Quantitation of Insult and Injury to the Preterm Brain

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DESCRIPTION (provided by applicant): Career development goals: To develop a model training program for mentoring and promoting patient-oriented research focused on injury to the immature brain and its prevention. Research goals: To develop in premature infants at risk for brain injury quantitative functional measures of cerebrovascular impairment and insult, and quantitative structural measures of the response to brain injury. Research project: This project combines two Specific Aims from ongoing research projects with the goal of training young researchers in quantitation of cerebral insult and outcome in neonatal neurology. The project will test two major hypotheses: 1) Transfer function analysis of continuously measured changes in blood pressure and cerebral perfusion (using near infrared spectroscopy; NIRS) will identify significant periods of pressure-passive cerebral perfusion preceding germinal matrix-intraventricular hemorrhage (GM-IVH) in premature infants; and that a multiparametric analysis will identify systemic hemodynamic factors that predispose to unstable cerebral hemodynamics. Time-locked continuous recording of systemic and cerebral hemodynamic changes over the first 5 days (i.e., risk period for GM-IVH) combined with brief 4-hourly truncated cranial ultrasound studies will be used to explore hemodynamic antecedents of GM-IVH. 2) Quantitative MRI measures in ex-preterm infants with either cerebral or cerebellar injury will demonstrate remote regional disturbances in development of projection areas of the contralateral cerebellar or cerebral hemispheres. Using a large existing MRI database and ongoing study recruitment, we will measure regional volumetric brain growth (by parcellated 3D-MRI) in remote projection areas, measure connectivity (diffusion tensor-based fiber tractography) between regions of injury and expected projection areas. Together these goals address a major void in neonatal neurology research, i.e., an inability to identify precise hemodynamic insults leading to injury, here specifically GM-IVH, and a lack of measurable regional structural responses of the immature brain to injury. This proposal seeks to develop these tools, and the specialists in their use, urgently needed for future clinical trials of neuroprotection. The aims of this mentoring award will be met by providing the candidate with the time to develop in trainees an understanding of brain injury mechanisms in the newborn, teaching them the basic skills of patient-oriented research in the newborn, and cultivating the necessary analytic skills for their own independent research and future collaborations in clinical trials of neuroprotection.