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

因此，22qDS代表了一个独特的窗口，可以了解SZ在已知遗传原因的疾病中的神经相关性。在22QDS中检查不同脑区之间的功能连接强度可以为这一连接失调假说提供经验支持。静息状态功能磁共振成像(rs-fMRI)越来越被认为是探索大脑内在功能结构的一种有价值的方法，对一些神经发育和精神障碍的大脑-行为关系产生了有价值的见解。这项拟议的项目的目的是绘制22QDS的大脑功能结构图，并探索这种连接与精神病症状和行为的关系，横断面和随时间推移。目标1将首先使用假设驱动(即基于种子)和数据驱动的方法(即独立成分分析)的组合来调查22qDS患者中与RSFC相关的异常；并将使用这些方法来表征22qDS患者在关键青春期相对于对照组的RSFC改变的发展轨迹。AIM 3将使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22q11.2突变对功能网络的特征和拓扑造成不利影响的程度。[拟议的项目将允许申请者利用他对最先进的神经成像分析技术的持续兴趣，以及他将在这里描述的培训计划中获得的发展精神病理学的临床经验和知识，以便]在这个遗传上截然不同的样本中扩大目前关于大脑功能、行为和精神病风险之间关系的知识范围。

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.