Fear learning in adolescents with chronic pain: Neural and behavioral mechanisms

项目摘要 儿童慢性疼痛是一个重要的公共卫生问题，中位患病率为11%至38%， 3 - 5%的儿童患有严重的疼痛相关残疾（美国约350万儿童）。 尽管对整体健康的生理和心理后果， 导致高水平的医疗保健利用，并可能使成年期慢性疼痛的发展成为可能。 恐惧是对疼痛结果的特别显著的影响，也是当前研究提案的重点。一 有相当一部分患有慢性疼痛青年赞同疼痛相关的恐惧加剧。疼痛相关的恐惧是 与高水平的残疾、抑郁症状和学校障碍有关。超越个人， 情境的影响实质上影响恐惧学习。当他们的孩子 经历疼痛和他们的（错误）适应性反应影响结果。因此，定义青少年恐惧学习 必须考虑到父母的痛苦和行为。在治疗方面，减轻疼痛- 相关的恐惧与改善的身体和心理功能有关，而高初始疼痛相关 恐惧是降低治疗反应的一个危险因素。尽管人们认识到高水平的疼痛相关的 恐惧可能是有害的，获得和消除恐惧的神经生物学机制还没有被发现。 疼痛患者的定义。这在青春期尤为重要，因为在青春期，神经元的特性是 通过经验准备进行修改，并且在儿童期出现慢性疼痛的高峰发作。此外，委员会认为， 灭绝是消除恐惧的主要手段，但并不总是有效的，因为恐惧可能会在新的环境中卷土重来。 背景或压力下。因此，需要更强大的技术来减少与上下文无关的恐惧。 时尚.防止恐惧回归的一种方法是破坏恐惧记忆的重新巩固， 消退发生在恐惧记忆不稳定的时间窗内。这种方法，建立在啮齿动物 和人类，尚未在儿科疼痛患者中得到证实。本提案探讨了 慢性疼痛青少年的潜在恐惧学习、恐惧消退和恐惧再巩固的破坏 使用行为和神经影像学方法，长期目标是改善 青少年慢性疼痛的治疗方法。目标1考察了 慢性疼痛和轻度或高度疼痛相关的青少年的行为学和神经生物学恐惧学习 恐惧和健康控制，考虑父母恐惧和回避行为的影响。目的2 研究了恐惧消退的增强与恐惧记忆重新巩固的破坏。目前 慢性疼痛的治疗是次优的。重大突破需要对关键技术的机械性理解， 疼痛相关功能障碍的潜在过程。定义恐惧的行为和神经生物学机制 学习和灭绝将导致我们对持续性疼痛的理解和治疗的进步， 青少年。

PROJECT SUMMARY Chronic pain in childhood is a significant public health concern with median prevalence rates of 11 to 38%, with 3 to 5% of children suffering from significant pain-related disability (~3.5 million children in the US). Notwithstanding the physical and psychological consequences on overall health, chronic pain in childhood results in high levels of healthcare utilization and can predispose the development of chronic pain in adulthood. Fear is a particularly salient influence on pain outcomes and is the focus of the current research proposal. A significant proportion of youth with chronic pain endorse elevated pain-related fear. Pain-related fear is associated with high levels of disability, depressive symptoms, and school impairment. Beyond the individual, contextual influences substantially impact fear learning. Parents are profoundly affected when their child experiences pain and their (mal)adaptive response impacts outcomes. Thus, defining adolescent fear learning in chronic pain must incorporate parent distress and behavior. In the context of treatment, decreasing pain- related fear is associated with improved physical and psychological functioning, while high initial pain-related fear is a risk factor for less treatment responsiveness. Although it is recognized that high levels of pain-related fear can be detrimental, the neurobiological mechanisms for acquisition and extinction of fear have yet to be defined in pain patients. This is particularly germane during adolescence where neuronal properties are primed for modification by experience and the peak onset of chronic pain in childhood occurs. Moreover, extinction, the primary means of eradicating fear, is not consistently effective as fear may return when in a new context or under stress. Thus, more robust techniques are needed to diminish fear in a context-independent fashion. One method to prevent the return of fear is disruption of fear memory reconsolidation, where extinction occurs in a time window during which the fear memory is labile. This method, established in rodents and humans, has yet to be demonstrated in pediatric pain patients. This proposal investigates the mechanisms underlying fear learning, fear extinction, and disruption of fear reconsolidation in adolescents with chronic pain and healthy controls using behavioral and neuroimaging measures with the long-term goal of improving exposure-based treatments for adolescents with chronic pain. Aim 1 examines acquisition and extinction of fear learning behaviorally and neurobiologically in adolescents with chronic pain and low or high pain-related fear and healthy controls with consideration of the influence of parent fear and avoidance behavior. Aim 2 examines enhancement of fear extinction with disruption of fear memory reconsolidation. Currently, the treatment of chronic pain is suboptimal. Significant breakthroughs require a mechanistic understanding of key processes underlying pain-related dysfunction. Defining behavioral and neurobiological mechanisms of fear learning and extinction will lead to advancements in our understanding and treatment of persistent pain in adolescents.