Determinants of functional brain connectivity after subarachnoid hemorrhage

项目摘要/摘要 我是一名神经强化医师，有生物化学、生物物理学和分子生物学的背景。我在寻找 成为一名独立的翻译神经学家，这样我就可以改善脑部幸存者的结果 动脉瘤破裂。拟议的研究和职业发展计划利用了 马萨诸塞州综合医院和哈佛医学院的导师团队为我提供 获得R01学位和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，它影响 超过3万美国人，每年花费56亿美元。即使是有好结果的幸存者 常见的结果量表长期存在认知缺陷，无法重返工作岗位。使用功能磁共振成像进行研究 脑磁图显示，这些认知缺陷与休息时间的改变有关。 状态功能大脑连通性，这是远程神经元网络完整性的指标。然而，一个主要的差距是 在知识方面：尚不清楚SAH受损的大脑是如何导致大脑连接发生变化的。 根据试验数据和已发表的报告，我提出了SAH(I)后早期弥漫性神经元的假设 死亡和轴突/髓鞘损伤通过减少 脑区之间的结构连接的数量和(Ii)一种称为扩散性去极化的现象 (SD)可导致同侧大脑局部连通性(“过多”连通性)增加。 SD通过增加突触可塑性的介体来实现。试点数据表明，这两个过程都可能导致更糟糕的情况 在行为评估方面的表现。我将在三个综合目标中检验这一假设。 在目标1中，我将单独确定SAH对功能连接性和行为的影响。在《目标2》中，我会 确定SAH早期复发抑郁对功能连通性和行为的影响。在……里面 目标3，我将研究蛛网膜下腔出血后功能连接性改变的潜在机制 十二烷基硫酸钠。为了实现这些目标，我将使用重建SAH和SDS的新型小鼠模型，并考虑到 功能脑连接的活体光学和局部场电位测量。向…迈出第一步 评估连接性改变的原因，我将结合使用免疫组织化学、分子工具、 和皮质诱发电位。只要有可能，我就会利用创新的非侵入性 例如，在十二烷基硫酸钠的诱导和功能连接性的光学测量中。 这项建议的最终目标是为我提供必要的经验，以实现科学 独立，过渡到我自己的实验室，成为那种能够找到改进方法的调查员 动脉瘤破裂和其他形式的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.