Quantitation of Insult and Injury to the Preterm Brain

职业发展目标：建立一个模范培训项目，指导和促进以患者为导向的研究，重点关注未成熟大脑的损伤及其预防。研究目的：建立脑损伤高危早产儿脑血管损伤和损伤的定量功能测量和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，目标是培训年轻研究人员量化新生儿神经病学的脑损伤和结果。该项目将测试两个主要假设：1)对连续测量的血压和脑灌注变化的传递函数分析（使用近红外光谱；NIRS）将确定早产儿在生发基质-脑室内出血（gmivh）之前的压力被动脑灌注的重要时期；多参数分析将识别出易导致脑血流动力学不稳定的全身血流动力学因素。前5天（即GM-IVH的危险期）的系统和脑血流动力学变化的时间锁定连续记录，结合简短的4小时截断颅超声检查，将用于探索GM-IVH的血流动力学前因。2)对脑或小脑损伤的早产儿进行定量MRI检查，可发现对侧小脑或大脑半球投射区发育出现远端区域性障碍。利用现有的大型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区域体积脑生长（通过分割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图）。总之，这些目标解决了新生儿神经学研究中的一个主要空白，即无法确定导致损伤的精确血流动力学损伤，特别是GM-IVH，以及缺乏可测量的未成熟大脑对损伤的区域结构反应。本提案旨在开发这些工具，以及使用这些工具的专家，这是未来神经保护临床试验迫切需要的。该指导奖的目的是通过为候选人提供时间来发展对新生儿脑损伤机制的理解，教他们以患者为导向的新生儿研究的基本技能，培养他们自己独立研究和未来在神经保护临床试验中的合作所必需的分析技能。

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.