Defining the remote effects of cortical spreading depolarizations on hippocampus after traumatic brain injury

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 cause remote effects in hippocampus of TBI brain that contribute to poor outcomes. We will test this hypothesis in an experimental model of TBI and CSDs. We will define CSDs remote effects on electrophysiology, histopathology, and adult neurogenesis. Additionally, it will be tested whether CSDs cause remote effects via a trans-synaptic mechanism. Understanding the remote effects of CSDs will provide a paradigm shift in how we think about CSDs when they are observed clinically, and provide insight into TBI therapeutics.