Sex, Neural Networks, and Behavioral Symptoms Among Adolescents With Multisite Pain
Authors: Esmeralda Hidalgo-Lopez, Tristin Smith, Mike Angstadt, Hannah C. Becker, Andrew Schrepf, Daniel J. Clauw, Steven E. Harte, Mary M. Heitzeg, Jodi A. Mindell, Chelsea M. Kaplan, Adriene M. Beltz
Journal: JAMA Network Open (2025)

Importance Multisite pain disproportionately affects females starting in adolescence and is associated with central nervous system dysregulation. Understanding the heterogeneity of underlying neural networks and behavioral symptoms is essential. Objective To characterize sex-related resting-state neural networks and co-occurring symptoms, including sleep and behavioral problems, in youth with multisite pain. Design, Setting, and Participants This cross-sectional analysis leverages the 2-year follow-up data from the Adolescent Brain and Cognitive Development Study. A total of 684 youth aged 11 to 12 years with multisite pain were compared with 1368 youth with no pain or with regional pain, matched by pubertal status, handedness, and race and ethnicity. Data were collected from July 2018 to February 2021 and released October 2021. Data were analyzed from June 2023 to July 2024. Exposure Youth-reported number of painful regions during the last month classified into multisite (≥3), regional (1-2), and no pain groups. Main Outcomes and Measures Sex-stratified group iterative multiple model estimation was used for sparse network estimation of regions from the salience network (SLN), sensorimotor network (SMN), and default mode network (DMN). Individual within-network and between-network densities were calculated. Symptoms were behavioral problems and sleep disturbances. Sex-stratified differences in network densities and symptoms were examined between groups. Associations between brain networks and co-occurring symptoms were explored. Results Of 2052 participants (1044 [50.88%] female), mean (SD) pubertal status was 2.23 (0.65) and mean (SD) age was 12.02 (0.66) years; 25 (1.22%) were Asian, 149 (7.26%) were Black, 361 (17.59%) were Hispanic, 1307 (63.69%) were White, and 210 (10.23%) were other race or ethnicity. A total of 1646 participants (80.21%) were right-handed, 100 (4.87%) were left-handed, and 306 (14.91%) were ambidextrous. Multisite pain was associated with lower within-SMN connectivity in male ( F 2,1005 = 61.40; η 2 = 0.11; false discovery rate [FDR] P &amp;amp;lt; .001) and female ( F 2,1041 = 13.38; η 2 = 0.03; FDR P &amp;amp;lt; .001) participants and was associated with greater behavioral problems in male ( F 2,918 = 28.12; η 2 = 0.04; FDR P &amp;amp;lt; .001) and female ( F 2,945 = 9.12; η 2 = 0.02; FDR P &amp;amp;lt; .001) participants compared with the subgroup with no pain. Male participants with multisite pain had heightened DMN-SMN connectivity ( F 2,1005 = 3.55; η 2 = 0.007; FDR P = .04). Female participants with multisite pain had heightened sleep disturbances ( F 2,1039 = 10.64; η 2 = 0.02; FDR P = .002), partially explained by reduced within-SMN connectivity (indirect effect estimate, 0.15; 95% CI, 0.03-0.34). Conclusions and Relevance In this cross-sectional study of 2052 adolescents, sex-related neurophysiological mechanisms were associated with multisite pain. Brain connectivity partially explained the sleep-pain association in female participants only. On replication and evidence of persistence, these findings suggest that female adolescents with pain may especially benefit from interventions targeting sleep disturbances.