Dynamics of Inflammation and its Blockade on Motivational Circuitry in Depression

抑郁症中炎症的动态及其对动机回路的封锁

• 批准号: 9318578
• 负责人: Michael Tilghman Treadway
• 金额: $ 41.01万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-20 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9318578
• 关键词: Address; Adult; Affect; Anhedonia; Anti-Inflammatory Agents; Anti-inflammatory; Basal Ganglia; Behavior assessment; Behavioral; C-reactive protein; Clinical; Clinical assessments; Corpus striatum structure; Data; Decision Making; Development; Disease; Dopamine; Double-Blind Method; Enrollment; Ensure; Exhibits; Fatigue; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Genetic Markers; Goals; Hour; Human; Immune system; Impairment; Individual Differences; Inflammation; Inflammatory; Infusion procedures; Interleukin-6; Laboratory Animals; Learning; Link; Major Depressive Disorder; Measures; Mediating; Mediation; Mental Depression; Mental disorders; Metabolism; Modeling; Molecular; Monoclonal Antibodies; Motivation; Nature; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Placebo Control; Placebos; Plasma; Prevention strategy; Procedures; Psychological reinforcement; Recruitment Activity; Research; Rewards; Role; Sampling; Schizophrenia; Signal Pathway; Signal Transduction; Symptoms; TNF gene; Testing; Time; Validation; Ventral Striatum; base; behavior measurement; clinically relevant; cytokine; depressed patient; depressive symptoms; hedonic; inflammatory marker; infliximab; learned behavior; neural circuit; neurobiological mechanism; neuroimaging; novel; patient subsets; personalized medicine; protein biomarkers; protein expression; reduce symptoms; relating to nervous system; response; response biomarker; reward anticipation; reward circuitry; targeted biomarker; therapeutic target; treatment strategy

Project Summary Motivational anhedonia–a subset of anhedonic symptoms involving dopamine-linked impairments in effort- based decision-making, reward anticipation and reinforcement learning–are common in psychiatric disorders such as major depression, and are notoriously difficult to treat. In recent years, these symptoms have been associated with alterations in dopaminergic corticostriatal circuitry, yet the underlying causes of this circuit dysfunction remain unknown. One candidate mechanism is inflammation; increased inflammatory cytokines have been reliably found in depressed patients, and administration of inflammatory cytokines or cytokine inducers has been shown to foment depressive symptoms of apathy, anhedonia and fatigue. In addition, inflammatory cytokines have been found to disrupt dopamine synthesis, alter basal-ganglia metabolism, and blunt striatal responsivity during reward anticipation. To date, however, the majority of data supporting the relationship between cytokines and symptoms in patients with major depression and other disorders is correlational in nature, and thus alternative experimental strategies are required to elucidate causal relationships. One strategy is to block inflammatory cytokines in a sample of depressed patients with high inflammation so as to determine which symptom domains are most affected and through which molecular pathways. Previously, we found that the TNF antagonist infliximab (a “biologic” monoclonal antibody that selectively inhibits TNF) selectively reduced symptoms of motivational anhedonia, but only in depressed patients with high inflammation as reflected by plasma c-reactive protein (CRP) of at least >3mg/L. Unfortunately, not all patients in this sample exhibited high inflammation, and these associations must therefore be considered preliminary, albeit promising. More critically, this study was unable to address target engagement at the level of neural circuitry. Building off of these initial data, the current study will assess neuroimaging measures of corticostriatal circuitry before and after a placebo-controlled pharmacologic blockade of inflammation in 80 depressed patients (n = 40 per group) recruited to ensure high levels of peripheral inflammation (CRP > 3mg/L). Primary aims are to evaluate whether 1) corticostriatal function during reward motivation and anticipation are associated with change in peripheral inflammation following pharmacologic blockade relative to placebo 2) the temporal dynamics of change in inflammation, gene- expression, reward motivation and reinforcement learning behavior and motivational symptoms assessed at baseline, and 24 hours, 3 days, 1 week and two weeks post infliximab infusion, and 3) test an integrative multi- level path model to determine whether change in corticostriatal circuitry following inflammation blockade mediates the relationship between change in inflammation and change in motivational anhedonia symptoms. These data will provide further validation of inflammatory cytokines as therapeutic targets for motivational symptoms in depression and will define symptom targets and biomarkers of response for future studies.

项目摘要 激励性抗议 - 厌氧症状的一个子集涉及多巴胺相关的努力障碍 - 基于决策，奖励预期和强化学习 - 在精神疾病中很常见 例如严重抑郁症，众所周知，很难治疗。近年来，这些符号已经 与多巴胺能皮质纹状体电路的改变有关，但该电路的根本原因 功能障碍仍然未知。一种候选机制是炎症。炎症细胞因子增加 在抑郁症患者中可靠发现，炎症细胞因子或细胞因子的给药 已显示诱导剂会引起冷漠，狂热和疲劳的抑郁症状。此外， 已经发现炎性细胞因子会破坏多巴胺的合成，改变基本的ganglia代谢和 在预期奖励期间，钝纹状体反应性。但是，迄今为止，支持该数据的大多数数据 严重抑郁症和其他疾病患者的细胞因子与符号之间的关系是 本质上的相关性，因此需要替代实验策略来阐明催化 关系。一种策略是阻止抑郁症患者样本中的炎症细胞因子 炎症，以确定哪些症状结构域受到影响最大，并且通过哪些分子 途径。以前，我们发现TNF拮抗剂英夫利昔单抗（一种“生物学”单克隆抗体 有选择地抑制TNF）选择性降低了动机抗激动人心的症状，但仅在沮丧中 血浆C反应蛋白（CRP）反映至少> 3mg/L的高注射患者。 不幸的是，并非所有样本中的患者都暴露了高注射，这些关联必须 因此，尽管有希望，因此被认为是初步的。更重要的是，这项研究无法解决目标 在神经电路的水平上参与。在这些初始数据的基础上，当前的研究将评估 安慰剂对照药理之前和之后的皮质纹状体电路的神经影像学测量 招募80名抑郁症患者（n = 40）的炎症阻塞，以确保高水平 外围注射（CRP> 3mg/L）。主要目的是评估1）是否在 奖励动机和期望与外周炎症的变化有关 相对于安慰剂2）炎症变化的暂时动态，基因 - 评估的表达，奖励动机和强化学习行为和动机符号 英夫利昔单抗输注后基线和24小时3天1周和两周 确定炎症阻塞后皮质纹状体电路的变化是否变化的水平路径模型 调解炎症变化与动机anhedonia符号变化之间的关系。 这些数据将提供进一步验证炎症细胞因子作为动机的治疗靶标 抑郁症的症状并将定义症状靶标和生物标志物的反应范围，以供将来研究。