Functional Connectivity as a Predictor of Psychosis in 22q11.2 Deletion Syndrome

描述（由申请人提供）：尽管对精神分裂症（SZ）易感基因进行了深入研究，但这种毁灭性疾病发展的神经生物学机制仍然难以捉摸。一个互补的策略，可能提供有价值的见解SZ的发病机制是一种疾病的研究与已知的遗传病因，共享其表型特征。22q11.2缺失综合征（Velocardiofacial/DiGeorge综合征; 22 qDS）是一个令人信服的模型，因为它代表了精神病发展的最常见的已知遗传风险因素（相对于普通人群增加30倍）。因此，22 qDS代表了了解已知遗传原因疾病中SZ神经相关性的独特窗口。 我们的假设是，由于对神经发育至关重要的特定基因的单倍不足而导致的终身生物脆弱性导致突触可塑性降低和断开连接，这为22 qDS患者青春期精神病的脆弱性增加奠定了基础。检查22 qDS中不同大脑区域之间的功能连接强度可以为这种连接障碍假说提供实证支持。静息态功能磁共振成像（rs-fMRI）越来越被认为是一种有价值的方法，用于探测大脑的内在功能结构，产生有价值的见解，在一些神经发育和精神疾病的脑行为关系。然而，几乎没有人知道22 qDS中的静息状态功能连接（RSFC），也不知道它如何与临床结果的变异性相关。该项目的目的是绘制22 qDS中大脑的功能结构，并探索这种连接与精神病症状和行为的关系，横截面和时间。目标1将首先使用假设驱动的组合（即，基于种子的）和数据驱动的方法（即，独立成分分析（Independent Component Analysis）;&将使用这些方法来表征22 qDS患者相对于对照组在整个关键青春期的RSFC改变的发展轨迹。目标2将研究目标1衍生的静息状态网络作为22 qDS患者精神病症状和心理社会功能的预测因子，横截面和纵向。目标3将采用从图论领域的rs-fMRI数据的分析技术，试图进一步量化功能网络的特征和拓扑结构受到22q11.2突变的不利影响的程度。[The所提出的项目将允许申请人利用他在最先进的神经成像分析技术方面的持续兴趣，以及他将在本文所述的培训计划中获得的发展性精神病理学的临床经验和知识，以扩展关于该遗传上不同的样本中的脑功能、行为和精神病风险之间的关系的当前知识领域。在这个独特的临床人群中的进一步研究将加强遗传变异与脑功能障碍之间的联系，希望有助于阐明SZ可能出现的复杂神经生物学机制。

DESCRIPTION (provided by applicant): Despite intensive search for schizophrenia (SZ) susceptibility genes, the neurobiological mechanisms underlying the development of this devastating illness remain elusive. A complementary strategy that may provide valuable insights into the pathogenesis of SZ is the study of a disorder with known genetic etiology that shares its phenotypic characteristics. The 22q11.2 Deletion Syndrome (Velocardiofacial/DiGeorge syndrome; 22qDS) is a compelling model, as it represents the most common known genetic risk factor for the development of psychosis (30-fold increase relative to the general population). As such, 22qDS represents a unique window into the neural correlates of SZ in a disorder with known genetic cause. Our hypothesis is that a life-long biological vulnerability, resulting from haploinsufficiency for specific genes critical for neurodevelopment, leads to reduced synaptic plasticity & disconnectivity, which sets the stage for increased vulnerability to psychosis in adolescence in 22qDS patients. Examining the strength of functional connections between different brain regions in 22qDS can offer empirical support for this dysconnection hypothesis. Resting state fMRI (rs-fMRI) is increasingly recognized as a valuable method for probing the brain's intrinsic functional architecture, yielding valuable insights into brain-behavior relationships in several neurodevelopmental & psychiatric disorders. However, almost nothing is known about resting state functional connectivity (RSFC) in 22qDS, nor how it may relate to variability in clinical outcomes. The purpose of the proposed project is to map the functional architecture of the brain in 22qDS, & probe the relationship of this connectivity to psychotic symptoms and behavior, cross-sectionally & over time. Aim 1 will first investigate 22qDS-related anomalies in RSFC using a combination of hypothesis-driven (i.e., seed-based) & data-driven approaches (i.e., Independent Component Analysis); & will use these methods to characterize the developmental trajectory of RSFC alterations throughout the critical adolescent period in 22qDS patients, relative to controls. Aim 2 will examine the Aim 1-derived resting state networks as predictors of psychotic symptoms & psychosocial functioning within 22qDS patients, cross-sectionally & longitudinally. Aim 3 will employ analysis techniques from the field of Graph Theory to the rs-fMRI data in an attempt to further quantify the degree to which the character and topology of functional networks are adversely impacted by the 22q11.2 mutation. [The proposed project will allow the applicant to leverage his ongoing interest in state-of-the-art neuroimaging analysis techniques with the clinical experience & knowledge of developmental psychopathology he will gain in the training program described herein, in order to] expand the current sphere of knowledge about the relationship between brain function, behavior & psychosis risk in this genetically distinct sample. Further research within this unique clinical population will strengthen the link between genetic variation & brain dysfunction, hopefully helping to elucidate the complex neurobiological mechanisms by which SZ may arise.