Modeling the Impact of Trauma Experience upon Post-Traumatic Outcomes and Epilepsy
Abstract
Epilepsy frequently develops after traumatic brain injury (TBI). Post-traumatic epilepsy (PTE) often poorly responds to anti-seizure medications and worsens the course of other chronic consequences of TBI, such as post-traumatic depression. Overall, PTE has highly detrimental effects on the person’s quality of life. Having good animal models of PTE is essential for making a tangible progress in understanding mechanisms and developing effective treatments of this debilitating disease. Ideally, a good animal model of PTE should closely reproduce conditions and experiences that are present in the immediate run-up to, during, and shortly after TBI, as it has been shown that these elements play an important role in the developing of PTE, and are also important for its early diagnosis. For example, the lengthy loss of consciousness and the presence of seizures immediately after TBI are regarded as strong risk factors for PTE. Furthermore, the presence of specific contextual elements at the time of TBI (e.g., sounds, light, and microenvironment) often triggers episodes of post-traumatic stress disorder (PTSD) if the person is exposed to these elements even years after trauma, and PTSD, while being harmful on its own, is also known to promote PTE. There is also an ethical consideration, whereby the experimental TBI should not induce excessive mortality in experimental animals. Presently, most of paradigms that are used to model PTE involve the introduction of TBI when the animal is anesthetized and unconscious. Anesthesia is used as a matter of technical convenience and/or as a misguided attempt to reduce animal’s suffering during trauma. As a result, the used paradigms are (a) lacking critical elements immediately surrounding trauma, such as the awareness of the conditions in the run-up to TBI; (b) cannot be used to adequately analyze such features of TBI as the loss of consciousness and seizures as early diagnostic factors of PTE, as they are masked by anesthesia; and (c) by modifying immediate clinical characteristics of TBI (as mentioned under b), distort natural history of PTE, thus complicating proper mechanistic and experimental treatment studies. Further, contrary to expectations, the introduction of anesthesia raises significant ethical concerns as it increases mortality and suffering (e.g., arrested breathing, hypoxia, and delayed motor recovery) beyond those that are induced by TBI itself. Here, we propose to develop and to optimize a novel model of PTE, which would take into the account the complexity of factors and conditions surrounding TBI. TBI will be induced in awake, conscious animals, and in the presence of well-defined memorable cues, which will include a combination of specific sound, light, and microenvironment. During a remote period (up to 9 months after TBI), the cues will be presented again, and this is expected to facilitate the development of PTE. We will characterize in details a natural evolution of PTE, starting from the trauma episode, its immediate outcomes (loss of consciousness, seizures, physiological parameters), and chronic epilepsy. We expect that the proposed paradigm will create a better model of PTE in terms of predictability, reproducibility, and lower mortality. This model will offer a new refined platform for studying mechanisms of PTE, developing its early diagnosis and treatments. Having such a platform should facilitate the development of novel PTE treatments and thus will serve to improving the quality of life of those TBI patients who suffer from PTE.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210510
Entities
People
- Aristea S Galanopoulou
Organizations
- Albert Einstein College of Medicine
- United States Army