Behavioral and neurobiological predictors of widespread pain in early adolescence and sex-specific trajectories of pain during puberty

摘要 儿童和青少年时期的慢性疼痛是一个重大的个人和社会负担，影响20-25% 年轻的时候。不幸的是，治疗是困难的，长期结果是穷人，部分原因是有限的， 了解慢性疼痛如何在生命的前二十年表现出来。慢性广泛性疼痛是 常见于成人，并且经常在组织损伤或炎症不存在或不成比例的情况下发生。在 在成年人中，广泛的疼痛与中枢神经系统（CNS）的处理改变有关， 常见于女性，并伴有一组共同发生的中枢介导的躯体症状， 包括疲劳、睡眠障碍、记忆困难和抑郁/焦虑。中枢神经系统的改变 加工通常分为两大类：增加的原伤害感受和减少的抗伤害感受 活动和功能连接。虽然有强有力的证据表明，患有以下疾病的成年人 广泛的疼痛，如纤维肌痛，可以追溯到他们的痛苦回到童年和青春期，缺乏 关于儿童广泛疼痛发展的信息使人们无法判断这些疼痛是否会发生。 共同出现的症状和CNS变化在疼痛之前、与疼痛相关或者是疼痛的后果。的 青少年大脑和认知发展（ABCD）研究，一项针对儿童的大型前瞻性队列研究 发展，提供了一个无与伦比的机会，探索广泛的早期起源和轨迹， 青春期的疼痛我们的总体假设是，中枢神经系统因素和临床结果显示， 与成人广泛疼痛相关的，也存在于儿童中， 早期的广泛疼痛。此外，我们假设在这些因素中存在与性别相关的差异 在青春期发育期间，导致女性疼痛敏感性和脆弱性增加， 男性减少。为了验证这些假设，我们提出了三个具体目标。目的1：检查临床和 神经生物学差异的儿童广泛疼痛。我们会比较症状，休息状态下的大脑 报告广泛疼痛与无痛儿童（11/12岁）的连接性和灰质结构 对照目的2：在一个新的无痛儿童队列中，确定 两年后出现了广泛的疼痛我们将比较常见的共同发生的非疼痛症状， 无疼痛儿童（11/12岁）的大脑结构和连接，这些儿童在 13/14岁的儿童，与没有疼痛的儿童相比。目的3：探索临床和神经生物学性别 随着青春期的过渡，广泛疼痛的轨迹存在差异。拟定的研究将 是第一个适当的动力纵向研究，以检查新发生的广泛疼痛的儿童和 检查临床和神经影像学预测指标。这些知识可以帮助识别处于高风险的儿童， 成年期慢性广泛性疼痛，并为早期干预策略提供了机会之窗。

Abstract Chronic pain during childhood and adolescence is a significant personal and societal burden, affecting 20–25% of youth. Unfortunately, treatment is difficult and long-term outcomes are poor, in part due to the limited understanding of how chronic pain manifests across the first two decades of life. Chronic widespread pain is common in adults, and often occurs in absence or not in proportion to tissue damage or inflammation. In adults, widespread pain is associated with altered processing in the central nervous system (CNS), is more common in females, and is accompanied by a cluster of co-occurring centrally-mediated somatic symptoms, including fatigue, sleep disturbances, memory difficulties and depression/anxiety. The alterations in CNS processing typically fall into two broad categories: increased pronociceptive and decreased antinociceptive activity and functional connectivity. While there is strong evidence that adults with conditions characterized by widespread pain, such as fibromyalgia, can trace their pain back to childhood and adolescence, the lack of information about the development of widespread pain in children has made it impossible to tell whether these co-occurring symptoms and CNS changes precede, correlate with, or are consequences of pain. The Adolescent Brain and Cognitive Development (ABCD) study, a large prospective cohort study of childhood development, provides an unparalleled opportunity to explore the early genesis and trajectory of widespread pain in adolescence. Our overarching hypothesis is that CNS factors and clinical outcomes shown to be associated with widespread pain in adults, are also present in children who are at risk for developing widespread pain early in life. Moreover, we hypothesize that there is a sex-related divergence in these factors during pubertal development which leads to an increase in pain sensitivity and vulnerability in females and a decrease in males. To test these hypotheses, we propose three specific aims. Aim 1: Examine clinical and neurobiological differences in children with widespread pain. We will compare symptoms, resting state brain connectivity and gray matter structure in children (ages 11/12) who report widespread pain versus pain-free controls. Aim 2: In a new cohort of pain-free children, determine clinical and neurobiological risk factors for developing widespread pain two years later. We will compare commonly co-occurring non-painful symptoms, brain structure and connectivity from pain-free children (ages 11/12) who develop new widespread pain at ages 13/14, versus children who do not develop pain. Aim 3: Explore clinical and neurobiological sex differences in the trajectories of widespread pain as youth transition through puberty. The proposed study will be the first appropriately powered longitudinal study to examine newly incident widespread pain in children and examine both clinical and neuroimaging predictors. This knowledge could help identify children at high-risk for chronic widespread pain in adulthood and provide a window of opportunity for early interventional strategies.