Graph theory reveals functional connectome disruptions in adolescent major depressive disorder with childhood trauma

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Abstract
Background Childhood trauma (CT) is a major risk factor for adolescent major depressive disorder (MDD), yet its neurobiological underpinnings and longitudinal treatment effects remain poorly characterized. Methods Leveraging graph theory and resting-state fMRI, we analyzed in 343 adolescents with MDD aged 10 − 18 years, including 211 with a history of childhood trauma (MDD-CT) and 106 without childhood trauma (MDD-NCT), as well as 149 healthy controls. Machine learning models were applied to baseline functional network data to distinguish between treatment responders and non-responders. Results We identified CT-associated functional connectome disruptions marked by increased network randomness and topological deficits in default mode network (DMN) hubs (left parahippocampal gyrus, posterior cingulate gyrus, temporal pole). Longitudinal neuroimaging revealed post-treatment normalization of these abnormalities, particularly in the left precuneus and amygdala, paralleling symptom improvement. Machine learning models using baseline connectomes predicted antidepressant response with 82% accuracy. Conclusion Our findings establish CT-driven connectome disturbances in adolescent MDD, map dynamic network reorganization to therapeutic recovery, and position functional connectivity as a clinically actionable biomarker. This work bridges neurobiological mechanisms of trauma-related depression with precision treatment strategies, offering a path toward biomarker-guided interventions.

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