Quantitation of Insult and Injury to the Preterm Brain

职业发展目标：开发一个模型培训计划，用于指导和促进以患者为导向的研究，重点是对未成熟大脑的损伤及其预防。研究目标：在有脑损伤风险的早产儿中开发脑血管损伤和损伤的定量功能测量，以及脑损伤反应的定量结构测量。研究项目：该项目结合了正在进行的研究项目的两个具体目标，其目标是培训年轻研究人员在新生儿神经病学中定量脑损伤和结果。该项目将测试两个主要假设：1）连续测量血压和脑灌注变化的传递函数分析（使用近红外光谱; NIRS）将确定早产儿脑出血前的压力被动脑灌注的重要时期;多参数分析将确定易导致脑血流动力学不稳定的全身血流动力学因素。在前5天（即，GM-IVH的风险期）结合简短的4小时截短颅骨超声研究将用于探索GM-IVH的血流动力学前因。2)定量磁共振成像测量的前早产儿无论是大脑或小脑损伤将证明远程区域干扰的发展对侧小脑或大脑半球的投影区。使用现有的大型MRI数据库和正在进行的研究招募，我们将测量远程投影区域的局部体积脑生长（通过包裹的3D-MRI），测量损伤区域和预期投影区域之间的连通性（基于扩散张量的纤维束成像）。这些目标共同解决了新生儿神经学研究中的一个主要空白，即，无法识别导致损伤的精确血流动力学损伤，这里特别是GM-IVH，并且缺乏未成熟大脑对损伤的可测量的区域结构反应。该提案旨在开发这些工具，以及未来神经保护临床试验迫切需要的专家。该指导奖的目的将通过为候选人提供时间来培养学员对新生儿脑损伤机制的理解，教授他们新生儿以患者为导向的研究的基本技能，并培养必要的分析技能，以便他们自己独立研究和未来在神经保护临床试验中的合作。

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.