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.

项目概要 精神分裂症患者动机缺陷背后的中枢神经系统机制尚不清楚。 这些缺陷显着导致阴性症状，而阴性症状与功能不良密切相关。 我们小组和其他人的数据表明，结果和抗精神病药物无反应。 外周炎症标志物的增加，例如肿瘤坏死因子（TNF），与 关于精神分裂症患者的动机缺陷和阴性症状的机制。 我们的数据表明，在精神分裂症患者中，TNF 与 腹侧纹状体对奖励预期的反应以及前岛叶的激活增加 这些数据与之前接受治疗的个人的结果一致。 炎症刺激和抑郁症患者的刺激表明炎症针对腹侧纹状体 和前岛叶导致奖励处理和动机相关行为的下游变化。 总而言之，这些发现支持了这样的假设：炎症在动机缺陷和 通过对腹侧纹状体和前岛叶的影响，精神分裂症患者出现阴性症状。 然而，我们的团队和其他人的工作仍不清楚这种关系的因果关系。 表明用 TNF 拮抗剂英夫利昔单抗减轻炎症可改善动机相关行为 患有抑郁症和高炎症的患者，我们的初步数据表明英夫利昔单抗可以改善 通过对腹侧纹状体的影响，抑郁症中基于努力的动机然而，先前的研究表明， 精神分裂症患者的炎症药物（包括细胞因子拮抗剂）因缺乏 针对炎症加剧且缺乏对炎症相关行为的关注的患者的特异性 在此，我们提出了一项机械临床试验，其中精神分裂症患者。 患有高炎症和动机缺陷的人将被随机接受抗炎挑战 然后我们将检验英夫利昔单抗（与安慰剂相比）会增加腹侧纹状体的假设。 响应奖励预期的激活并减少前岛叶响应的激活 此外，我们将评估客观和临床措施的反应。 因此，拟议研究的目标是使用生物标记驱动的方法来确定。 英夫利昔单抗（与安慰剂相比）抑制 TNF 是否会增加腹侧纹状体的激活以及 在基于努力的奖励任务（目标 1）期间减少前岛叶的激活，同时改善 动机的客观和临床测量（目标 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，本研究将揭示中枢神经系统的动机缺失机制。 精神分裂症，并提供生物标志物和目标，将重点关注未来的研究并支持精神分裂症的开发 针对相关精神分裂症亚组的动机丧失和最终阴性症状的精准治疗。