Cognition-related connectome gradient dysfunctions of thalamus and basal ganglia in drug-naïve first-episode major depressive disorder

Background: Subcortical functional abnormalities are believed to contribute to clinical symptoms and cognitive impairments in major depressive disorder (MDD). By introducing functional gradient mapping, the present study evaluated subcortical gradients in MDD patients and their association with cognitive features.

Methods: Organization patterns and between-group differences in the principal subcortical gradient were investigated in 145 never-treated first-episode MDD patients and 145 healthy controls (HCs) across limbic, thalamic, and basal ganglia (BG) systems and their structural and functional subregions. We also assessed the associations between significant gradient alterations and clinical characteristics and neuropsychological functioning.

Results: Overall, MDD patients showed a relatively compressed and disturbed gradient organization than HCs, with limbic and BG regions located at the two extreme ends of the principal gradient. Specifically, MDD patients had lower principal gradient values in thalamus and limbic system but higher values in BG than HCs. These gradient alterations, associated with intrinsic Euclidian distance and functional connectivity patterns, manifested as spatial rearrangements of gradient values within each respective subregion. Lower gradient values in thalamic subregion projecting to default mode network were associated with higher principal gradient values in BG subregion projecting to ventral attention network, and these gradient alterations were correlated with poorer episodic memory performance in MDD patients.

Limitations: The specific neuropathological mechanisms driving the gradient alterations still require further investigation.

Conclusions: Opposing gradient alterations in the thalamic and BG regions synergistically impact episodic memory performance in MDD, revealing an internally differentiated and cognition related pattern of subcortical gradient dysfunction in MDD.