We hypothesize that 1) a key pathologic substrate of mild traumatic brain injury (MTBI) is diffuse axonalinjury (DAI), 2) DAI in MTBI can be detected non-invasively, and 3) and the pathophysiology of DAI includesthe dysregulation of voltage gated sodium channels (NaChs) on axons following trauma. In parallel studieswith MTBI patient evaluation performed in Project 1, we will use a pig model of MTBI to determine thesensitivity of non-invasive techniques to elucidate brain pathology, using advanced magnetic resonanceimaging techniques and a panel of surrogate protein markers. We will also evaluate functional outcome afterMTBI in the pig using a new functional assessment paradigm. Importantly, the pig model allows us tocorrelate non-invasive findings with histopathology. The data from the pig can then be extrapolated to thenon-invasive data from MTBI patients in Project 1. To test our hypothesis of posttraumatic axonal NaChdysfunction we will use a stepwise in vitro to in vivo approach. Using an in vitro model of axon stretch injury,we will determine the thresholds of axon trauma that trigger a deleterious feed-forward pathway of NaChdysfunction, including acute calcium influx and NaCh proteolysis followed by hyperexpression of NaChs onaxons. These efforts will be supported by in vitro studies in Project 3 examining the micromechanics ofaxonal trauma and mechanisms of proteolysis. We will examine the potential clinical relevance offeed-forward pathway of NaCh dysregulation using the pig MTBI model. In particular, we will evaluate acuteregional changes in axonal NaChs linked with immediate loss of consciousness and axon degeneration. Wewill also examine potential hyperexpression of NaChs on white matter axons in relation to long-term axondegeneration. Success of the proposed project could lead to new diagnostic criteria to identify thepathologies and mechanisms in MTBI and provide targets for new therapeutic interventions.
| Chen, H Isaac; Wolf, John A; Smith, Douglas H (2017) Multichannel activity propagation across an engineered axon network. J Neural Eng 14:026016 |
| Smith, Douglas H; Stewart, William (2016) Tackling concussion, beyond Hollywood. Lancet Neurol 15:662-663 |
| Stewart, William; Smith, Douglas H (2016) Time to be blunt about blast traumatic brain injury. Lancet Neurol 15:896-898 |
| Wilde, Elisabeth A; Hunter, Jill V; Li, Xiaoqi et al. (2016) Chronic Effects of Boxing: Diffusion Tensor Imaging and Cognitive Findings. J Neurotrauma 33:672-80 |
| Ali, Zarina S; Johnson, Victoria E; Stewart, William et al. (2016) Neuropathological Characteristics of Brachial Plexus Avulsion Injury With and Without Concomitant Spinal Cord Injury. J Neuropathol Exp Neurol 75:69-85 |
| Hay, Jennifer; Johnson, Victoria E; Smith, Douglas H et al. (2016) Chronic Traumatic Encephalopathy: The Neuropathological Legacy of Traumatic Brain Injury. Annu Rev Pathol 11:21-45 |
| Johnson, Victoria E; Stewart, William; Weber, Maura T et al. (2016) SNTF immunostaining reveals previously undetected axonal pathology in traumatic brain injury. Acta Neuropathol 131:115-35 |
| Rabinowitz, Amanda R; Li, Xiaoqi; McCauley, Stephen R et al. (2015) Prevalence and Predictors of Poor Recovery from Mild Traumatic Brain Injury. J Neurotrauma 32:1488-96 |
| Levin, Harvey S; Diaz-Arrastia, Ramon R (2015) Diagnosis, prognosis, and clinical management of mild traumatic brain injury. Lancet Neurol 14:506-17 |
| Patel, Tapan P; Man, Karen; Firestein, Bonnie L et al. (2015) Automated quantification of neuronal networks and single-cell calcium dynamics using calcium imaging. J Neurosci Methods 243:26-38 |
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