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

在所有寻求治疗的创伤后应激障碍（PTSD）退伍军人中， 酒精的问题，但目前还不清楚目前的酒精使用如何影响调解恢复的关键过程， 外伤尽管有强有力的临床前证据表明，最近，大量饮酒会对恐惧产生不利影响， 灭绝，恐惧灭绝是从创伤后应激障碍中恢复的核心，目前的直接影响， 在PTSD和酒精使用障碍患者中，酒精使用对恐惧消退的影响并不明显 （PAUD）.类似地，情境恐惧处理，或准确区分环境中的威胁， 与PTSD的维持有关，但从未在PAUD中探索过。重度症状特征，小 PAUD退伍军人的治疗收益和高治疗辍学率强调了了解PAUD的必要性 当前大量饮酒对恐惧消退机制和情境性恐惧加工的影响。 由于没有研究说明酒精对创伤后应激障碍康复过程的影响， PAUD的创新可能仍然有限。 先前的工作和我们实验室的初步数据表明，PTSD患者在以下方面存在特定的缺陷： 恐惧消退和回忆，腹内侧前额叶皮层（vmPFC），海马体（HPC），杏仁核， 背侧前扣带皮层（dACC）在恐惧的抑制和表达中起着重要作用 处理.此外，我们的初步数据显示，目前在创伤后应激障碍的背景下， 与较高的治疗脱落率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影响。而 临床前模型提供了令人信服的机制证据，表明长期酒精暴露会破坏恐惧 灭绝和回忆，迄今为止还没有临床类似的工作。相关地，情境恐惧处理 在创伤后应激障碍中是不正常的，海马体（HPC）的损伤会削弱这一过程。以前使用的任务 评估情境恐惧处理可能无法可靠地调用HPC依赖的过程，并且没有人评估过 尽管已知酒精对HPC结构和功能有有害影响，但酒精的影响仍然存在。 在拟议的设计中，我们将比较退伍军人与创伤后应激障碍和正在进行的，大量饮酒（“饮酒”或 D-PAUD）适用于持续禁欲30至90天（A-PAUD）的患者，使用经过验证的2天方案 同时进行心理生理学和功能性脑成像测量恐惧获得，消退学习， 灭绝回忆，以及一个新验证的周边威胁学习措施的背景恐惧处理 调用HPC相关进程。我们预测D-PAUD的退伍军人将表现出生理反应， 表明更大的恐惧恢复，以及与减少的恐惧抑制一致的神经反应（即，少 在恐惧消退学习和回忆过程中的vmPFC激活），以及减少的背景恐惧处理（即，少 HPC激活）。我们还将使用定向功能连接来识别神经元 参与恐惧消退回忆的网络，并证明与不同群体相关的电路适应， 将采用计算预测模型来确定专门跟踪美国动态预期的地区 并比较两个临床组之间的这些模式。 这项拟议中的研究将提供第一个数据，说明在PAUD的背景下， 影响恐惧消退和背景恐惧处理，这是PTSD恢复的中心机制，使用 黄金标准和创新方法。发现特定的神经反应模式可以奠定 为神经调节和药物干预的研究以及临床试验奠定基础 调查现有或新的治疗方法的疗效，这些方法作用于恢复的关键机制。总之， 拟议的研究将确定关键的酒精特异性损伤机制，为 制定有针对性的干预措施，以提高PAUD治疗的疗效、效率和创新。

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.