Brain Mechanisms Underlying Childhood Generalized Anxiety Disorder

描述(由申请人提供)：焦虑症在儿童中很普遍，并日益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的抑郁症状有关，加剧其他医学疾病，并增加后来发展为焦虑症、抑郁症以及共病的药物和酒精滥用的风险。尽管广泛性焦虑症(GAD)发生在儿童时期很重要，但人们对调节其发展和病理生理的大脑变化知之甚少。这项建议的总体目标是通过识别与早期人类儿童GAD有关的中间大脑表型，在我们在年轻的非人类灵长类动物中的工作基础上再接再厉。前额叶-杏仁核连接改变和杏仁核计时改变与GAD症状相关的假说将通过结构和功能磁共振结合相关的生理和行为测量进行评估。虽然这些方法在成年人中普遍使用，在青少年中使用较少，但很少有研究检查这些方法与青春期前儿童的临床显著焦虑之间的关系。这一点尤其重要，因为成年人和青少年的焦虑和抑郁通常在生命的早期就开始出现临床上的显著焦虑。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记物提供理论基础。具体地说，这些数据将为前瞻性纵向研究奠定基础，以检验评估杏仁核计时和前额叶-杏仁核连接在早期发现和治疗这些儿童疾病方面的效用。这项提案旨在为以下项目的初期阶段提供资金 这项研究具有长期计划，以获得非常大的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分析GAD及其相关症状与不同的潜在神经变化的关系。这有可能为目前GAD的概念化提供新的见解，并将为临床上有显著焦虑的儿童的新的基于大脑的症状模式分类奠定基础。在广泛性痴呆症儿童中进行这些研究的机会很多。它们将为理解大脑回路的结构和功能提供一个发展框架，这些回路与精神病理学的最早表达有关。此外，这一知识可能为发展心理社会和药物干预提供理论基础，这些干预针对所涉及的神经回路的关键组件，并考虑到发育中儿童大脑的可塑性。早期更有效的干预措施建立在健全的神经发育理论基础上，有望预防青少年和成年人后来的焦虑、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.