PROJECT SUMMARY/ABSTRACT Epilepsy is a prevalent pediatric neurologic condition that remains treatment-resistant for 30% of patients. It is increasingly recognized as a disorder of brain networks, with network changes shown to underlie seizures, neurodevelopmental impairments, and treatment effects. Limited targeted therapies for epilepsy have been most successful in high-risk populations when administered before seizures start, suggesting that they may prevent pathologic brain network changes. Assessing the development of brain networks using functional connectivity (fc) is therefore a promising technique for early prediction of epilepsy and neurodevelopmental outcomes. Thus, to evaluate network changes as susceptibility markers, fc must be studied prospectively in populations at risk for epilepsy. Very preterm infants (VPT; ≤32 weeks’ gestation) with high-grade intraventricular hemorrhage (IVH) have increased rates of childhood epilepsy and may provide important insights into risk stratification if studied early. This innovative proposal capitalizes on a time-sensitive opportunity to capture a critical period before/during the development of epilepsy in an understudied, high-risk sample, enabling the identification of risk biomarkers translatable to future clinical screening and interventions. To identify prospective biomarkers of epilepsy susceptibility in VPT infants with IVH, the applicant will collect high-density (HD)-EEG data at the bedside in the Neonatal Intensive Care Unit (NICU) in parallel with a longitudinal R01 study collecting functional (f)MRI data and developmental assessments of VPT infants with and without high-grade IVH. This K23 also adds collection of early life epilepsy outcomes through a parent questionnaire and medical record review. The applicant will use HD-EEG to detect clinical EEG abnormalities among VPT infants with high-grade IVH (Aim 1), reductions in HD-EEG and fMRI measures of brain network connectivity, particularly in injured brain regions (Aims 1 & 2), relationships between HD-EEG and fMRI connectivity measures (Aim 2), and relationships between the strength of HD-EEG connectivity metrics, developmental outcomes, and a diagnosis of epilepsy in early life (Aim 3). This award provides the applicant, a uniquely qualified pediatric epileptologist, formal training in quantitative HD-EEG analyses and source localization, multimodal fc analyses, and developmental assessments at an institution deeply committed to early career physician scientists, featuring field leaders in epilepsy, neuroimaging, computational neuroscience, neurodevelopment, and one of the country’s largest NICUs. The applicant’s multidisciplinary mentoring team assembles senior investigators with expertise in early life epilepsy, neonatology, neurodevelopment, electrophysiology, functional neuroimaging, and advanced computational methods. The foundational data and training from this K23 award will play a pivotal role in launching the applicant’s i...