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

摘要 焦虑症起病于童年或青春期，通常会持续到成年，并增加 有抑郁和自杀的风险。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/或加重--即广泛性焦虑障碍(GAD)和社交 焦虑症(SAD)--女孩的症状水平高于男孩。在此期间，额叶杏仁核 支持情绪调节的回路经历了重要的成熟变化。虽然更改了 这种回路在焦虑症中已有报道，焦虑症是性行为的神经发育机制 焦虑症状水平的差异仍然知之甚少。与不焦虑的年轻人相比，焦虑的年轻人 青少年在加工时表现出更大的杏仁核激活和额叶-杏仁核功能连接减少 与威胁相关的刺激。杏仁核活动对威胁的这种自上而下的调节减少与 焦虑的成年人对腹内侧部γ-氨基丁酸和谷氨酸浓度升高感到焦虑 前额叶皮质(VmPFC)和杏仁核。它也被认为，包括焦虑的年轻人，与 连接vmPFC和杏仁核(即钩束和扣带)的白质束完整性降低。 虽然vmPFC对杏仁核活动的抑制随着年龄的增长而增加，但我们和其他人在健康和 青春期荷尔蒙，尤其是睾丸素升高的风险青年与vmPFC降低有关。 杏仁核与威胁的功能连接。我们将测试在青春期荷尔蒙增加的模型 青春期早期会加剧焦虑青年额叶-杏仁核回路的改变，并有助于 更强的威胁反应性和焦虑症状的增加，特别是在女孩。我们对这一假设进行了测试 140名未服用药物的青少年(50%为女性)的样本，焦虑程度各不相同，其中2/3被过度抽样 GAD和SAD症状的临床水平。我们将在五个时间点反复评估参与者。在基线上 大约两年后，我们将评估焦虑(临床访谈、问卷调查)、青春期状况 (坦纳，自我报告)，青春期激素(脱氢表雄酮、睾酮和雌二醇)，真实世界中的威胁反应性 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(威胁处理和静止时的功能磁共振、脑白质连接和磁共振 光谱学(MRS)测量GABA和谷氨酸)。症状的变化将通过以下方式每两年评估一次 基线访问后超过两年的在线问卷调查。我们使用7特斯拉的超高场核磁共振，这将产生 焦虑青年vmpfc-杏仁核神经发育的史无前例的特征。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和检查的影响 随着时间的推移，每个神经指数如何相互关联。我们的目标与RDoC倡议是一致的 和NIMH战略2.2，鼓励及早识别生物和环境风险并进行保护 影响预防和干预工作继续发展的因素及其基本机制。

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.