The Role of Neuroimmune Activation in Chronic Pain and Negative Affect

描述（由申请人提供）：小胶质细胞是一种正常休眠的巨噬细胞亚群，在各种病理条件下（如炎症、神经退行性变）迅速激活，以破坏入侵的微生物，清除潜在的有害碎片和促进组织修复。然而，动物研究现在令人信服地表明，这种反应在持续疼痛的情况下变得不受控制，诱导化学物质的释放，包括促炎细胞因子，进一步使疼痛通路敏感。此外，动物和人类研究已经提供证据支持大脑小胶质细胞的激活与负面情绪（NA）之间的联系，包括压力和焦虑。例如，暴露在压力条件下的啮齿动物在大脑的几个区域（丘脑、下丘脑、海马体、黑质和中央灰质）显示出小胶质细胞的激活。尽管有这些观察结果，人类大脑中NA或疼痛相关的神经免疫激活从未在体内得到证实。由于慢性疼痛患者表现出高患病率（~40-50%）的情绪障碍，我们将验证慢性腰痛（cLBP）患者表现出脑小胶质细胞活化的证据，并且这种现象至少部分与NA相关的假设。由于小胶质细胞积极参与突触的修饰或消除，我们也将确定激活的小胶质细胞对功能性脑连接的影响。我们将比较NA水平大范围的cLBP患者和NA水平低的健康志愿者之间的小胶质细胞激活和脑功能连接模式。受试者将使用同步磁共振/正电子发射断层扫描（MR-PET）进行扫描，这是一种协同两种领先成像方法的新技术。PET扫描将使用[11C]PBR28，一种新的小胶质细胞激活标记物。与PET数据同时收集的MR数据将使我们能够a)在小胶质细胞活动测量期间估计脑功能连接，以及b)对PET数据进行基于MR的运动校正（一种显着提高PET数据保真度，灵敏度和特异性的新程序）。认识到小胶质细胞的作用

DESCRIPTION (provided by applicant): Microglia are a normally dormant subpopulation of macrophages, which rapidly activate in response to a variety of pathological conditions (e.g., inflammation, neurodegeneration), to enable the destruction of invading micro-organisms, the removal of potentially deleterious debris and the promotion of tissue repair. However, animal studies have now convincingly shown that this reaction becomes uncontrolled in conditions of persistent pain, inducing the release of chemicals, including proinflammatory cytokines, which further sensitize the pain pathways. Furthermore, animal and human studies have presented evidence in support of a link between the activation of brain microglia and negative affect (NA), including stress and anxiety. For instance, rodents exposed to stressful conditions were shown to exhibit microglial activation in several regions of the brain (thalamus, hypothalamus, hippocampus, substantia nigra and central gray). Despite these observations, NA- or pain-related neuroimmune activation in the human brain has never been demonstrated in vivo. As chronic pain patients exhibit high prevalence (~40-50%) of mood disorders, we will test the hypothesis that patients with chronic low back pain (cLBP) demonstrate evidence of activated brain microglia, and that this phenomenon is at least partly related to NA. Since microglia actively contribute to the modification or elimination of synapses, we will also determine the influence of activated microglia on functional brain connectivity. We will compare microglial activation and patterns of functional brain connectivity between cLBP patients with a wide range of NA levels and low-NA healthy volunteers. Subjects will be scanned using simultaneous Magnetic Resonance/Positron Emission Tomography (MR-PET), a novel technology synergizing two leading imaging methodologies. PET scanning will use [11C]PBR28, a novel marker of microglial activation. MR data collected simultaneously to PET data will allow us to a) estimate functional brain connectivity during microglia activity measurement, as well as b) perform an MR-based motion correction of the PET data (a novel procedure that significantly improves the fidelity, sensitivity, and specificity of PET data). Recognizing the role of microglia in human pain and negative affect would likely have important clinical implications, including improved diagnosis and the identification of objective markers for a wide range of neurological and psychiatric disorders.