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）易感基因进行了大量的研究，但这种毁灭性疾病发展的神经生物学机制仍然难以捉摸。一个补充策略是研究一种已知遗传病因的疾病，这种疾病具有相同的表型特征，这可能为SZ的发病机制提供有价值的见解。22q11.2缺失综合征（心面/DiGeorge综合征；22qDS）是一个令人信服的模型，因为它代表了最常见的已知精神疾病发展的遗传风险因素（相对于一般人群增加30倍）。因此，22qDS代表了一个独特的窗口，了解已知遗传原因的疾病中SZ的神经相关因素。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，导致终身的生物脆弱性，导致突触可塑性降低和断开连接，这为22qDS患者在青春期增加患精神病的脆弱性奠定了基础。研究22qDS中不同脑区之间的功能连接强度可以为这种连接障碍假说提供经验支持。静息状态功能磁共振成像（rs-fMRI）越来越被认为是探测大脑内在功能结构的一种有价值的方法，对几种神经发育和精神疾病的大脑行为关系产生了有价值的见解。然而，关于22qDS的静息状态功能连接（RSFC）几乎一无所知，也不知道它如何与临床结果的变异性相关。该计划的目的是绘制22qDS中大脑的功能结构，并横断面和随时间探索这种连通性与精神病症状和行为的关系。目标1将首先使用假设驱动（即基于种子的）和数据驱动方法（即独立成分分析）的组合来研究RSFC中22qds相关的异常；我们将使用这些方法来描述22qDS患者相对于对照组在青春期关键时期RSFC改变的发展轨迹。Aim 2将横断面和纵向研究Aim 1衍生的静息状态网络作为22qDS患者精神病症状和心理社会功能的预测因子。目的3将采用图论领域的分析技术对rs-fMRI数据进行分析，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。[拟议的项目将允许申请人利用他在这里描述的培训计划中获得的临床经验和发展精神病理学知识，利用他对最先进的神经成像分析技术的持续兴趣，以]扩展当前关于大脑功能，行为和精神疾病风险之间关系的知识领域在这个基因不同的样本中。在这一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可能产生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.