Impact of Inflammation on Reward Circuits, Motivational Deficits and Negative Symptoms in Schizophrenia

炎症对精神分裂症奖励回路、动机缺陷和负面症状的影响

• 批准号: 10208667
• 负责人: David Ryan Goldsmith
• 金额: $ 19.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10208667
• 关键词: Accounting; Address; Anhedonia; Anti-Inflammatory Agents; Award; Basal Ganglia; Behavioral; Brain; Brain region; C-reactive protein; Clinical; Clinical Research; Corpus striatum structure; Data; Data Collection; Development; Development Plans; Disease; Education; Educational workshop; Employment; Ensure; Equipment and supply inventories; Ethics; Exhibits; Expenditure; Foundations; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Healthcare Systems; Human; Immune; Immune system; Immunology; Immunotherapy; Impairment; Individual; Inflammation; Inflammatory; Interleukin 2 Receptor; Interleukin-1 beta; Interleukin-10; Interleukin-6; Laboratory Animals; Link; Measures; Mediating; Mental Depression; Mentored Patient-Oriented Research Career Development Award; Mentorship; Meta-Analysis; Morbidity - disease rate; Motivation; Pathway interactions; Patient Self-Report; Patients; Peripheral; Placebos; Play; Positive Valence; Prefrontal Cortex; Public Health; Publishing; Randomized; Recovery of Function; Research; Research Domain Criteria; Research Methodology; Research Personnel; Research Training; Resistance; Resources; Rest; Rewards; Role; Schizophrenia; Stimulus; Symptoms; System; TNF gene; Techniques; Testing; Time; Training; Translational Research; United States National Institutes of Health; Ventral Striatum; Withdrawal; Work; anakinra; base; burden of illness; career; career development; cohort; cost; cytokine; depressed patient; design; falls; financial incentive; functional disability; functional outcomes; improved; inflammatory marker; infliximab; intrinsic motivation; monocyte; mortality; neural circuit; neuroimaging; neuromechanism; novel; novel therapeutic intervention; patient subsets; peripheral blood; pleasure; recruit; relating to nervous system; response; reward anticipation; reward circuitry; reward processing; social; socioeconomics

Project Summary/Abstract The proposed research and training plan is designed to promote my development as an independent investigator in the field of brain-immune interactions as they relate to negative symptoms in schizophrenia. Negative symptoms, including motivational deficits, are some of the most debilitating aspects of the disorder, being both difficult to treat and representing one of the most significant barriers to functional recovery. Regarding potential mechanisms of these deficits, individuals with schizophrenia reliably show decreased activation of the ventral striatum in reward-based neuroimaging tasks. One pathophysiologic pathway that may contribute to alterations in reward circuitry in schizophrenia is inflammation. Previous work has demonstrated that inflammatory stimuli decrease neural activity in the ventral striatum and decrease connectivity in reward- relevant neural circuitry. In addition, my published work and that of others has found that patients with schizophrenia reliably exhibit elevated concentrations of inflammatory markers, and my preliminary data indicate that inflammatory cytokines of monocytic origin, including tumor necrosis factor (TNF), are related to negative symptoms including decreased motivation and decreased functional connectivity in reward circuitry in these patients. Based on these findings, I hypothesize that increased inflammation in schizophrenia contributes to negative symptoms by disrupting neural activity in reward circuits leading to motivational deficits. To test this hypothesis, I propose the following Specific Aims: (1) To determine the association of inflammation with objective and clinical measures of motivation and negative symptoms, such as the Effort Expenditure for Reward Task, the Intrinsic Motivation Inventory, the Snaith Hamilton Pleasure Scale, and the Brief Negative Symptom Scale. (2) To determine the association of inflammation with reward circuitry in patients with schizophrenia using both task-based and resting state functional magnetic resonance imaging. (3) To explore whether the TNF antagonist, infliximab, will increase connectivity in reward circuitry leading to improvements in motivational deficits and negative symptoms. This work will inform future studies of novel therapeutic strategies to treat negative symptoms in patients with schizophrenia. As part of this proposal, I will also train in clinical research methods, neuroimaging techniques and analysis, immunology, assessments of motivation and negative symptoms in schizophrenia, and the ethical conduct of research. My development plan combines formal didactics, workshops, and hands-on training in neuroimaging, immunology, and schizophrenia, in addition to the proposed research. I have also assembled a team of recognized leaders in brain-immune interactions, schizophrenia and neuroimaging to provide mentorship during the award period. A K23 award is critical to my career development because it provides the needed protected time and resources to achieve my goals. The K23 award will also allow for data collection that will serve as the basis for R01 applications focused on translational research on the immune system and negative symptoms in schizophrenia.

项目摘要/摘要 拟议的研究和培训计划旨在促进我作为独立的发展 脑免疫相互作用领域的研究者与精神分裂症的负面症状有关。 负面症状，包括动机缺陷，是该疾病中最令人沮丧的方面 既难以治疗，又代表了功能恢复的最重要障碍之一。 关于这些缺陷的潜在机制，精神分裂症的个体可靠地显示 基于奖励的神经影像学任务中腹侧纹状体的激活。可能的一种病理生理途径 有助于精神分裂症中奖励电路的改变是炎症。以前的工作已经证明了 炎症性刺激会降低腹侧纹状体中的神经活动，并降低奖励的连通性 - 相关的神经回路。此外，我发表的工作和其他工作发现 精神分裂症可靠地表现出较高的炎症标记和我的初步数据 表明单核细胞起源的炎症细胞因子，包括肿瘤坏死因子（TNF），与 负面症状，包括减少动机和奖励电路功能连接性降低 这些患者。基于这些发现，我假设精神分裂症的炎症增加有助于 通过破坏奖励电路中的神经活动，导致动机赤字，来出现负面症状。测试这个 假设，我提出以下具体目的：（1）确定炎症与 动机和负面症状的客观和临床措施，例如努力支出 奖励任务，内在动机清单，Snaith Hamilton愉悦量表和简短的负面 症状量表。 （2）确定炎症与奖励电路的关联 精神分裂症都使用基于任务的和静止状态功能磁共振成像。 （3）探索 TNF拮抗剂英夫利昔单抗是否会增加奖励电路中的连接性，从而改善 动机缺陷和负面症状。这项工作将为未来的新型治疗策略提供信息 治疗精神分裂症患者的阴性症状。作为该提案的一部分，我还将在临床上进行培训 研究方法，神经影像技术和分析，免疫学，动机评估和 精神分裂症的负面症状和研究的道德行为。我的发展计划结合了 在神经影像，免疫学和精神分裂症方面的形式教学，讲习班和动手培训 补充拟议的研究。我还召集了一个在脑免疫的公认领导者团队 相互作用，精神分裂症和神经影像学在奖励期间提供指导。 K23奖是 对我的职业发展至关重要，因为它提供了所需的受保护时间和资源来实现我的 目标。 K23奖还将允许数据收集，以作为R01应用程序的基础 关于免疫系统的翻译研究和精神分裂症的负面症状。