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.

项目概要/摘要创伤后应激障碍 (PTSD) 是最普遍、最慢性、最致残的疾病之一尽管在生物学特征方面取得了一些进展，但退伍军人的精神疾病。与 PTSD 相关的因素，这种疾病的神经生物学仍然不完全阐明 PTSD 的神经生物学很重要，因为它有潜力。提高对病因的了解，并为制定更有针对性的、为此，我们提出了一种基于机制的个性化治疗方法。最先进的多模态功能磁共振成像-正电子发射断层扫描（fMRI-PET）研究将首次确定功能性神经和功能恐惧逆转学习的分子（即大麻素 1 型 [CB1] 受体）基础， PTSD的核心特征是灵活控制和操纵获得性恐惧的能力退伍军人的反应呈现出与战斗相关的全维度谱鉴于 PTSD 患者的恐惧逆转学习受到损害，并导致了 PTSD 症状。这种疾病的慢性性，其组成部分的神经生物学因素的特征过程可以为这种疾病的病因学和个性化治疗提供信息。为什么有些退伍军人从战场回来后会出现创伤后应激障碍（PTSD），但一个主要的理论是，患有创伤后应激障碍的人的能力明显受损。他们消除和逆转恐惧学习的能力。首先获得对恐惧预测线索的条件反应，同时忽略另一个暗示然后，个体灵活地切换恐惧反应。在线索之间，当条件线索不再预测可怕的结果时，以前安全的人会这样做（逆转阶段），就像在战斗和其他有压力的情况下一样，恐惧。逆向学习同时涉及两个过程——学习恐惧什么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。创伤后应激障碍（PTSD）的恐惧逆转学习模型已经很成熟，但研究很少该信息对于了解这种疾病的核心组成部分至关重要。了解退伍军人如何处理恐惧相关信息的神经生物学局势复杂多变，特别是在部署后适应平民生活时。为了解决文献中的这一空白，我们提出了一项针对神经网络的多模态 fMRI-PET 研究。退伍军人恐惧逆转学习的相关性呈现全维度拟议的研究直接解决了与战斗相关的创伤后应激障碍症状。 CSR&D PTSD 研究的高度优先领域，将对神经、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。采用 PET 分子成像方法与 [11C]OMAR CB1 示踪剂结合先进的功能磁共振成像方法，拟议研究的结果将告知：（1）了解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学；(2) 发展；针对内源性大麻素系统的基于机制的新型治疗方法，可能最终有助于促进患有创伤后应激障碍 (PTSD) 的退伍军人进行更具适应性的恐惧逆转学习。