Determinants of functional brain connectivity after subarachnoid hemorrhage

蛛网膜下腔出血后大脑功能连接的决定因素

• 批准号: 10009482
• 负责人: David Young Chung
• 金额: $ 20.09万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10009482
• 关键词: Acute Brain Injuries; Affect; American; Aneurysmal Subarachnoid Hemorrhages; Animal Model; Axon; Behavior; Behavior assessment; Biochemistry; Biophysics; Blood flow; Brain; Brain Aneurysms; Brain Injuries; Brain region; Brain-Derived Neurotrophic Factor; Calcium; Cell Death; Cells; Climacteric; Cognitive deficits; Data; Development Plans; Diffuse; Evoked Potentials; Functional Magnetic Resonance Imaging; General Hospitals; Goals; Human; Image; Immunohistochemistry; Individual; Injury; Ischemia; Knowledge; Lead; Light; Lighting; Longitudinal Studies; Magnetoencephalography; Massachusetts; Measurement; Measures; Mediator of activation protein; Mentorship; Methods; Molecular; Molecular Biology; Mus; Myelin; Neurocognitive; Neurocognitive Deficit; Neurons; Optics; Outcome; Patient-Focused Outcomes; Patients; Performance; Process; Publishing; Recurrence; Reporting; Research Personnel; Rest; Role; Rupture; Ruptured Aneurysm; Side; Signal Transduction; Structure; Subarachnoid Hemorrhage; Survivors; Synaptic plasticity; Testing; Time; Training; Transgenic Organisms; Translating; Work; base; behavioral outcome; career; career development; cell injury; cognitive testing; cost; cranium; experience; field study; fluorophore; hemodynamics; hippocampal pyramidal neuron; imaging modality; improved; improved outcome; in vivo; innovation; insight; medical schools; morris water maze; mouse model; multimodality; neuron loss; novel; novel therapeutics; object recognition; optogenetics; patient population; prevent; reconstitution; research and development; skills; time use; tool

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.

项目概要/摘要 我是一名执业神经重症医师，具有生物化学、生物物理学和分子生物学背景。 成为一名独立的转化神经科学家，这样我就可以改善大脑幸存者的结果 拟议的研究和职业发展计划利用了动脉瘤破裂的专业知识。 马萨诸塞州总医院和哈佛医学院的导师团队为我提供了 获得 R01 并达到科学独立性所需的额外技能和经验。 脑动脉瘤破裂导致的蛛网膜下腔出血 (SAH) 是一种改变生活的疾病，影响 超过 30,000 名美国人每年损失 56 亿美元，即使幸存者的结局良好。 常见结果量表患有持续性认知缺陷，无法重返工作岗位。 脑磁图表明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，是远程神经网络完整性的指标。然而，这是一个重大差距。 知识仍然存在：尚不清楚 SAH 受损的大脑如何导致大脑连接的变化。 根据试点数据和已发表的报告，我提出以下假设：SAH 后早期 (i) 弥漫性神经 死亡和轴突/髓磷脂损伤通过减少 大脑区域之间的结构连接数量以及（ii）一种称为扩散去极化的现象 （SD）会导致大脑同一半球的局部大脑连接性增加（“太多”连接性） 通过增加突触可塑性的介质来实现 SD。 试验数据表明，这两个过程都会导致更糟的情况。 我将在 3 个综合目标中测试这个假设。 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 对功能连接和行为的影响。 确定 SAH 背景下早期复发性 SD 对功能连接和行为的影响。 目标 3，我将研究有或没有 SAH 后功能连接改变的潜在机制 为了实现这些目标，我将使用新的小鼠模型来重建 SAH 和 SD，并允许在 功能性大脑连接的体内光学和局部场电位测量迈出了第一步。 评估连接改变的原因，我将结合使用免疫组织化学、分子工具、 只要有可能，我都会利用创新的非侵入性方法。 例如，SD 的感应和功能连接的光学测量。 该提案的最终目标是为我提供实现科学目标所必需的经验 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研究者 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。