Neural response to inflammatory challenge in major depressive disorder

项目摘要：慢性炎症可能是抑郁症发病机制的基础 (MDD)，但我们不明白为什么这些人会被困在 炎症状态。我们假设这一亚组抑郁症患者体内平衡存在缺陷或 对炎性刺激的调节反应，使得适当的急性炎症反应不能消除， 导致慢性炎症，这增加了(A)发展为抑郁症，(B)复发，以及 (C)治疗失败。为了验证这一假设，我们建议挑战两个MDD受试者的免疫系统 和健康对照组(HC)，用炎症刺激(内毒素，LPS)诱导体内平衡 回应。具体来说，90名MDD和90名HC参与者将被随机分为脂多糖(0.8 ng/kg)或生理盐水(2：1)。 将获得连续抽血来量化炎症反应的模式，使用几种炎性 记号笔。同时，参与者将完成临床评分，并接受脂多糖治疗前后的核磁共振检查 扫描以测量短暂性炎症反应如何影响大脑对内感(身体-- 相关)刺激。参与者还将在注射脂多糖/生理盐水后一天和一周内返回完成 相同的心理测量和抽血结果。只有MDD组，也将完成心理 每月评估一次，为期6个月，以确定对内毒素的急性反应是否预测 MDD的临床病程。主要的假设是：(1)相对于HC，MDD组将表现出 炎症介质的急剧增加，但神经回路介导的急性反应迟钝 内毒素与安慰剂条件下的感觉间过程(脑岛和扣带回)。对于严重后果 我们将重点放在炎症反应的高峰期，即输液后2小时。(2)。 在MDD组内，内毒素相关的感觉间处理和功能连接的变化将是 与急性促炎反应的强度相关。(3)这些急性影响将会更大 在伴有慢性炎症的MDD参与者中显著(基线C-反应蛋白3 mg/L)。也就是说，相对于低点 炎症性MDD组(CRPGB 1 mg/L)，高炎性MDD组表现钝化 内聚焦注意时脑岛和扣带回的血流动力学反应。在探索性分析中 我们还将通过诊断来检验是否存在性行为对炎症和胰岛的交互作用 对内毒素的反应以及内毒素的急性影响是否与6个月内的抑郁症状有关 后续行动。这项研究具有创新性和高度的影响力，因为它将开辟一种新的研究方案 这将使我们能够对未能解决的生物机制得出强有力的结论 炎症相关的抑郁行为。这些知识最终可以用来开发新的大脑或 基于免疫的治疗，以启动通常由炎症刺激激活的神经回路，并 将这些干预措施针对特定的患者群体。

PROJECT SUMMARY: Chronic inflammation likely underlies the pathogenesis of major depressive disorder (MDD) in a significant number of cases but we do not understand why these individuals get stuck in an inflammatory state. We hypothesize that this subgroup of depressed patients has a defective homeostatic or regulatory response to inflammatory stimuli such that appropriate, acute inflammatory responses fail to resolve, leading to chronic inflammation which increases the risk for (a) developing depression, (b) its recurrence, and (c) treatment failure. To test this hypothesis, we propose challenging the immune system of both MDD subjects and healthy controls (HC) with an inflammatory stimulus (lipopolysaccharide, LPS) to induce a homeostatic response. Specifically, 90 MDD and 90 HC participants will be randomized (2:1) to LPS (0.8ng/kg) or saline. Serial blood draws will be obtained to quantify the pattern of inflammatory response using several inflammatory markers. At the same time, participants will complete clinical ratings and undergo a pre- and post-LPS MRI scan to measure how the transient inflammatory response affects the brain processing of interoceptive (bodily- relevant) stimuli. Participants will also return one day and one week after LPS/saline infusion to complete identical psychometric measures and blood draws. The MDD group, only, will also complete psychological assessments once per month for 6 months in order to determine whether the acute response to LPS predicts the clinical course of MDD. The main hypotheses are that: (1) relative to HC, the MDD group will show a greater acute increase in inflammatory mediators but a blunted acute response of the neural circuitry mediating interoceptive processes (insula and cingulate cortex) in the LPS vs. placebo condition. For the acute outcomes we focus on the changes that occur at the peak of the inflammatory response, i.e. 2 hours post-infusion. (2). Within the MDD group, LPS-associated changes in interoceptive processing and functional connectivity will be correlated with the strength of the acute pro-inflammatory response. (3) These acute effects will be more salient in MDD participants with chronic inflammation (baseline CRP ³3mg/L). That is, relative to the low inflammation MDD group (CRP £1mg/L), the high inflammation MDD group will display a blunted hemodynamic response of the insula and cingulate during internally-focused attention. In exploratory analyses we will also examine whether there is a sex by diagnosis interaction effect on inflammatory and insular response to LPS and whether the acute effects of LPS will relate to depressive symptoms over the 6-month follow-up. This research is innovative and highly impactful because it will open up a new program of research that will allow us to draw strong conclusions about the biological mechanisms underlying the failure to resolve inflammation-related depressive behavior. This knowledge can ultimately be used to develop new brain or immune-based treatments to jump-start the neural circuitry normally engaged by inflammatory stimuli, and to target these interventions at specific patient populations.