Traumatic brain injury is the leading cause of death and disability in childhood. While many treatments are effective at limiting damage in animal models, more than 20 large multicenter clinical trials have failed to show conclusive treatment efficacy in human head injury. Analyses of this discrepancy have suggested that models and trials need to take into account more variables such as acute injury conditions, age, and gender effects. The problem is compounded in pediatric head injury, with only a few animal models and even fewer clinical trials. Most research on traumatic brain injury utilizes rodents, which have major limitations in modeling the immature human brain. For several years our laboratory has been utilizing a model of scaled focal brain injury in piglets, a species which closely parallels the brain morphology and development of human infants and children. This model precisely scales the biomechanical injury input for growth of the brain, enabling us to study injury at maturational stages comparable to human infants, """"""""toddlers"""""""", and adolescents. We have discovered significant age effects in both acute and chronic injury responses which are relevant to designing age-appropriate treatments. Swine are genetically and anatomically more heterogeneous than rodents, and before moving to treatment trials, acute predictors of outcome are necessary for treatment stratification. Age-dependent repair processes and functional outcomes also must be quantified so that treatment effects and toxicities during immaturity can be measured. In this proposal, we seek to: A) Quantify the degree to which acute variables including ischemia, seizures, and gender contribute to differences in injury severity seen among subjects at each age; B) Determine the extent to which serum injury markers (S100B and neuron-specific enolase) serve as surrogate markers of injury severity after scaled cortical impact and rotational inertial injury in the developing piglet; C) Measure age-dependent differences in functional recovery of the piglet somatosensory cortex using serial functional magnetic resonance imaging and somatosensory evoked potentials. The overall goal of this research is to use these data to develop a stratified treatment trial design for use in this scaled immature gyrencephalic brain injury model which takes these important age differences in injury response into account. We believe this approach will help """"""""bridge the gap"""""""" between rodent models and effective treatment for the many thousands of children who suffer traumatic brain injury each year.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD045364-01A1
Application #
6826017
Study Section
Special Emphasis Panel (ZRG1-DBD (01))
Program Officer
Nicholson, Carol E
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2004-07-01
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$358,650
Indirect Cost
Name
Dartmouth College
Department
Surgery
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Costine, Beth A; Missios, Symeon; Taylor, Sabrina R et al. (2015) The subventricular zone in the immature piglet brain: anatomy and exodus of neuroblasts into white matter after traumatic brain injury. Dev Neurosci 37:115-30
Costine, Beth A; Quebeda-Clerkin, Patricia B; Dodge, Carter P et al. (2012) Neuron-specific enolase, but not S100B or myelin basic protein, increases in peripheral blood corresponding to lesion volume after cortical impact in piglets. J Neurotrauma 29:2689-95
Missios, Symeon; Harris, Brent T; Dodge, Carter P et al. (2009) Scaled cortical impact in immature swine: effect of age and gender on lesion volume. J Neurotrauma 26:1943-51
Saatman, Kathryn E; Duhaime, Ann-Christine; Bullock, Ross et al. (2008) Classification of traumatic brain injury for targeted therapies. J Neurotrauma 25:719-38
Duhaime, Ann-Christine; Saykin, Andrew J; McDonald, Brenna C et al. (2006) Functional magnetic resonance imaging of the primary somatosensory cortex in piglets. J Neurosurg 104:259-64