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

• 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
• 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

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.

在所有寻求治疗的患有创伤后应激障碍(PTSD)的退伍军人中，约有一半 酒精问题，但目前尚不清楚目前酒精使用如何影响调解康复的关键过程 精神创伤。尽管有强有力的临床前证据表明，最近接触大量酒精会对恐惧产生不利影响 消除恐惧是从创伤后应激障碍中恢复的核心，这是当前存在问题的直接影响 在患有创伤后应激障碍和酒精使用障碍的患者中，酒精对消除恐惧的作用尚未得到证实。 (波特率)。同样，情境恐惧处理，或对环境中威胁的准确辨别，是 与创伤后应激障碍的维持有关，但在波德从未被探索过。严重症状，小幅 患有PAUD的退伍军人的治疗收益和高治疗丢失率强调了了解以下问题的必要性 当前大量饮酒对恐惧消退和背景恐惧处理机制的影响。 在没有研究酒精对创伤后应激障碍康复过程的影响的情况下，治疗 对于Paud来说，创新可能仍然有限。 以前的工作和我们实验室的初步数据表明，患有创伤后应激障碍的人在 恐惧消退和回忆，而腹内侧额前皮质(VmPFC)，海马体(HPC)，杏仁核， 岛叶和背侧前扣带回(DACC)在恐惧的抑制和表达中起关键作用 正在处理。此外，我们的初步数据显示，目前在创伤后应激障碍背景下使用有问题的酒精是 与基于暴露的应对措施相比，更高的治疗丢失率和更少的治疗收益相关 技能疗法，潜在地表明酒精使用对临床结果的特定灭绝影响。而当 临床前模型提供了令人信服的机械证据，表明长期接触酒精会扰乱恐惧 灭绝和回忆，到目前为止还没有临床上类似的工作。与之相关的是，情境恐惧处理 在创伤后应激障碍中是异常的，而对海马体(HPC)的损伤会损害这一过程。以前使用的任务 评估情景恐惧处理可能不会可靠地调用HPC依赖过程，而且没有人进行过评估 酒精对HPC结构和功能的影响，尽管已知酒精对HPC结构和功能的有害影响。 在建议的设计中，我们将比较退伍军人患有创伤后应激障碍和持续大量饮酒(饮酒或 D-PAUD)给那些持续戒酒30至90天(A-PAUD)的人，使用经过验证的2天方案 同步的心理生理学和脑功能成像测量恐惧获得，消退学习， 消亡回忆，以及新验证的情境恐惧处理的配置威胁学习测量 这将调用依赖于HPC的进程。我们预测患有D-PAUD的退伍军人将表现出生理反应 表明恐惧恢复更快，神经反应与减少的恐惧抑制一致(即减少 在恐惧消退学习和回忆期间的vmPFC激活)，以及减少上下文恐惧处理(即更少 HPC激活)相对于A-PAUD患者。我们还将使用定向功能连接性来识别神经 参与恐惧消退回忆的网络，并展示不同的群体相关回路适应，以及 将使用计算预测建模来确定具体跟踪动态美国预期的区域 并比较两个临床组之间的这些模式。 这项拟议的研究将提供第一批数据，说明目前大量饮酒是如何在波特的背景下发生的 影响恐惧消退和情景恐惧处理，这是创伤后应激障碍康复的核心机制，使用 金本位和创新的方法。发现特定的神经反应模式可以为 为研究神经调节和药物干预以及临床试验奠定基础 研究作用于关键康复机制的现有或新型治疗方法的疗效。总而言之， 拟议的研究将确定关键的酒精特有的损害机制，以提供路线图 开发有针对性的干预措施，以提高PAUD治疗的疗效、效率和创新性。