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。现有的药理学和心理社会干预措施显示，对这些症状的益处有限。根据NIMH关于识别和解决这一未得到满足的治疗需求的障碍的共识会议的建议，由PI发挥领导作用的推进阴性症状评估的合作已经批准了一项新的面谈，以评估两个基本领域的阴性症状：经验性(动机和寻求奖励减少)和表现性(表达交流减少)。越来越多的兴趣集中在经验性症状上。我们发现，这些症状更多地与功能不良有关，似乎源于认知扭曲，如失败主义信念(例如，“实现一个目标不值得等待”)。经验性症状也更容易接受基于奖励加工动物模型的转译研究。我们建议通过两种方式来解决开发新的经验性阴性症状治疗方法的剩余障碍。首先，我们将确定生物行为标志物。借鉴动物模型，我们选择了进入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，b)显示足够的纵向稳定性，以用作临床试验的结果衡量标准。第二，我们将测试一个神经和心理机制的功能结果的综合模型。我们认为，基于大脑的奖赏处理缺陷会导致信念功能障碍，进而导致经验性症状，最终导致功能低下。该项目的目标将在SCZ患者中实现，这些患者被分成高(n=80)或低(n=80)经验性阴性症状组(基于我们新的临床访谈)和健康对照样本(n=40)。参与者将完成四项奖赏处理任务，涉及不同的皮质-边缘-纹状体回路。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：体验对奖励的快乐，学习：调整一个人的行为，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级别的决策过程：(3)努力评估：(3)努力评估：回报是否值得为获得它所需的努力？(4)延迟评估：回报是否值得为获得它所需的时间延迟？对SCZ中这些奖赏加工成分的系统研究一直很少见。根据我们先前的行为和脑电研究，我们假设具有高度阴性症状的SCZ组将表现出完整的喜欢，但在其他一个或多个成分上存在损害。学习、努力和延迟评估任务的有效性将通过确定它们在综合结果模型中预测经验性负面症状的程度来进一步评估。在混合的SCZ样本(n=160)中，结构方程模型将检验功能障碍信念和经验性负面症状是否在基于大脑的奖励加工任务与功能结果之间的关系中起中介作用。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，建立一个指导临床前和临床研究的理论框架，并在临床试验中提供测试创新治疗的结果衡量标准。

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.