Determinants of Functional Brain Connectivity After Subarachnoid Hemorrhage

项目总结/摘要 我是一名具有生物化学、生物物理学和分子生物学背景的神经重症监护医师。我寻求 成为一名独立的翻译神经科学家，这样我就可以改善脑损伤幸存者的预后， 动脉瘤破裂拟议的研究和职业发展计划利用了 马萨诸塞州总医院和哈佛医学院的导师团队给了我 获得R 01并实现科学独立所需的额外技能和经验。 脑动脉瘤破裂引起的蛛网膜下腔出血（SAH）是一种改变生活的疾病， 超过30，000名美国人，每年花费56亿美元。即使是结果良好的幸存者， 常见的结果量表遭受持续的认知缺陷，妨碍返回工作。使用fMRI的研究 脑磁图显示，这些认知缺陷与静息状态的改变有关， 状态功能性大脑连接，远程神经网络完整性的指标。然而，一个主要的差距 目前还不清楚蛛网膜下腔出血损伤的大脑如何导致大脑连接的变化。 基于试验数据和已发表的报告，我提出假设，SAH后早期（i）弥漫性神经元 死亡和轴突/髓鞘损伤通过减少神经元的功能，导致整体功能连接的减少。 大脑区域之间的结构连接的数量和（ii）称为扩散去极化的现象 (SD)可能会导致同一半球的局部大脑连接增加（“太多”连接）。 SD通过增加突触可塑性的介质。试点数据表明，这两个过程都可能导致更糟的结果。 行为评估的表现。我将在三个综合目标中检验这一假设。 在目标1中，我将确定SAH单独对功能连接和行为的影响。在目标2中，我将 确定SAH背景下早期复发SD对功能连接和行为的影响。在 目的3，我将研究SAH后功能连接改变的潜在机制， SD。为了实现这些目标，我将使用新的小鼠模型，重建SAH和SD，并允许在 功能性脑连接的体内光学和局部场电位测量。迈出第一步 评估连接改变的原因，我将使用免疫组织化学，分子工具， 和皮质-皮质诱发电位。只要有可能，我将利用创新的非侵入性 方法，例如，在SD的诱导和功能连接的光学测量。 这个建议的最终目的是为我提供必要的经验，以实现科学的 独立，过渡到我自己的实验室，并成为那种可以找到改进方法的调查员 动脉瘤破裂和其他形式急性脑损伤幸存者的神经认知结果。

PROJECT SUMMARY / ABSTRACT I am a practicing neurointensivist with a background in biochemistry, biophysics, and molecular biology. I seek to become an independent translational neuroscientist so that I can improve outcomes in survivors of brain aneurysm rupture. The proposed research and career development plan leverages the expertise of a mentorship team based at Massachusetts General Hospital and Harvard Medical School to give me the additional skills and experience necessary to obtain an R01 and reach scientific independence. Subarachnoid hemorrhage (SAH) from a ruptured brain aneurysm is a life-changing condition which affects more than 30,000 Americans at a cost of $5.6 billion annually. Even survivors with a good outcome on common outcome scales suffer from persistent cognitive deficits precluding return to work. Studies using fMRI and magnetoencephalography suggest that these cognitive deficits are associated with alterations in resting state functional brain connectivity, an indicator of long range neuronal network integrity. However, a major gap in knowledge remains: it is unclear how the SAH-damaged brain leads to changes in brain connectivity. Based on pilot data and published reports, I propose the hypothesis that early after SAH (i) diffuse neuronal death and axonal/ myelin damage lead to a decrease in global functional connectivity by decreasing the number of structural connections between brain regions and (ii) a phenomenon called spreading depolarization (SD) can cause an increase in local brain connectivity (“too much” connectivity) in the same hemisphere of the SD by increasing mediators of synaptic plasticity. Pilot data suggest that both processes can lead to worse performance on behavioral assessments. I will test this hypothesis in 3 integrated aims. In Aim 1, I will determine the effect of SAH alone on functional connectivity and behavior. In Aim 2, I will determine the effect of early recurrent SDs in the setting of SAH on functional connectivity and behavior. In Aim 3, I will investigate potential mechanisms of altered functional connectivity following SAH with or without SDs. To accomplish the aims, I will use novel mouse models which reconstitute SAH and SDs and allow for in vivo optical and local field potential measures of functional brain connectivity. To take the first steps towards assessing causes of altered connectivity, I will use a combination of immunohistochemistry, molecular tools, and cortico-cortical evoked potentials. Whenever possible, I will make use of innovative non-invasive approaches, for example, in the induction of SDs and in optical measurements of functional connectivity. The ultimate goal of this proposal is to provide me with the experience essential to achieve scientific independence, transition to my own lab, and become the kind of investigator who can find ways to improve neurocognitive outcomes in survivors of aneurysm rupture and other forms of acute brain injury.