Reducing Intrusions of Real-World Stimuli via Memory Reconsolidation

描述（由申请人提供）：在痛苦事件后，侵入性再体验症状（即提示记忆、噩梦、突如其来的侵入）通常会持续存在，对一些人来说，甚至会变成病态（例如，Brewin等人，2010）。对入侵的研究还不够充分，而且会使人衰弱，因此我们必须加强对其发展、持续和减少背后机制的理解。旨在减少入侵的暴露疗法源于恐惧调节和消退模型（例如，Garakani et al., 2006）；加强灭绝的方法可能转化为改进的治疗方法。增强记忆消失的一个可能途径是通过记忆再巩固（Duvarci & Nader, 2004; Monfils et al., 2009）。当蛋白质合成时，被检索的记忆进入一种不稳定状态，而在蛋白质合成过程中发生的新学习的影响更加强大（例如，Nader等人，2000）。在动物中，通过条件刺激（CS）线索检索记忆，然后在特定的再巩固窗口内通过恐惧消退对检索到的记忆进行行为修改，可能会导致更强大的消退效应（例如，Monfils等人，2009；Rao-Ruiz等人，2011）。迄今为止，使用基本恐惧习得和消退范式的人类记忆再巩固研究，仅限于不能反映病理恐惧学习和消退中所见刺激的临床复杂性的方法。此外，这些研究都没有检查侵入性的再体验或神经生物学机制，如去甲肾上腺素能活性和皮质醇与再巩固窗口内的行为改变有关。在两个研究序列中，我们将研究记忆再巩固的行为和生物学机制，首先在非临床成人样本中，然后在创伤暴露的成年人样本中，有和没有临床水平的侵入性再体验。我们将使用恐惧学习和灭绝痛苦电影范式来诱导并随后减少侵入性的再体验。在消失之前，参与者将被随机分配到重新巩固窗口内外的CS提示条件。在灭绝后24小时和72小时评估侵入性再体验。此外，皮质醇和唾液α淀粉酶（在非临床研究中）和去甲肾上腺素（在临床研究中），与压力和记忆相关的生物标志物将在整个过程中进行评估。本研究将使用真实世界的刺激将动物记忆再巩固模型转化为非临床样本，然后将进一步扩展到临床样本，在两项研究中检查真实的临床表型，侵入性再体验。记忆再巩固可能是一种增强人类恐惧消退的机制，并且在改善针对侵入性再体验的治疗方面具有潜在的重要和令人兴奋的临床应用。

DESCRIPTION (provided by applicant): After a distressing event, intrusive reexperiencing symptoms (i.e., cued memories, nightmares, out-of-the- blue intrusions) often persist and, for some, become pathological (e.g., Brewin et al., 2010). Intrusions are understudied and debilitating, and it is thus imperative that we enhance our understanding of the mechanisms behind their development, persistence, and reduction. Exposure-based therapies aimed at reducing intrusions are derived from fear conditioning and extinction models (e.g., Garakani et al., 2006); methods that enhance extinction may translate to improved treatments. One possible opportunity for enhancing extinction is through memory reconsolidation (Duvarci & Nader, 2004; Monfils et al., 2009). A retrieved memory enters a labile state as proteins are synthesized, and the effects of new learning that occurs during protein synthesis are more robust (e.g., Nader et al., 2000). In animals, retrieving a memory via a conditioned stimulus (CS) cue and then modifying the retrieved memory behaviorally through fear extinction within a specific reconsolidation window may lead to more robust effects of extinction (e.g., Monfils et al., 2009; Rao-Ruiz et al., 2011). To date, memory reconsolidation research in humans, using basic fear acquisition and extinction paradigms, have been limited to methods that do not mirror clinical complexity of stimuli seen in pathological fear learning and extinction. Further, none of this research has examined intrusive reexperiencing or neurobiological mechanisms such as noradrenergic activity and cortisol linked to behavioral modifications within the reconsolidation window. In a two-study sequence, we will examine both behavioral and biological mechanisms underlying memory reconsolidation, first in a non-clinical adult sample, and then in a sample of trauma- exposed adults with and without clinical levels of intrusive reexperiencing. We will use a fear learning and extinction distressing film paradigm in order to induce and later reduce intrusive reexperiencing. Prior to extinction, participants will be randomized to CS cueing conditions inside and outside of the reconsolidation window. Intrusive reexperiencing will be assessed 24 h and 72 h after extinction. In addition, cortisol and salivary alpha amylase (in non-clinical study) and norepinephrine (in clinical study), biomarkers associated with stress and memory, will be assessed throughout. This study will use real-world stimuli to translate animal models of memory reconsolidation to a non-clinical sample, and then will further extend to a clinical sample, examining a real clinical phenotype, intrusive reexperiencing, in both studies. Memory reconsolidation may be a mechanism to enhance fear extinction in humans, and has potentially important and exciting clinical applications for improving therapies that target intrusive re-experiencing.