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

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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.