Puberty-related development of fronto-amygdala circuitry in anxious youth: A multimodal neuroimaging study with ultra-high resolution MRI scanner (7T)

总结 焦虑症，在儿童或青春期发病，往往持续到成年，并增加了 抑郁和自杀的风险。青春期早期，随着青春期的开始，是一个重要的时期， 焦虑症状的发展和/或恶化-即，广泛性焦虑症（GAD）与社会 焦虑症（SAD）-女孩的症状水平高于男孩。在此期间，额杏仁核 支持情绪调节的回路经历重要的成熟变化。尽管在 这种回路在焦虑症中有报道，焦虑症是性行为背后的神经发育机制。 人们对焦虑症状的不同程度仍然知之甚少。与不焦虑的年轻人相比，焦虑 年轻人在处理信息时表现出更强的杏仁核激活和减少的额杏仁核功能连接 与威胁有关的刺激。杏仁核活动对威胁的自上而下的调节作用减弱， 焦虑的成年人在腹内侧的γ-氨基丁酸（GABA）和谷氨酸浓度升高 前额叶皮层（vmPFC）和杏仁核。它还与以下因素有关，包括在焦虑的青年中， 连接VMPFC和杏仁核的白色物质束的完整性降低（即，钩束和扣带）。 虽然杏仁核活动的vmPFC抑制随着年龄的增长而增加，但我们和其他人在健康和 青春期激素增加的风险青年，特别是睾酮，与VMPFC减少有关， 杏仁核与威胁的功能联系我们将测试青春期激素增加的模型， 青春期早期会加剧焦虑青年的额杏仁核回路的改变， 更大的威胁反应和焦虑症状的增加，特别是在女孩中。我们测试这个假设在一个 140名无药物治疗的青少年（50%为女性）的样本，焦虑水平各不相同，其中2/3的样本过度采样， GAD和SAD症状的临床水平。我们将在五个时间点重复评估参与者。基线时 大约2年后，我们将评估焦虑（临床访谈，问卷调查），青春期状态， （坦纳，自我报告），青春期激素（脱氢表雄酮，睾酮和雌二醇），在现实世界中的威胁反应 背景与威胁反应的生理和主观测量，以及vmPFC-杏仁核的神经指标 电路（威胁处理期间和静止时的fMRI、白色物质连接和磁共振 GABA和谷氨酸的MRS测量）。将通过以下方式每半年评估一次症状变化 基线访视后2年的在线问卷。我们用7特斯拉的超高场磁共振成像 在焦虑的青年中前所未有的表征vmPFC-杏仁核神经发育。我们还将探索 青春期激素、焦虑和威胁反应对全脑功能网络的影响， 每一个神经指标是如何随着时间的推移相互关联的。我们的目标与RDoC倡议一致 和NIMH战略2.2，鼓励识别早期生物和环境风险， 这些因素及其基本机制为预防和干预的持续发展提供了信息。

Summary Anxiety disorders, which onset during childhood or adolescence, often persist into adulthood, and increase the risk of depression and suicide. Early adolescence, with the onset of puberty, is an important period for the development and/or exacerbation of anxiety symptoms – i.e., Generalized Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD) – with higher levels of symptoms in girls than boys. During this time, fronto-amygdala circuitry, which supports emotion regulation, undergoes important maturational changes. Although alterations in this circuitry has been reported in anxiety disorders, the neurodevelopmental mechanisms underlying the sex differences in levels of anxiety symptoms remain poorly understood. Compared to non-anxious youth, anxious youth exhibit greater amygdala activation and reduced fronto-amygdala functional connectivity when processing threat-related stimuli. Such reduced top–down modulation of amygdala activity to threat has been linked in anxious adults to elevated concentrations in γ-aminobutyric acid (GABA) and glutamate in the ventromedial prefrontal cortex (vmPFC) and amygdala, respectively. It has also been linked, including in anxious youth, to reduced integrity of white matter tracts connecting vmPFC and amygdala (i.e., uncinate fasciculus and cingulum). While vmPFC inhibition of amygdala activity increases with age, we and others have shown in healthy and at- risk youth that increases in pubertal hormones, particularly testosterone, are associated with reduced vmPFC- amygdala functional connectivity to threat. We will test the model that increases in pubertal hormones during early adolescence will exacerbate alterations in fronto-amygdala circuitry in anxious youth and contribute to greater threat reactivity and increases in anxiety symptoms, especially in girls. We test this hypothesis in a sample of medication-free 140 adolescents (50% female), varying in levels of anxiety, with 2/3 oversampled for clinical levels of GAD and SAD symptoms. We will repeatedly assess participants at five timepoints. At baseline and approximately 2 years later, we will assess anxiety (clinical interviews, questionnaires), pubertal status (Tanner, self-report), pubertal hormones (DHEA, testosterone, and estradiol), threat reactivity in a real-world context with physiological and subjective measures of threat reactivity, and neural indices of vmPFC-amygdala circuitry (fMRI during threat processing and at rest, white matter connectivity, and magnetic resonance spectroscopy (MRS) measures of GABA and glutamate). Change in symptoms will be assessed bi-annually via online questionnaires over 2 years post baseline visit. We use an ultra high-field MRI at 7 Tesla, which will yield unprecedented characterization of vmPFC-amygdala neurodevelopment in anxious youth. We will also explore the effects of pubertal hormones, anxiety, and threat reactivity on whole brain functional networks and examine how each of the neural indices relate to each other over time. Our goals are consistent with the RDoC initiative and NIMH Strategy 2.2, encouraging identification of early biological and environmental risk and protective factors and their underlying mechanisms to inform the continued development of prevention and intervention.