Traumatic brain injury is the most common cause of death in childhood, yet etiology and treatment of pediatric head injuries remain controversial. Previously, we established an interdisciplinary research paradigm using acute animal experiments, biomechanical tissue tests, retrospective clinical studies, anthropomorphic """"""""doll"""""""" studies, and computational simulations. Our data show that children do indeed have injury mechanisms that are distinct from the adult, and require age-specific injury prevention strategies and treatments. In this competitive renewal, we build on the foundation we have established, both to deepen our understanding of basic injury mechanisms and to enhance the clinical relevance of our findings. We will supplement our current platforms with novel preparations - survival studies, porcine behavioral outcomes, cerebral blood flow (CBF) measures, post-injury respiratory insufficiency, and injury treatment studies - to enhance translation of research findings from the laboratory to the clinical setting. Our overall hypothesis is that rapid rotations of the immature brain without impact produce brain injury via both mechanical and biochemical signals, resulting in sustained functional and histological abnormalities. We will compare long-term outcomes after single and multiple head injuries to determine if injury interval modulates injury severity and if axonal injury is reduced with folate supplementation (Aim 1). We will use human computational models to extend our animal studies to cyclic shaking motions to estimate contribution of harmonic amplification to injury risk (Aim 2). Using animal experiments and computer models, we will identify cerebral strains associated with rapid regional decreases in CBF and brainstem deformations associated with loss of cerebral autoregulation (Aim 3). We will modulate regional deformations by altering rotation direction, and endothelial response with hypertonic saline to validate acute mechanical and biochemical signaling pathways. In piglets with respiratory insufficiency after head injury (Aim 4), we hypothesize that resuscitation with 100% FiO2 results in exacerbated neuropathology mediated by free radical release, and we will compare outcomes with room air and 100% FiO2, as well as with and without free radical scavengers to verify functionality. The proposed studies address our long-term goal of elucidating injury mechanisms and potential treatment strategies for traumatic brain injuries in children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039679-08
Application #
7616081
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Hicks, Ramona R
Project Start
1999-12-01
Project End
2012-04-30
Budget Start
2009-05-01
Budget End
2010-04-30
Support Year
8
Fiscal Year
2009
Total Cost
$385,792
Indirect Cost
Name
University of Pennsylvania
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Atlan, Lorre S; Smith, Colin; Margulies, Susan S (2018) Improved prediction of direction-dependent, acute axonal injury in piglets. J Neurosci Res 96:536-544
Pasquesi, Stephanie A; Margulies, Susan S (2017) Failure and Fatigue Properties of Immature Human and Porcine Parasagittal Bridging Veins. Ann Biomed Eng 45:1877-1889
Ferguson, Michael A; Sutton, Robert M; Karlsson, Michael et al. (2016) Increased platelet mitochondrial respiration after cardiac arrest and resuscitation as a potential peripheral biosignature of cerebral bioenergetic dysfunction. J Bioenerg Biomembr 48:269-79
Maltese, Matthew R; Margulies, Susan S (2016) Biofidelic white matter heterogeneity decreases computational model predictions of white matter strains during rapid head rotations. Comput Methods Biomech Biomed Engin 19:1618-29
Olson, Emily; Badder, Carlie; Sullivan, Sarah et al. (2016) Alterations in Daytime and Nighttime Activity in Piglets after Focal and Diffuse Brain Injury. J Neurotrauma 33:734-40
Sullivan, Sarah; Coats, Brittany; Margulies, Susan S (2015) Biofidelic neck influences head kinematics of parietal and occipital impacts following short falls in infants. Accid Anal Prev 82:143-53
Jaber, Samer M; Sullivan, Sarah; Margulies, Susan S (2015) Noninvasive metrics for identification of brain injury deficits in piglets. Dev Neuropsychol 40:34-9
Clevenger, Amy C; Kilbaugh, Todd; Margulies, Susan S (2015) Carotid artery blood flow decreases after rapid head rotation in piglets. J Neurotrauma 32:120-6
Sullivan, Sarah; Eucker, Stephanie A; Gabrieli, David et al. (2015) White matter tract-oriented deformation predicts traumatic axonal brain injury and reveals rotational direction-specific vulnerabilities. Biomech Model Mechanobiol 14:877-96
Friess, Stuart H; Bruins, Benjamin; Kilbaugh, Todd J et al. (2015) Differing effects when using phenylephrine and norepinephrine to augment cerebral blood flow after traumatic brain injury in the immature brain. J Neurotrauma 32:237-43

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