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 动机性快感缺失--一种与多巴胺相关的努力障碍有关的快感缺失症状-- 基于决策、奖励预期和强化学习--在精神疾病中很常见 如重度抑郁症，并且众所周知很难治疗。近年来，这些症状已经被 与多巴胺能皮质纹状体回路的改变有关，但这种回路的根本原因是 功能障碍仍然未知。一个可能的机制是炎症;增加炎症细胞因子 已经在抑郁症患者中可靠地发现，并且给予炎性细胞因子或细胞因子 诱导剂已被证明会引起冷漠、快感缺乏和疲劳等抑郁症状。此外，本发明还提供了一种方法， 已经发现炎性细胞因子破坏多巴胺合成，改变基底神经节代谢， 在奖励预期中纹状体反应迟钝。然而，到目前为止，大多数数据支持 细胞因子与抑郁症和其他疾病患者症状之间的关系， 相关的性质，因此需要替代实验策略来阐明因果关系 关系。一种策略是阻断高血压抑郁症患者样本中的炎性细胞因子， 炎症，以确定哪些症状域最受影响，并通过哪些分子 途径。以前，我们发现TNF拮抗剂英夫利昔单抗（一种“生物”单克隆抗体， 选择性抑制TNF）选择性减少动机性快感缺失的症状，但仅在抑郁症 血浆C-反应蛋白（CRP）至少> 3 mg/L反映的高度炎症患者。 不幸的是，并不是所有的患者在这个样本中表现出高度炎症，这些协会必须 因此被认为是初步的，尽管有希望。更重要的是，这项研究无法解决目标 在神经回路层面的参与。基于这些初步数据，目前的研究将评估 安慰剂对照药物治疗前后皮质纹状体回路的神经影像学测量 在招募的80名抑郁症患者（每组n = 40）中阻断炎症，以确保高水平的 外周炎症（CRP > 3 mg/L）。主要目的是评估1）皮质纹状体功能是否在 奖励动机和预期与外周炎症的变化相关， 2）炎症、基因表达和/或免疫原性改变的时间动力学， 表达，奖励动机和强化学习行为和动机症状评估 基线，以及英夫利西单抗输注后24小时、3天、1周和2周，以及3）测试整合的多- 水平路径模型，以确定炎症阻断后皮质纹状体回路是否发生变化 介导炎症变化和动机性快感缺失症状变化之间的关系。 这些数据将进一步验证炎症细胞因子作为动机性炎症的治疗靶点。 抑郁症的症状，并将确定症状的目标和生物标志物的反应，为未来的研究。