Brain Mechanisms Underlying Childhood Generalized Anxiety Disorder

描述（由申请人提供）：儿童焦虑症很普遍，并且越来越被认为是一个主要的公共卫生问题。除了与儿童期焦虑症相关的心理痛苦和残疾外，这些症状通常与共病性抑郁症状相关，加剧其他医学疾病，并增加后来发展为焦虑症、抑郁症和共病性药物和酒精滥用的风险。尽管儿童期发生的广泛性焦虑障碍（GAD）很重要，但人们对介导其发育和病理生理的大脑改变知之甚少。这项提议的总体目标是建立在我们对年轻的非人类灵长类动物的研究基础上，通过识别与早期人类儿童广泛性焦虑症相关的中间大脑表型。前额叶-杏仁核连通性改变和杏仁核计时器改变与广泛性焦虑症症状相关的假设将通过结构和功能MRI，结合相关的生理和行为测量进行评估。虽然这些方法通常用于成人，较少用于青少年，但很少有研究检查这些措施与青春期前儿童临床显着焦虑的关系。这一点尤其重要，因为成人和青少年的焦虑和抑郁往往在生命早期就开始表现为临床显著的焦虑。了解青春期前儿童GAD表达背后的神经回路变化，将为使用旨在早期检测的生物标志物提供依据。具体来说，这些数据将为前瞻性纵向研究奠定基础，这些研究将检验评估杏仁核计时和前额叶-杏仁核连通性在早期发现和治疗这些儿童疾病中的效用。这项提议的目的是为项目的初始阶段提供资金

DESCRIPTION (provided by applicant): Anxiety disorders in children are prevalent and are increasingly recognized as a major public health concern. In addition to the psychological suffering and disability associated with childhood anxiety disorders, these symptoms are commonly associated with comorbid depressive symptoms, exacerbate other medical illnesses, and increase the later risk to develop anxiety disorders, depression and comorbid drug and alcohol abuse. Despite the importance of generalized anxiety disorder (GAD) occurring during childhood, little is known about the brain alterations that mediate its development and pathophysiology. The overall aim of this proposal is to build on our work in young nonhuman primates by identifying intermediate brain phenotypes that are linked to early human childhood GAD. The hypothesis that altered prefrontal-amygdala connectivity and altered amygdala chronometry is associated with symptoms of GAD will be evaluated with structural and functional MRI, in conjunction with relevant physiological and behavioral measures. While these methods have been commonly used in adults and less frequently in adolescents, very few studies have examined these measures in relation to clinically significant anxiety in pre-adolescent children. This is particularly important since anxiety and depression in adults and adolescents frequently begins as clinically significant anxiety earlier in life. Understanding alterations in the neural circuitry that underlie the expression of GAD in preadolescent children will provide a rationale for using biomarkers aimed at early detection. Specifically, these data will lay the foundation for prospective longitudinal studies examining the utility of assessing amygdala chronometry and prefrontal-amygdala connectivity in relation to the early detection and treatment of these childhood illnesses. This proposal is intended to fund the initial stages of this research with the long-term plan to obtain a very large sample of children with GAD. Because of the heterogeneity of comorbid symptoms, obtaining a large sample will allow us to parse GAD and associated symptoms in relation to distinct underlying neural alterations. This has the potential to provide new insight into the current conceptualization of GAD and will set the stage for novel brain based classification of symptom patterns in children with clinically significant anxiety. The opportunities from performing these studies in GAD children are numerous. They will provide a developmental framework for understanding the structure and function of brain circuits that are associated with the earliest expression of psychopathology. In addition, this knowledge may provide a rationale for the development of psychosocial and pharmacologic interventions that target key components of the involved neural circuit and take into account the plasticity of the developing child's brain. Early more effective interventions tha are based on a sound neurodevelopmental rationale hold the promise for the prevention of later adolescent and adult anxiety, depression and substance abuse.