A Pre-Clinical Model of TBI Heterogeneity. The majority of traumatic brain injuries are considered mild. Mild TBI (mTBI) is difficult to diagnose, and despite recent progress in public awareness and clinical management, mTBI (or concussion) is a persistent problem in sports, the military, and in the general population. In order to further understand injury mechanisms, identify more sensitive diagnostic tools, and begin to delve into the apparent risk for neurodegeneration, there is a need to improve pre-clinical laboratory studies. This is no easy task given patient heterogeneity and the physiological complexity of TBI. Despite decades of basic research, successful translation of potential treatments from animal to patients is extremely poor. Clinical population heterogeneity is not captured in pre-clinical studies, gravely limiting the ability to validate animal models as reliabl research surrogates. The long-term goal of this research is to improve lab-to-clinic translation using a bi- directional systems approach. The overall goal of this R21 Research Proposal is to reflect the heterogeneity of the mTBI patient population in a pre-clinical animal study and use informatics-based analysis to determine features that contribute to the injury response. The central hypothesis is that systematic institution of animal heterogeneity will result in more reproducible and robust pre- clinical TBI studies and the emergence of clinically relevant risk factors. The experimental aims are: 1) Develop a pre-clinical experimental design for mTBI that selects patient-relevant variables (gender, age, genetic variety, previous mTBI, and chronic stress) and applies them to a heterogeneous rat population using stratified randomization; and, 2) Assess acute neurological response, balance, working memory, and biomarker signature acutely following mTBI using a heterogeneous rat population. Informatics tools will be used in place of traditional multivariate statistics to extract common features of the injury response, classify them, and build predictive knowledge models. Several imbedded hypotheses will be tested to examine the response to mTBI as a function of animal sex, age, strain, previous mTBI, and chronic stress. It is expected that unanticipated relationships among the data will emerge as a result of the robust experimental design and knowledge-based model. The experimental platform presented here is novel and, if successful, can be used as a template for other studies. Addressing patient heterogeneity and clinically relevant acute outcome measures is highly significant and will increase understanding of the complexity of mTBI.
LaPlaca, M.C. The research proposed is highly relevant to public health because of the prevalence of mild traumatic brain injury and the difficulty in accurate diagnosis and clinical management. Both the breadth of injury circumstances and individual patient variables contribute to these difficulties. This research introduces a new experimental and analytical framework for preclinical animal studies in order to better reflect patient variables, leading to more robust preclinical models to better translate findings to humans.
