Resting-state functional connectivity of the fronto-limbic and default mode network as neural correlates of...

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet antidepressant response remains highly variable, with many patients failing to achieve remission. Resting-state functional connectivity (RSFC) studies have linked MDD to large-scale brain network dysregulation, but methodological inconsistencies and limited focus on treatment response have hindered clinical translation.

We conducted a resting-state fMRI study as part of an 8-week antidepressant trial on 86 patients with MDD and 93 healthy controls (HCs). Utilizing a seed-to-voxel approach based on prior studies of neural networks implicated in antidepressant response, we examined RSFC patterns associated with treatment outcomes. Additionally, we explored their relationships with cognitive function and depressive severity to elucidate neural mechanisms underlying treatment response.

Compared to the non-responder group, antidepressant responders exhibited significantly higher ROI-to-ROI FC between the posterior cingulate cortex (PCC) and subgenual anterior cingulate cortex (sgACC), with follow-up seed-to-voxel maps showing higher PCC couplings with the prefrontal cortex, thalamus, and amygdala. In responders, FC between the left amygdala and supramarginal gyrus, and between the ventromedial prefrontal cortex (VMPFC) and lateral occipital cortex, was negatively correlated with cognitive scores. Conversely, in the non-responder group, FC between the left subgenual anterior cingulate cortex (sgACC) and lateral occipital cortex was negatively correlated with digit span but positively with other tasks. FCs involving the amygdala, thalamus, and VMPFC were correlated with depression scale scores.

Enhanced connectivity within networks related to emotion regulation, cognitive control, and attention in responders suggests neural mechanisms supporting improved emotional and cognitive flexibility.