Shared and distinct alterations in brain connectivity and cognitive function in subthreshold and major depression

Subthreshold depression (StD) is considered a prodromal stage of major depressive disorder (MDD). This study aims to investigate the neurobiological mechanisms of StD by analyzing functional connectivity (FC) and cognitive function in comparison to MDD.

A total of 153 StD individuals, 188 MDD patients, and 110 healthy controls (HCs) were studied using resting-state functional magnetic resonance imaging (fMRI). Whole-brain FC was calculated using seeds from the default mode network (DMN), salience network (SN), executive control network, and affective network (AN). Cognitive function was assessed across seven domains.

StD showed only a deficit in social cognition, while MDD exhibited multidomain cognitive impairments compared to HCs. Both MDD and StD exhibited reduced FC between the right anterior insula (AI) and the left inferior frontal gyrus (IFG), and increased FC between the right subcallosal cingulate cortex and the left posterior cingulate cortex (PCC), key areas of the SN and AN, compared to HCs. MDD particularly showed decreased connectivity between the left PCC and the left middle temporal gyrus, and within the left PCC, while no abnormal FC of the DMN was found in StD. Altered AI-IFG FC was positively correlated with social cognition in StD.

Abnormal connectivity patterns of the SN and AN may contribute to the development of depressive symptoms in StD and MDD, while altered FC of the DMN may be involved in the onset of the disease. A social cognition deficit appeared first in StD, relating to the abnormal connectivity of the SN.