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

摘要 焦虑症仍然是精神疾病最常见的形式之一，也是第六大原因。 全世界的残疾人。焦虑病理往往出现在青春期早期， 性别之间存在差异，青春期后女孩的发病率比男孩高2至3倍。因此，在本发明中， 识别易患焦虑症的特定因素对于识别风险至关重要 个人早期，在轨迹结晶之前，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， 在向青春期过渡期间出现的能力下降。我们和其他人建议， 青少年焦虑的发展部分是由于大脑网络成熟轨迹的差异 支持情绪调节（即，情绪失调是焦虑发展的关键内在表型）。 然而，支持情绪发展的青少年和性别特异性神经生物学机制 调节及其对焦虑病理学表现的影响还没有得到很好的理解。我们将测试 一个包含两个风险因素的模型：青春期睾酮和前额叶皮层下轴突髓鞘形成 电路.我们将收集纵向（3波，每隔1年）多模态（例如，扩散，超快功能磁共振成像） 神经影像学数据从个人过渡到青春期，其中一半是在高风险的发展 焦虑症目标1：我们最近提出了一个模型，其中睾酮抑制了 关键情绪调节回路，而回路中白色物质髓鞘形成具有相反的效果。目的 1将通过测试（i）青春期睾酮随时间的增加是否与 眶额皮层（OFC）和杏仁核之间的功能解耦，以及（ii）这种解耦预测情绪 失调和随之而来的焦虑增加。这一目标也将测试是否稀疏的基线髓鞘形成， 钩束（连接OFC-杏仁核）与较弱的功能耦合，较高的失调， 和焦虑目的2：赋予女性更大焦虑风险的生物学机制仍然未知。 我们在健康青少年中的研究表明，女性眶额皮层对睾酮的敏感性更高， 杏仁核回路，并且有一些证据表明该回路中的髓鞘形成差异。目标2将测试是否 睾酮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至关重要，以便检测 在轨迹形成之前，让个人承担风险。AIM 3将测试睾酮和髓鞘形成是否可以使用 来预测未来焦虑的出现。总之，本项目旨在确定神经和激素机制 导致青少年焦虑的原因这项工作有巨大的公共卫生潜力 通过利用尖端方法来发现和验证焦虑的新风险轨迹。

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.