Modification of Brain Connectome on Association Between Adverse Childhood Experiences and Development of Mental Disorders in Preadolescence

Featured Paper of the Month – April 2026

Published in JAMA Network Open by Xiang Xiao and Yihong Yang et al. of the NIDA IRP Magnetic Resonance Imaging and Spectroscopy Section.

Summary

In this study, we addressed the question of whether a brain marker moderates the association between childhood adversity and psychiatric disorders during the transition to adolescence. Using data from the Adolescent Brain Cognitive Development (ABCD) Study, we show that a brain connectome variate derived from resting-state functional magnetic resonance imaging buffered against the development of psychiatric disorders in those exposed to adverse childhood experiences (ACEs). These findings provide preliminary evidence that the brain connectome variate may serve as a neural marker of resilience against ACE-related psychopathology during early adolescence.

Publication Information

Xiao, Xiang; Hammond, Christopher J; Salmeron, Betty Jo; Wang, Danni; Gu, Hong; Zhai, Tianye; Murray, Laura; Quam, Annika; Hill, Justine; Nguyen, Hieu; Lu, Hanbing; Hoffman, Elizabeth A; Janes, Amy C; Ross, Thomas J; Yang, Yihong

Modification of Brain Connectome on Association Between Adverse Childhood Experiences and Development of Mental Disorders in Preadolescence Journal Article

In: JAMA Netw Open, vol. 8, no. 9, pp. e2533136, 2025, ISSN: 2574-3805.

Abstract | Links

@article{pmid40982276,

title = {Modification of Brain Connectome on Association Between Adverse Childhood Experiences and Development of Mental Disorders in Preadolescence},

author = {Xiang Xiao and Christopher J Hammond and Betty Jo Salmeron and Danni Wang and Hong Gu and Tianye Zhai and Laura Murray and Annika Quam and Justine Hill and Hieu Nguyen and Hanbing Lu and Elizabeth A Hoffman and Amy C Janes and Thomas J Ross and Yihong Yang},

url = {https://pubmed.ncbi.nlm.nih.gov/40982276/},

doi = {10.1001/jamanetworkopen.2025.33136},

issn = {2574-3805},

year  = {2025},

date = {2025-09-01},

urldate = {2025-09-01},

journal = {JAMA Netw Open},

volume = {8},

number = {9},

pages = {e2533136},

abstract = {IMPORTANCE: Adverse childhood experiences (ACEs) are common and account for more than 25% of psychiatric disorders in youths, but the underlying neurobiological mechanisms associated with risk and resilience among children exposed to ACEs are poorly understood.nnOBJECTIVES: To examine associations between ACEs and transdiagnostic psychopathology during the transition to adolescence and to test whether these associations are modified by whole-brain functional connectivity.nnDESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the longitudinal Adolescent Brain Cognitive Development (ABCD) Study's baseline through 2-year follow-up assessments. A total of 6813 children aged 9 to 11 years at baseline were recruited from 21 US sites between June 1, 2016, and October 31, 2018. Data were analyzed from September 2023 to April 2025.nnEXPOSURE: Lifetime ACEs, assessed from child and parent reports, through 2-year follow-up.nnMAIN OUTCOMES AND MEASURES: Cumulative number of current DSM-5 psychiatric disorders obtained from the computerized self-administered Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5 (KSADS-5) through 2-year follow-up and a machine learning-based latent connectome variate (CV) score derived from baseline resting-state functional magnetic resonance imaging data.nnRESULTS: Among 6813 children (mean [SD] age at baseline, 10.0 [0.6] years; 3413 girls [50.1%]) with available baseline neuroimaging, behavioral, and covariate data, the mean (SD) ACE score was 2.3 (1.7) at baseline. ACE scores were significantly associated with the cumulative number of KSADS-5 diagnoses at baseline (β = 0.11; 95% CI, 0.10-0.12; P < .001) and 2-year follow-up (β = 0.14; 95% CI, 0.12-0.15; P < .001). Baseline CV score modified associations between ACEs and psychiatric disorders across the 2 years (β = -0.02; 95% CI, -0.03 to -0.01; t = -3.34; P < .001). Post hoc investigation showed that the modification of the CV score on associations between ACEs and psychopathology was specific to the threat-related ACEs (β = -0.04; 95% CI, -0.06 to -0.02; t = -3.67; P < .001) and was pronounced for girls (β = -0.06; 95% CI, -0.09 to -0.02; t = -3.33; P < .001).nnCONCLUSIONS AND RELEVANCE: In this cohort study of children, a whole-brain functional connectivity score derived from neuroimaging data modified the association between ACEs and psychiatric disorders. This modification was particularly seen against threat-related ACEs and was pronounced for female youths. These findings suggest that functional connectivity strength in a broad system relevant to cognitive control may protect preadolescents who have experienced lifetime ACEs-especially girls and those experiencing threat-related ACEs-from developing transdiagnostic psychopathology.},

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pubstate = {published},

tppubtype = {article}

}

IMPORTANCE: Adverse childhood experiences (ACEs) are common and account for more than 25% of psychiatric disorders in youths, but the underlying neurobiological mechanisms associated with risk and resilience among children exposed to ACEs are poorly understood.nnOBJECTIVES: To examine associations between ACEs and transdiagnostic psychopathology during the transition to adolescence and to test whether these associations are modified by whole-brain functional connectivity.nnDESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the longitudinal Adolescent Brain Cognitive Development (ABCD) Study's baseline through 2-year follow-up assessments. A total of 6813 children aged 9 to 11 years at baseline were recruited from 21 US sites between June 1, 2016, and October 31, 2018. Data were analyzed from September 2023 to April 2025.nnEXPOSURE: Lifetime ACEs, assessed from child and parent reports, through 2-year follow-up.nnMAIN OUTCOMES AND MEASURES: Cumulative number of current DSM-5 psychiatric disorders obtained from the computerized self-administered Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5 (KSADS-5) through 2-year follow-up and a machine learning-based latent connectome variate (CV) score derived from baseline resting-state functional magnetic resonance imaging data.nnRESULTS: Among 6813 children (mean [SD] age at baseline, 10.0 [0.6] years; 3413 girls [50.1%]) with available baseline neuroimaging, behavioral, and covariate data, the mean (SD) ACE score was 2.3 (1.7) at baseline. ACE scores were significantly associated with the cumulative number of KSADS-5 diagnoses at baseline (β = 0.11; 95% CI, 0.10-0.12; P < .001) and 2-year follow-up (β = 0.14; 95% CI, 0.12-0.15; P < .001). Baseline CV score modified associations between ACEs and psychiatric disorders across the 2 years (β = -0.02; 95% CI, -0.03 to -0.01; t = -3.34; P < .001). Post hoc investigation showed that the modification of the CV score on associations between ACEs and psychopathology was specific to the threat-related ACEs (β = -0.04; 95% CI, -0.06 to -0.02; t = -3.67; P < .001) and was pronounced for girls (β = -0.06; 95% CI, -0.09 to -0.02; t = -3.33; P < .001).nnCONCLUSIONS AND RELEVANCE: In this cohort study of children, a whole-brain functional connectivity score derived from neuroimaging data modified the association between ACEs and psychiatric disorders. This modification was particularly seen against threat-related ACEs and was pronounced for female youths. These findings suggest that functional connectivity strength in a broad system relevant to cognitive control may protect preadolescents who have experienced lifetime ACEs-especially girls and those experiencing threat-related ACEs-from developing transdiagnostic psychopathology.