Neural response to inflammatory challenge in major depressive disorder

重度抑郁症对炎症挑战的神经反应

基本信息

批准号：
10612922
负责人：
Jonathan Savitz
金额：
$ 64.15万
依托单位：
LAUREATE INSTITUTE FOR BRAIN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-14 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612922
关键词：
Acute Affect Anhedonia Attention Behavior Biological Blood Brain Characteristics Chronic Clinical Clinical assessments Color Communication Data Depressed mood Development Diagnosis Double-Blind Method Emotions Failure Functional Magnetic Resonance Imaging Heart Homeostasis Hour Human Immune Immune system Immunologics Immunotherapy In Vitro Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Infusion procedures Insula of Reil Interleukin-6 Interoception Intervention Knowledge Lipopolysaccharides MRI Scans Major Depressive Disorder Measures Mediating Medicine Mental Depression Mood Disorders Moods Outcome Participant Pathogenesis Pathway interactions Patients Pattern Persons Placebo Control Placebos Process Psychometrics Public Health Randomized Recovery Recurrence Research Rest Risk Role Saline Sex Differences Signal Transduction Sleep Stimulus Stomach Subgroup Symptoms System Testing Time Treatment Failure Visit cingulate cortex clinical predictors cytokine depressed patient depressive behavior depressive symptoms early life stress experimental study follow-up hemodynamics in vivo inflammatory marker innovation monocyte neural neural circuit patient population patient subsets placebo controlled study pleasure primary outcome programs psychologic recurrent depression response safety assessment sex symptomatology

项目摘要

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.

项目摘要：慢性炎症可能是重度抑郁症发病机制的基础（MDD）在相当多的案例中，但我们不明白为什么这些人会陷入困境我们认为这一亚群的抑郁症患者体内平衡或状态有缺陷。对炎症刺激的调节反应使得适当的急性炎症反应无法解决，导致慢性炎症，从而增加 (a) 患抑郁症、(b) 抑郁症复发的风险，以及 (c) 治疗失败为了检验这一假设，我们建议挑战两名 MDD 受试者的免疫系统。和健康对照（HC）用炎症刺激物（脂多糖，LPS）诱导稳态具体来说，90 名 MDD 和 90 名 HC 参与者将被随机 (2:1) 接受 LPS (0.8 ng/kg) 或生理盐水。将进行连续抽血，以使用多种炎症指标来量化炎症反应模式。同时，参与者将完成临床评级并接受 LPS 前后的 MRI 检查。扫描以测量短暂的炎症反应如何影响大脑的内感受（身体- 参与者还将在 LPS/盐水输注完成后一天和一周返回。仅 MDD 组也将完成相同的心理测量和抽血。每月进行一次评估，持续 6 个月，以确定对 LPS 的急性反应是否可预测 MDD的临床病程主要假设是：（1）相对于HC，MDD组将表现出炎症介质急剧增加，但神经回路介导的急性反应减弱 LPS 与安慰剂条件下的内感受过程（岛叶和扣带皮层）对于急性结果。我们关注炎症反应高峰时发生的变化，即输注后 2 小时 (2)。在 MDD 组中，内感受处理和功能连接中与 LPS 相关的变化将是 (3)这些急性影响会更大在患有慢性炎症的 MDD 参与者中显着（基线 CRP 3mg/L），即相对于低水平而言。炎症MDD组（CRP £1mg/L），高炎症MDD组会表现出钝化在探索性分析中，岛叶和扣带回的血流动力学反应。我们还将通过诊断来检查性别对炎症和岛叶是否存在交互作用对 LPS 的反应以及 LPS 的急性影响是否与 6 个月内的抑郁症状有关这项研究具有创新性且极具影响力，因为它将开辟一个新的研究计划。这将使我们能够对未能解决问题的生物学机制得出强有力的结论这些知识最终可以用于开发新的大脑或与炎症相关的抑郁行为。基于免疫的治疗可以启动通常由炎症刺激参与的神经回路，并针对特定患者群体实施这些干预措施。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Elevated Systemic Inflammation Is Associated with Reduced Corticolimbic White Matter Integrity in Depression.

抑郁症中全身炎症升高与皮质边缘白质完整性降低有关。

DOI：
发表时间：
2021-12-28
期刊：
影响因子：
0
作者：
Thomas, MacGregor;Savitz, Jonathan;Zhang, Ye;Burrows, Kaiping;Smith, Ryan;Figueroa;Kuplicki, Rayus;Khalsa, Sahib S;Taki, Yasuyuki;Teague, Tracy Kent;Irwin, Michael R;Yeh, Fang;Paulus, Martin P;Zheng, Haixia;On Behalf Of T
通讯作者：
On Behalf Of T

Acute administration of ibuprofen increases serum concentration of the neuroprotective kynurenine pathway metabolite, kynurenic acid: a pilot randomized, placebo-controlled, crossover study.

布洛芬的急性给药会增加神经保护性犬尿氨酸途径代谢物犬尿酸的血清浓度：一项随机、安慰剂对照、交叉试验研究。

DOI：
发表时间：
2022-12
期刊：
影响因子：
3.4
作者：
Savitz, Jonathan;Ford, Bart N;Kuplicki, Rayus;Khalsa, Sahib;Teague, T Kent;Paulus, Martin P
通讯作者：
Paulus, Martin P

Association between cytomegalovirus infection, reduced gray matter volume, and resting-state functional hypoconnectivity in major depressive disorder: a replication and extension.

重度抑郁症中巨细胞病毒感染、灰质体积减少和静息态功能连接低下之间的关联：复制和延伸。

DOI：
发表时间：
2021-09-07
期刊：
影响因子：
6.8
作者：
Zheng, Haixia;Ford, Bart N;Kuplicki, Rayus;Burrows, Kaiping;Hunt, Peter W;Bodurka, Jerzy;Kent Teague, T;Irwin, Michael R;Yolken, Robert H;Paulus, Martin P;Savitz, Jonathan
通讯作者：
Savitz, Jonathan

C-Reactive protein and the kynurenic acid to quinolinic acid ratio are independently associated with white matter integrity in major depressive disorder.

C反应蛋白和犬尿酸与喹啉酸的比例与重度抑郁症的白质完整性独立相关。

DOI：
发表时间：
2022-10
期刊：
影响因子：
0
作者：
Zheng, Haixia;Teague, T Kent;Yeh, Fang;Burrows, Kaiping;Figueroa;Aupperle, Robin L;Khalsa, Sahib S;Paulus, Martin P;Savitz, Jonathan
通讯作者：
Savitz, Jonathan

Herpesviruses and neuropsychiatric disorders: overlooked adversaries or innocent bystanders?

疱疹病毒和神经精神疾病：被忽视的对手还是无辜的旁观者？