Testing a Dual Mechanism Model of Adolescent Anxiety Development & Related Sex Differences

摘要 焦虑症仍然是最常见的精神疾病形式之一，是导致精神疾病的第六大原因 全球范围内的残疾。焦虑病理往往出现在青春期早期，这一过程就会发生。 性别之间存在差异，青春期后女孩(相对于男孩)的发病率会高出2到3倍。因此， 确定青春期易患焦虑症的特定因素对于确定高危因素至关重要 在轨迹明确之前，早期的个体，并提供新的干预目标。有趣的是， 焦虑的发展过程与情绪调节能力的成熟呈负相关， 在过渡到青春期期间出现的能力减退。我们和其他人已经提出， 青春期焦虑的发展部分是由于大脑网络成熟轨迹的不同 支持情绪调节(即，情绪调节失调是焦虑发展的一个关键内表型)。 然而，支持情绪发展的青春期和性别特有的神经生物学机制 调节，以及它们对焦虑病理表现的影响，还没有被很好地理解。我们将测试 包含青春期睾酮和前额叶下皮质轴突髓鞘形成两种危险因素的动物模型 电路。我们将收集纵向(3个波，每个间隔1年)多模式(例如，扩散、超快fMRI) 来自过渡到青春期的人的神经成像数据，其中一半人有很高的发展风险 一种焦虑症。目的1：我们最近提出了一种模型，在该模型中，睾丸素抑制了 关键的情绪调节回路，而该回路中白质的髓鞘形成则有相反的效果。目标 1将通过测试(I)青春期睾丸激素随时间增加是否与 眶前叶皮质(OFC)和杏仁核之间的功能去偶联和(Ii)这种去偶联预测情绪 监管失调和随之而来的焦虑加剧。这一目标还将测试更稀疏的基线髓鞘形成 钩状束(连接OFC-杏仁核)与较弱的功能耦合，较高的调节失调， 和焦虑。目的2：女性患焦虑症风险更大的生物学机制尚不清楚。 我们在健康青少年中的研究表明，女性对OFC中的睾丸素有更高的敏感性。 杏仁体环路，有一些证据表明这个环路中的髓鞘形成不同。Aim 2将测试 睾丸激素和髓鞘形成对女孩的情绪调节回路/病理性焦虑有更大的影响。 目的3：确定预测未来焦虑发展的基线生物标志物，以检测- 在轨迹明朗化之前让个人处于危险之中。目标3将测试是否可以使用睾丸激素和髓鞘形成 来预测未来焦虑的出现。总而言之，这个项目旨在确定神经和荷尔蒙机制。 对青少年焦虑的发展负有责任。这项工作具有极大的公共卫生潜力 通过利用尖端方法发现和验证焦虑症的新风险轨迹来产生影响。

ABSTRACT Anxiety disorders remain one of the most common forms of mental illness and the 6th leading cause of disability worldwide. Anxiety pathology tends to emerge during early adolescence, and this process occurs differentially between the sexes, with rates becoming 2- to 3-fold higher in girls (vs. boys) post-puberty. Thus, identifying adolescence-specific factors that predispose towards anxiety disorders is crucial for identifying at-risk individuals early, before trajectories crystalize, and for providing novel intervention targets. Interestingly, the developmental course of anxiety is inversely related to the maturation of emotion-regulation capacity, with decrements in capacity appearing during the transition into adolescence. We and others have proposed that the development of adolescent anxiety is due, in part, to differences in the maturational trajectories of brain networks supporting emotion regulation (i.e., emotion dysregulation is a key endophenotype for anxiety development). However, the adolescent- and sex-specific neurobiological mechanisms that support the development of emotion regulation, and their implications for the manifestation of anxiety pathology, are not well understood. We will test a model incorporating two risk factors: pubertal testosterone and axonal myelination of prefrontal-subcortical circuits. We will collect longitudinal (3 waves, each 1 year apart) multi-modal (e.g., diffusion, ultra-fast fMRI) neuroimaging data from individuals at the transition into adolescence, half of whom are at high risk for developing an anxiety disorder. Aim 1: We recently proposed a model in which testosterone dampens the effectiveness of key emotion-regulation circuitry, whereas myelination of white matter in that circuit has the opposite effect. Aim 1 will evaluate this model by testing whether (i) increases over time in pubertal testosterone are linked to functional decoupling between orbitofrontal cortex (OFC) and amygdala and (ii) this decoupling predicts emotion dysregulation and consequent anxiety increases. This aim will also test whether sparser baseline myelination of uncinate fasciculus (connecting OFC-amygdala) is linked to weaker functional coupling, higher dysregulation, and anxiety. Aim 2: The biological mechanisms that confer greater risk for anxiety in females remain unknown. Our work in healthy adolescents suggests that females have a higher sensitivity to testosterone in the OFC- amygdala circuit, and there is some evidence of myelination differences in this circuit. Aim 2 will test whether testosterone and myelination have a greater impact on emotion-regulation circuitry/pathological anxiety in girls. Aim 3: It is critical to identify baseline biomarkers predictive of future anxiety development in order to detect at- risk individuals before trajectories crystalize. Aim 3 will test whether testosterone and myelination can be used to predict the emergence of future anxiety. In sum, this project aims to identify neural and hormonal mechanisms responsible for the development of adolescent anxiety. This work has the potential for tremendous public health impact by harnessing cutting-edge methods to uncover and validate novel risk trajectories for anxiety.