Longitudinal multi-modal neuroimaging of irritability in youth

 描述（由申请人提供）：易怒存在于青年的多种疾病中，表明它是跨越传统分类诊断边界的精神病理学的一个维度。我们建议利用费城神经发育队列（PNC）的资源和数据来研究异常的大脑发育如何产生维度定义的易怒症状。作为PNC的一部分，一个8-21岁青年的大样本（n= 1，601）完成了横断面神经成像沿着临床和认知表型，包括易怒的筛选问题。我们将进行纵向随访 对140名患有不同精神病理学的青少年进行多模态神经成像，这些青少年对易怒症状筛查呈阳性，以及60名匹配的典型发育对照。我们将重复在基线进行的成像序列，包括脑结构的T1成像，脑灌注的动脉自旋标记MRI，功能连接的静息状态扫描，以及n-back工作记忆任务的分形版本。这些纵向措施将补充横断面收购序列，特别是相关的易怒，包括高时间分辨率静息状态序列，以检查动态执行情感连接以及社会情感反馈功能磁共振成像范式，招募腹侧纹状体和杏仁核。通过这些措施提供的大脑结构和功能的综合评估，将使测试模型，假定易怒的结果不断变化的组合的执行缺陷，情感失调，和执行情感的连接障碍。因此，在目标1中，我们将描述通过多模态成像测量的大脑发育的纵向变化如何与易怒相关。在目标2中，我们将使用在随访时获得的专门功能成像序列证明易怒与异常情感激活和连接相关。在目标3中，由于先前的工作已经证明了在易怒和大脑发育模式方面的性别差异，我们将研究与易怒相关的大脑表型如何因性别而异。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态成像数据并预测易怒。此应用程序利用了 PI的临床经验、多模态发育神经成像的专业知识、建立的合作关系以及对PNC数据集的熟悉程度。通过提出的多层次分析，这项创新的研究将提供一个实质性的进步，我们的理解的神经发育底物的易怒。

 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.