Subthreshold depression is associated with impaired resting-state functional connectivity of the cognitive control network

Subthreshold depression (StD) is a prevalent condition associated with social morbidity and increased service utilization, as well as a high risk of developing into a major depressive disorder (MDD). The lack of well-defined diagnostic criteria for StD has limited research on this disorder, with very few brain-imaging studies examining the neurobiology of StD. Yet, identifying the neural pathology of StD has the potential to elucidate risk factors and prognostic markers for major depression and is crucial for developing tailored treatments for patients at mild stages of depression. We investigated resting-state functional connectivity (rs-FC) of the cognitive control network (CCN), known to be dysregulated in MDD, using the bilateral dorsolateral prefrontal cortex (DLPFC) as a seed, focusing on two cohorts of StD subjects (young and middle aged) as well as matched controls. Irrespective of age, we found a significant rs-FC decrease in the CCN of the StD subjects, compared with matched controls, particularly between the DLPFC and the brain regions associated with the representation of self and other mental states (temporo-parietal junction (TPJ) and precuneus), as well as salience detection and orienting (insula). The functional connectivity between the DLPFC and the left TPJ was also associated with depressive symptom scores measured by the Center for Epidemiologic Studies Depression Scale. This finding may shed light on the neural pathology of StD, leading to better understanding of mild stages of depression, its diagnosis and the development of new treatments.