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.

项目摘要 /摘要 我是一位具有生物化学，生物物理学和分子生物学背景背景的神经激体主义者。我寻找 成为一种独立的翻译神经科学家，以便我可以改善大脑生存的结果 动脉瘤破裂。拟议的研究和职业发展计划利用了 位于马萨诸塞州综合医院和哈佛医学院的Menorship团队给我 获得R01并达到科学独立所需的其他技能和经验。 来自破裂的大脑动脉瘤的蛛网膜下腔出血（SAH）是一种影响生活的疾病，会影响 超过30,000名美国人，每年耗资56亿美元。即使是生存，有很好的结果 持续认知的共同结果量表定义了排除恢复工作的范围。使用fMRI的研究 磁脑摄影表明这些认知定义与静止的改变有关 状态功能大脑连接，这是远距离神经元网络完整性的指标。但是，一个主要差距 在知识中仍然存在：目前尚不清楚SAH受损的大脑如何导致大脑连通性的变化。 根据试点数据和发布的报告，我提出了以下假设：SAH（i）弥漫性神经元之后 死亡和轴突/髓磷脂损伤通过降低而导致全球功能连通性降低 大脑区域之间的结构连接数量和（ii）一种称为扩散沉积的现象 （SD）在同一半球的同一半球中会导致局部大脑连通性的增加（“太多”连接） SD通过增加突触可塑性的介体。飞行员数据表明​​，这两个过程都会导致更糟 行为评估的表现。我将在3个综合目的中检验这一假设。 在AIM 1中，我将确定单独使用SAH对功能连通性和行为的影响。在AIM 2中，我会 确定早期复发性SD在SAH设置中对功能连通性和行为的影响。在 AIM 3，我将调查SAH之后有或没有的潜在功能连接的潜在机制 SDS。为了实现目标，我将使用新颖的鼠标模型来重构SAH和SD，并允许 功能性脑连接性的体内光学和局部现场潜在测量。迈出第一步 评估连通性改变的原因，我将使用免疫组织化学，分子工具的组合， 和皮质皮质诱发潜力。尽可能，我将利用创新的非侵入性 例如，在诱导SD和功能连接性的光学测量中的方法。 该提议的最终目标是为我提供实现科学必不可少的经验 独立，过渡到我自己的实验室，并成为可以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生存的神经认知结果。