Framing Major Depressive Disorder as a Condition of Network Imbalance at the Compartment Level: A Proof-of-Concept Study

Background: Hypoactivity in the frontoparietal (FP) system and hyperactivity in the limbic system have been observed in major depressive disorder (MDD). Among the neuropathological theories of MDD, the cortico-limbic dysregulation model has been prominent, and it was recently extended and refined by the framework of imbalanced reciprocal suppression between the FP and limbic compartments. This research aims to examine this refined theory. Methods: Sixty MDD and sixty healthy control datasets, including structural magnetic resonance imaging and resting-state functional MRI (rsfMRI), were selected from the CAN-BIND database. The cerebral cortex in rsfMRI was parcellated by MOSI (modular analysis and similarity measurements). For each parcellated node, the mean amplitude of low-frequency fluctuation (mALFF) was computed. Correlation analyses were employed to construct an adjacency matrix between partitioned nodes and to examine the relationship between nodal power and nodal degree. Results: Two-sample t-tests revealed that the limbic system in MDD was associated with a higher partition number and mALFF (p < 0.005). A negative correlation between nodal degree and nodal power was replicated (p < 1E-10), indicating that higher functional input may more effectively suppress regional neural activity. For FP nodal power and Limbic-FP connectivity, the MDD group exhibited a more negative correlation (stronger suppression), while for limbic nodal power and FP-Limbic connectivity, the MDD group showed a less negative correlation (weaker suppression). Conclusions: Consistent with the inter-compartmental network imbalance framework, MDD is characterized by abnormal cortical signal organization and aberrant reciprocal suppression between the FP and limbic systems.