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.

项目总结