Targeting Inflammation-Induced Changes in Brain Reward Signaling and Motivational Deficits in Patients with Schizophrenia Using an Anti-Inflammatory Challenge

使用抗炎挑战来针对精神分裂症患者炎症引起的大脑奖赏信号变化和动机缺陷

• 批准号: 10568058
• 负责人: David Ryan Goldsmith
• 金额: $ 54.7万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568058
• 关键词: Address; Anhedonia; Anterior; Anti-Inflammatory Agents; Antipsychotic Agents; Behavior; Behavioral; Biological Markers; Brain; Brain region; C-reactive protein; Cells; Clinical; Clinical Trials; Clinical assessments; Corpus striatum structure; Data; Development; Dimensions; Double-Blind Method; Enrollment; Exhibits; Expenditure; Female; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Gene Expression; Goals; Immune; Impairment; Individual; Inflammation; Inflammatory; Insula of Reil; Literature; Measures; Mediating; Mental Depression; Mental disorders; Morbidity - disease rate; Motivation; National Institute of Mental Health; Nature; Patients; Performance; Peripheral; Pharmaceutical Preparations; Placebos; Plasma; Positive Valence; Precision therapeutics; Publishing; Punishment; Randomized; Research; Research Domain Criteria; Rest; Rewards; Sampling; Schizophrenia; Severities; Signal Transduction; Specificity; Stimulus; Strategic Planning; Subgroup; Symptoms; System; TNF gene; Testing; Ventral Striatum; Work; antagonist; biomarker driven; blood oxygen level dependent; brain behavior; cognitive system; cytokine; depressive symptoms; design; functional MRI scan; functional outcomes; improved; inflammatory marker; infliximab; innovation; insight; male; mortality; motivated behavior; neurobiological mechanism; novel; patient subsets; peripheral blood; personalized medicine; pleasure; response; reward anticipation; reward processing; sex

Project Summary The CNS mechanisms underlying motivational deficits in patients with schizophrenia are poorly understood. These deficits significantly contribute to negative symptoms, which are strongly related to poor functional outcomes and nonresponse to antipsychotic therapies. Data from our group and others have shown that increased peripheral inflammatory markers, such as tumor necrosis factor (TNF), are associated with motivational deficits and negative symptoms in patients with schizophrenia. Regarding the mechanisms involved, our data indicate that in patients with schizophrenia, TNF is associated with decreased activation in ventral striatum in response to reward anticipation as well as increased activation in anterior insula in response to increasing perceived effort. These data are consistent with previous results from individuals administered inflammatory stimuli and from patients with depression that indicate that inflammation targets ventral striatum and anterior insula to lead to downstream changes in reward processing and motivation-related behaviors. Taken together, these findings support the hypothesis that inflammation plays a role in motivational deficits and negative symptoms in patients with schizophrenia through effects on the ventral striatum and anterior insula. Nevertheless, the cause and effect nature of this relationship remains unclear. Work from our group and others suggest that reducing inflammation with the TNF antagonist infliximab improves motivated-related behaviors in patients with depression and high inflammation, and our preliminary data indicate that infliximab improves effort-based motivation in depression through effects on ventral striatum. However, previous studies of anti- inflammatories, including cytokine antagonists, in patients with schizophrenia have been limited by a lack of specificity for patients with increased inflammation and a lack of focus on inflammation-related behavioral changes (e.g. amotivation). Herein, we propose a mechanistic clinical trial in which patients with schizophrenia with high inflammation and motivational deficits will be randomized to an anti-inflammatory challenge with infliximab or placebo. We will then test the hypothesis that infliximab (vs placebo) will increase ventral striatal activation in response to reward anticipation and decrease activation of the anterior insula in response to increasing effort using fMRI. In addition, we will assess the response of objective and clinical measures of motivation. Thus, the goals of the proposed research are to use a biomarker-driven approach to determine whether inhibition of TNF with infliximab (compared to placebo) increases activation of the ventral striatum and decreases activation of the anterior insula during an effort-based reward task (Aim 1), while improving objective and clinical measures of motivation (Aim 2) and exploring infliximab’s effects on other brain regions and behaviors to address specificity (Aim 3). In sum, this study will reveal CNS mechanisms of amotivation in schizophrenia and provide biomarkers and targets that will focus future research and support development of precision therapies for amotivation and ultimately negative symptoms in relevant schizophrenia subgroups.

项目摘要 精神分裂症患者的中枢神经系统机制对精神分裂症患者的理解很少。 这些定义明显导致负面症状，这与功能较差密切相关 结果和对抗精神病药疗法的无反应。我们小组和其他人的数据表明 增加的外周炎症标志物（例如肿瘤坏死因子（TNF））与 精神分裂症患者的动机定义和负面症状。关于机制 参与，我们的数据表明，在精神分裂症患者中，TNF与降低的激活有关 腹侧纹状体响应奖励预期以及在前绝缘的激活增加而增加 增加感知的努力。这些数据与管理的个人以前的结果一致 炎症刺激和抑郁症患者，表明注射靶向腹纹状体 前岛导致奖励处理和与动机相关的行为的下游变化。 综上所述，这些发现支持以下假设：炎症在动机定义和 精神分裂症患者的负面症状通过对腹侧纹状体和前岛的影响。 然而，这种关系的原因和影响性质尚不清楚。我们小组和其他人的工作 建议减少TNF拮抗剂英夫利昔单抗的炎症可改善与动机相关的行为 抑郁症和高注射的患者，我们的初步数据表明英夫利昔单抗有所改善 通过对腹侧纹状体的影响，基于努力的动机。但是，先前关于抗的研究 精神分裂症患者的炎症，包括细胞因子拮抗剂，受到缺乏的限制 感染增加且缺乏关注与感染相关行为的患者的特异性 变化（例如，动机）。在此，我们提出了一项机械临床试验，精神分裂症患者 具有高炎症和动机定义，将随机分配给抗炎挑战 英夫利昔单抗或安慰剂。然后，我们将检验以下假设，即英夫利昔单抗（VS安慰剂）将增加腹侧纹状体 响应于奖励预期和减少前岛的激活而激活前岛的激活 使用fMRI越来越大的努力。此外，我们将评估客观和临床测量的响应 动机。这是拟议研究的目标是使用生物标志物驱动的方法来确定 用英夫利昔单抗抑制TNF（与安慰剂相比）是否会增加腹侧纹状体的激活和 在基于努力的奖励任务（AIM 1）中减少前岛的激活，同时改善 动机的客观和临床措施（AIM 2）并探索英夫利昔单抗对其他大脑区域的影响 和解决特异性的行为（目标3）。总而言之，这项研究将揭示CNS动机的中枢神经系统机制 精神分裂症并提供生物标志物和靶标，将集中于未来的研究和支持的发展 相关精神分裂症亚组的精确疗法和最终导致负面症状。