Structural constraints on large-scale brain activity in psychosis associated with chromosome 22q11.2 deletion syndrome

项目摘要 在健康大脑中，大规模白质构筑和局部神经元膜特性 促进认知状态之间的无缝转换。精神分裂症患者的临床表现 脑部活动紊乱的显著脑白质异常。然而，在多大程度上 精神病患者的脑功能障碍源于结构或功能的病理残留物 未知。在这一队列中确定确凿的神经影像发现受到了挑战。 由于1)评估分布式多模式病理表型的方法不足，以及2) 精神分裂症的显著病因学异质性。实际上，后一种挑战可能在一定程度上 通过对染色体22q11.2缺失综合征(22qDS)的研究来解决，其中患病率 临床精神分裂症的发病率是健康人的25倍。前一项挑战可能是 由网络科学和机器学习的最新进展解决，这些进展产生了 对健康大脑中结构-功能关系的洞察。利用这些方法来研究 有明确基因损伤的人群中的精神病症状谱是一个有希望的 精神病病理生理学研究方向。 在这个建议中，我们描述了一种新的基于时间点的泛函分析的发展 用神经影像资料研究22qDS患者的结构-功能关系 目前在宾夕法尼亚大学医院接受治疗。使用来自 通过费城神经发育队列获得的大样本青年(n=690)， 我们的初步分析证明了以前未被描述的大脑之间的关系 结构、大脑活动和工作记忆表现。在这份提案中，我们的目标是1)比较 22qDS精神病谱的脑状态转换动力学，2)比较 22QDS与健康对照的结构-功能耦合及其相关结构-功能 与精神症状严重程度的耦合，以及3)将状态转换动态与工作联系起来 22qDS的内存性能。 更好地了解精神病谱系症状的潜在机制将为 为开发针对精神病的靶向疗法奠定基础。此外，利用队列 一个已知的基因损伤提供了一个独特的机会来沟通我们对分子的理解 神经影像生物标记物对精神病谱系症状的作用机制。

Project Summary In the healthy brain, large-scale white matter architecture and local neuronal membrane properties facilitate seamless transitions between cognitive states. Patients with schizophrenia display significant white matter abnormalities with disorganized brain activity. However, the degree to which dysfunctional brain activity in psychosis arises from structural or functional pathology remains unknown. The identification of conclusive neuroimaging findings in this cohort has been challenged by 1) inadequate methods to assess distributed multimodal pathological phenotypes, and 2) the significant pathogenetic heterogeneity in schizophrenia. Practically, the latter challenge can be in part addressed by the study of chromosome 22q11.2 deletion syndrome (22qDS), where the prevalence of clinical schizophrenia is 25-fold higher than that of healthy individuals. The former challenge can be addressed by recent advances in network science and machine learning, which have generated insights about structure-function relationships in the healthy brain. Utilizing these methods to study the spectrum of psychotic symptoms in a population with a defined genetic lesion is a promising direction for investigating psychosis pathophysiology. In this proposal, we describe the development of a novel time-point-based analysis of functional neuroimaging data to study structure-function relationships in a sample of patients with 22qDS currently being seen at the Hospital for the University of Pennsylvania. Using neuroimaging data from a large sample of youths (n = 690) acquired through the Philadelphia Neurodevelopmental Cohort, our preliminary analyses demonstrate previously uncharacterized relationships between brain structure, brain activity, and working memory performance. In this proposal, we aim to 1) compare brain state transition dynamics across the psychotic spectrum of 22qDS, 2) compare structure-function coupling in 22qDS to healthy controls and relate structure-function coupling to psychotic symptom severity, and 3) relate state transition dynamics to working memory performance in 22qDS. A better understanding of the underlying mechanism of psychosis-spectrum symptoms would lay the groundwork for the development of targeted therapies for psychosis. Furthermore, utilizing a cohort with a known genetic lesion provides a unique opportunity to bridge our understanding of molecular mechanisms with neuroimaging biomarkers for psychosis-spectrum symptoms.