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

该建议旨在为PI提供有指导的临床研究经验，以促进 在神经科学、精神病学和免疫学之间发展独立的研究事业。 这项拟议的工作将检验炎症、皮质-杏仁核环路之间的因果关系。 严重抑郁障碍(MDD)患者的功能障碍和焦虑症状。约85%的 MDD患者也有明显的焦虑症状，但焦虑的病理生理机制 人们对抑郁症患者的了解还不够充分。一种生物途径可能导致脑瘫的症状 抑郁症中的焦虑是炎症对与焦虑相关的皮质-边缘回路的影响。神经成像 研究表明，对健康受试者给予急性炎症刺激会降低功能 杏仁核和前额叶皮质(PFC)之间的连接导致暂时的焦虑症状。 在焦虑症患者中，皮质-杏仁核回路紊乱的报道一直是一致的。 创伤性应激障碍；这些患者中的许多人也可靠地表现出细胞因子增加和急性期 C-反应蛋白(CRP)等反应物。我们最近报道，高炎症(由血浆决定) C反应蛋白和细胞因子)与杏仁核和杏仁核之间的功能连接性降低有关 MDD患者的腹内侧PFC(VmPFC)。杏仁核-vmPFC的连接反过来又是负的 与焦虑症状的严重程度相关，并且这种关系在合并有焦虑症状的患者中最强 焦虑症和/或创伤后应激障碍。与治疗MDD的焦虑症状相关，我们先前也发现 英夫利昔单抗是一种抗肿瘤坏死因子的单抗，可降低焦虑症状的严重程度 伴有高C反应蛋白的抑郁症患者。综上所述，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 精神疾病患者群体中炎症和杏仁皮质环路功能障碍之间的关系尚未得到证实 已经成立了。这项拟议的工作将利用NIMH赞助的一项正在进行的研究的资源来测试 假设英夫利昔单抗急性抑制炎症将改善大鼠大脑皮质-杏仁核连接 伴有高度炎症的MDD患者焦虑症状减轻的相关性。为了研究这个中心 假设，我们将评估英夫利昔单抗与安慰剂急性激发对杏仁核的影响。 2)杏仁核-vmPFC连接、焦虑症状和 合并症的作用，以及3)炎性生物标志物与皮质-杏仁核连接性之间的关系 和焦虑症状。该项目是朝着开发新型抗炎和抗炎药物迈出的第一步 高度炎症的MDD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下获得临床研究培训的机会 免疫学、精神病学和神经成像，以便为独立调查人员的职业生涯做准备。

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.