Epileptogenic Network Mechanisms Following Focal Traumatic Brain Injury in a Large Animal Model
Abstract
PTE Mechanisms/Treatment Development from a Large Animal Model: Military traumatic brain injury (TBI) is a mixture of different injuries to the brain, often involving both focal (contusion) and diffuse components. The high rate of post-traumatic epilepsy (PTE) following TBI is well-established. However, the degree to which aspects of TBI leads to alterations in brain activity that ultimately results in PTE is unknown, as is the mechanism of this transition. In order to address these problems, a preclinical model of PTE must accurately reproduce the mechanical as well as biological aspects of the brain injury. Since it is known that injury to the connections between neurons, or white matter, is a key and often overlooked aspect of most brain injury, we are convinced that a large animal model (pig) may be the only way to investigate the contributions of these components of TBI to the development of epilepsy. Rat and mouse models do not have enough white matter or folds in the brain (gyri), to accurately reproduce aspects of many types of TBI. This may be one of the reasons it is hard to translate treatments developed in rodents to humans. In comparison to rodent models, the pig brain has adequate white matter pathways and a shape and mass much closer to that of the human brain. In order to understand how and when PTE develops and how to treat or prevent it, we must first understand what happens in the brain between the traumatic insult and the development of seizures. We have recently discovered that the hippocampus, a structure in the brain often associated with epilepsy, is abnormally excitable after traumatic injury in our pig model of TBI, displaying characteristic activity that is sometimes seen in human patients who develop epilepsy. This is likely due to injury to the white matter (as distinct from loss of brain tissue, for example). Our findings suggest that damage to the pathways into the hippocampus can alter its circuitry, which may predispose it to developing seizures. We hypothesize that trauma to the white matter may lead to the loss of inputs into the neurons that they support, leading to a loss of connectivity. We hypothesize that over time this loss of input leads to a compensatory mechanism, whereby these regions acquire a stronger response to input, leading to abnormal patterns of activity that can then lead to epilepsy. We also believe that breakdown in the blood-brain barrier as well as inflammation in the white matter may contribute to this process. We have already demonstrated that a single focal contusion (bruise) to the brain can lead to epileptic activity in the cortex using this model, but the mechanisms of this change are unclear, and further experiments are required to understand the circuitry changes. In addition, we need to know initially how many (what percentage) of pigs develop epilepsy following this injury in order to start developing treatment strategies using this platform. Biomarkers for PTE: As well as helping to define mechanisms, certain aspects of a TBI can help to determine whether new TBI patients will go on to develop PTE or not. These “biomarkers” can be utilized to predict whether or not patients will get PTE as well as helping to guide treatment options. These markers can also be affected by treatment and can be utilized to predict whether a certain treatment is working. It is unknown at this time which biomarkers will predict PTE development, but we will be testing a number of candidates in the pig model, including blood biomarkers, brain imaging, and early EEG [electroencephalogram] signals that were collected immediately after injury. After validation, this new model will serve as a platform for future treatment targets and therapy development. The strength of our proposal is the unique combination of large animal TBI, pathology, electrophysiology, and biomarkers that will allow us to address fundamental questions of how PTE develops. Our proposal
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010901
Entities
People
- John A Wolf
Organizations
- United States Army
- University of Pennsylvania