Neuroinflammation and Executive Function in Bipolar Disorder: A PET-fMRI Study

患有双相情感障碍(BD)的人在执行功能方面有严重和持续的困难，如 作为抑制性对照。BD的抑制性控制困难可能通过其对大脑的影响而与炎症有关 功能正常。然而，直接测量脑部炎症标志物(即神经胶质细胞的激活)在BD中是有限的。 还需要进一步了解胶质细胞激活是如何在BD的抑制性脑功能障碍中起作用的。这个 这项建议的目的是研究抑制控制的神经炎性基础，并确定新的神经免疫 情绪障碍的执行功能障碍的治疗目标。为此，候选人提出：(1)培训 目的建立将同步PET-MRI作为研究工具的专业知识，作为一种跨学科的研究工具 心理神经免疫学的知识基础，以及完全独立于功能磁共振成像方法学，这两者将一起 进一步发展成为双相情感障碍的临床翻译专家；(2)研究 目的探讨神经胶质细胞激活在抑制控制脑功能障碍和认知功能中的作用。 在BD中的表现；(3)确保应聘者成功的导师和顾问团队，具有以下专业知识 双相情感障碍(安德鲁·尼伦伯格博士)，多模式精神神经成像(达林·多尔蒂博士)，分子 成像和同步PET-fMRI(雅各布·胡克博士)，精神神经免疫学(贝丝·史蒂文斯博士)，fMRI 抑制性控制范式(斯科特·朗格内克博士)和神经影像统计学(马克·范格尔博士)。这个 拟议项目的理由是，尽管有证据表明BD发生了炎症性改变，但审问 体内的脑炎性标志物及其在执行功能中的作用是有限的。新奇的人体影像 需要放射性药物来显示神经胶质细胞的激活及其在抑制脑功能中的作用。中环 该提议的假设是，神经胶质细胞的激活对额纹状体脑回路产生不利影响，进而， BD中的抑制性控制。提出的具体目标是确定：(1)神经胶质细胞激活的差异 BD(n=20)和健康对照组(HC；n=20)之间的关系；(2)胶质细胞激活和抑制之间的联系 在BD中控制神经回路；(3)神经胶质细胞激活与抑制控制性能之间的关系 BD中的认知测试。这项拟议的研究在检查脑部炎症标志物方面具有创新性 用尖端同步正电子发射计算机断层扫描研究BD执行功能负荷的新机制 功能磁共振成像技术。这项拟议的研究具有重要意义，因为它可以产生新的神经免疫治疗方法。 PET-fMRI用于了解未满足的临床问题的目标和关键的先导数据 BD的抑制性功能障碍。总体而言，该项目和培训计划将促进候选人的职业生涯 通过促进在精神病学界面上的独立研究计划的发展 神经成像和神经免疫学。这是推进候选人职业目标的关键的第一步 研究认知的神经炎性基础并为未来的实验寻找新的神经免疫靶点 情绪障碍的治疗学。

Individuals with bipolar disorder (BD) experience severe and persistent difficulties with executive functions, such as inhibitory control. Inhibitory control difficulties in BD could be related to inflammation via its effects on brain functioning. However, direct measurement of brain inflammation markers (i.e. glial activation) in BD is limited and further understanding of how glial activation contributes to inhibitory brain dysfunction in BD is needed. The goal of this proposal is to study the neuroinflammatory basis of inhibitory control and identify novel neuroimmune treatment targets for executive dysfunction in mood disorders. To this end, the candidate proposes: (1) training objectives to establish expertise in the use of simultaneous PET-MRI as a research tool, an interdisciplinary knowledge base in psychoneuroimmunology, and full independence with fMRI methodology, which together will further career development into an expert clinical translational researcher in bipolar disorder; (2) a research objective to examine glial activation as a mechanism of inhibitory control brain dysfunction and cognitive performance in BD; (3) a team of mentors and advisors to ensure the candidate’s success, with expertise in bipolar disorder (Dr. Andrew Nierenberg), multi-modal psychiatric neuroimaging (Dr. Darin Dougherty), molecular imaging and simultaneous PET-fMRI (Dr. Jacob Hooker), psychiatric neuroimmunology (Dr. Beth Stevens), fMRI inhibitory control paradigms (Dr. Scott Langenecker), and neuroimaging statistics (Dr. Mark Vangel). The rationale for the proposed project is that despite evidence for inflammatory alterations in BD, interrogation of brain inflammatory markers in-vivo and their role in executive functioning is limited. Human imaging with novel radiopharmaceuticals to visualize glial activation and its role in inhibitory brain function is needed. The central hypothesis of the proposal is that glial activation adversely impacts frontostriatal brain circuitry and, in turn, inhibitory control in BD. The proposed specific aims are to determine the: (1) difference in glial activation between BD (n = 20) and healthy controls (HC; n = 20); (2) association between glial activation and inhibitory control neural circuitry in BD; (3) association between glial activation and inhibitory control performance on cognitive testing in BD. This proposed research is innovative for examining markers of brain inflammation as a novel mechanism of the understudied burden of executive function in BD using cutting edge simultaneous PET- fMRI technology. The proposed research is significant because it could yield novel neuroimmune treatment targets and crucial pilot data towards the use of PET-fMRI for understanding the unmet clinical problem of inhibitory dysfunction in BD. Overall, this project and training plan will promote the candidate’s career development by facilitating an independent program of program of research at the interface of psychiatric neuroimaging and neuroimmunology. This is a critical first step in furthering the candidate’s career goals to study the neuroinflammatory basis of cognition and to identify novel neuroimmune targets for future experimental therapeutics in mood disorders.