PROJECT SUMMARY Neonatal seizures due to brain injury (acute symptomatic seizures) are associated with high risk of neurodevelopmental disability in infancy. Although prognosis in early childhood is a critical question for parents and providers, outcomes beyond infancy are largely unknown. Further, parents of infants with neonatal seizures are at risk for mental health disorders, which can undermine their ability to care for a child with medical complexity and may contribute to impaired child development. The proposed “Neonatal Seizure Registry – Developmental functional EValuation (NSR-DEV)” study will test the central hypothesis that risk factors for developmental disabilities can be identified in infancy and are modified by parent well-being. This observational study will leverage the infrastructure of the 9 center Neonatal Seizure Registry, to which we have recruited >300 children with acute symptomatic neonatal seizures (NCT02789176). With support for the current proposal, this unique cohort will be available at ages 2-7 years to participate in annual validated parent- reported developmental evaluations to characterize cognition, adaptive behavior, executive function, behavior, epilepsy and cerebral palsy, as well as in-person, gold standard IQ testing with the WPPSI-IV at age 5 years. Using neonatal clinical, EEG and MRI measures, as well as 3-month EEG, and longitudinal measures of parent well-being, we will build robust models to predict developmental outcome in this high risk population. We will test our hypotheses by pursuing the following specific aims: Aim 1a: Identify predictors of disability in children with prior acute symptomatic neonatal seizures; Aim 1b: Examine risk factors for decline in adaptive behavior in children with prior acute symptomatic neonatal seizures; Aim 2a: Determine whether parent well- being (validated measures for symptoms of anxiety or depression, post-traumatic stress, and resilience) alters the risk for disability among children with prior acute symptomatic neonatal seizures; Aim 2b: Determine whether parent well-being alters the adaptive behavior trajectory in children with prior acute symptomatic neonatal seizures; Aim 3: Build robust risk prediction models for childhood disability after neonatal seizures. This innovative proposal will maintain an existing, multicenter cohort enrolled from US centers that employ state-of-the-art technology for diagnosis and investigation of neonatal seizures, and targets research priorities of parents and clinicians. This carefully designed study will provide novel, clinically-relevant answers to key questions about long term outcomes in this highly vulnerable patient population. Results will inform the subsequent design of neuromodulatory intervention studies and programs designed to optimize parent-related factors with the goal of improving neurodevelopmental outcomes.

PROJECT NARRATIVE The proposed research is relevant to public health because the results will have immediate positive impact for children with neonatal seizures due to early brain injury, their families, and the providers who care for them. Through this study, we will take innovative steps to understand the multifaceted contributions of biological and parent-related contributors to neurodevelopmental outcomes after neonatal seizures. The proposed research is directly relevant to the NIH mission, which calls for the development of methods to enhance health and reduce illness and disability, to seek fundamental knowledge about the brain and nervous system, and to use that knowledge to help all children to achieve their full potential through reduction of the burden of neurological disease.