Brain Mechanisms Underlying Childhood Generalized Anxiety Disorder

描述（由申请人提供）：儿童焦虑症很普遍，越来越被认为是一个主要的公共卫生问题。除了与儿童焦虑症相关的心理痛苦和残疾外，这些症状通常与共病抑郁症状相关，加剧其他医学疾病，并增加后期发展焦虑症，抑郁症和共病药物和酒精滥用的风险。尽管广泛性焦虑症（GAD）发生在儿童时期的重要性，很少有人知道大脑的变化，介导其发展和病理生理。这项提案的总体目标是建立在我们的工作，在年轻的非人灵长类动物中，通过识别中间脑表型，与早期人类儿童GAD。改变前额叶杏仁核连接和改变杏仁核计时与GAD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著焦虑的关系。这一点尤其重要，因为成年人和青少年的焦虑和抑郁往往在生命的早期就开始表现为临床上显著的焦虑。了解GAD在青春期前儿童中表达的神经回路的改变将为使用旨在早期检测的生物标志物提供理论基础。具体而言，这些数据将奠定基础的前瞻性纵向研究，检查评估杏仁核计时和前额杏仁核连接的早期发现和治疗这些儿童疾病的效用。这项建议的目的是为下列项目的初期阶段提供资金： 本研究以长期计划获得非常大的GAD儿童样本。由于共病症状的异质性，获得大样本将使我们能够解析GAD和相关症状与不同的潜在神经改变的关系。这有可能提供新的见解，目前的概念化广泛性焦虑症，并将设置新的大脑为基础的临床显着焦虑儿童的症状模式的分类阶段。在GAD儿童中进行这些研究的机会很多。他们将提供一个发展框架，了解与精神病理学的最早表达有关的大脑回路的结构和功能。此外，这方面的知识可能会提供一个合理的心理和药理干预措施的发展，目标涉及的神经回路的关键组成部分，并考虑到可塑性的发展中儿童的大脑。早期更有效的干预，是基于一个健全的神经发育的理由持有的承诺，为预防后期青少年和成人的焦虑，抑郁和药物滥用。

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.