Understanding the heterogeneity of dynamic functional connectivity patterns in first-episode drug naïve depression using normative models

The heterogeneity of the clinical symptoms and presumptive neural pathologies has stunted progress toward identifying reproducible biomarkers and limited therapeutic interventions' effectiveness for the first episode drug-naïve major depressive disorders (FEDN-MDD). This study combined the dynamic features of fMRI data and normative modeling to quantitative and individualized metrics for delineating the biological heterogeneity of FEDN-MDD. Two hundred seventy-four adults with FEDN-MDD and 832 healthy controls from International Big-Data Center for Depression Research were included. Subject-specific dynamic brain networks and network fluctuation characteristics were computed for each subject using the group information-guided independent component analysis. Then, we mapped the heterogeneity of the dynamic features (network fluctuation characteristics and dynamic functional connectivity within brain networks) in the patients group via normative modeling. The FEDN-MDD whose network fluctuation characteristics deviate from the normative model also showed significant differences within the default mode network, executive control network, and limbic network compared with healthy controls. Furthermore, the network fluctuation characteristics are significantly increased in patients with FEDN-MDD. About 4.74 % of the patients showed a deviation of dynamic functional connectivity, and only 3.35 % of the controls deviated from the normative model in above 100 connectivities. More patients than healthy controls showed extreme dynamic variabilities in above 100 connectivities. This work evaluates the efficacy of an individualized approach based on normative modeling for understanding the heterogeneity of abnormal dynamic functional connectivity patterns in FEDN-MDD, and could be used as complementary to classical case-control comparisons.