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：
10535458
负责人：
Priti Balchandani
金额：
$ 52.04万
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

来源：
https://reporter.nih.gov/project-details/10535458
关键词：
Address Anatomy Animal Model Anxiety Anxiety Disorders Architecture Arousal Brain Cell Nucleus Characteristics Clinical Collaborations Data Diagnosis Diagnostic Diffusion Magnetic Resonance Imaging Dimensions Disease Fright Functional Magnetic Resonance Imaging Functional disorder Generalized Anxiety Disorder Human Image Laboratories Link Magnetic Resonance Imaging Maps Measurement Measures Medial Metric System Midbrain structure Modeling Multimodal Imaging National Institute of Mental Health Negative Valence Neurites Neuroanatomy Norepinephrine Panic Disorder Pathological anxiety Patients Post-Traumatic Stress Disorders Pre-Clinical Model Prefrontal Cortex Psychopathology Questionnaires Regulation Research Research Domain Criteria Resolution Role Source Structure Subgroup System Translational Research United States Variant Work anxiety symptoms anxious clinical anxiety clinical diagnosis clinical predictors connectome density design diagnostic strategy human disease human imaging human model in vivo in-vivo diagnostics innovation locus ceruleus structure mood symptom multimodality neural circuit neuropsychiatric disorder neuropsychiatry non-invasive imaging novel novel therapeutics patient population precision medicine response stress related disorder tractography ultra high resolution

项目摘要

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.

焦虑和与压力有关的疾病，包括恐慌症（PD），广义焦虑症（GAD），创伤后应激障碍（PTSD）是最残疾的神经精神病疾病之一美国。这些疾病的核心特征是病理焦虑（即适应不良的唤醒和恐惧）。动物模型强烈指向病理焦虑的共同机制，涉及该基因座 COERULEUS（LC），CNS中去甲肾上腺素的主要来源和唤醒调节的调节剂和对威胁的反应。但是，液晶在人类病理焦虑中的具体作用尚不清楚，在小核（例如LC）的非侵入性成像的过去技术局限性的一部分。因此，尽管有 LC的作用的普遍假设，焦虑症的病理生理仍然很大程度上仍然是未被发现。这一差距阻碍了转化研究，旨在开发更基于生物学的模型人类焦虑和与压力有关的疾病，排除这些疾病的精确药物。为了解决这一差距，我们向焦虑中的LC进行了首次转诊研究，利用了尖端 PD，PTSD，GAD患者的7 Tesla（7 T）MRI。我们的中心假设是LC失调基础跨神经精神疾病的心理病理学的共同维度，其特征是病理焦虑。在这里，我们开发并应用MRI创新进行7 t结构，连接组和 LC在诊断边界的病理焦虑驱动因素方面的功能表征。我们的7 t MRI方法可在3 t MRI的三个左右分辨率和灵敏度上提供多个多数模态成像患者人群中的LC。我们的初步7 T MRI数据证明了神经解剖学 LC的功能结构以及连接的皮质 - 毛皮电路都在两者中都具有牢固特征患者和对照。使用定量磁化转移（MT）成像和神经突方向分散密度成像（NODDI），我们的建议将允许精确定位，定量和 LC在人类中的微观结构表征。在我们的飞行员数据的基础上，AIM 1将确定病理焦虑中的LC微观结构。 AIM 2将确定LC功能与解剖连通性和病理焦虑。 AIM 3将确定LC在功能响应中的作用病理焦虑的威胁。在每种情况下，LC的成像度量与尺寸之间的共同变异焦虑措施将在四个研究组中进行反诊断[PTSD（n = 30），PD（n = 30）， GAD（n = 30），横截面设计中的健康对照（n = 30）。其次，组间差异将被检查。最后，在AIM 4中，我们将使用数据驱动的方法来探索LC的特定度量微结构，连通性和功能与诊断之间的特定维度临床特征有关。