The role of the subcortical structures in subthreshold depression: evidence from static and dynamic functional...

Subthreshold depression (StD) is considered a significant precursor to major depressive disorder (MDD). MDD has been associated with abnormalities in dopamine-coupled brain regions, particularly a few specific subcortical structures, which are considered a key pathophysiological mechanism. However, the precise role that subcortical structures play in the pathophysiology of StD is still unclear. We compared the seed-based whole-brain static and dynamic functional connectivity (sFC/dFC) of subcortical regions between 50 individuals with StD and 50 healthy controls (HC). Static and dynamic subcortical networks were constructed for each group, followed by graph theory, network-based statistical (NBS), and K-means clustering analyses. Individuals with StD exhibited decreased sFC/dFC in the amygdala, caudate, putamen, pallidum, and brainstem, with primary involvement of the prefrontal cortex, precuneus, and supramarginal gyrus. The global topological properties of static subcortical networks, including small-world property and local efficiency, were reduced in StD. In dynamic subcortical networks, two recurring FC patterns were identified, exhibiting altered temporal properties in StD. Additionally, exploratory analyses further suggested that dynamics of subcortical structures, particularly the amygdala and caudate, were modestly associated with the severity of depressive symptoms and showed predictive value in distinguishing StD from HC. These findings offer new perspectives on the neural mechanisms underlying subcortical disruptions in StD, highlighting dysfunction within the amygdala and caudate as potentially core neurobiological features.