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

项目总结/摘要 建议的研究和培训计划旨在促进我作为一个独立的发展 脑免疫相互作用领域的研究者，因为它们与精神分裂症的阴性症状有关。 消极症状，包括动机缺陷，是这种疾病最令人衰弱的方面， 其既难以治疗又是功能恢复的最重要障碍之一。 关于这些缺陷的潜在机制，精神分裂症患者可靠地表现出降低的 腹侧纹状体的激活在奖励为基础的神经成像任务。一种病理生理途径， 导致精神分裂症患者奖赏回路改变的是炎症。先前的研究表明， 炎症刺激会降低腹侧纹状体的神经活动，降低奖赏的连通性， 相关的神经回路此外，我和其他人发表的研究发现， 精神分裂症确实表现出炎症标志物浓度升高，我的初步数据显示， 表明单核细胞来源炎性细胞因子，包括肿瘤坏死因子（TNF），与 阴性症状包括动机降低和奖励回路功能连接减少， 这些病人。基于这些发现，我假设精神分裂症中炎症的增加有助于 通过扰乱奖励回路中的神经活动导致动机缺陷而导致负面症状。为了验证这一 假设，我提出以下具体目的：（1）确定炎症与 动机和阴性症状的客观和临床测量，例如 奖励任务、内在动机量表、Snaith汉密尔顿快乐量表和简短否定量表 症状量表。(2)为了确定炎症与奖赏回路的关联， 精神分裂症使用基于任务和静息状态功能磁共振成像。(3)探讨 TNF拮抗剂英夫利西单抗是否会增加奖赏回路的连通性，从而改善 动机缺陷和阴性症状。这项工作将为未来新的治疗策略的研究提供信息 来治疗精神分裂症患者的阴性症状作为这项提议的一部分，我还将接受临床培训， 研究方法，神经成像技术和分析，免疫学，动机评估和 精神分裂症的阴性症状，以及研究的道德行为。我的发展计划 正式的教学法，研讨会，并在神经影像学，免疫学和精神分裂症的动手训练，在 除了拟议的研究。我还组建了一个由脑免疫领域公认的领导者组成的团队 互动，精神分裂症和神经影像学，在奖励期间提供指导。K23奖项 对我的职业发展至关重要，因为它提供了实现我的职业发展所需的时间和资源。 目标. K23奖还将允许数据收集，作为R 01应用程序的基础， 关于免疫系统和精神分裂症阴性症状的转化研究。

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.