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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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NST-2 Subcommittee (NST)
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Hicks, Ramona R
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Children's Hospital Boston
United States
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Tarui, Tomo; Limperopoulos, Catherine; Sullivan, Nancy R et al. (2014) Long-term developmental outcome of children with a fetal diagnosis of isolated inferior vermian hypoplasia. Arch Dis Child Fetal Neonatal Ed 99:F54-8
Limperopoulos, Catherine; Chilingaryan, Gevorg; Sullivan, Nancy et al. (2014) Injury to the premature cerebellum: outcome is related to remote cortical development. Cereb Cortex 24:728-36
Ranger, Manon; Celeste Johnston, C; Rennick, Janet E et al. (2013) A Multidimensional Approach to Pain Assessment in Critically Ill Infants During a Painful Procedure. Clin J Pain 29:613-620
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Clouchoux, Cedric; Guizard, Nicolas; Evans, Alan Charles et al. (2012) Normative fetal brain growth by quantitative in vivo magnetic resonance imaging. Am J Obstet Gynecol 206:173.e1-8
Heldt, Thomas; Kashif, Faisal M; Sulemanji, Mustafa et al. (2012) Continuous quantitative monitoring of cerebral oxygen metabolism in neonates by ventilator-gated analysis of NIRS recordings. Acta Neurochir Suppl 114:177-80
Bolduc, Marie-Eve; du Plessis, Adre J; Sullivan, Nancy et al. (2012) Regional cerebellar volumes predict functional outcome in children with cerebellar malformations. Cerebellum 11:531-42
Bolduc, Marie-Eve; Du Plessis, Adre J; Evans, Alan et al. (2011) Cerebellar malformations alter regional cerebral development. Dev Med Child Neurol 53:1128-34
Bolduc, Marie-Eve; Du Plessis, Adre J; Sullivan, Nancy et al. (2011) Spectrum of neurodevelopmental disabilities in children with cerebellar malformations. Dev Med Child Neurol 53:409-16
Limperopoulos, Catherine; Chilingaryan, Gevorg; Guizard, Nicolas et al. (2010) Cerebellar injury in the premature infant is associated with impaired growth of specific cerebral regions. Pediatr Res 68:145-50

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