Brain Entropy as a Biomarker of Major Depression in Adolescents and young adults: Insights from Multimodal Resting-State fMRI

Abstract Background Major depressive disorder (MDD) in adolescents and young adults is increasingly prevalent, yet accurate diagnosis remains challenging due to the limitations of conventional neuroimaging metrics. Traditional resting-state fMRI (rs-fMRI) measures such as amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity density (FCD) primarily capture static aspects of brain activity and may overlook critical neural dynamics. Brain entropy (BEN), which quantifies temporal irregularity in rs-fMRI signals, may offer a complementary approach to better characterize neural alterations in MDD. Methods We analyzed multimodal rs-fMRI data from 204 individuals aged 12–24 years (119 with MDD and 85 healthy controls). BEN was computed alongside ALFF, ReHo, and FCD to extract region-wise features across the brain. A support vector machine with recursive feature elimination (SVM-RFE) was used to classify MDD and healthy controls based on various feature combinations. Classification performance was evaluated using repeated cross-validation and permutation testing. Additionally, partial Spearman correlations were performed between selected brain features and clinical measures including depression severity, childhood trauma, sleep quality, and cognitive control. Results Models incorporating BEN consistently outperformed those using traditional rs-fMRI features alone. The combination of BEN, ALFF, and FCD achieved the highest classification accuracy (AUC = 0.877, p 0.001). The most frequently selected brain regions contributing to MDD classification included the putamen, paracentral lobule, cuneus, middle frontal gyrus, and rectus. BEN features also showed preliminary correlations with clinical variables such as childhood trauma and sleep quality, suggesting functional relevance. Conclusions This study demonstrates that BEN provides complementary diagnostic information to traditional rs-fMRI features in classifying adolescent and young adult MDD. BEN-related alterations in brain activity may reflect underlying neurobiological disruptions and show potential as a functional neuroimaging biomarker for depression during a critical stage of brain development.