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

双相情感障碍的神经炎症和执行功能：PET-fMRI 研究

• 批准号: 10521262
• 负责人: Amy Peters
• 金额: $ 19.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10521262
• 关键词: Active Biological Transport; Adult; Afferent Pathways; Age; Attention; Attenuated; Autopsy; Basal Ganglia; Behavior; Binding; Bipolar Disorder; Brain; Brain imaging; Clinical; Cognition; Cognitive; Cognitive deficits; Consultations; Data; Development; Disinhibition; Encephalitis; Ensure; Executive Dysfunction; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Goals; Imaging Device; Imaging technology; Immune; Immunologic Markers; Immunology; Immunotherapy; Impulsivity; Individual; Inflammation; Inflammatory; Investigational Therapies; Link; Magnetic Resonance Imaging; Measurement; Measures; Mental Depression; Mentors; Mentorship; Methodology; Mood Disorders; National Institute of Mental Health; Neurobehavioral Manifestations; Neurobiology; Neuroglia; Neuroimmune; Neurons; Organ; Participant; Performance; Peripheral; Positron-Emission Tomography; Prefrontal Cortex; Productivity; Proteins; Psychoneuroimmunology; Radiopharmaceuticals; Research; Research Project Grants; Rest; Role; Scanning; Schizophrenia; Self Destructive Behavior; Specificity; Training; Unemployment; Visualization; Work; brain circuitry; brain dysfunction; career; career development; clinical translation; clinically significant; cognitive performance; cognitive testing; cytokine; density; executive function; experience; follow-up; glial activation; human imaging; imaging study; immune activation; improved; in vivo; indexing; inflammatory marker; innovation; knowledge base; mind control; molecular imaging; multimodality; neural; neural circuit; neuroimaging; neuroimmunology; neuroinflammation; neuroregulation; novel; programs; radioligand; receptor; response; statistics; success; suicidal; tool; translational scientist

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.

双相情感障碍 (BD) 患者在执行功能方面会经历严重且持续的困难，例如 作为抑制对照。 BD 的抑制控制困难可能与炎症对大脑的影响有关 发挥作用。然而，BD 中脑部炎症标志物（即神经胶质激活）的直接测量是有限的 需要进一步了解胶质细胞激活如何导致 BD 患者的抑制性脑功能障碍。这 该提案的目标是研究抑制控制的神经炎症基础并确定新的神经免疫 情绪障碍执行功能障碍的治疗目标。为此，候选人建议：（1）培训 目标是建立使用同步 PET-MRI 作为研究工具、跨学科的专业知识 心理神经免疫学的知识基础，以及功能磁共振成像方法的完全独立性，这些共同将 进一步职业发展成为双相情感障碍的临床转化专家专家； (2) 研究 目的是检查神经胶质细胞激活作为抑制控制脑功能障碍和认知的机制 BD 表现； (3) 由导师和顾问组成的团队，以确保候选人的成功，并具有以下方面的专业知识 双相情感障碍（Andrew Nierenberg 博士）、多模式精神神经影像学（Darin Dougherty 博士）、分子 成像和同步 PET-fMRI（Jacob Hooker 博士）、精神神经免疫学（Beth Stevens 博士）、fMRI 抑制控制范式（Scott Langenecker 博士）和神经影像统计学（Mark Vangel 博士）。这 该项目的基本原理是，尽管有证据表明 BD 存在炎症改变，但 体内脑炎症标志物及其在执行功能中的作用是有限的。人体成像新颖 需要放射性药物来可视化神经胶质激活及其在抑制性脑功能中的作用。中央 该提案的假设是，神经胶质细胞激活会对额纹状体大脑回路产生不利影响，进而， BD 中的抑制控制。提出的具体目标是确定：（1）神经胶质激活的差异 BD (n = 20) 和健康对照 (HC; n = 20) 之间； (2) 胶质细胞激活与抑制的关联 控制 BD 中的神经回路； (3) 神经胶质细胞活化与抑制控制性能之间的关联 BD 中的认知测试。这项拟议的研究对于检查大脑炎症标志物作为一种方法具有创新性。 使用尖端同步 PET- 研究 BD 执行功能负担的新机制 功能磁共振成像技术。拟议的研究意义重大，因为它可以产生新的神经免疫治疗 使用 PET-fMRI 来了解未满足的临床问题的目标和关键试点数据 BD 的抑制功能障碍。总体而言，该项目和培训计划将促进候选人的职业生涯 通过促进精神病学接口的独立研究计划来发展 神经影像学和神经免疫学。这是推进候选人职业目标的关键的第一步 研究认知的神经炎症基础并确定未来实验的新神经免疫靶点 情绪障碍的治疗。