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

基本信息

批准号：
10683712
负责人：
ILAN HARPAZ-ROTEM
金额：
--
依托单位：
VA CONNECTICUT HEALTHCARE SYSTEM
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：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683712
关键词：
Address Amygdaloid structure Area Arousal Attenuated Behavior Behavioral Behavioral Model Biological Factors CNR1 gene Chemosensitization Chronic Chronic Disease Clinical Complex Conditioned Reflex Corpus striatum structure Cues Development Dimensions Disease Endocannabinoids Environment Etiology Extinction Fright Functional Magnetic Resonance Imaging Glucocorticoids Hormones Impairment Individual Intervention Knowledge Laboratories Learning Life Literature Measures Mediating Memory Mental disorders Methods Military Personnel Modeling Molecular Neurobiology Norepinephrine Outcome Phase Phenotype Play Positron-Emission Tomography Post-Traumatic Stress Disorders Predictive Value Prefrontal Cortex Process Psychophysiology Research Reversal Learning Role Safety Severities Shock Stimulus Symptoms Synaptic Cleft Testing Time Tracer Update Ventral Striatum Veterans Work anxious combat combat veteran density endogenous cannabinoid system experience fear memory flexibility imaging modality improved insight learning engagement molecular imaging multimodality neural neural circuit neural correlate neurobiological mechanism neuroimaging neurotransmission noradrenaline transporter novel personalized medicine presynaptic response theories treatment strategy

项目摘要

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，慢性和残疾的一种战斗退伍军人的精神疾病。尽管在表征生物学方面取得了一些进步与PTSD相关的因素，这种疾病的神经生物学仍然不完全理解。阐明PTSD神经生物学很重要，因为它有潜力提高对病因的理解并告知更多针对性的发展，基于机制的这种疾病的个性化治疗方法。为此，我们提出了一个最先进的多模式功能磁共振成像 - 符号发射断层扫描（fMRI-PET）研究将首次确定功能性神经和分子（即1型大麻素1 [CB1]受体）恐惧逆转学习的基础 PTSD的核心特征的特征是能够灵活地控制和操纵恐惧的能力战斗退伍军人的反应与战斗有关 PTSD症状。鉴于恐惧逆转学习在PTSD中受到损害，并有助于这种疾病的慢性性，神经生物学因素的表征是其成分的基础过程可以告知这种疾病的病因和个性化。从战场返回后，为什么有些战斗退伍军人发展为PTSD，但其他人没有？一个主要的理论是，患有PTSD的个体在他们熄灭和扭转恐惧学习的能力。在恐惧反向学习中，一个人首先获得对恐惧预测提示的条件回应，同时忽略了另一个提示什么都没有预测（采集阶段）。然后，个人灵活切换恐惧反应在提示之间，当有条件的人不再预测可怕的结果时，而是以前安全的人（反转阶段）。就像在战斗和其他压力下的情况一样，恐惧逆转学习简单地参与了两个过程 - 学习恐惧和学习的内容什么是安全的 - 反过来有助于促进灵活适应恐惧。 PTSD中的恐惧逆转学习模型已经确定，稀缺研究已经检查了这种疾病的核心组成部分的神经生物学。此信息对于了解对抗退伍军人如何处理与恐惧相关信息的神经生物学复杂而充满活力的情况，特别是当它们适应部署后的平民生活时。为了解决文献中的这一差距，我们提出了一项神经元的多模式fMRI-PET研究恐惧的恐惧逆转学习与战斗退伍军人的相关性与战斗有关的PTSD症状的频谱。拟议的研究，直接解决 PTSD研究的CSR＆D高优先级领域将产生对神经的新见解与战斗有关的PTSD中恐惧逆转学习的分子和行为基础。经过与[11C] Omar CB1示踪剂一起使用PET分子成像方法高级fMRI方法，拟议研究的结果将告知：（1）了解与战斗有关的PTSD中恐惧逆转学习的神经生物学病因；（2）发展针对内源性大麻素系统的新型基于机制的治疗方法最终有助于通过PTSD在战斗退伍军人中促进更适应性的恐惧逆转学习。