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 精神分裂症患者动机缺陷的中枢神经系统机制尚不清楚。 这些缺陷显着有助于阴性症状，这是密切相关的不良功能 结果和对抗精神病治疗无反应。我们小组和其他人的数据表明， 外周炎性标志物，如肿瘤坏死因子（TNF）的增加与 精神分裂症患者的动机缺陷和阴性症状。关于机制 我们的数据表明，在精神分裂症患者中，TNF与细胞因子激活减少有关。 腹侧纹状体对奖励预期的反应以及前额叶的激活增加 to increasingly增加perceived感知effort努力.这些数据与先前的结果一致， 炎症刺激和抑郁症患者，表明炎症靶向腹侧纹状体 和前额叶，导致下游的奖励处理和动机相关行为的变化。 总之，这些发现支持了炎症在动机缺陷中起作用的假设， 精神分裂症患者的阴性症状通过腹侧纹状体和前额叶的影响。 然而，这种关系的因果性质仍然不清楚。我们团队和其他人的工作 提示用TNF拮抗剂英夫利西单抗减轻炎症可以改善 我们的初步数据表明，英夫利西单抗可以改善抑郁症和高度炎症的患者， 通过腹侧纹状体的影响，抑郁症中基于努力的动机。然而，以前的研究表明， 包括细胞因子拮抗剂在内的炎性药物在精神分裂症患者中的应用受到缺乏 对于炎症增加和缺乏炎症相关行为关注的患者的特异性 变化（例如，动机）。在此，我们提出了一个机制的临床试验，其中精神分裂症患者 具有高度炎症和动机缺陷的患者将被随机分配至抗炎挑战， 英夫利昔单抗或安慰剂。然后，我们将检验英夫利西单抗（与安慰剂相比）将增加腹侧纹状体的 前额叶皮层的激活和减少前额叶皮层的激活 使用功能性磁共振成像技术。此外，我们将评估以下客观和临床指标的反应： 动机因此，拟议研究的目标是使用生物标记驱动的方法来确定 英夫利西单抗抑制TNF（与安慰剂相比）是否增加腹侧纹状体的激活， 在基于努力的奖励任务（目标1）中，减少前额叶的激活， 动机的客观和临床测量（目标2），并探索英夫利西单抗对其他大脑区域的影响 和行为，以解决特异性（目标3）。总之，这项研究将揭示中枢神经系统的失动机制， 精神分裂症，并提供生物标志物和目标，将重点放在未来的研究和支持发展， 精确治疗相关精神分裂症亚组的失动和最终阴性症状。