Preventing the return of fear in humans: Reconsolidation and control

描述（由申请人提供）：焦虑症的患病率估计高达美国成年人口的18%。焦虑障碍的主要治疗方法是暴露疗法，这是基于恐惧消除的原则。尽管基于消退的疗法可能是有效的，但它们的效果是有限的，部分原因是消退学习本身的性质。有大量证据表明，消退学习不会导致原始恐惧记忆的显著改变，而是导致以前害怕的事件现在是安全的新学习。一个结果是，最初的恐惧记忆和消失记忆可能会竞争表达。一系列的情况，如时间的流逝（自发恢复），环境的改变（更新）和压力（恢复），都可能导致恐惧的回归。即使经过广泛的消除训练，这种恐惧记忆恢复的潜力强调了发现更持久、更有效的方法来减少恐惧的必要性。使用简单的经典恐惧条件反射范式，对非人类动物的研究已经确定了两种防止恐惧回归的潜在机制。第一种是通过操纵原始恐惧记忆的重新巩固或重新存储。第二种方法是让动物体验对压力源的控制，这已经被证明对减少恐惧恢复的可能性有持久的影响。拟议研究的目的是评估人类技术的有效性、特异性和潜在的神经机制，这些技术已被证明可以防止非人类动物恐惧的回归。目标1的研究考察了破坏或改变人类条件恐惧重新巩固的技术。具体来说,

DESCRIPTION (provided by applicant): The prevalence of anxiety disorders is estimated to be up to 18% of the US adult population. A primary treatment for anxiety disorders is exposure therapy, which is based on the principles of fear extinction. Although extinction based therapies can be effective, their efficacy is limited, in part due to the nature of extinction learning itsel. There is abundant evidence that extinction learning does not result in a significant alteration of the original fear memory, but rather results in new learning that the previously feared event is now safe. One consequence is that the original fear memory and the extinction memory may compete for expression. A range of circumstances, such as the passage of time (spontaneous recovery), alterations in context (renewal), and stress (reinstatement), can result in the fear returning. This potential for fear memory recovery even after extensive extinction training highlights the need to discover more persistent and robust techniques to diminish fear. Using simple classical fear conditioning paradigms, research in non-human animals has identified two potential mechanisms to prevent the return of fear. The first is by manipulating the reconsolidation or re-storage of the original fear memory. The second is by allowing the animal experience with control over the stressor, which has been shown to have lasting effects on reducing the likelihood of fear recovery. The goal of the proposed research is to assess in humans the efficacy, specificity, and underlying neural mechanisms of techniques that have been shown to prevent the return of fear in non- human animals. Studies under Aim 1 examine techniques to disrupt or alter the reconsolidation of conditioned fear in humans. Specifically, the pharmacological disruption of reconsolidation is explored and the specificity and the psychological and neural consequences of behavioral interference techniques used to alter the reconsolidation of conditioned fear are examined. Aim 2 examines whether experience with control over a stressor can diminish the likelihood that a fear memory returns. Finally, the studies under Aim 3 examine the success of these techniques in patients who suffer from PTSD to determine if the neural consequences of this anxiety disorder alters the effectiveness of these procedures. The overarching goal of all the proposed studies is to discover how and when we might be able to prevent the return of fear in humans, which has the potential to lead to novel and more effective treatments for anxiety disorders.