PROJECT SUMMARY Over 223,000 patients with traumatic brain injury (TBI) are hospitalized in the United States annually, with more than 166 deaths each day. It has been demonstrated over the past two decades of clinical research that cortical spreading depolarizations (CSDs), also known as “brain tsunamis,” are waves of electrical activity that occur in 60% of patients with TBI. CSDs are waves of massive neuronal depolarization that cause periods of electrical silencing and are independently associated with worse 6-month outcomes in TBI patients. It is unknown whether CSDs cause damage beyond the area of local cortical spread, and it is unknown how CSDs cause poor outcomes after TBI. We hypothesize that CSDs disrupt connections between the cortex and hippocampus and hence contribute to poor cognitive outcomes. We will test this hypothesis in an experimental model of TBI and CSDs. We will define CSDs effects on axonal pathology and synaptic connections. Understanding how CSDs influence local and remote brain connectivity will provide insight into how CSDs after TBI may contribute to poor outcomes. Additionally, this project will allow Ms. Bishop to develop critical thinking skills, advance her scientific knowledge, and help her reach her career goal of being a physician-scientist.