Does Acute Inhibition of Inflammation Improve Cortico-amygdala Circuitry and Symptoms of Anxiety in Depression?

急性抑制炎症是否可以改善皮质杏仁核回路和抑郁症的焦虑症状？

• 批准号: 10153472
• 负责人: Mandakh Bekhbat
• 金额: $ 6.86万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153472
• 关键词: Acute; Acute-Phase Proteins; Affect; Amygdaloid structure; Anti-Inflammatory Agents; Anxiety; Anxiety Disorders; Biological; Biological Markers; Blood specimen; Brain; Brain region; C-reactive protein; Chronic; Clinical Research; Cross-Sectional Studies; Development; Diagnosis; Disease Outcome; Exhibits; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Generalized Anxiety Disorder; Human; Immunology; Inflammation; Inflammatory; Infusion procedures; Laboratory Animals; Lead; Link; Major Depressive Disorder; Measurement; Mental Depression; Mental disorders; Mentors; Monoclonal Antibodies; National Institute of Mental Health; Neurosciences; Pathway interactions; Patient Self-Report; Patients; Peripheral; Pharmaceutical Preparations; Placebos; Plasma; Post-Traumatic Stress Disorders; Prefrontal Cortex; Psychiatry; Reporting; Research; Research Personnel; Research Training; Resources; Rest; Role; Sampling; Seeds; Severities; Stimulus; Stress; Symptoms; TNF gene; Testing; Work; aged; anxiety symptoms; anxiety-related disorders; career; comorbid depression; comorbidity; cortico-limbic circuits; cytokine; depressed patient; depressive symptoms; design; emotion regulation; experience; improved; infliximab; neural circuit; neuroimaging; novel; patient population; patient subsets; peripheral blood; personalized medicine; reduce symptoms; symptom treatment; symptomatic improvement; therapy resistant; treatment strategy

This proposal is designed to provide a mentored clinical research experience for the PI that will facilitate the development of an independent research career at the interface of neuroscience, psychiatry, and immunology. The proposed work will examine causal relationships between inflammation, cortico-amygdala circuit dysfunction, and symptoms of anxiety in patients with major depressive disorder (MDD). Approximately 85% of MDD patients also suffer from significant anxiety symptoms, yet the pathophysiologic mechanisms of anxiety in patients with depression are not fully understood. One biological pathway that may contribute to symptoms of anxiety in depression is the effect of inflammation on anxiety-relevant cortico-limbic circuitry. Neuroimaging studies have demonstrated that acute inflammatory stimuli given to healthy subjects reduce functional connectivity between the amygdala and prefrontal cortex (PFC) to lead to temporary symptoms of anxiety. Disrupted cortico-amygdala circuitry has been consistently reported in patients with anxiety disorders and post- traumatic stress disorder; a number of these patients also reliably exhibit increased cytokines and acute phase reactants like C-reactive protein (CRP). We recently reported that high inflammation (as determined by plasma CRP and cytokines) was associated with decreased functional connectivity between the amygdala and ventromedial PFC (vmPFC) in patients with MDD. Amygdala-vmPFC connectivity was in turn negatively correlated with severity of anxiety symptoms, and this relationship was strongest in patients with a comorbid anxiety disorder and/or PTSD. Relevant to treating anxiety symptoms in MDD, we also previously found that infliximab, a monoclonal antibody against tumor necrosis factor (TNF), reduced anxiety symptom severity in depressed patients with high CRP. Together, these findings suggest that inflammation affects cortico- amygdala connectivity to drive symptoms of anxiety in patients with depression; however, a causal relationship between inflammation and cortico-amygdala circuit dysfunction in psychiatric patient populations has yet to be established. The proposed work will utilize resources from an ongoing NIMH-sponsored study to test the hypothesis that acute inhibition of inflammation with infliximab will improve cortico-amygdala connectivity in association with reduced symptoms of anxiety in MDD patients with high inflammation. To examine this central hypothesis, we will assess the impact of acute challenge with infliximab compared to placebo on 1) amygdala- vmPFC functional connectivity, 2) relationships between amygdala-vmPFC connectivity, anxiety symptoms and the role of comorbidities, and 3) associations between inflammatory biomarkers, cortico-amygdala connectivity and anxiety symptoms. This project represents a first step toward developing novel anti-inflammatory and personalized treatment strategies for symptoms of anxiety in MDD patients with high inflammation. This project also provides an opportunity for the PI to obtain clinical research training under a team with expertise in immunology, psychiatry, and neuroimaging in order to prepare for a career as an independent investigator.

本提案旨在为PI提供指导性临床研究经验， 在神经科学，精神病学和免疫学的界面上发展独立的研究生涯。 这项工作将研究炎症、皮质-杏仁核回路之间的因果关系。 功能障碍和焦虑症状。大约85%的 MDD患者也有明显的焦虑症状，但抑郁症患者焦虑的病理生理机制尚不清楚。 对抑郁症患者的了解还不够。一种生物途径可能导致 抑郁症中的焦虑是炎症对焦虑相关的皮质边缘回路的影响。神经影像 研究已经证明给予健康受试者的急性炎症刺激降低了功能性炎症 杏仁核和前额叶皮层（PFC）之间的连接，导致暂时的焦虑症状。 在焦虑症患者和术后患者中，一直有皮质杏仁核回路中断的报道。 创伤应激障碍;这些患者中的一些也可靠地表现出增加的细胞因子和急性期 反应物如C-反应蛋白（CRP）。我们最近报道，高炎症（由血浆 CRP和细胞因子）与杏仁核和 MDD患者的腹内侧PFC（vmPFC）。杏仁核-VMPFC连接依次为负 与焦虑症状的严重程度相关，并且这种关系在患有共病的患者中最强。 焦虑症和/或PTSD。与治疗MDD中的焦虑症状相关，我们以前也发现， 英夫利昔单抗是一种抗肿瘤坏死因子（TNF）的单克隆抗体， 抑郁症患者CRP升高。总之，这些发现表明炎症影响皮质- 杏仁核连接驱动抑郁症患者的焦虑症状;然而，因果关系 在精神病患者人群中炎症和皮质杏仁核回路功能障碍之间的关系还有待进一步研究。 确立了习拟议的工作将利用NIMH正在进行的一项研究的资源， 假设英夫利西单抗急性抑制炎症将改善皮质-杏仁核连接， 与抑郁症患者的焦虑症状减轻高度炎症。为了检查这个中央 假设，我们将评估与安慰剂相比，英夫利西单抗急性激发对1）杏仁核- VMPFC功能连接，2）杏仁核-VMPFC连接，焦虑症状和 合并症的作用，和3）炎症生物标志物，皮质-杏仁核连接之间的关联 和焦虑症状。该项目代表了开发新型抗炎药和 针对高度炎症的抑郁症患者焦虑症状的个性化治疗策略。这个项目 还为PI提供了在具有以下专业知识的团队中获得临床研究培训的机会： 免疫学，精神病学和神经影像学，以准备作为一个独立的调查员的职业生涯。