Reducing Intrusions of Real-World Stimuli via Memory Reconsolidation

通过记忆重新巩固减少现实世界刺激的侵入

• 批准号: 9124947
• 负责人: Elizabeth H. Marks
• 金额: $ 3.87万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124947
• 关键词: Adult; Animal Model; Animals; Behavior Therapy; Behavioral; Biological; Biological Markers; Clinical; Complex; Conditioned Stimulus; Cues; Demographic Factors; Development; Diagnostic and Statistical Manual of Mental Disorders; Distress; Etiology; Event; Extinction (Psychology); Film; Frequencies; Fright; Goals; Health; Hippocampus (Brain); Hour; Human; Hydrocortisone; Individual; Lead; Learning; Link; Long-Term Potentiation; Maintenance; Major Depressive Disorder; Memory; Methods; Modeling; Molecular; Negative Valence; Neurobiology; Nightmare; Norepinephrine; Participant; Pathway interactions; Phenotype; Post-Traumatic Stress Disorders; Protein Biosynthesis; Protein Synthesis Inhibitors; Proteins; Psychopathology; Psychotherapy; Randomized; Research; Retrieval; Salivary; Sample Size; Sampling; Stimulus; Stress; Symptoms; Synaptic plasticity; Time; Translating; Translations; Trauma; Update; Work; alpha-amylase; base; clinical application; clinical phenotype; conditioned fear; design; experience; flexibility; improved; learning extinction; long term memory; memory consolidation; memory process; multisensory; neurobiological mechanism; noradrenergic; novel; targeted treatment

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.

描述（由申请人提供）：在令人痛苦的事件后，侵入性重新经历症状（即，线索记忆、噩梦、突然闯入）经常持续存在，并且对于某些人来说，变成病态（例如，Brewin等人，2010年）。入侵是研究不足和削弱，因此，我们必须加强我们的理解背后的机制，他们的发展，持久性和减少。旨在减少侵扰的基于暴露的疗法源自恐惧条件反射和消退模型（例如，Garakani等人，2006）;增强灭绝的方法可能转化为改进的治疗。增强灭绝的一个可能的机会是通过记忆重新巩固（Duvarci & Nader，2004; Monfils等人，2009年）。当蛋白质合成时，检索到的记忆进入不稳定状态，并且在蛋白质合成期间发生的新学习的效果更鲁棒（例如，Nader等人，2000年）。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在行为上修改检索到的记忆，可能会导致更强大的消退效应（例如，Monfils等人，2009; Rao-Ruiz等人，2011年）。迄今为止，人类记忆再巩固研究，使用基本的恐惧获得和消退范例，已被限制为不反映病理性恐惧学习和消退中所见的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再体验或神经生物学机制，如去甲肾上腺素能活动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人样本中，有和没有临床水平的侵入性再体验。我们将使用一个恐惧学习和灭绝痛苦电影范例，以诱导和后来减少侵入性的再体验。在消退前，受试者将被随机分配至再巩固窗内外的CS提示条件。将在消退后24小时和72小时评估侵入性再体验。此外，将在整个过程中评估皮质醇和唾液α淀粉酶（非临床研究）和去甲肾上腺素（临床研究），这些生物标志物与应激和记忆相关。本研究将使用真实世界的刺激，将记忆再巩固的动物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。记忆再巩固可能是增强人类恐惧消退的一种机制，并且在改善针对侵入性重新体验的疗法方面具有潜在的重要和令人兴奋的临床应用。

项目成果

Can't get it out of my mind: A systematic review of predictors of intrusive memories of distressing events.

• DOI: 10.1037/bul0000132
• 发表时间: 2018-06
• 期刊: Psychological bulletin
• 影响因子: 22.4
• 作者: Marks EH;Franklin AR;Zoellner LA
• 通讯作者: Zoellner LA