TRAUMA TO THE DEVELOPING BRAIN--RESPONSE AND TREATMENT

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DESCRIPTION: (Applicant's Abstract): Traumatic brain injury is the most common cause of death and acquired disability in childhood in the United States. It has long been recognized in the clinical realm that infants and young children exhibit brain injury syndromes which are unique to this age group and are associated with particularly high morbidity and mortality. Because the brain changes dramatically during early development with respect to its mechanical properties, regional metabolism, myelination, vascular supply, neurotransmitter activity, and gene expression, its response to trauma is likely to differ significantly from that seen in adults. Therapies based on the response of the mature brain to injury therefore may be ineffective or even counterproductive in the immature nervous system. The few studies of brain injury in immaturity to date have relied primarily on rodent models, which differ in major morphologic and developmental characteristics from humans. Because of the morphometric and developmental similarities between the piglet and human brain we have developed a focal contusion model which is scaled for use in piglets at ages corresponding to human infants, toddlers, and adolescents. Use of this model will allow for the determination of age-specific differences in the histologic and pathophysiologic response of the brain to this common form of pediatric brain injury, and we hypothesize that vulnerability will be greatest in the youngest ages. These differences also will be visible in vivo using magnetic resonance imaging and spectroscopy in piglets after sealed focal injury, using the latest techniques for characterizing injury response in children. Similar age- dependent vulnerability of the immature brain to damage after trauma will correlate with a) physiologic instability after injury. Finally, because of these interrelated developmental changes including susceptibility to excitotoxic insult, we hypothesize that the neuroprotective efficacy of NMDA receptor antagonists will vary significantly with age. This important information will be useful in the development and testing of head injury therapies appropriate for infants and children.