Abstract
Pre-clinical models of traumatic brain injury (TBI) have been the primary experimental tool for understanding the potential mechanisms and cellular alterations that follow brain injury, but the human relevance and translational value of these models are often called into question. Efforts to better recapitulate injury biomechanics and the use of non-rodent species with neuroanatomical similarities to humans may address these concerns and promise to advance experimental studies toward clinical impact. In addition to improving translational aspects of animal models, it is also advantageous to establish pre-clinical outcomes that can be directly compared with the same outcomes in humans. Non-invasive imaging and particularly MRI is promising for this purpose given that MRI is a primary tool for clinical diagnosis and at the same time increasingly available at the pre-clinical level. The objective of this study was to identify which commonly used radiologic markers of TBI outcomes can be found also in a translationally relevant pre-clinical model of TBI. The ferret was selected as a human relevant species for this study with folded cortical geometry and relatively high white matter content and the closed head injury model of engineered rotation and acceleration (CHIMERA) TBI model was selected for biomechanical similarities to human injury. A comprehensive battery of MRI protocols based on common data elements (CDEs) for human TBI was collected longitudinally for the identification of MRI markers and voxelwise analysis of T2, contrast enhancement and diffusion tensor MRI values. The most prominent MRI findings were consistent with focal hemorrhage and edema in the brain stem region following high severity injury as well as vascular and meningeal injury evident by contrast enhancement. While conventional MRI outcomes were not highly conspicuous in less severe cases, quantitative voxelwise analysis indicated diffusivity and anisotropy alterations in the acute and chronic periods after TBI. The main conclusions of this study support the translational relevance of closed head TBI models in intermediate species and identify brain stem and meningeal vulnerability. Additionally, the MRI findings highlight a subset of CDEs with promise to bridge pre-clinical studies with human TBI outcomes.
Highlights
Advancement in scientific knowledge and therapeutics for neurologic disorders is largely based on pre-clinical studies at the animal model level
A comprehensive in vivo ferret MRI battery was established and applied in this study by adapting the human common data elements (CDEs) MRI protocols and when possible quantitative maps were generated from the scans to enable voxelwise analysis
We evaluated both a promising ferret model of closed head rotation/acceleration injury and MRI markers based on current clinical protocols
Summary
Advancement in scientific knowledge and therapeutics for neurologic disorders is largely based on pre-clinical studies at the animal model level. At the center of these gaps is the challenge of faithfully recapitulating in a pre-clinical paradigm the same pathomechanisms that occur in humans. If this cannot be accomplished, basic TBI research and therapeutic development is hindered or even misleading and so there is a need both to develop human-similar TBI models and to evaluate the translational relevance of experimental outcomes across these models. While focal, penetrating models remain fundamental tools for TBI research there has been considerable progress toward developing models based on biomechanical aspects of prevalent or population-specific human TBI, especially concussions and blast exposure
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