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

• 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
• 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

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）是世界上最严重的神经精神疾病之一 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恐惧）。 动物模型强烈指出病理性焦虑背后的共同机制涉及该基因座 蓝藻 (LC)，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，因为 部分解决了过去对小核（如 LC）非侵入性成像的技术限制。因此，尽管 尽管关于 LC 作用的普遍假设，焦虑症的病理生理学仍然在很大程度上 未被发现。这一差距阻碍了旨在开发更多基于生物学的模型的转化研究 人类焦虑和压力相关疾病，排除了针对这些疾病的精准医疗。为了 为了解决这一差距，我们建议利用尖端技术开展 LC 在焦虑症中的首次跨诊断体内研究 PD、PTSD、GAD 患者的 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的共同维度，其特征是 病理性焦虑。在这里，我们开发并应用 7 T 结构、连接组和 LC 在跨越诊断边界的病理性焦虑驱动因素方面的功能特征。 我们的 7 T MRI 方法可提供比 3 T MRI 高三倍的分辨率和灵敏度，用于多 对患者群体中的 LC 进行模态成像。我们的初步 7 T MRI 数据证明了神经解剖学 LC 的功能架构和连接的皮层-皮层下电路在这两个方面都有鲁棒的特征 患者和对照。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定位、量化和 人类LC的微观结构特征。基于我们的试点数据，目标 1 将确立以下角色： 病理性焦虑中的 LC 微观结构。目标 2 将建立 LC 泛函与 解剖连接性和病理性焦虑。目标 3 将确立 LC 在功能性反应中的作用 病理性焦虑的威胁。在每种情况下，LC 和尺寸的成像测量之间的协方差 焦虑测量将在四个研究组中进行跨诊断检查[PTSD (n=30)、PD (n=30)、 横断面设计中的 GAD (n=30)、健康对照 (N=30)]。其次，组间差异 被检查。最后，在目标 4 中，我们将使用数据驱动的方法来探索 LC 的具体措施如何 微观结构、连接性和功能与诊断中特定维度的临床特征相关。