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

焦虑和压力相关障碍，包括惊恐障碍（PD）、广泛性焦虑障碍（GAD）、 和创伤后应激障碍（PTSD），是美国最具致残性的神经精神疾病之一。 美国的这些疾病的核心特征是病理性焦虑（即，适应不良的觉醒和恐惧）。 动物模型强烈地指向病理性焦虑的共同机制， 蓝斑（LC），CNS中去甲肾上腺素的主要来源，以及唤醒调节的调节剂 和对威胁的反应。然而，LC在人类病理性焦虑中的具体作用尚不清楚， 部分归因于过去对小细胞核（例如LC）的非侵入性成像的技术限制。所以尽管 尽管关于LC作用的流行假设，焦虑症的病理生理学仍然主要是 未被发现这一差距阻碍了旨在开发更多基于生物学的模型的转化研究。 人类焦虑和压力相关的疾病，排除了对这些疾病的精确医学。为了 为了解决这一差距，我们提出了第一个跨诊断体内研究LC在焦虑，利用尖端 PD、PTSD、GAD患者的7 T MRI。我们的中心假设是LC失调是 神经精神障碍中精神病理学的共同维度，其特征在于 病理性焦虑在这里，我们开发和应用MRI创新的7 T结构，连接， LC的功能表征在诊断边界的病理性焦虑的驱动因素方面。 我们的7 T MRI方法提供了3倍以上的分辨率和灵敏度超过3 T MRI的多， 在患者群体中对LC进行模态成像。我们初步的7 T MRI数据表明， LC和连接的皮质-皮质下回路的功能结构， 患者和对照组。使用定量磁化传递（MT）成像和神经突定位 弥散密度成像（NODDI），我们的建议将允许精确的定位，定量和 人类LC的显微结构特征。在我们的试点数据的基础上，目标1将确定以下方面的作用： 病理性焦虑的LC微结构目标2将建立LC泛函与 解剖连接和病理焦虑目的3将确定LC在功能反应中的作用， 病理性焦虑的威胁在每种情况下，LC的成像测量值和尺寸测量值之间的协方差 将在四个研究组[PTSD（n=30），PD（n =30）， GAD组（n=30），健康对照组（N=30）]。其次，组间差异将 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讨如何对LC的具体措施 微结构、连通性和功能与诊断中的特定维度临床特征有关。

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.