4/4-Psychosis and Affective Research Domains and Intermediate Phenotypes (PARDIP)

描述（由申请人提供）：精神病症状存在于双相情感障碍（BD）患者的一个重要子集中，并且具有破坏性的个人和临床影响。大多数关于双相障碍的生物医学研究都忽略了精神病的可变表现，可能忽略了双相障碍在生物学上的显著异质性；这种异质性可能会导致文献将双相障碍视为同质类别7,18。一些BD患者有精神病的表达（BD- p），而另一些患者没有精神病（BD- np），这可能表明不同的疾病过程具有重要的分科和临床意义。PARDIP利用大量的BD样本，全面的电池和复杂的分析工具来确定BD- p和BD- np是否代表程度上的差异或种类上的差异。长期目标：这项工作将对双相障碍的分类和研究产生重大影响，为未来有效的病因学研究提供强有力的目标，并阐明可用于重大精神障碍的生物标志物的效用。PARDIP代表着朝着基于机制的精神疾病分类迈出了一步。具体目标:PARDIP将(i)确定标志精神病（BD- p）或一般情绪不稳定（BD健康比较）的双认知中断模式，（ii）探索这些生物标志物如何相互关联以及与双相障碍中存在的精神病理的其他方面的关系。（iii）利用多变量数据集的潜在类和聚类分析来验证双相障碍与精神病的分类，并为未来的基因分型和病因学研究发现潜在的精神病学亚群。方法：为期三年的PARDIP项目将招募135名精神病性双相障碍、135名非精神病性双相障碍和135名精神健康对照受试者（均为新兵），对精神病理学的精神病和躁狂领域进行全面的研究。我们将获得神经生理学（眼球平滑追踪运动、抗扫视、听觉erp）、认知（认知电池、反应抑制、空间工作记忆）、神经解剖学（结构磁共振成像[MRI]）、情绪处理（erp到情绪图片）、大脑内在状态（静息功能MRI连接）和昼夜节律功能（活动图）的测量结果。我们将比较BD-P、BD-NP和H组之间的生物标志物，以确定哪一组是精神病，哪一组是情感障碍。我们将在联合ica和PCA方法中确定常见的差异来源，并研究生物标志物和生物标志物复合物如何与临床异质性的其他方面相关。分类程序（MAXCOV- HITMAX及其多元扩展maxeg -HITMAX和k-means聚类）将与多元数据集一起进行，以经验识别不同的受试者亚群。PARDIP将由4个经验丰富的研究小组（横跨3个收集点）进行，他们有着长期密切和富有成效的合作历史。

DESCRIPTION (provided by applicant): Psychotic symptoms are present in a significant subset of individuals with Bipolar Disorder (BD) and carry devastating personal and clinical implications. Most biomedical research on BD has ignored the variable presentation of psychosis possibly overlooking biologically significant heterogeneity in BD; such heterogeneity may cause inconsistencies in the literature by treating BD as a homogenous category 7,18. The expression of psychosis in some BD patients (BD-P) and absence in others (BD-NP) may indicate divergent disease processes of critical nosological and clinical relevance. PARDIP leverages a large sample of BD, a comprehensive battery, and sophisticated analytic tools to establish whether BD-P and BD-NP represent a difference in degree or a difference in kind. Long-term goals: This work will critically impact how BD is classified and studied, provide robust targets for effective future etiological studies, and clarify the utility of available biomarkers o major psychiatric disturbance. PARDIP represents a step toward mechanistically based classification of psychiatric disorders. Specific Aims: PARDIP will (i) identify the patterns of bo-cognitive disruptions which mark psychosis (BD-P`BD-NP) or mood instability in general (BD`healthy comparisons), (ii) explore how these biomarkers relate to one another and to other dimensions of psychopathology present in BD, and (iii) utilize latent class and cluster analyses of the multivariate dataset to verify taxonicity within BD with regard to psychosis and uncover latent psychiatric subgroups of interest for future genotyping and etiological research. Methods: The three-year PARDIP project will recruit 135 psychotic BD, 135 non-psychotic BD, and 135 psychiatrically healthy comparison subjects (all new recruits), administering a comprehensive battery focused on the psychosis and mania domains of psychopathology. We will obtain measures of neurophysiology, (smooth pursuit eye movements, antisaccades, auditory ERPs), cognition (cognitive battery, response inhibition, spatial working memory), neuroanatomy (structural magnetic resonance imaging [MRI]), emotional processing (ERPs to emotional pictures), intrinsic brain state (resting functional MRI connectivity), and circadian function (Actigraphy). We will compare biomarkers between BD-P, BD-NP, and H groups to determine which track with psychosis and which track with affective disturbance. We will identify common sources of variance among measures with joint-ICA and PCA approaches, and examine how biomarkers and biomarker composites relate to other aspects of clinical heterogeneity. Taxometric procedures (MAXCOV- HITMAX and its multivariate extension MAXEIG-HITMAX and k-means clustering) will be carried out with the multivariate dataset to empirically identify distinct subgroups of subjects. PARDIP will be conducted by 4 experienced research groups (across 3 collection sites) with a long history of close and productive collaboration.