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

功能连接作为 22q11.2 缺失综合征精神病的预测因子

基本信息

批准号：
8716560
负责人：
MATTHEW JAMES SCHREINER
金额：
$ 3.63万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8716560
关键词：
22q11 Deletion Syndrome 22q11.2 Adolescence Adolescent Affect Age Anatomy Architecture Behavior Biological Biological Neural Networks Brain Brain region Characteristics Child Clinical Cognitive Complex Data Databases Development DiGeorge Syndrome Disease Functional Magnetic Resonance Imaging Functional disorder Funding General Population Genes Genetic Genetic Predisposition to Disease Genetic Variation Graph Heterogeneity Human Individual Knowledge Life Light Link Longitudinal Studies Maps Medial Mental disorders Mentors Methods Metric Minority Modeling Mutation Neurodevelopmental Disorder Neurons Outcome Parietal Pathogenesis Patients Pattern Phenotype Population Property Psychopathology Psychotic Disorders Relative (related person)Research Research Infrastructure Rest Risk Sampling Scanning Schizophrenia Seeds Severities Shprintzen syndrome Societies Staging Structure Susceptibility Gene Symptoms Synaptic plasticity Syndrome System Techniques Time Training Programs Work base brain behavior experience follow-up frontal lobe genetic risk factor independent component analysis indexing insight interest migration myelination network dysfunction neurobiological mechanism neurodevelopment neurogenetics neuroimaging novel psychosocial psychotic symptoms public health relevance relating to nervous system theories white matter

项目摘要

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.

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，但这种破坏性疾病发展背后的神经生物学机制仍然难以捉摸。一种补充策略可能为了解 SZ 的发病机制提供有价值的见解，即研究具有已知遗传病因且具有相同表型特征的疾病。 22q11.2 缺失综合征（Velocardiofacial/DiGeorge 综合征；22qDS）是一个令人信服的模型，因为它代表了导致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了 30 倍）。因此，22qDS 代表了了解已知遗传原因的疾病中 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体不足而导致终生的生物学脆弱性，导致突触可塑性和断开性降低，这为 22qDS 患者青春期精神病的脆弱性增加奠定了基础。检查 22qDS 中不同大脑区域之间功能连接的强度可以为这种脱节假说提供经验支持。静息态功能磁共振成像 (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，可以为多种神经发育和精神疾病中的大脑行为关系提供有价值的见解。然而，我们对 22qDS 中的静息态功能连接 (RSFC) 几乎一无所知，也不知道它与临床结果的变异性有何关系。该项目的目的是绘制 22qDS 中大脑的功能结构图，并随着时间的推移，横向探讨这种连接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）和数据驱动方法（即独立成分分析）的组合来调查 RSFC 中与 22qDS 相关的异常；将使用这些方法来描述 22qDS 患者在整个关键青春期期间相对于对照的 RSFC 变化的发展轨迹。目标 2 将检查源自目标 1 的静息状态网络，作为 22qDS 患者中精神病症状和心理社会功能的预测因子，横向和纵向。目标 3 将采用从图论领域到 rs-fMRI 数据的分析技术，试图进一步量化 22q11.2 突变对功能网络的特征和拓扑结构产生不利影响的程度。 [拟议的项目将允许申请人利用他对最先进的神经影像分析技术的持续兴趣以及他将在此处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]扩展当前的关于这个基因不同的样本中大脑功能、行为和精神病风险之间关系的知识领域。在这个独特的临床人群中进行进一步的研究将加强遗传变异与大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。