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

项目总结 儿童慢性疼痛是一个重大的公共卫生问题，患病率中位数为11%至38%， 3%至5%的儿童患有严重的疼痛相关残疾(美国约有350万儿童)。 尽管对整体健康造成生理和心理上的后果，但儿童时期的慢性疼痛 导致高水平的医疗保健利用，并可能容易在成年后发展为慢性疼痛。 恐惧是对疼痛结果的一个特别显著的影响，也是当前研究提案的重点。一个 相当大比例的患有慢性疼痛的年轻人支持与疼痛相关的恐惧加剧。与疼痛相关的恐惧是 与高度残疾、抑郁症状和学习障碍有关。在个人之外， 情境影响对恐惧学习有很大的影响。父母深受影响，当他们的孩子 体验疼痛及其(不良)适应性反应影响结果。因此，定义青少年恐惧学习 在慢性疼痛中，必须结合父母的痛苦和行为。在治疗的背景下，减少疼痛- 相关的恐惧与身体和心理功能的改善有关，而最初的高疼痛与 恐惧是治疗反应性较低的一个风险因素。尽管人们认识到与疼痛相关的高水平 恐惧可能是有害的，但获取和消除恐惧的神经生物学机制尚未形成 在疼痛患者中的定义。这在青春期尤其重要，因为在青春期，神经元的特性 根据经验做好修改的准备，慢性疼痛的高峰出现在儿童时期。此外， 灭绝，消除恐惧的主要手段，并不总是有效的，因为恐惧可能会在新的 背景或压力下。因此，需要更健壮的技术来在与上下文无关的情况下减少恐惧 时尚。防止恐惧卷土重来的一种方法是破坏恐惧记忆的重新巩固，其中 灭绝发生在恐惧记忆不稳定的时间窗内。这种方法是在啮齿类动物身上建立的 和人类，尚未在儿科疼痛患者中得到证实。这项提案调查了这些机制 患有慢性疼痛的青少年潜在的恐惧学习、恐惧消退和恐惧再巩固的中断 和健康对照组，使用行为和神经成像方法，长期目标是改善 以暴露为基础的青少年慢性疼痛治疗。目标1考察了人类的获取和灭绝 慢性疼痛和低或高疼痛相关青少年的恐惧学习行为和神经生物学研究 恐惧和健康对照，考虑父母恐惧和回避行为的影响。目标2 研究了通过破坏恐惧记忆重新巩固来增强恐惧消退。目前， 慢性疼痛的治疗并不理想。重大突破需要对关键的机械性理解 疼痛相关功能障碍的潜在过程。界定恐惧的行为和神经生物学机制 学习和消退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.