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

项目总结/摘要 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）是最致残的神经精神疾病之一 在美国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）是CNS中去甲肾上腺素的主要来源，也是调节 对威胁的反应然而，LC在人类病理性焦虑中的具体作用却并非如此 已知，部分由于过去对小核（例如LC）的非侵入性成像的技术限制。因此，在本发明中， 尽管对LC的作用有流行的假设，但焦虑症的病理生理学仍然是 大部分未被发现。这一差距阻碍了旨在开发更多生物学基础的转化研究 人类焦虑和压力相关疾病的模型，排除了这些疾病的精确医学。在 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 在PD、PTSD、GAD患者中使用尖端的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的基础， 以病态的焦虑为特征。在这里，我们开发和应用MRI创新的7 T结构， 连接组学和功能表征的LC的驱动程序的病理性焦虑， 诊断边界我们的7 T MRI方法提供了三倍高的分辨率， 在患者人群中对LC进行多模式成像的灵敏度超过3 T MRI。我们初步的7 T MRI数据 显示LC的神经解剖学和功能结构以及连接的皮质-皮质下 在患者和对照组中均表现出强烈的电路特征。使用定量磁化转移（MT） 成像和神经突方向弥散密度成像（NODDI），我们的建议将允许精确的 在人类中LC的定位、定量和微观结构表征。根据我们的试播集 数据，目的1将建立病理性焦虑症中的LC微结构的作用。目标2将建立 LC功能和解剖连接与病理性焦虑之间的关系。目标3将建立 LC在病理性焦虑威胁功能反应中的作用在每种情况下， LC的影像学测量和焦虑的维度测量将进行跨诊断检查 在四个研究组[PTSD（n=30），PD（n=30），GAD（n=30），健康对照组（N=30）]中进行交叉研究。 分段设计其次，将检查组间差异。最后，在目标4中，我们将使用 数据驱动的方法，探讨如何具体措施的LC微观结构，连接，和功能 与诊断中的特定维度临床特征相关。

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.