Neural Systems Underlying Severe Worry in Anxious Adolescents and Young Adults

项目摘要 慢性和严重的担忧是焦虑症（AD）的一个关键特征，AD的患病率最高 在整个生命周期中，通常从儿童和青少年开始，并增加抑郁和自杀的风险 在青春期。长期的严重忧虑也是一种跨诊断的现象，并且与风险增加有关。 青少年心境障碍的发病、复发和治疗抵抗。然而，人们对它知之甚少。 焦虑的神经机制可能导致情绪障碍的发作。成人神经影像学研究 表明慢性严重焦虑与额边缘网络缺陷有关， 青春期的成熟变化。我们在患有严重忧虑的老年人中的初步fMRI结果显示， 在焦虑诱导过程中，边缘系统/边缘系统结构的激活增强，以及连接减少， 显著性网络（SN）和执行控制网络（ECN）的区域之间的差异以及杏仁核的增强。 在忧虑重评过程中的丘脑-室旁核（PVN）连接。基于抑郁症的研究结果， 这种神经功能模式可能代表了一种神经标记，它将长期的担忧与增加的风险联系起来。 萧条然而，尚不清楚在老年人中观察到的这些模式是否会在焦虑中转化为焦虑。 青少年和年轻人，以及他们是否因年龄和性别而异。此外，鉴于证据表明，安西- 心脏病可能与γ-氨基丁酸（GABA）和多巴胺能系统的失衡有关， 这些系统在青春期和成年早期经历重要的成熟变化，我们将 胺这些系统的功能，因为它们涉及到焦虑的个人的担忧调节。R21 Pro- 这将为一个更大的纵向R 01提案提供种子，该提案将测试一个总体假设， 担心有明显的和累积的年龄相关的后果，由于改变神经发育的协调， 青春期SN和ECN内的神经区域内和之间的作用。这些变化有助于 慢性唤醒增加，无效的情绪调节，并导致抑郁症等结果。颗粒， pants将包括40名青春期中期/晚期青少年（12-17岁; 20名女性）和40名年轻成人（18-30岁; 20名 女性），根据担忧的严重程度进行跨诊断招募，其中2/3报告了严重的担忧水平。平行 参与者将完成精神评估、焦虑诱导和重新评估功能磁共振成像任务以及休息状态 上网时段为了表征额边缘网络的分子基础，我们还将获得新的mag- 与焦虑相关的脑代谢物的核磁共振波谱成像测量（例如，GABA和Glu- tamate）在前额叶皮层和边缘/边缘皮层下区域。该研究旨在描述年龄- 焦虑诱导和调节过程中神经激活和功能连接的相关模式， 确定GABA和谷氨酸浓度与神经功能相关的程度， 焦虑和焦虑症状。这些发现可能会导致识别新的神经发育靶点- 对慢性和严重焦虑的干预以及对高危人群抑郁症的预防。

PROJECT SUMMARY Chronic and severe worry is a key characteristic of Anxiety Disorders (AD), which have the highest prevalence across the lifespan, typically start in childhood and adolescence, and increase risk for depression and suicide during adolescence. Chronic severe worry is also transdiagnostic and has been associated with increased risk of onset, relapse, and treatment resistance in mood disorders in adolescents. Yet, little is known about the neural mechanisms of worry that may contribute to onset of mood disorders. Neuroimaging studies in adults indicate that chronic severe worry is associated with deficits in frontolimbic networks, which undergo important maturational changes in adolescence. Our preliminary fMRI findings in older adults with severe worry show heightened activation in limbic/paralimbic structures during worry induction as well as reduced connectivity be- tween regions of the Salience Network (SN) and the Executive Control Network (ECN) and heightened amyg- dala-paraventricular nucleus (PVN) connectivity during worry reappraisal. Based on findings in depression, such patterns of neural function could represent a neural marker linking chronic worry with increased risk for depression. However, it remains unclear whether these patterns observed in older adults translate in anxious adolescents and young adults and whether they vary with age and sex. Furthermore, given evidence that anxi- ety may be associated with an imbalance in γ-aminobutyrate (GABA) and glutamatergic systems and that these systems undergo important maturational changes during adolescence and early adulthood, we will ex- amine the functioning of these systems as they relate to worry regulation in anxious individuals. This R21 pro- posal will serve to seed a larger, longitudinal R01 proposal that will test an overarching hypothesis that severe worry has distinct and cumulative age-related consequences due to altered neurodevelopment of the coordina- tion within and between neural regions within the SN and ECN in adolescence. These alterations contribute to increases in chronic arousal, ineffective emotion regulation, and lead to outcomes such as depression. Partici- pants will include 40 mid-/late-pubertal adolescents (12-17 yrs; 20 females) and 40 young adults (18-30 yrs; 20 females), recruited transdiagnostically based on worry severity, with 2/3 reporting severe levels of worry. Par- ticipants will complete psychiatric assessments, a worry induction and reappraisal fMRI task and a resting state session. To characterize the molecular underpinnings of frontolimbic networks, we will also acquire novel mag- netic resonance spectroscopy imaging measures of brain metabolites relevant to anxiety (e.g., GABA and glu- tamate) in the prefrontal cortical and limbic/paralimbic subcortical regions. The study aims to characterize age- related patterns of neural activation and functional connectivity during worry induction and regulation and to determine the extent to which GABA and glutamate concentrations are associated with neural functioning and worry and anxiety symptoms. Findings could lead to the identification of targets for novel neurodevelopmental- ly-based interventions of chronic and severe worry and prevention of depression in at-risk individuals.