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

摘要 儿童期和青春期的慢性疼痛是一种重大的个人和社会负担，影响20%-25% 青春的象征。不幸的是，治疗是困难的，长期效果很差，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，常缺如或与组织损伤或炎症不成比例。在……里面 成年人的广泛性疼痛与中枢神经系统(CNS)的处理过程改变有关， 在女性中很常见，并伴随着一系列共同出现的中枢调节的躯体症状， 包括疲劳、睡眠障碍、记忆障碍和抑郁/焦虑。中枢神经系统的变化 加工通常分为两大类：增加的前伤害性和减少的反伤害性 活动和功能连接。虽然有强有力的证据表明，患有这种疾病的成年人 广泛性疼痛，如纤维肌痛，其疼痛可追溯到童年和青春期，缺乏 有关儿童普遍疼痛的发展情况的信息使人们无法判断这些 同时出现的症状和中枢神经系统改变先于疼痛，与疼痛相关，或是疼痛的后果。这个 青少年大脑和认知发展研究(ABCD)，一项关于童年的大型前瞻性队列研究 发展，提供了一个无与伦比的机会来探索早期起源和广泛传播的轨迹 青春期的疼痛。我们的主要假设是中枢神经系统因素和临床结果显示 与成人广泛的疼痛有关，也存在于有发展风险的儿童中 在生命早期广泛的疼痛。此外，我们假设这些因素中存在与性别相关的差异 在青春期发育期间，这会导致女性对疼痛的敏感性和脆弱性增加， 男性数量减少。为了检验这些假设，我们提出了三个具体目标。目标1：检查临床和 广泛性疼痛儿童的神经生物学差异。我们会比较症状，休息状态的大脑 报告广泛疼痛与无疼痛的儿童(11/12岁)的连接性和灰质结构 控制。目的2：在新的无痛儿童队列中，确定临床和神经生物学危险因素 两年后出现广泛的疼痛。我们将比较常见的共同出现的非疼痛症状， 无痛儿童(11/12岁)出现新的广泛性疼痛的大脑结构和连接 年龄为13/14岁的儿童与不会出现疼痛的儿童。目标3：探讨临床和神经生物学性别 青春期过渡期间广泛性疼痛轨迹的差异。拟议的研究将 是第一个适当推动的纵向研究，以检查新发生的儿童广泛性疼痛和 检查临床和神经影像预测指标。这一知识可以帮助识别高危儿童 成年期的慢性广泛性疼痛，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.