Spreading Depolarizations as a Predictive Biomarker of Post-Traumatic Epilepsy
Abstract
Traumatic brain injury (TBI) results from mechanical forces, direct cranial impact or pressure wave, causing injury to the brain. TBI happens to tens of thousands of military personnel and hundreds of thousands of civilians every year and is a significant public health concern. The effects of TBI can be life changing and permanent. One of the common consequences of TBI is the development of new-onset seizures, termed post-traumatic epilepsy (PTE). PTE develops weeks, months, or years after TBI and can have significant negative impact on quality of life. We currently have a poor understanding of the processes underlying the development of PTE and very little ability to predict who may be at risk. After TBI, a large number of secondary cellular and molecular processes expand the injury. One of the more dramatic processes occurring after TBI is cortical spreading depolarizations (CSDs), also known as brain tsunamis. CSDs are periods of complete silencing of electrical activity that move in a slow wave across the brain surface. We have shown in our clinical studies, that when CSDs occur after TBI, they can be associated with seizures within the first week of hospitalization. However, it is not known whether CSDs contribute to the development of seizures in weeks to months after TBI, and whether CSDs cause pathology that predisposes one to PTE. One of the consequences of CSDs is increased neurogenesis, the generation of adult-born neurons in a specialized area of the brain. Improper regulation of neurogenesis, a process that includes proliferation, maturation, and integration of new neurons into neural circuits, is associated with development of epilepsy. We also know that neuronal cell death in this region of the brain can be associated with seizures. We hypothesize that CSDs serve as a second hit after injury, causing excess neuronal cell death and accumulation of abnormal adult-born neurons, thereby facilitating later development of PTE. We will test whether the combination of TBI+CSDs increases the incidence of seizures 3-6 months after injury. We will evaluate for excess neuronal cell death as a consequence of CSDs in injured brain. Lastly, we will determine if abnormal adult-born neurons contribute to the development of seizures in TBI+CSDs by blocking creation of new neurons for 2 weeks after injury and observing for differences in seizure frequency at 3-6 months. Our team has expertise in both basic science and clinical management of TBI, epilepsy, and CSDs. We have recently demonstrated that in TBI patients we can detect and treat CSDs at bedside. Therefore, success of this project will define CSDs as a pathology that predicts later development of seizures, and our team is poised to translate our findings to the bedside to help prevent development of PTE.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310483
Entities
People
- Laura Ngwenya
Organizations
- United States Army
- University of Cincinnati