Major Reassessment of the Fluid Percussion and Controlled Cortical Impact Models of Posttraumatic 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, the biological changes in the brain between initial injury and the appearance of seizures, 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, an injury that mimics closed head injury in humans. 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 (many 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 a decade ago with the discovery of non-convulsive "electrographic epileptiform events" (EEEs) 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, we have recently published compelling evidence that EEEs exactly like those described by D Ambrosio occur equally in both FPI-injured and uninjured rats and are identical in every way (duration, frequency, wave shape) to "spike-wave discharge" (SWD) commonly recorded in a variety of species of laboratory rats by us and numerous other laboratories. We concluded that EEE are normal brain activity in the rat and are not post-traumatic seizures. Preventative strategies that affect EEEs cannot be expected to affect PTE. While this is a critical finding, it also represents a major setback to PTE research since it removes what would have been a highly efficient model for drug discovery and preventative treatments. The present project has three major aims: (1) to conclusively demonstrate in both the FPI model and a controlled cortical impact model of traumatic brain injury that EEEs do not reflect PTE, (2) to demonstrate that subtle but clearly epileptic non-convulsive seizures we have uncovered using computer-based methods of pattern recognition in other rat models of acquired (as opposed to genetic) epilepsy also occur early after brain trauma with a much higher success rate than convulsive seizures and may replace EEEs as an efficient but valid measure PTE, and (3) to adapt a neurological severity score introduced by our colleague Dr. David Poulsen as a means of predicting early on which rats are likely to develop PTE and thus prescreen rats de
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610636
Entities
People
- Daniel S Barth
Organizations
- United States Army
- University of Colorado Boulder