Resting State Connectivity Networks Underpinning Multisite Pain in Adolescent Girls and Boys

Multisite pain disproportionately affects women and is associated with central nervous system dysregulation (i.e., nociplastic pain). As sex differences emerge during adolescence, there may be an intersection between neurodevelopmental sex differences and the neurobiology of nociplastic pain, but this has not been examined. The present study investigates sex differences in the neural networks underlying multisite pain using resting state fMRI data from the Adolescent Brain Cognitive Development Study (n=1,254, ages 11-12). Youth were classified by number of self-reported painful regions: multisite (3+), regional (1-2), and no pain (0). Sex-stratified group iterative multiple model estimation was used for data-driven sparse network estimation of salience (SLN), sensorimotor (SMN), and default mode (DMN) network regions. Networks were characterized by within- and between-density. Adolescent boys and girls with multisite pain showed reduced within-SMN density compared to those with no pain (boys: OR:0.66; 95%CI:0.53-0.81, pFDR<0.001; girls: OR:0.67; 95%CI:0.54-0.82, pFDR<0.001). However, only girls with multisite pain show increased connectivity within the DMN (OR:1.42; 95%CI:1.16-1.72, pFDR<0.001) and between the SLN and SMN (OR:1.32; 95%CI:1.09-1.60, pFDR=0.02). As findings are consistent with studies of juvenile fibromyalgia and adults with nociplastic pain, these connectivity patterns may be an early signature of nociplastic pain, with sex differences continuing to emerge and strengthen as youth develop. Future work will explore sex-linked mechanisms underlying the differences. Funded by the National Institute of Nursing Research, National Institutes of Health (R01NR020013, awarded to Kaplan and Beltz).