Longitudinal multi-modal neuroimaging of irritability in youth

 描述(由申请人提供)：易怒存在于青少年的多种障碍中，这表明这是精神病理学的一个维度，跨越了传统的分类诊断界限。我们建议通过利用费城神经发育队列(PNC)的资源和数据来调查大脑发育异常如何产生维度定义的易怒症状。作为PNC的一部分，一个8-21岁的年轻人的大样本(n=1,601)完成了横断面神经成像以及临床和认知表型，包括筛选易怒问题。我们将进行纵向跟踪 对140名患有不同精神病理学、易怒症状筛查呈阳性的年轻人以及60名匹配的典型发育中的对照组进行了多模式神经成像。我们将重复基线时执行的成像序列，包括脑结构的T1成像、脑灌注的动脉自旋标记MRI、功能连接性的静息状态扫描，以及n-back工作记忆任务的分形版。对这些纵向测量的补充将是对与应激性特别相关的序列的横断面获取，包括用于检查动态执行-情感连接的高时间分辨率休息状态序列，以及招募腹侧纹状体和杏仁核的社会情感反馈功能磁共振范式。这些措施提供的对大脑结构和功能的全面评估将使测试一个模型成为可能，该模型假设易怒导致执行缺陷、情感调节失调和执行-情感连接失调的不断演变的组合。因此，在目标1中，我们将描绘通过多模式成像测量的大脑发育的纵向变化是如何与易怒相关的。在目标2中，我们将使用在随访中获得的特殊功能成像序列来证明易怒与异常的情感激活和连接有关。在目标3中，由于先前的工作已经证明了易怒和大脑发育模式的性别差异，我们将研究与易怒相关的大脑表型如何因性别而不同。最后，在探索性目标4中，我们将使用先进的多变量模式分析技术来整合高维多模式成像数据，并预测应激性。该应用程序充分利用了 PI的临床经验、在多模式发育神经成像方面的专业知识、已建立的合作以及对PNC数据集的熟悉程度。通过拟议的多层次分析，这项创新研究将为我们对易怒的神经发育底物的理解提供实质性的进步。

 DESCRIPTION (provided by applicant): Irritability is present in multiple disorders in youth, suggesting that it is a dimension of psychopathology that cuts across traditional categorical diagnostic boundaries. We propose to investigate how abnormal brain development produces dimensionally defined symptoms of irritability by leveraging the resources and data of the Philadelphia Neurodevelopmental Cohort (PNC). As part of the PNC, a large sample (n=1,601) of youth ages 8-21 completed cross-sectional neuroimaging along with clinical and cognitive phenotyping, including screening questions for irritability. We will conduct longitudinal follow-up multi-modal neuroimaging in 140 youth with diverse psychopathology who screened positive for symptoms of irritability, as well as 60 matched typically developing controls. We will repeat the imaging sequences performed at baseline including T1 imaging of brain structure, arterial spin labeled MRI of cerebral perfusion, a resting-state scan of functional connectivity, and a fractal version of the n-back working memory task. These longitudinal measures will be supplemented by the cross-sectional acquisition of sequences that are particularly relevant to irritability, including a high temporal resolution resting state sequence to examine dynamic executive-affective connectivity as well as a social affective feedback fMRI paradigm that recruits both the ventral striatum and the amygdala. The comprehensive assessment of brain structure and function provided by these measures will enable testing a model which posits that irritability results an evolving combination of executive deficits, affective dysregulation, and executive-affective dysconnectivity. Accordingly, in Aim 1 we will delineate how longitudinal changes in brain development as measured by multi-modal imaging are associated with irritability. In Aim 2, we will demonstrate that irritability is associated abnormal affective activation and connectivity using specialized functional imaging sequences acquired at follow-up. In Aim 3, as prior work has demonstrated sex differences in the both irritability and patterns of brain development, we will examine how brain phenotypes associated with irritability differ by sex. Finally, in Exploratory Aim 4 we will use advanced multivariate pattern analysis techniques to integrate high-dimensional multi-modal imaging data and predict irritability. This application capitalizes on the PI's clinical experience, expertise in multi-modal developmental neuroimaging, established collaborations, and intimate familiarity with the PNC dataset. Through the proposed multi-level analysis, this innovative research will provide a substantial advance in our understanding of the neurodevelopmental substrates of irritability.