Effects of Childhood Maltreatment on Neurocircuitry in Adolescent Depression

 描述（由申请人提供）：抑郁症是世界上最令人衰弱的疾病之一，其社会和经济负担是一项重大的公共卫生挑战。童年虐待是抑郁症的一个常见风险因素，当存在时，进一步损害适应功能。有和没有虐待的抑郁症之间存在重要的临床差异，这表明它们构成了两种不同的表型，需要不同的治疗指南。来自成人遗传和神经生物学研究的初步数据也支持这一观点。这项建议的目的是确定是否有抑郁症和虐待史的青少年有明显的差异，在结构和功能的神经回路相比，抑郁症的青少年没有虐待。这项研究将侧重于青春期，因为除婴儿期外，青春期是神经变化和成熟的最大时期，虐待对大脑的影响出现在这一发育阶段。将招募四组人员：患有临床抑郁症且有儿童期虐待史的青少年、患有临床抑郁症且无虐待史的青少年、无精神障碍但有儿童期虐待史的青少年以及无精神障碍或虐待史的青少年。参与者将接受结构磁共振成像和弥散张量成像研究，以测量与抑郁症核心症状相关的关键神经网络中的宏观和微观结构连接/纤维束成像概况（特别是消极情绪的额边缘回路和快感缺乏的额纹状体回路）。他们将接受静息状态和基于任务的功能磁共振成像研究，以测量这些神经网络中的功能连接概况。除了确定两种抑郁症亚型/表型之间的组差异外，我们还将评估虐待是否会调节特定抑郁症症状特征的维度评级之间的关联（例如，快感缺乏、负面情绪、反刍）和神经回路。据我们所知，这项研究是第一个利用多模态成像来区分与抑郁症和虐待相结合的结构和功能神经基质与抑郁症相关的。四组（2 × 2）设计将使我们能够确定两个抑郁组之间观察到的差异是虐待的主要（加性）效应还是相互作用效应（即，与抑郁症相关的神经特征因虐待而改变）。该研究的结果将增加我们对现有抑郁症神经模型的理解，并有可能通过增强治疗指南和算法来改善临床实践。与两种抑郁症亚型相关的神经标志物的分化可用于更有效地预测治疗结果，并更有选择性地指示对治疗的临床反应。确定与虐待受害者抑郁症相关的独特神经基质也将有助于为那些对当前方法反应不佳的人开发和测试新的治疗方法（正如在一些临床试验中观察到的那样）。

 DESCRIPTION (provided by applicant): Depression is one of the most debilitating diseases worldwide, and the social and economic burden is a major public health challenge. Childhood maltreatment is a common risk factor for depression and when present further compromises adaptive functioning. Important clinical differences exist between depression with and without maltreatment, suggesting that they constitute two distinct phenotypes and require different treatment guidelines. Preliminary data from genetic and neurobiological studies in adults also support this notion. The aim of this proposal is to determine whether adolescents with depression and a history of maltreatment have distinct differences in structural and functional neural circuits compared to depressed adolescents without maltreatment. The study will focus on adolescence because, except for infancy, it is the greatest period of neural change and maturation, and the effects of maltreatment on the brain appear during this developmental stage. Four groups will be recruited: adolescents with clinical depression and a history of childhood maltreatment, adolescents with clinical depression and no maltreatment history, adolescents with no psychiatric disorder but have a history of childhood maltreatment, and adolescents with no psychiatric disorder or maltreatment history. The participants will undergo structural magnetic resonance imaging and diffusion tensor imaging studies to measure macro- and micro-structural connectivity/tractography profiles in key neural networks that are associated with core symptoms of depression (specifically the fronto-limbic circuit for negative mood and the fronto-striatal circuit for anhedonia). They will undergo resting-state and task-based functional magnetic resonance imaging studies to measure functional connectivity profiles in these neural networks. In addition to identifying group differences between the two depression subtypes/phenotypes, we will assess whether maltreatment moderates the associations between dimensional ratings of specific depressive symptom profiles (e.g., anhedonia, negative affect, rumination) and neural circuits. To our knowledge, this study is the first to utilize multi-modal imaging to differentiate structural and functional neural substrates associated with the combination of depression and maltreatment relative to those associated with depression. The four group (2 x 2) design will enable us to determine if the observed differences between the two depressed groups are a function of a main (additive) effect of maltreatment or an interaction effect (i.e., the neural characteristics associated with depression are altered by maltreatment). The results of the study will increase our understanding of the existing neural models of depression and have the potential to improve clinical practice by enhancing treatment guidelines and algorithms. Differentiation of the neural markers associated with the two depression subtypes could be used to predict treatment outcome more effectively and to more selectively index clinical responses to treatment. Identifying the unique neural substrates associated with depression in victims of maltreatment would also facilitate the development and testing of new treatments for those who do not respond well to current approaches (as observed in some clinical trials).