PROJECT SUMMARY Medically-refractory epilepsy affects nearly 1 in 300 people, and for these patients resective brain surgery may be the only change for seizure freedom. Patients with abnormal neuroimaging findings which correlate with abnormal electroencephalography (EEG) activity have the best chance of seizure freedom after epilepsy surgery. In patients without clear neuroimaging abnormalities, stereo-EEG (sEEG) can localize an epileptic lesion and increase the success of a future resective surgery. sEEG is a minimally invasive procedure where electrodes are placed throughout, and within the brain to identify the seizure onset zone, peri-epileptic network and nonepileptic brain regions. After sEEG electrode removal, adherent cells can be used to evaluate genomic material in order to better understand the molecular processes that define an epileptic network. The overall objective of this application is to understand the mechanisms in the development of intractable epilepsy with the goal of developing a precision medicine approach to therapy. We will evaluate the genetics and transcriptomics of brain tissue resected in children and young adults with intractable epilepsy undergoing sEEG followed by resective surgery. Our central hypothesis that patients who develop intractable epilepsy have 1) somatic mutations in epilepsy-related molecular pathways which are not present in the germline and 2) unique gene expression profiles will be identified in epileptic tissue with dysregulation of known neurotransmitter and inflammatory pathways, compared to peri-epileptic and non-epileptic brain tissue.