Treatment-naïve first episode depression classification based on high-order brain functional network

Background: Recent functional connectivity (FC) studies have proved the potential value of resting-state functional magnetic resonance imaging (rs-fMRI) in the study of major depressive disorder (MDD); yet, the rs-fMRI-based individualized diagnosis of MDD is still challenging. Methods: We enrolled 82 treatment-naïve first episode depression (FED) adults and 72 matched normal control (NC). A computer-aided diagnosis framework was utilized to classify the FEDs from the NCs based on the features extracted from not only traditional “low-order” FC networks (LON) based on temporal synchronization of original rs-fMRI signals, but also “high-order” FC networks (HON) that characterize more complex functional interactions via correlation of the dynamic (time-varying) FCs. We contrasted a classifier using HON feature (C_HON) and compared its performance with using LON only (C_LON). Finally, an integrated classification model with both features was proposed to further enhance FED classification. Results: The C_HON had significantly improved diagnostic accuracy compared to the C_LON (82.47% vs. 67.53%). Joint classification further improved the performance (83.77%). The brain regions with potential diagnostic values mainly encompass the high-order cognitive function-related networks. Importantly, we found previously less-reported potential imaging biomarkers that involve the vermis and the crus II in the cerebellum. Limitations: We only used one imaging modality and did not examine data from different subtypes of depression. Conclusions: Depression classification could be significantly improved by using HON features that better capture the higher-level brain functional interactions. The findings suggest the importance of higher-level cerebro-cerebellar interactions in the pathophysiology of MDD.