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

测试青少年焦虑发展的双重机制模型

• 批准号: 10620790
• 负责人: Jeffrey Martin Spielberg
• 金额: $ 69.95万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10620790
• 关键词: Adolescence; Adolescent; Adolescent Development; Affect; Affective; Amygdaloid structure; Anxiety; Anxiety Disorders; Area; Axon; Biological; Biological Assay; Brain; Child; Coupling; Data; Development; Developmental Course; Diffusion; Effectiveness; Evaluation; Exposure to; Family history of; Female; Functional Magnetic Resonance Imaging; Future; Heritability; Home environment; Hormonal; Hormones; Individual; Intervention; Link; Literature; Longitudinal Studies; Measures; Mediating; Mental disorders; Methods; Modeling; Myelin; Parents; Pathological anxiety; Pathology; Pathway interactions; Phenotype; Predisposing Factor; Process; Puberty; Public Health; Regulation; Research; Risk; Risk Factors; Role; Sampling; Sex Differences; Siblings; Stimulus; Structure; Testing; Testosterone; Time; Work; biomarker identification; boys; disability; early adolescence; emotion dysregulation; emotion regulation; endophenotype; follow-up; girls; high risk; male; multimodality; myelination; neural; neural circuit; neurobiological mechanism; neuroimaging; novel; predictive marker; recruit; sex; support network; symptomatology; white matter

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.

抽象的 焦虑症仍然是最常见的精神疾病形式之一，也是导致精神疾病的第六大原因。 全世界的残疾。焦虑病理往往在青春期早期出现，并且这个过程发生 性别之间存在差异，青春期后女孩（与男孩）的发病率高出 2 至 3 倍。因此， 识别容易患焦虑症的青春期特定因素对于识别高危人群至关重要 在轨迹具体化之前，尽早对个体进行干预，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程度呈负相关， 进入青春期期间出现能力下降。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表现的影响尚不清楚。我们将测试 包含两个风险因素的模型：青春期睾酮和前额皮质下轴突髓鞘形成 电路。我们将收集纵向（3 个波，每个波间隔 1 年）多模态（例如扩散、超快 fMRI） 来自处于青春期过渡阶段的个体的神经影像数据，其中一半的人处于发展的高风险中 焦虑症。目标 1：我们最近提出了一个模型，其中睾酮抑制了 关键的情绪调节回路，而该回路中白质的髓鞘化则具有相反的作用。目的 1 将通过测试 (i) 青春期睾酮随时间的增加是否与以下因素相关来评估该模型： 眶额皮层（OFC）和杏仁核之间的功能解耦，以及（ii）这种解耦可以预测情绪 失调和随之而来的焦虑增加。该目标还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。目标 2：导致女性焦虑风险增加的生物学机制仍不清楚。 我们对健康青少年的研究表明，女性的 OFC 中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。 目标 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 - 在轨迹具体化之前对个人进行风险评估。目标3将测试是否可以使用睾酮和髓鞘形成 来预测未来焦虑的出现。总之，该项目旨在确定神经和激素机制 导致青少年焦虑的发生。这项工作具有巨大的公共卫生潜力 通过利用尖端方法发现和验证新的焦虑风险轨迹来产生影响。