Mechanisms of Negative Symptoms in Veterans with Schizophrenia

描述（由申请人提供）： 阴性症状是许多退伍军人精神分裂症（SCZ）功能恢复的主要障碍。现有的药物和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种未满足的治疗需求的障碍的建议，合作推进阴性症状评估，其中PI具有领导作用，已经验证了一种新的访谈，以评估两个基本领域内的阴性症状：经验（减少动机和寻求奖励）和表达（减少表达沟通）。越来越多的兴趣集中在经验症状上。我们发现，这些症状与功能障碍有更强的相关性，似乎源于认知扭曲，如失败主义信念（例如，“实现目标不值得等待”）。经验症状也更适合基于奖励处理动物模型的转化研究。 我们建议以两种方式解决开发经验性阴性症状新疗法的剩余障碍。首先，我们将识别生物行为标记。利用动物模型，我们选择了利用不同神经回路的奖励处理任务，以评估它们是否：a）显示与症状的假设关系，以及B）显示足够的纵向稳定性，以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功能失调的信念，然后导致经验症状，最终导致功能不良。 本项目的目的将在SCZ患者中进行，这些患者分为高（n = 80）或低（n = 80）经验阴性症状组（基于我们新的临床访谈），以及健康对照样本（n = 40）。参与者将完成四个涉及不同皮质-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：学习：适应一个人的行为以应对持续的奖励和惩罚。新的行为任务将被用来评估更高层次的决策过程：（3）努力价值评估：是否值得付出努力获得它？(4)延迟评估：奖励值得为获得它而延迟的时间吗？对SCZ中这些奖赏加工成分的系统研究很少。根据我们先前的行为和脑电图研究，我们假设，具有高阴性症状的SCZ组将显示完整的喜欢，但在一个或多个其他组件中受损。 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的综合模型中预测经验性阴性症状的程度来进一步评估。在合并的SCZ样本（n = 160），结构方程模型将测试功能失调的信念和经验的负面症状是否调解之间的关系，以大脑为基础的奖励处理任务，一方面和功能的结果。最后，所有参与者将在4周后（临床试验的典型间隔）重新测试，以确定任务是否显示出用作临床试验终点所需的高水平稳定性。 研究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治疗的结果指标。

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.