权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

人类病理性焦虑中蓝斑的跨诊断多模态 7 特斯拉 MRI

基本信息

批准号：
10685147
负责人：
Priti Balchandani
金额：
$ 9.7万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-15 至 2024-06-30
项目状态：
已结题

项目摘要

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.

项目概要/摘要焦虑和压力相关疾病，包括恐慌症 (PD)、广泛性焦虑症（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（即适应不良的唤醒和害怕）。动物模型强烈指出病理性焦虑背后的共同机制蓝斑 (LC)，中枢神经系统去甲肾上腺素的主要来源，也是调节的调节剂的唤醒和对威胁的反应。然而，LC在人类病理性焦虑中的具体作用尚不明确。众所周知，部分原因是过去对小核（如 LC）进行非侵入性成像的技术限制。因此，尽管人们普遍假设 LC 的作用，但焦虑症的病理生理学仍然存在很大程度上未被发现。这一差距阻碍了旨在开发更多基于生物学的转化研究人类焦虑和压力相关疾病的模型，排除了针对这些疾病的精准医学。在为了弥补这一差距，我们建议开展首次 LC 在焦虑症中的跨诊断体内研究，利用针对 PD、PTSD、GAD 患者的尖端 7 Tesla (7 T) MRI。我们的中心假设是 LC 失调是神经精神疾病的精神病理学共同维度的基础，这些疾病是以病理性焦虑为特征。在这里，我们开发并应用 7 T 结构的 MRI 创新， LC在病理性焦虑驱动因素方面的连接组学和功能特征诊断边界。我们的 7 T MRI 方法可提供三倍更高的分辨率患者群体中 LC 多模态成像的灵敏度超过 3 T MRI。我们的初步 7 T MRI 数据展示 LC 和连接的皮质-皮质下的神经解剖学和功能结构在患者和对照中均对电路进行了稳健的表征。使用定量磁化转移 (MT) 成像和神经突定向色散密度成像（NODDI），我们的建议将允许精确人类LC的定位、定量和微观结构表征。以我们的试点为基础根据数据，目标 1 将建立 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焦虑之间的关系。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，之间的协方差 LC 的影像测量和焦虑的维度测量将进行跨诊断检查四个研究组 [PTSD (n=30)、PD (n=30)、GAD (n=30)、健康对照 (N=30)] 进行交叉研究剖面设计。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来探索液晶微观结构、连接性和功能的具体测量与跨诊断的特定维度临床特征相关。