Tissue Softening in Traumatic Brain Injury

Traumatic brain injury (TBI) is a devastating cause of death and disability. Progression of non-fatal cases of TBI often leaves patients at increased risk for subsequent injury and disease. Improved understanding of the mechanisms of TBI is fundamental to improving strategies for both prevention and treatment. Recent experiments show evidence that the brain softens (i.e., its stiffness is reduced) following TBI. Little is known about the significance or mechanisms of this softening, but it is typically believed to result from edema. Recent data from our team show that overstretch (deformation beyond typical physiological conditions) changes the structure and function of cerebral arteries. These changes include softening, with reductions in stiffness as high as 80% for large, but still sub-rupture, deformations. Given the predictions of finite element (FE) models that cerebral vessels significantly influence the structural response of the brain, it follows that softened blood vessels likely contribute to overall brain softening. It is, of course, also possible that brain tissue itself softens with deformation. Based on these data, our guiding hypothesis is that TBI-induced deformation directly softens the brain and its associated tissues, leading to reduced constraint of brain motion and thus contributing to increased risk of injury in subsequent trauma. We further hypothesize that softening is a direct function of strain and that it correlates with both injury severity and subsequent injury susceptibility. If these hypotheses are true, softening has significant potential as a quantifiable biomarker of both injury severity and subsequent susceptibility. This is particularly notable since softening can be quantified non-invasively, and within specific regions, using magnetic resonance elastography (MRE), with potential to be used in diagnosis, treatment, and definition of recovery status for individual patients. Such data is also expected to be useful for validation of FE TBI models. Additionally, given that vessel softening occurs at deformations well below those that result in hemorrhage, this biomarker could provide novel insight into the mechanics of mild TBI. As a step toward pursuing these hypotheses, the overall objective of this R03 proposal is to obtain preliminary data demonstrating softening in a large animal model of inertial TBI. This will be accomplished through two aims. Aim 1 will characterize TBI in the pig. The pig is commonly utilized as a model of inertial TBI because of its gyrencephalic brain. We have previously utilized this model to study mild, repeated loading and here propose to extend our model to investigate single loading events producing mild to moderate injury. We will characterize the new model by defining the relationship between loading conditions and injury severity, described through both magnetic resonance imaging and histology. Aim 2 will quantify TBI-induced brain tissue softening using MRE. In addition to the imaging protocol mentioned for Aim 1, MRE will be performed before and after TBI to allow determination of brain stiffness. We hypothesize that brain softening will be detectable following mild loading and will increase as a function of injury severity.