Transdiagnostic Multimodal 7 Tesla MRI of the Locus Coeruleus in Human Pathological Anxiety

项目摘要/摘要 焦虑和压力相关障碍，包括惊恐障碍(PD)、广泛性焦虑症 (GAD)和创伤后应激障碍(PTSD)是最具致残性的神经精神疾病 在美国。这些障碍的一个核心特征是病理性焦虑(即，适应不良的觉醒和 恐惧)。动物模型强烈指出病理性焦虑的共同机制涉及 蓝斑(LC)是中枢神经系统去甲肾上腺素的主要来源，也是这种调节的调节器 对威胁的唤醒和反应。然而，LC在人类病理性焦虑中的具体作用并不是 已知，部分原因是过去对小核团(如LC)进行非侵入性成像的技术限制。因此， 尽管普遍存在LC的作用假说，但焦虑症的病理生理学仍然存在 很大程度上没有被发现。这一差距阻碍了旨在开发更多生物学基础的翻译研究 人类焦虑和压力相关疾病的模型，排除了治疗这些疾病的精确药物。在……里面 为了解决这一差距，我们提出了第一个LC在焦虑中的体内跨诊断研究，利用 尖端7特斯拉(7T)核磁共振在帕金森病、创伤后应激障碍、广泛性痴呆患者中的应用。我们的中心假设是LC 调节障碍是神经精神障碍的精神病理学共同维度的基础，这些障碍是 以病态焦虑为特征的。在这里，我们为7T Structure开发和应用MRI创新， 从病理性焦虑的驱动因素看LC的连接性和功能性特征 诊断界限。我们的7T磁共振成像方法提供了大约三倍的更高分辨率和 在患者群体中对LC进行多模式成像的灵敏度超过3T MRI。我们初步的7T磁共振数据 显示LC和连接的皮质下皮质的神经解剖和功能构筑 回路在患者和对照组中都表现出强烈的特征。使用定量磁化转移(MT) 成像和轴突定向弥散密度成像(NODI)，我们的建议将允许精确 人类LC的定位、定量和微结构特征。以我们的试点项目为基础 数据，目标1将确定LC微观结构在病理性焦虑中的作用。目标2将建立 LC功能和解剖连接与病理性焦虑的关系。目标3将建立 LC在病理性焦虑中对威胁的功能反应中的作用在每种情况下， 将对LC的成像测量和焦虑的维度测量进行跨诊断检查 跨四个研究组[PTSD(n=30)，PD(n=30)，GAD(n=30)，健康对照组(N=30)] 横断面设计。其次，将检查组之间的差异。最后，在目标4中，我们将使用 数据驱动的方法，探索LC微观结构、连通性和功能的具体测量 与不同诊断的特定维度临床特征有关。

Project Summary/Abstract Anxiety and stress-related disorders, including panic disorder (PD), generalized anxiety disorder (GAD),and posttraumatic stress disorder (PTSD), are among the most disabling neuropsychiatric conditions in the United States. A core feature of these disorders is pathological anxiety (i.e., maladaptive arousal and fear). Animal models point strongly towards shared mechanisms underlying pathological anxiety to involve the locus coeruleus (LC), the primary source of norepinephrine in the CNS, and modulator of the regulation of arousal and response to threat. However, the specific role of the LC in human pathological anxiety is not known, due inpart to past technical limitations of non-invasive imaging for small nuclei such as the LC. Thus, despite the prevailing hypothesis of the role of the LC, the pathophysiology of anxiety disorders remains largely undiscovered. This gap impedes translational research aimed at developing more biologically based models of human anxiety and stress-related disorders, precluding precision medicine for these disorders. In order to address this gap, we propose to the first transdiagnostic in vivo study of LC in anxiety, leveraging cutting-edge 7 Tesla (7 T) MRI in patients with PD, PTSD, GAD. Our central hypothesis is that LC dysregulation underlies shared dimensions of psychopathology across neuropsychiatric disorders that are characterized by pathological anxiety. Here we develop and apply MRI innovations for 7 T structural, connectomic, and functional characterization of the LC in terms of drivers of pathological anxiety across diagnostic boundaries. Our 7 T MRI approach affords on the order of three-fold higher resolution and sensitivity over 3 T MRI for multi-modal imaging the LC in patient populations. Our preliminary 7 T MRI data demonstrate the neuroanatomical and functional architecture of LC and connected cortico-subcortical circuitry robustly characterized in both patients and controls. Using quantitative magnetization transfer (MT) imaging and neurite orientation dispersion density imaging (NODDI), our proposal will allow for the precise localization, quantification and microstructural characterization of the LC in humans. Building on our pilot data, Aim 1 will establish the role of LC microstructure in pathological anxiety. Aim 2 will establish the relationship between LC functional and anatomical connectivity and pathological anxiety. Aim 3 will establish the role of LC in functional response to threat in pathological anxiety. In each case, co-variance between imaging measures of the LC and dimensional measures of anxiety will be examined trans-diagnostically across four study groups [PTSD (n=30), PD (n=30), GAD (n=30), healthy controls (N=30)] in a cross- sectional design. Secondarily, between-group differences will be examined. Finally, in Aim 4, we will use a data-driven approach to explore how specific measures of LC microstructure, connectivity, and function relate to specific dimensional clinical features across diagnoses.