Fear Reversal Learning in Combat-Related PTSD: A Multi-Model fMRI-PET Approach

战斗相关 PTSD 中的恐惧逆转学习：多模型 fMRI-PET 方法

• 批准号: 10292414
• 负责人: ILAN HARPAZ-ROTEM
• 金额: --
• 依托单位: VA CONNECTICUT HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292414
• 关键词: Address; Amygdaloid structure; Area; Arousal; Attenuated; Behavior; Behavioral; Behavioral Model; Biological Factors; CNR1 gene; Cannabinoids; Chemosensitization; Chronic; Chronic Disease; Clinical; Complex; Conditioned Reflex; Cues; Development; Dimensions; Disease; Endocannabinoids; Environment; Etiology; Extinction (Psychology); Fright; Functional Magnetic Resonance Imaging; Glucocorticoids; Hormones; Impairment; Individual; Intervention; Knowledge; Laboratories; Learning; Life; Literature; Measures; Mediating; Mental disorders; Methods; Military Personnel; Modeling; Molecular; Neurobiology; Norepinephrine; Outcome; Phase; Phenotype; Play; Positron-Emission Tomography; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; Psychophysiology; Research; Reversal Learning; Role; Safety; Severities; Shock; Stimulus; Symptoms; Synapses; Testing; Time; Tracer; Update; Ventral Striatum; Veterans; Work; anxious; base; combat; combat veteran; density; endogenous cannabinoid system; experience; fear memory; flexibility; imaging modality; improved; insight; molecular imaging; multimodality; neural circuit; neural correlate; neurobiological mechanism; neuroimaging; neurotransmission; noradrenaline transporter; novel; personalized medicine; presynaptic; relating to nervous system; response; theories; treatment strategy

Project Summary/Abstract Posttraumatic stress disorder (PTSD) is one of the most prevalent, chronic, and disabling psychiatric disorders in combat veterans. Despite some advances in characterizing biological factors associated with PTSD, the neurobiology of this disorder remains incompletely understood. Elucidation of the neurobiology of PTSD is important, as it has the potential to improve understanding of the etiology and inform the development of more targeted, mechanism-based, and personalized treatments for this disorder. To this end, we propose a state-of-the-art, multi-modal functional magnetic resonance imaging-positron emission tomography (fMRI-PET) study that will determine, for the first time, functional neural and molecular (i.e., cannabinoid type 1 [CB1] receptor) underpinnings of fear reversal learning, a core feature of PTSD characterized by the ability to flexibly control and maneuver acquired fear responses in combat veterans presenting with the full dimensional spectrum of combat-related PTSD symptoms. Given that fear reversal learning is impaired in PTSD and contributes to the chronicity of this disorder, characterization of neurobiological factors that underlie its component processes can inform both the etiology and personalization of treatments for this disorder. Upon returning from the battlefield, why is it that some combat veterans develop PTSD but others do not? A predominant theory is that individuals with PTSD are markedly impaired in their ability to extinguish and reverse fear learning. During fear reversal learning, an individual first acquires a conditioned response to a fear predictive cue while ignoring another cue that predicts nothing (acquisition phase). Then, the individual flexibly switches the fear response between cues, when the conditioned one does not predict the fearful outcome anymore, but the previously safe one does (reversal phase). As in combat and other stressful situations, fear reversal learning engages two processes simultaneously—learning what to fear and learning what is safe—which in turn helps to promotes flexible adaptation to fear.. While behavioral models of fear reversal learning in PTSD are well established, scarce research has examined the neurobiology of this core component of this disorder. This information is essential to understanding the neurobiology of how combat veterans process fear-related information in complex and dynamic situations, particularly as they adapt to civilian life after deployment. To address this gap in the literature, we propose a multi-modal fMRI-PET study of the neural correlates of fear reversal learning in combat veterans presenting with the full dimensional spectrum of combat-related PTSD symptoms. The proposed study, which directly addresses the CSR&D high priority area of PTSD research, will generate novel insights into the neural, molecular, and behavioral underpinnings of fear reversal learning in combat-related PTSD. By employing PET molecular imaging methods with the [11C]OMAR CB1 tracer in combination with advanced fMRI methods, results of the proposed study will inform: (1) understanding of the neurobiological etiology of fear reversal learning in combat-related PTSD; and (2) development of novel, mechanism-based treatments that target the endocannabinoid system, which may ultimately help promote more adaptive fear reversal learning in combat veterans with PTSD.

项目摘要/摘要 创伤后应激障碍(PTSD)是最普遍的、慢性的和致残的 退伍军人的精神障碍。尽管在生物学特性方面取得了一些进展 与创伤后应激障碍相关的因素，这种疾病的神经生物学仍然不完全 明白了。阐明创伤后应激障碍的神经生物学很重要，因为它有可能 提高对病因的理解，并为制定更有针对性的 针对这种疾病的基于机制的和个性化的治疗。为此，我们提出一项 最先进的多模式功能磁共振成像-正电子发射 断层扫描(fMRI-PET)研究，将首次确定功能神经和 恐惧逆转学习的分子基础(即大麻素1型[CB1]受体) 创伤后应激障碍的核心特征是能够灵活地控制和操纵获得性恐惧 退伍军人的反应呈现了与战斗相关的全维光谱 创伤后应激障碍症状。鉴于恐惧逆转学习在创伤后应激障碍中受损，并有助于 这种疾病的慢性，构成其组成部分的神经生物学因素的特征 治疗过程可以为这种疾病的病因和个人化治疗提供信息。 从战场回来后，为什么有些退伍军人会患上创伤后应激障碍 其他人不是吗？一种占主导地位的理论是，患有创伤后应激障碍的个体在 他们消除和逆转恐惧学习的能力。在恐惧逆转学习过程中，个体 首先获得对恐惧预测线索的条件性反应，而忽略另一个线索 没有任何预测(收购阶段)。然后，个体灵活地切换恐惧反应 在提示之间，当条件反射的人不再预测可怕的结果时，但 以前安全的是这样做的(反转阶段)。就像在战斗和其他紧张的情况下，恐惧 反转学习同时涉及两个过程--学习害怕的东西和学习 什么是安全的--这反过来又有助于促进对恐惧的灵活适应。在行为上 很少有研究表明，创伤后应激障碍中恐惧逆转学习的模型已经建立起来 这种疾病的核心组成部分的神经生物学。此信息对以下各项至关重要 了解退伍军人如何处理恐惧相关信息的神经生物学 复杂和动态的局势，特别是在部署后适应平民生活的情况下。 为了解决文献中的这一空白，我们提出了一种神经的多模式fMRI-PET研究 退伍军人全维恐惧反转学习的相关性 一系列与战斗相关的创伤后应激障碍症状。建议的研究，直接针对 CSR&D的高度优先领域的创伤后应激障碍研究，将产生对神经的新见解， 战斗相关创伤后应激障碍中恐惧逆转学习的分子和行为基础。通过 用[11C]Omar CB1示踪剂结合PET分子成像方法 先进的功能磁共振成像方法，建议的研究结果将告知：(1)对 战斗相关创伤后应激障碍中恐惧逆转学习的神经生物学病因；和(2)发展 以内源性大麻素系统为靶点的新型、基于机制的治疗方法，这可能 最终有助于促进患有创伤后应激障碍的退伍军人更具适应性的恐惧逆转学习。