Localizing and modulating competing memories of fear and safety in the human brain

项目摘要。以过度恐惧和焦虑为特征的病理是最常见的精神疾病。 这种疾病在12个月内的患病率估计约为4000万美国成年人。的主要治疗方法 焦虑和压力相关的障碍是暴露疗法，这是由理论和技术方面的通知 巴甫洛夫灭绝然而，在各种情况下，熄灭的行为容易复发。 此外，临床研究表明，在许多精神疾病中， 恢复消失的记忆，这可能导致基于预防的治疗后复发。 因此，有强烈的动机去更好地理解灭绝记忆是如何编码、储存和表达的。 以增强临床治疗的强度和推广。啮齿类动物的开创性研究 揭示了恐惧条件反射和消退产生了独立的、可测量的记忆痕迹， 离散的大脑区域人类大脑中是否存在这样的组织尚不清楚。更精确 关于威胁和安全记忆如何在人脑中表现和相互作用的知识将进一步发展 基于学习和记忆神经科学的病理性焦虑症的创新疗法。的 这项研究的目的是更好地了解恐惧和安全的竞争记忆是如何形成，储存和 在人类大脑中恢复。为了直接建立在动物模型的机械见解上，我们利用巴甫洛夫 在功能性磁共振成像（fMRI）过程中，成年人的恐惧条件反射和消退。的 研究利用多变量模式分析技术的进步，并将理论和技术 从动物模型中进行的恐惧消退研究的进展， 研究人类记忆每项研究都包括健康的成年人和患有创伤后应激障碍的个体 （PTSD），因为将恐惧消退研究的进展与PTSD的病理生理学联系起来可以直接受益 暴露疗法--基于灭绝原则的黄金标准疗法。我们也评估 在24小时和1个月时再次进行消退记忆。评估人类的长期灭绝恢复是 非常罕见，但符合评估创伤后应激障碍的诊断标准，因此进一步加强了桥梁， 翻译相关性目标1试图识别独立和稳定的记忆痕迹的恐惧和灭绝， 通过识别与恐惧的形成和恢复相关的神经活动之间的对应（重叠）， 随着时间的推移而灭绝。Aim 2解码多变量神经签名，选择上下文编码 消失的记忆Aim 3使用非药物行为策略来调节 灭绝，以确定增强的恐惧灭绝如何影响灭绝记忆的多变量神经信号 随着时间的推移恢复。这些发现有可能为焦虑症建立新的风险和弹性因素， 压力相关的病理，并可能最终有助于创新的神经科学为基础的治疗， 以过度恐惧和无法控制不必要的情绪反应为特征的精神状况。

PROJECT SUMMARY. Pathologies characterized by excessive fear and anxiety are the most common mental illness with a 12-month prevalence estimate of about 40 million American adults. The primary treatment for anxiety and stress-related disorders is exposure therapy, which is informed by theoretical and technical aspects of Pavlovian extinction. However, extinguished behaviors are prone to relapse under a variety of circumstances. Further, clinical research reveals serious deficits across a host of psychiatric conditions in the ability to form and retrieve extinction memories, which likely contributes to relapse following extinction-based therapies. Accordingly, there is strong motivation to better understand how extinction memories are encoded, stored, and expressed so as to bolster the strength and generalization of clinical treatment. Pioneering research in rodents reveals that fear conditioning and extinction generate separate and measurable memory traces within and across discrete brain regions. Whether such an organization exists in the human brain is unknown. More precise knowledge on how threat and safety memories are represented and interact in the human brain will advance innovative treatments for pathological anxiety that are built on the neuroscience of learning and memory. The goal of this research is to better understand how competing memories of fear and safety are formed, stored, and retrieved in the human brain. To build directly on mechanistic insights from animal models, we utilize Pavlovian fear conditioning and extinction in adult humans during functional magnetic resonance imaging (fMRI). The research leverages advances in multivariate pattern analysis techniques, and integrates theoretical and technical advancements of fear extinction research from animal models with computational approaches developed to study human memory. Each study includes healthy adults and individuals with posttraumatic stress disorder (PTSD), as linking advances in fear extinction research to the pathophysiology of PTSD can have direct benefit to exposure therapy—the gold-standard treatment based on the principles of extinction. We also evaluate extinction memory at 24-hours and again at 1 month. Assessing long-term extinction retrieval in humans is extremely rare, but consistent with diagnostic criteria for assessing PTSD, and thus furthers the bridge to translational relevance. Aim 1 attempts to identify separate and stable memory traces of fear and extinction in by identifying the correspondence (overlap) between neural activity related to the formation and retrieval of fear and extinction over time. Aim 2 decodes a multivariate neural signature selective to the contextual encoding of extinction memories. Aim 3 uses a non-pharmacological behavioral strategy to modulate the strength of extinction to determine how enhanced fear extinction affects multivariate neural signature of extinction memory retrieval over time. These findings have the potential to establish new risk and resilience factors for anxiety and stress-related pathologies, and may ultimately contribute to innovative neuroscience-based treatments for psychiatric conditions marked by excessive fear and the inability to regulate unwanted emotional responses.