The Role of Preinjury Stress in Development of Post-Traumatic Epilepsy
Abstract
Post-traumatic epilepsy (PTE) with spontaneous and re-occurring epileptic seizures is a major outcome of severe trauma to the brain, such as that produced by explosions or direct impacts to the head. For this reason, PTE is of critical interest to the Department of Defense since these kinds of head injuries are quite common in the battlefield. The problem of PTE is particularly important because at present we have little understanding of the biological reasons why it develops after an injury, and for this reason we do not know how to prevent it. In the same vein, in contrast to most other forms of human epilepsy, PTE is particularly difficult to treat either with drugs or with brain surgery. As with all human diseases, progress on understanding biological mechanisms, and thus methods for prevention and/or treatment, depend in large part on the development of realistic animal models of the disease process and its manifestations. In terms of PTE, specifically, there is a pressing need for rodent models that realistically mimic the initial head trauma, and the electrical and behavioral features of the seizures themselves, which ultimately define PTE in humans. Over the past 15 years, there has been substantial progress in the development of rat models of PTE using fluid percussion injury (FPI; where a column of water is briefly driven against the exposed brain under manual or computer control) and controlled cortical impact (CCI; where a solenoid is driven against the exposed brain); injuries that mimic closed head injury in humans, which is a common form of injury on the battlefield due to impacts and/or explosive devices. While this has been shown to eventually result in convulsive seizures of PTE, there are two problems with the model that have impeded progress in PTE research. The first is that the success rate can be quite low (13%) and the delay from injury to convulsive seizures quite high (6-12 months). Very many rats would need to be run over long periods of time to investigate even a single prevention strategy. These problems appeared to be solved by D’Ambrosio and colleagues 15 years ago with the discovery of non-convulsive electrographic epileptiform events (EEE) recordable in the brainwaves of rats within weeks (instead of months) of injury, occurring many times per day (as opposed to convulsive seizures, which only occur on a monthly basis) and with a 100% success rate. These brief (seconds) EEEs were interpreted as non-convulsive seizures and have received substantial attention and funding for the investigation of PTE prevention. However, since 2015, and through a series of six published papers, Barth and Dudek (the two Principal Investigators on the present Research Partnership proposal) have demonstrated that EEEs exactly like those described by D’Ambrosio are actually not seizures but normal brain waves in the rat and therefore not a model of PTE. While this work has set the field of PTE research back on track, it has also left us with a pressing need to develop realistic rat models – with actual seizures – that may be used for anti-PTE drug discovery and intervention strategies. Yet, when we restricted PTE research to bonafide seizures (instead of EEEs), we found very little epilepsy in the two leading models of PTE. This was until we tried preceding brain injury with severe psychological stress (approximating that encountered in the battlefield). To our surprise, before-injury stress appeared to have a substantial facilitating influence on the development of epilepsy. Over half of our animals developed PTE within several months after injury. The objective of this proposal is to leverage our established collaborative team to verify these promising results in FPI and CCI models by conducting coordinated parallel experiments in both laboratories (Barth and Dudek). We hope by the end of this project to have finally developed a thoroughly cross-validated and efficient rat model of PTE that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210366
Entities
People
- Daniel S Barth
Organizations
- United States Army
- University of Colorado Boulder