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）患者的重要子集中，并具有毁灭性的个人和临床影响。大多数关于BD的生物医学研究忽略了精神病的可变表现，可能忽略了BD的生物学显著异质性;这种异质性可能导致文献中将BD视为同质类别7，18。在某些BD患者（BD-P）中表达精神病，而在其他患者（BD-NP）中不表达精神病，可能表明具有重要疾病分类学和临床相关性的不同疾病过程。PARDIP利用BD的大样本，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BD的分类和研究产生重要影响，为未来有效的病因学研究提供强有力的目标，并澄清可用的生物标志物对主要精神障碍的效用。PARDIP代表了向基于机制的精神疾病分类迈出的一步。 具体目标：PARDIP将（i）识别标志精神病的生物认知中断模式（BD-P`BD-NP）或一般情绪不稳定（BD`健康比较），（ii）探索这些生物标志物如何相互关联以及与BD中存在的精神病理学的其他维度相关，以及（iii）利用多变量数据集的潜在类和聚类分析来验证BD中关于精神病的分类性，并揭示潜在的精神病性为将来的基因分型和病因学研究提供了感兴趣的亚组。 研究方法：为期三年的PARDIP项目将招募135名精神病性BD，135名非精神病性BD和135名精神健康的对照受试者（所有新兵），管理集中在精神病和躁狂领域的精神病理学的全面电池。我们将获得神经生理学（平稳追踪眼球运动、反扫视、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（情绪图片的ERP）、内在脑状态（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，以确定哪些轨道与精神病，哪些轨道与情感障碍。我们将通过联合ICA和PCA方法确定测量之间的共同方差来源，并研究生物标志物和生物标志物复合物与临床异质性的其他方面的关系。将使用多变量数据集进行Taxometric程序（MAXCOV-HITMAX及其多变量扩展MAXEIG-HITMAX和k均值聚类），以凭经验识别不同的受试者亚组。PARDIP将由4个经验丰富的研究小组（跨越3个采集地点）进行，这些研究小组具有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.