Distance-related functional connectivity alterations in first-episode, drug-naïve major depressive disorder: a resting-state fMRI study with atlas-based neurotransmitter correlates.

BACKGROUND

Major depressive disorder (MDD) has been associated with large-scale functional dysconnectivity, yet it remains unclear whether these abnormalities differ as a function of anatomical distance. We investigated distance-related functional connectivity strength (FCS) alterations in first-episode, drug-naïve MDD and examined whether their spatial distribution corresponds to atlas-based neurotransmitter receptors/transporters profiles.

METHODS

Resting-state functional MRI data were acquired from 191 patients with first-episode, drug-naïve MDD and 130 healthy controls. Whole-brain global, long-range, and short-range FCS were quantified voxel-wise. Distance-constrained seed-based connectivity analyses were performed to characterize the circuit-level contributions underlying abnormal FCS findings. To provide a molecular context, regional maps of FCS abnormalities were compared with neurotransmitter receptors/transporters distributions derived from a publicly available positron emission tomography atlas.

RESULTS

Compared with healthy controls, patients with MDD showed reduced long-range FCS in the left orbital superior frontal gyrus and left medial superior frontal gyrus, together with increased short-range FCS in the right inferior parietal lobule. Seed-based analyses indicated that reduced long-range FCS was mainly related to weaker long-range connectivity between the left orbital superior frontal gyrus and right inferior temporal gyrus, and between the left medial superior frontal gyrus and right hippocampus. Increased short-range FCS in the right inferior parietal lobule was associated with stronger short-range connectivity with the right inferior frontal operculum, right superior temporal gyrus, and left paracentral lobule. The spatial pattern of FCS abnormalities showed significant correspondence with atlas-based neurotransmitter receptors/transporters distributions; short-range abnormalities spatially covaried with an atlas-derived regional excitation-inhibition balance.

CONCLUSIONS

First-episode, drug-naïve MDD is characterized by a distance-related pattern of reduced long-range prefrontal connectivity and increased short-range parietal connectivity. Atlas-based molecular mapping provides a biologically informed, population-level spatial context for these macroscale functional abnormalities.