Neural correlates of fear conditioning and extinction in veterans with PTSD and alcohol use disorder

患有创伤后应激障碍和酒精使用障碍的退伍军人的恐惧调节和消退的神经相关性

基本信息

批准号：
10580416
负责人：
ANDREA SPADONI TOWNSEND
金额：
--
依托单位：
VA SAN DIEGO HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580416
关键词：
Abstinence Accounting Affect Alcohol abuse Alcohol consumption Alcoholism Alcohols Amygdaloid structure Anterior Brain imaging Chronic Clinical Clinical Trials Coping Skills Data Development Discrimination Disparity population Dorsal Dropout Environment Extinction Failure Fright Functional Magnetic Resonance Imaging Galvanic Skin Response Heavy Drinking Hippocampus Human Hyperactivity Impairment Individual Insula of Reil Intervention Investigation Learning Link Maintenance Measures Mediating Molecular Outcome Pattern Physiological Play Population Post-Traumatic Stress Disorders Pre-Clinical Model Prefrontal Cortex Process Protocols documentation Psychophysiology Recovery Research Role Safety Signal Transduction Structure Symptoms Trauma recovery Veterans Work alcohol exposure alcohol use disorder analog cingulate cortex conditioned fear design drinking expectation innovation learning extinction neural neural circuit neural correlate neural network neural patterning neuroimaging neuromechanism neuroregulation novel pharmacologic pre-clinical predictive modeling prolonged abstinence response therapy development

Abstinence Accounting Affect Alcohol abuse Alcohol consumption Alcoholism Alcohols Amygdaloid structure Anterior Brain imaging Chronic Clinical Clinical Trials Coping Skills Data Development Discrimination Disparity population Dorsal Dropout Environment Extinction Failure Fright Functional Magnetic Resonance Imaging Galvanic Skin Response Heavy Drinking Hippocampus Human Hyperactivity Impairment Individual Insula of Reil Intervention Investigation Learning Link Maintenance Measures Mediating Molecular Outcome Pattern Physiological Play Population Post-Traumatic Stress Disorders Pre-Clinical Model Prefrontal Cortex Process Protocols documentation Psychophysiology Recovery Research Role Safety Signal Transduction Structure Symptoms Trauma recovery Veterans Work alcohol exposure alcohol use disorder analog cingulate cortex conditioned fear design drinking expectation innovation learning extinction neural neural circuit neural correlate neural network neural patterning neuroimaging neuromechanism neuroregulation novel pharmacologic pre-clinical predictive modeling prolonged abstinence response therapy development

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项目摘要

Approximately half of all treatment seeking Veterans with posttraumatic stress disorder (PTSD) have problems with alcohol, yet it is unclear how current alcohol use affects critical processes mediating recovery from trauma. Despite strong preclinical evidence that recent, heavy alcohol exposure adversely impacts fear extinction, and that fear extinction is central to recovery from PTSD, the direct effects of current, problematic alcohol use on fear extinction have not been characterized in those with PTSD and alcohol use disorders (PAUD). Similarly, contextual fear processing, or the accurate discrimination of threat in the environment, is implicated in the maintenance of PTSD but has never been explored in PAUD. Severe symptom profiles, small treatment gains, and high treatment dropout rates in Veterans with PAUD underscore the need to understand the effects of current heavy drinking on the mechanisms of fear extinction and contextual fear processing. Without studies accounting for the influence of alcohol on processes central to PTSD recovery, treatment innovation for PAUD is likely to remain limited. Previous work and preliminary data from our lab suggest that individuals with PTSD have specific deficits in fear extinction and recall, and that the ventromedial prefrontal cortex (vmPFC), hippocampus (HPC), amygdala, insula, and dorsal anterior cingulate cortex (dACC) play critical roles in the inhibition and expression of fear processing. Moreover, our preliminary data show that current problematic alcohol use in the context of PTSD is associated with higher treatment drop-out and fewer treatment gains from exposure-based relative to coping skills therapy, potentially suggesting an extinction-specific impact of alcohol use on clinical outcomes. While preclinical models provide compelling mechanistic evidence that chronic alcohol exposure disrupts fear extinction and recall, as yet there is no clinical analogue to this work. Relatedly, contextual fear processing is abnormal in PTSD, and damage to the hippocampus (HPC) impairs this process. Tasks used previously to assess contextual fear processing may not reliably invoke HPC dependent processes, and none have assessed the impact of alcohol despite the known deleterious impact of alcohol on HPC structure and function. In the proposed design, we will compare Veterans with PTSD and ongoing, heavy alcohol use (“Drinking” or D-PAUD) to those with 30- to 90-days of sustained abstinence (A-PAUD) using a validated 2-day protocol of concurrent psychophysiological and functional brain imaging measures of fear acquisition, extinction learning, extinction recall, as well as a newly validated configural threat learning measure of contextual fear processing that invokes HPC dependent processes. We predict that Veterans with D-PAUD will show physiological response indicative of greater fear recovery, and neural response consistent with decreased fear inhibition (i.e., less vmPFC activation) during fear extinction learning and recall, and decreased contextual fear processing (i.e., less HPC activation) relative to those with A-PAUD. We will also use directed-functional connectivity to identify neural networks involved in fear extinction recall and to demonstrate differential group-related circuit adaptations, and will employ computational predictive modeling to identify regions specifically tracking dynamic US expectations and compare these patterns between the two clinical groups. The proposed research will provide the first data on how current heavy drinking in the context of PAUD affects fear extinction and contextual fear processing, which are central mechanisms of PTSD recovery, using gold-standard and innovative approaches. Discovery of specific patterns of neural response can lay the groundwork for the investigation of neuromodulatory and pharmacological interventions, as well as clinical trials investigating the efficacy of existing or novel treatments that act at key mechanisms of recovery. In sum, the proposed study will identify critical alcohol-specific mechanisms of impairment to provide a roadmap for the development of targeted interventions to increase the efficacy, efficiency, and innovation of PAUD treatments.

