Multiscale Neural Modeling of Resting-state fMRI Reveals Executive-Limbic Malfunction as a Core Mechanism in Major Depressive Disorder

Computational neuroimaging has played a central role in characterizing functional abnormalities in major depressive disorder (MDD). However, most of existing non-invasive analysis tools based on functional magnetic resonance imaging (fMRI) are largely descriptive and superficial, thus cannot offer a deep mechanistic understanding of neural circuit dysfunction in MDD. To overcome this limitation, we significantly improved a previously developed Multiscale Neural Model Inversion (MNMI) framework that can link mesoscopic neural interaction with macroscale network dynamics and enable the estimation of both intra-regional and inter-regional effective connectivity. We applied the improved MNMI approach to test two well-established competing hypotheses of MDD pathophysiology (default mode-salience network disruption vs. executive-limbic network malfunction) based on resting-state fMRI with a relatively large sample size. Results indicate that MDD is primarily characterized by aberrant circuit interactions within the executive-limbic network, rather than the default mode-salience network. Specifically, we observed reduced frontoparietal effective connectivity that potentially contributes to hypoactivity in the dorsolateral prefrontal cortex (dlPFC), and decreased intrinsic inhibition combined with increased excitation from the superior parietal cortex (SPC) that potentially leads to amygdala hyperactivity, together resulting in connectivity imbalance in the PFC-amygdala circuit that pervades in MDD. Moreover, the model unravels reduced PFC-to-hippocampus excitation but decreased SPC-to-thalamus inhibition in MDD population that potentially leads to hypoactivity in hippocampus and hyperactivity in thalamus, consistent with previous experimental data. Overall, our findings provide strong support for the long-standing limbic-cortical dysregulation model in major depression but also offer novel insights into the multi-scale pathophysiology of this deliberating disease.