Mechanisms of Negative Symptoms in Veterans with Schizophrenia

精神分裂症退伍军人出现阴性症状的机制

• 批准号: 8768461
• 负责人: WILLIAM P. HORAN
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768461
• 关键词: Address; Animal Model; Attitude; Base of the Brain; Behavior; Behavioral; Belief; Benchmarking; Brain; Clinical; Clinical Research; Clinical Trials; Cognitive; Collaborations; Communication; Consensus; Control Groups; Corpus striatum structure; Costs and Benefits; Decision Making; Development; Equation; Feedback; Foundations; Goals; Health; Heterogeneity; Impairment; Intervention; Intervention Trial; Interview; Lead; Leadership; Learning; Measures; Mediating; Modeling; Motivation; National Institute of Mental Health; Outcome; Outcome Measure; Participant; Patients; Performance; Pharmaceutical Preparations; Pre-Clinical Model; Preparation; Process; Property; Psychological reinforcement; Psychometrics; Public Health; Punishment; Recommendation; Recovery of Function; Recruitment Activity; Research; Rewards; Role; Sampling; Schizophrenia; Signal Transduction; Specific qualifier value; Symptoms; Testing; Time; Translational Research; Veterans; base; behavior measurement; biobehavior; discounting; experience; follow-up; functional outcomes; innovation; interest; neural circuit; neural model; novel; pleasure; pre-clinical research; preclinical study; psychologic; psychosocial; response; reward processing; stem; symposium; therapy development

DESCRIPTION (provided by applicant): Negative symptoms are a major impediment to functional recovery for many Veterans with schizophrenia (SCZ). Available pharmacological and psychosocial interventions show only limited benefits for these symptoms. Following recommendations from a NIMH consensus conference on identifying and addressing obstacles to this unmet treatment need, the Collaboration to Advance Negative Symptom Assessment, in which the PI has a leadership role, has validated a new interview to assess negative symptoms within two basic domains: experiential (diminished motivation and reward-seeking) and expressive (diminished expressive communication). Increasing interest has focused on the experiential symptoms. We have found that these symptoms are more strongly related to poor functioning and appear to stem from cognitive distortions, such as defeatist beliefs (e.g., "Achieving a goal isn't worth the wait"). Experiential symptoms are also much more amenable to translational research based on animal models of reward processing. We propose to address remaining obstacles to the development of new treatments for experiential negative symptoms in two ways. First, we will identify biobehavioral markers. Drawing on animal models, we selected reward-processing tasks that tap into distinct neural circuits to evaluate whether they: a) show hypothesized relations to symptoms and b) show sufficient longitudinal stability for use as outcome measures in clinical trials. Second, we will test an integrative model of neural and psychological mechanisms of functional outcome. We propose that brain-based reward processing deficits lead to dysfunctional beliefs that then lead to experiential symptoms and, ultimately, poor functioning. The aims of this project will be addressed in SCZ patients stratified into high (n = 80) or low (n 80) experiential negative symptom groups (based on our new clinical interview), and a healthy control sample (n = 40). Participants will complete four reward-processing tasks that involve different cortico-limbic-striatal circuits. We will use electrophysiological (EEG) tasks to assess two basic reward processes: Liking: experience of pleasure in response to rewards, and Learning: adapting one's behavior in response to ongoing rewards and punishments. Novel behavioral tasks will be used to assess to higher-level decision making processes: (3) Effort valuation: is a reward worth the effort required to obtain it? (4) Delay valuation: is a reward worth the time delay required to obtain it? Systematic research on these reward-processing components in SCZ has been rare. Based on our prior behavioral and EEG research, we hypothesize that the SCZ group with high negative symptoms will show intact Liking but impairment in one or more of the other components. The validity of the Learning, Effort, and Delay valuation tasks will be further evaluated by determining how well they predict experiential negative symptoms within an integrative model of outcome. In the pooled SCZ sample (n = 160), Structural Equation Modeling will test whether dysfunctional beliefs and experiential negative symptoms mediate the relation between brain-based reward-processing tasks on the one hand, and functional outcome on the other. Finally, all participants will be re-tested after 4-weeks (a typical interval for clinical trials) to determine whether the tasks show the high level o stability required for use as clinical trial endpoints. Results will help isolate neural circuits hat contribute to negative symptoms, establish a theoretical framework to guide preclinical and clinical research, and provide outcome measures testing innovative treatments in clinical trials.

描述（由申请人提供）： 负面症状是许多精神分裂症退伍军人（SCZ）功能恢复的主要障碍。可用的药理学和社会心理干预措施仅显示这些症状的好处有限。遵循NIMH共识会议的建议，识别和解决这种未满足治疗需求的障碍，提高PI具有领导作用的负面症状评估的协作，已验证了一项新的访谈，以评估两个基本领域内的负面症状：经验性症状：经验。 （减少动机和寻求奖励）和表现力（表现力的交流减少）。越来越多的兴趣集中在体验症状上。我们发现，这些症状与功能较差的症状更加密切，并且似乎源于认知扭曲，例如失败主义信念（例如，“实现目标不值得等待”）。基于奖励处理的动物模型，体验症状也更适合转化研究。 我们建议通过两种方式解决经验性负面症状的新疗法的剩余障碍。首先，我们将确定生物行为标记。利用动物模型，我们选择了奖励处理任务，这些任务挖掘到不同的神经回路中，以评估它们是否：a）在临床试验中显示出足够的纵向稳定性，并显示出足够的纵向稳定性作为结果指标。其次，我们将测试功能结果的神经和心理机制的综合模型。我们建议基于大脑的奖励处理缺陷导致功能失调的信念，然后导致体验症状，最终导致功能较差。 该项目的目的将在SCZ患者中分为高（n = 80）或低（n 80）体验症状症状组（基于我们的新临床访谈）和健康对照样本（n = 40）。参与者将完成四项涉及不同Cortico-limbic-Striatal电路的奖励处理任务。 我们将使用电生理（EEG）任务来评估 两个基本的奖励过程：喜欢：回应奖励和学习的愉悦经验：根据持续的奖励和惩罚来调整自己的行为。新颖的行为任务将用于评估更高级别的决策过程：（3）努力估值：奖励值得获得它所需的努力吗？ （4）延迟估值：获得获得时间延迟的奖励值得吗？ SCZ中这些奖励处理组件的系统研究很少。基于我们先前的行为和脑电图研究，我们假设具有高症状的SCZ组将显示出完整的喜好，但在一个或多个其他组件中会受到损害。 学习，精力和延迟估值任务的有效性将通过确定它们在结果综合模型中预测体验性负面症状的能力来进一步评估。在合并的SCZ样品（n = 160）中，结构方程建模将测试功能失调的信念和体验式负面症状是否一方面介导了基于大脑的奖励处理任务之间的关系，另一方面是功能结果。最后，在4周（临床试验的典型间隔）之后，将对所有参与者进行重新测试，以确定任务是否显示使用用作临床试验终点所需的高水平O稳定性。 结果将有助于隔离神经回路的帽子有助于负面症状，建立一个理论框架来指导临床前和临床研究，并提供结果测试在临床试验中测试创新治疗的结果。