Sex-Specific Functional Connectivity Changes in Major Depressive Disorder

项目总结 该项目的目标是开发针对不同性别的重度抑郁症患者的功能磁共振生物标志物。 并确定其潜在的遗传相关性。我们的主要目标是确定 与MDD患者相关的性别特定功能连接性的位置和程度差异 与健康受试者进行比较，并测试这些性别特定的连接性差异是否定义了性别特定 MDD的亚型。实现这些目标的好处将是双重的：(1)在临床上，实现这些目标将 允许对MDD进行更准确的诊断和治疗反应预测算法，以减少 MDD患者的缓解。(2)在实验室中，我们的工作将指导发现新的性别特异性回路 MDD的发病机制和治疗。我们的第二个目标是确定特定性别的MDD是否会影响连接性 可以通过大脑中的区域基因表达来预测。脑基因与脑功能关系的研究 表达和MDD对功能连通性的影响可能涉及到新的基因在环路机制中的作用。 并确定在驱动MDD症状学中与性别相互作用的基因。为了实现这些目标，我们将 使用参数和非参数统计测试来定义特定性别的功能连接性差异 在抑郁和健康的男性之间，以及抑郁和健康的女性之间。二次分析将测试 区分MDD受试者和健康对照的性别分类指标(“诊断生物标志物”) 胜过在所有科目上接受过独立于性别的培训的分类员。以确定性别特异性的遗传相关性 MDD对功能连接性的影响，我们将使用偏最小二乘回归的多变量技术 寻找可预测男性和男性MDD相关连接性差异的线性基因组合 女性。最后，为了识别特定性别的MDD亚型，我们将使用正规化规范的组合 在先前发表的用于亚型发现的验证方法中的相关性分析和等级聚类 在康纳·利斯顿博士的实验室里。这个项目将填补我们在MDD性别差异方面的知识空白 功能连通性和这些差异的潜在遗传相关性。该项目还将涉及 执行具体的培训计划，使我能够发展fMRI分析和 机器学习技术、假设检验、数据解释和科学方面的概念技能 作为执业医生的沟通和临床能力，所有这些都在 该项目的发起人利斯顿博士和共同发起人弗朗西斯·李博士都是有成就的内科科学家。

PROJECT SUMMARY The goal of this project is to develop sex-specific resting state fMRI biomarkers for major depressive disorder (MDD) and to determine their underlying genetic correlates. Our primary aim is to determine the locations and the degree of sex-specific functional connectivity differences associated with MDD patients as compared to healthy subjects, and to test whether those sex-specific connectivity differences define sex-specific subtypes of MDD. The benefit of achieving these goals will be twofold: (1) in the clinic, achieving these goals will allow for more accurate diagnostic and treatment-response predictive algorithms for MDD, to reduce time to remission in MDD patients. (2) In the laboratory, our work will guide discovery of novel sex-specific circuit mechanisms and treatments for MDD. Our second aim is to determine if sex-specific MDD effects on connectivity can be predicted by regional gene expression in the brain. Investigating the relationship between brain gene expression and MDD effects on functional connectivity would implicate novel genes in the circuit mechanism of MDD and identify genes that interact with sex in driving MDD symptomatology. To achieve these aims, we will use parametric and non-parametric statistical testing to define sex-specific functional connectivity differences between depressed and healthy men, and between depressed and healthy women. Secondary analyses will test whether sex-specific classifiers for differentiating MDD subjects and healthy controls (“diagnostic biomarkers”) outperform classifiers trained on all subjects independent of sex. To identify genetic correlates of sex-specific MDD effects on functional connectivity, we will use the multivariate technique of partial least squares regression to locate linear combinations of genes which can predict MDD-related connectivity differences in males and in females. Finally, to identify sex-specific subtypes of MDD, we will use a combination of regularized canonical correlation analysis and hierarchical clustering in a validated method for subtype discovery previously published in Dr. Conor Liston’s lab. This project will fill a substantial gap in our knowledge of sex differences in MDD functional connectivity and the underlying genetic correlates of those differences. This project will also involve the execution of a concrete training plan to allow me to develop concrete technical skills in fMRI analysis and machine learning techniques, conceptual skill in hypothesis testing, data interpretation, and scientific communication, and clinical competency as a licensed physician, all under the guidance and mentorship of the project’s sponsor Dr. Liston and co-sponsor Dr. Francis Lee, who are both accomplished physician-scientists.