大约一半的治疗治疗后，有创伤后应激障碍的退伍军人（PTSD）具有酒精问题，但目前尚不清楚目前的酒精使用如何影响介导的关键过程创伤。尽管有强烈的临床前证据表明，最近的大量酒精暴露会对恐惧产生不利影响扩展，而恐惧延伸对于从PTSD恢复的核心是当前，问题的直接影响在PTSD和酒精使用障碍的患者中尚未表征恐惧的饮酒。（paud）。同样，上下文恐惧处理或对环境中威胁的准确歧视是在维护PTSD的维护中实施，但从未在Paud中探索过。严重的症状特征，小 Paud的退伍军人的治疗收益和高度治疗辍学率强调了了解当前大量饮酒对恐惧扩展和上下文恐惧处理的机制的影响。未经研究考虑酒精对PTSD恢复中心的过程的影响，治疗 Paud的创新可能会受到限制。我们实验室的先前工作和初步数据表明，具有PTSD的人在恐惧延伸和回忆，以及腹侧前额叶皮层（VMPFC），海马（HPC），杏仁核，岛岛和背部扣带回皮层（DACC）在抑制和表达中起关键作用加工。此外，我们的初步数据表明，当前有问题的饮酒在PTSD的背景下是与应对相对于应对的较高治疗辍学和较少的治疗收益相关技能疗法，可能表明酒精使用对临床结果的特定扩展影响。尽管临床前模型提供了令人信服的机械证据，表明慢性酒精暴露会破坏恐惧扩展和召回，到目前为止，这项工作还没有临床类似物。相关，上下文恐惧处理在PTSD中是异常的，海马（HPC）损害损害了这一过程。以前使用的任务评估上下文恐惧处理可能无法可靠地调用HPC依赖性过程，也没有评估酒精的影响造成了酒精对HPC结构和功能的已知有害影响。在拟议的设计中，我们将将退伍军人与PTSD和正在进行的大量酒精使用（“喝”或 D-paud）使用经过验证的2天协议的人30至90天的持续节制（A-PAUD）同时进行心理生理和功能性脑成像，恐惧获取，扩展学习，扩展回忆，以及新的可配置威胁学习测量上下文恐惧处理的测量这调用了HPC依赖性过程。我们预测具有D-PAUD的退伍军人将显示身体反应表明更大的恐惧恢复，神经反应与恐惧抑制的减少一致（即更少 VMPFC激活）在恐惧扩展学习和回忆期间，并改善了上下文恐惧处理（即更少 HPC激活）相对于具有A-PAUD的激活。我们还将使用定向功能连接来识别神经涉及恐惧延长召回并展示与差异群体相关的电路适应的网络，并且将采用计算预测建模来识别专门跟踪动态美国期望的区域并比较两个临床组之间的这些模式。拟议的研究将提供有关Paud中当前大量饮酒的第一个数据影响恐惧的扩展和上下文恐惧处理，这是PTSD恢复的核心机制，使用金标准和创新方法。发现特定神经反应的特定模式可以放置研究神经调节和药物干预措施以及临床试验的基础研究以关键恢复机制作用的现有或新型治疗的效率。总而言之拟议的研究将确定关键的酒精特异性损害机制，以提供为该路线图的路线图开发有针对性的干预措施，以提高PAUD治疗的效率，效率和创新。