Dynamics of Inflammation and its Blockade on Motivational Circuitry in Depression

项目摘要 激励性快感缺乏症--一组非快感症状的子集，涉及努力中的多巴胺相关损害-- 基于决策、奖励预期和强化学习--在精神障碍中很常见 比如严重的抑郁症，而且是出了名的难以治疗。近年来，这些症状一直是 与多巴胺能皮质纹状体回路的改变有关，但该回路的潜在原因 功能障碍仍不清楚。一种可能的机制是炎症；炎性细胞因子增加 在抑郁症患者中被可靠地发现，并给予炎性细胞因子或细胞因子 诱导剂已被证明会引发抑郁症状，如冷漠、快感缺乏和疲劳。此外, 已发现炎性细胞因子可扰乱多巴胺的合成，改变基底节的代谢，以及 在奖赏预期中纹状体反应迟钝。然而，到目前为止，大多数数据支持 重度抑郁症和其他疾病患者细胞因子与症状的关系 本质上是相关的，因此需要替代的实验策略来阐明因果关系 两性关系。一种策略是阻断高血压性抑郁症患者样本中的炎症细胞因子 炎症，以确定哪些症状域受影响最大，以及通过哪些分子 小路。此前，我们发现肿瘤坏死因子拮抗剂英夫利昔单抗(一种可以 选择性抑制肿瘤坏死因子)选择性地减轻激励性快感缺乏症的症状，但仅限于抑郁患者 C-反应蛋白(C-反应蛋白)水平在3 mg/L以上的高炎症患者。 不幸的是，在这个样本中，并不是所有的患者都表现出高度的炎症，这些相关性肯定 因此被认为是初步的，尽管很有希望。更关键的是，这项研究无法解决目标问题 神经回路层面的参与。在这些初始数据的基础上，目前的研究将评估 安慰剂对照药物治疗前后皮质纹状体环路的神经影像测量 80名抑郁症患者(每组40名)接受炎症阻断治疗，以确保高水平的 外周炎症(C反应蛋白和谷草转氨酶3 mg/L)。主要目的是评估1)皮质纹状体功能是否在 奖励动机和期望与以下外周炎症的变化有关 与安慰剂相关的药物阻断2)炎症、基因-2)变化的时间动态 表情、奖励动机和强化学习行为以及动机症状的评估 基础，以及英夫利昔单抗输注后24小时、3天、1周和2周，以及3)进行多因素综合试验。 水平通路模型确定炎症阻断后皮质纹状体回路是否发生变化 调节炎症变化和兴奋性快感缺乏症状变化之间的关系。 这些数据将进一步证实炎性细胞因子作为激励的治疗靶点。 抑郁症的症状，并将为未来的研究确定症状目标和反应的生物标记物。

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.