplasia (FCD) is the most common cause of surgically-remediable, pharmacoresistant epilepsy in children. FCD-related epilepsy often starts at a young age, placing children at risk of neurocognitive impairment and exposure to the side effects of antiseizure medications. Despite the regularity of FCDs, these lesions are often subtle which can lead to delays in detection; and even after detection, there are often long delays to epilepsy surgery. Current structural imaging and FCD pathological characteristics have failed to identify consistently those children at risk of developing pharmacoresistant epilepsy, and who would benefit from surgical intervention. Recent evidence has implicated that these focal lesions can cause widespread disruptions of distributed brain functional networks. Resting-state functional magnetic resonance imaging (rs-fMRI) is a validated, noninvasive imaging method that can identify stable functional networks across pediatric and adult subjects. Using advanced processing and statistical methods, these networks can be studied and compared quantitatively at the individual and group levels. This proposal tests the overall hypothesis that FCD-related epilepsy disrupts established cortical networks, and that the quantity and location of these perturbations determine which patients develop pharmacoresistant epilepsy. The aims of this research plan will identify 1) quantitative local, regional and remote network connectivity alterations and 2) network hub reorganizations associated with pharmacoresistance. This information will alter clinical practice by characterizing functional network markers of pharmacoresistance, allowing earlier identification and utilization of epilepsy surgery as guided by the 2021 NINDS Epilepsy Research benchmarks (IIA,C,IIIC). Nathan T. Cohen, MD (PI) is a board-certified pediatric epileptologist with clinical and research experience in advanced imaging of epilepsy. The proposed training plan will allow him to develop expertise in functional connectivity analysis, to master applied biostatistics, and to learn prospective and multicenter trial design. The candidate has organized a targeted mentorship team including William D. Gaillard, MD, and Chandan J. Vaidya, PhD whose expertise in functional imaging of pediatric epilepsy will allow him to achieve these goals. This K23 Career Development award will allow Dr. Cohen to transition to a line of independent investigation using functional imaging techniques to study the underpinnings of pharmacoresistance and the neurocognitive, behavioral, and psychiatric comorbidities of the epilepsies.
