Neural Systems Underlying Severe Worry in Anxious Adolescents and Young Adults

项目总结 慢性严重焦虑是焦虑症(AD)的一个重要特征，其患病率最高 在一生中，通常从童年和青春期开始，并增加抑郁和自杀的风险 在青春期。慢性严重焦虑也是跨诊断的，并与风险增加有关 青少年情绪障碍的发病、复发和治疗抵抗。然而，人们对这一现象知之甚少 焦虑的神经机制可能会导致情绪障碍的发生。成人的神经影像研究 表明慢性严重焦虑与额叶边缘网络的缺陷有关，额缘网络经历了重要的 青春期的成熟变化。我们在患有严重焦虑的老年人中的初步fMRI结果显示 焦虑诱导时边缘/边缘旁结构的激活增加，以及连接性降低。 突出网络(SN)和执行控制网络(ECN)的区域之间以及增强的AMG- 焦虑再评估中的达拉-室旁核(PVN)连接。根据对抑郁症的研究结果， 这种神经功能模式可能代表着一种神经标志，将慢性担忧与增加的风险联系在一起 抑郁症。然而，目前尚不清楚在老年人身上观察到的这些模式是否会转化为焦虑 青少年和青壮年，以及他们是否因年龄和性别而异。此外，鉴于有证据表明安息- TY可能与γ-氨基丁酸和谷氨酸能系统的失衡有关， 这些系统在青春期和成年初期经历了重要的成熟变化，我们将 注意这些系统的功能，因为它们与焦虑的个体的焦虑调节有关。这款R21 PRO- POSSAL将用于播种一个更大的、纵向的R01提案，该提案将测试一个总体假设，即严重 焦虑具有明显的和累积的年龄相关后果，这是由于协调神经发育的改变- 青春期SN和ECN内的神经区内和神经区之间的相互作用。这些变化有助于 慢性唤醒增加，情绪调节无效，并导致抑郁等后果。粒子- 裤子将包括40名青春期中后期青少年(12-17岁；20名女性)和40名年轻人(18-30岁；20 女性)，根据焦虑的严重程度进行跨诊断招募，三分之二的人报告严重的焦虑水平。标准杆- 参与者将完成精神评估、焦虑诱导和重新评估功能磁共振任务以及休息状态 会议。为了表征额缘网络的分子基础，我们还将获得新的MAG- 与焦虑相关的大脑代谢物的磁共振波谱成像测量(例如，GABA和Glu- Tamate)位于前额叶皮质和边缘/边缘下皮质区域。这项研究旨在描述年龄的特征-- 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和 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- 以LY为基础的干预措施，对高危个体的慢性和严重担忧和抑郁的预防。

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.