Dysregulated connectivity configuration of functional network model in first-episode, treatment-naive adolescents with major depressive disorder

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BACKGROUND: Major depressive disorder (MDD) is a highly prevalent psychiatric condition that frequently emerges during adolescence, a critical developmental stage characterized by heightened vulnerability to emotional dysregulation. Despite increasing evidence of large-scale brain network dysfunction in adult MDD, the static and dynamic connectivity alterations underlying adolescent MDD remain poorly understood. METHODS: We recruited 29 first-episode, treatment-naïve adolescents with MDD and 29 age- and sex-matched healthy controls (HCs). Resting-state functional magnetic resonance imaging (rs-fMRI) data were analyzed using group independent component analysis (ICA) combined with sliding-window clustering to evaluate both static functional network connectivity (sFNC) and dynamic functional network connectivity (dFNC) across the default mode network (DMN), salience network (SN), central executive network (CEN), and dorsal attention network (DAN). Correlation analyses were performed between connectivity metrics and clinical severity assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). RESULTS: Compared with HCs, adolescents with MDD exhibited significantly reduced intra- and inter-network connectivity within the DMN, SN, and CEN, alongside a trend toward increased DAN-SN connectivity. Dynamic analyses revealed reduced state transition frequency, shorter dwell time in low-connectivity states (e.g., DMN-CEN-SN interactions), and longer dwell time in high-connectivity states (e.g., DAN-SN coupling). Clinical analyses demonstrated that weaker intra-DMN and intra-DAN connectivity, as well as reduced DMN-CEN and DMN-SN connectivity, were negatively correlated with HAMD-17 scores. Conversely, prolonged dwell time in hyperconnected states positively correlated with greater symptom severity. CONCLUSION: Our findings highlight distinct static and dynamic network abnormalities in adolescent MDD, including disrupted DMN-CEN competitive balance and maladaptive DAN-SN hyperconnectivity. These alterations may hint at developmental-stage-specific neuropathological mechanisms that could differ from adult depression, although direct comparison with adult cohorts is lacking. Integrating static and dynamic FNC analyses may provide preliminary insights into candidate neuroimaging markers for early detection and intervention strategies in adolescent MDD, though these findings require validation in independent, larger cohorts.

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