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

焦虑和压力相关的障碍，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之一 美国。这些障碍的一个核心特征是病理性焦虑(即适应不良的唤醒和恐惧)。 动物模型强烈指出病理性焦虑背后的共同机制与基因座有关 蓝斑(LC)是中枢神经系统去甲肾上腺素的主要来源，也是觉醒调节的调节器 以及对威胁的反应。然而，LC在人类病理性焦虑中的具体作用尚不清楚，因为 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 关于LC作用的流行假说，焦虑症的病理生理学在很大程度上仍然存在 未被发现的。这一差距阻碍了旨在开发更多基于生物学的模型的翻译研究 人类焦虑和与压力相关的疾病，排除了治疗这些疾病的精确药物。为了 为了解决这一差距，我们提议利用尖端技术，进行第一个关于焦虑的LC的体内跨诊断研究 帕金森病、创伤后应激障碍、广泛性痴呆症患者的7T磁共振成像。我们的中心假设是LC失调是基础 神经精神障碍的精神病理学的共同维度，其特征是 病态焦虑症。在这里，我们开发和应用7T结构、连接和 在跨越诊断界限的病理性焦虑的驱动因素方面，LC的功能特征。 我们的7T MRI方法提供了比3T MRI高三倍的分辨率和灵敏度，适用于多个 对患者群体中的LC进行模式成像。我们初步的7T磁共振数据显示了神经解剖学 LC和连接的皮质-皮质下回路的功能结构在两个方面都有很强的特征 病人和对照组。使用定量磁化转移(MT)成像和轴突定位 弥散密度成像(NODI)，我们的建议将允许精确定位、量化和 人类LC的微结构特征。在我们试点数据的基础上，目标1将确定 病理性焦虑的LC显微结构。目标2将建立LC泛函和 解剖连接和病理性焦虑。目标3将确定LC在功能性反应中的作用 病态焦虑的威胁。在每种情况下，LC和维度的成像测量之间的协方差 焦虑的测量将在四个研究组中进行跨诊断检查[创伤后应激障碍(PTSD)(n=30)，PD(n=30)， GAD(n=30)，健康对照(N=30)]采用横断面设计。其次，集团之间的差异将 接受检查。最后，在目标4中，我们将使用数据驱动的方法来探索LC的具体措施 显微结构、连通性和功能与不同诊断的特定维度临床特征相关。

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 in part 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.