Hidalgo-Lopez Esmeralda, Smith Tristin, Angstadt Mike, Becker Hannah C, Schrepf Andrew, Clauw Daniel J, Harte Steven E, Heitzeg Mary M, Mindell Jodi A, Kaplan Chelsea M, Beltz Adriene M
Department of Psychology, University of Michigan, Ann Arbor.
Chronic Pain and Fatigue Research Center, University of Michigan Medical School, Ann Arbor.
JAMA Netw Open. 2025 Apr 1;8(4):e255364. doi: 10.1001/jamanetworkopen.2025.5364.
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.
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.
Youth-reported number of painful regions during the last month classified into multisite (≥3), regional (1-2), and no pain groups.
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.
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 (F2,1005 = 61.40; η2 = 0.11; false discovery rate [FDR] P < .001) and female (F2,1041 = 13.38; η2 = 0.03; FDR P < .001) participants and was associated with greater behavioral problems in male (F2,918 = 28.12; η2 = 0.04; FDR P < .001) and female (F2,945 = 9.12; η2 = 0.02; FDR P < .001) participants compared with the subgroup with no pain. Male participants with multisite pain had heightened DMN-SMN connectivity (F2,1005 = 3.55; η2 = 0.007; FDR P = .04). Female participants with multisite pain had heightened sleep disturbances (F2,1039 = 10.64; η2 = 0.02; FDR P = .002), partially explained by reduced within-SMN connectivity (indirect effect estimate, 0.15; 95% CI, 0.03-0.34).
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.
多部位疼痛对青春期开始的女性影响尤为严重，且与中枢神经系统调节异常有关。了解潜在神经网络和行为症状的异质性至关重要。
描述多部位疼痛青少年中与性别相关的静息态神经网络以及同时出现的症状，包括睡眠和行为问题。
设计、背景和参与者：本横断面分析利用了青少年大脑与认知发展研究的2年随访数据。将684名11至12岁有多部位疼痛的青少年与1368名无疼痛或有局部疼痛的青少年进行比较，根据青春期状态、利手以及种族和民族进行匹配。数据收集于2018年7月至2021年2月，并于2021年10月发布。数据分析于2023年6月至2024年7月进行。
青少年报告的上个月疼痛部位数量，分为多部位（≥3个）组、局部（1 - 2个）组和无疼痛组。
采用性别分层的组迭代多重模型估计法对突显网络（SLN）、感觉运动网络（SMN）和默认模式网络（DMN）中的区域进行稀疏网络估计。计算个体网络内和网络间的密度。症状包括行为问题和睡眠障碍。检查各组间网络密度和症状的性别分层差异。探索脑网络与同时出现的症状之间的关联。
在2052名参与者中（1044名[50.88%]为女性），平均（标准差）青春期状态为2.23（0.65），平均（标准差）年龄为12.02（0.66）岁；其中25名（1.22%）为亚洲人，149名（7.26%）为黑人，361名（17.59%）为西班牙裔，1307名（63.69%）为白人，210名（10.23%）为其他种族或民族。共有1646名参与者（80.21%）为右利手，100名（4.87%）为左利手，306名（14.91%）为双手灵活。多部位疼痛与男性（F2,1005 = 61.40；η2 = 0.11；错误发现率[FDR]P <.001）和女性（F2,1041 = 13.38；η2 = 0.03；FDR P <.001）参与者的感觉运动网络内连通性降低有关，并且与无疼痛亚组相比，男性（F2,918 = 28.12；η2 = 0.04；FDR P <.001）和女性（F2,945 = 9.12；η2 = 0.02；FDR P <.001）参与者的行为问题更多有关。有多部位疼痛的男性参与者的默认模式网络 - 感觉运动网络连通性增强（F2,1005 = 3.55；η2 = 0.007；FDR P = 0.04）。有多部位疼痛的女性参与者睡眠障碍增加（F2,1039 = 10.64；η2 = 0.02；FDR P = 0.002），部分原因是感觉运动网络内连通性降低（间接效应估计值为0.15；95%置信区间为0.03 - 0.34）。
在这项对2052名青少年的横断面研究中，与性别相关的神经生理机制与多部位疼痛有关。脑连通性仅部分解释了女性参与者中睡眠与疼痛的关联。经重复验证和持续性证据表明，这些发现提示有疼痛的女性青少年可能尤其受益于针对睡眠障碍的干预措施。
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