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）： 对于许多患有精神分裂症（SCZ）的退伍军人来说，阴性症状是功能恢复的主要障碍。现有的药物和社会心理干预措施对这些症状的益处有限。根据 NIMH 共识会议关于识别和解决这一未满足治疗需求的障碍的建议，由 PI 发挥领导作用的推进阴性症状评估合作组织已经验证了一项新的访谈，以在两个基本领域内评估阴性症状： （动机和寻求奖励减少）和表达性（表达性沟通减少）。人们对体验症状的兴趣日益浓厚。我们发现这些症状与功能不良密切相关，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”）。体验症状也更适合基于奖励处理动物模型的转化研究。 我们建议通过两种方式解决开发针对体验性阴性症状的新疗法的剩余障碍。首先，我们将识别生物行为标记。根据动物模型，我们选择了奖励处理任务，这些任务利用不同的神经回路来评估它们是否：a）显示与症状的假设关系，b）显示足够的纵向稳定性，可用作临床试验中的结果测量。其次，我们将测试功能结果的神经和心理机制的综合模型。我们认为，基于大脑的奖励处理缺陷会导致信念功能失调，进而导致体验症状，最终导致功能不良。 该项目的目标将针对 SCZ 患者，分为高（n = 80）或低（n = 80）体验性阴性症状组（基于我们新的临床访谈）和健康对照样本（n = 40）。参与者将完成四项涉及不同皮质-边缘-纹状体回路的奖励处理任务。 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：对奖励的反应所带来的快乐体验，以及学习：根据持续的奖励和惩罚来调整自己的行为。新的行为任务将用于评估更高级别的决策过程：（3）努力评估：奖励是否值得为获得它而付出努力？ (4) 延迟估价：奖励是否值得延迟获得它所需的时间？对 SCZ 中这些奖励处理组件的系统研究很少。根据我们之前的行为和脑电图研究，我们假设具有高度阴性症状的 SCZ 组将表现出完整的“喜欢”，但在一个或多个其他组成部分中存在损害。 学习、努力和延迟评估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效果来进一步评估。在汇总 SCZ 样本 (n = 160) 中，结构方程模型将测试功能失调的信念和体验性负面症状是否介导基于大脑的奖励处理任务和功能结果之间的关系。最后，所有参与者将在 4 周（临床试验的典型间隔）后重新进行测试，以确定任务是否表现出用作临床试验终点所需的高水平稳定性。 结果将有助于分离导致阴性症状的神经回路，建立指导临床前和临床研究的理论框架，并提供在临床试验中测试创新疗法的结果指标。