Striatal Connectivity and Clinical Outcome in Psychosis

摘要 越来越多的证据表明纹状体连接障碍在青光眼的病理生理中起着关键作用。 精神错乱。在拟议的研究中，我们将利用静息状态功能磁共振成像(RS-fMRI)， 以及从研究领域标准(RDoC)框架派生的功能磁共振任务，以：1)开发和 验证预测抗精神病药物治疗反应的预后生物标记物；以及2)对潜在的 精神病症状学中与状态变化相关的神经回路变化。作为一个预言家 生物标志物，纹状体连接性的神经成像分析，可能提供一种临床有用的工具 推进精准医疗目标。作为症状变化的纵向指标，我们的模型可以作为 衡量新开发的抗精神病药物治疗潜在疗效的客观指标。 一大群(n=120)首发主动性精神病患者的特征良好的队列 (不考虑DSM诊断)将被招募，以及匹配的对照组(n=50)。我们将利用两口井- 捕捉正价系统两个部分的有效fMRI任务：概率类别学习和 奖赏反应；这些任务被设计用来询问背侧和腹侧皮质纹状体回路， 分别进行了分析。我们的设计将是纵向的，为每个患者执行两次扫描： 基线，治疗12周后。所有患者的治疗将标准化，以减少 潜在的混淆，健康对照也将在基线和12周进行扫描，以控制 时间和实践的影响。精神病症状水平(幻觉、妄想和思维 无序)将使用一套全面的额定量表定期进行测量。我们将利用 Kaplan-Meier估计量和分层线性模型检验基线纹状体的关联性 连通性，以及连通性随时间的变化，以及精神病症状对 抗精神病药物治疗。交付成果将包括基线和纵向生物标记物，这些标记物可以 随后在更广泛、更异质的精神病患者群体中进行测试。

ABSTRACT Converging lines of evidence suggest a key role for striatal dysconnectivity in the pathophysiology of psychosis. In the proposed study, we will utilize resting state functional magnetic resonance imaging (rs-fMRI), as well as fMRI tasks derived from the Research Domain Criteria (RDoC) framework, to: 1) develop and validate a prognostic biomarker to predict antipsychotic treatment response; and 2) to model the underlying neural circuitry changes associated with state changes in psychotic symptomatology. As a prognostic biomarker, a neuroimaging assay of striatal connectivity can potentially provide a clinically useful tool to advance the goal of precision medicine. As a longitudinal index of symptom change, our model can serve as an objective index against which to measure potential efficacy of newly developed antipsychotic treatments. A large (n=120), well-characterized cohort of patients presenting with a first episode active psychosis (regardless of DSM diagnosis) will be recruited, along with matched controls (n=50). We will utilize two well- validated fMRI tasks capturing two portions of the positive valence system: probabilistic category learning and reward responsiveness; these tasks are designed to interrogate dorsal and ventral corticostriatal circuits, respectively. Our design will be longitudinal, with two scanning sessions performed for each patient: at baseline, and after 12 weeks of treatment. Treatment will be standardized across all patients to reduce potential confounds, and healthy controls will also be scanned at baseline and 12 weeks in order to control for effects of time and practice. Level of psychotic symptomatology (hallucinations, delusions, and thought disorder) will be measured at regular intervals using a comprehensive battery of rating scales. We will utilize Kaplan-Meier estimators and hierarchical linear modeling to examine the association of baseline striatal connectivity, and changes in connectivity over time, with clinical response of psychotic symptoms to antipsychotic treatment. Deliverables will include both baseline and longitudinal biomarkers that can subsequently be tested in broader, more heterogeneous populations of patients with psychosis.