Neural correlates of abnormal regional functional efficiency in major depressive disorder: a large, multi-scale study

Whether patients with major depressive disorder (MDD) are associated with abnormal regional functional efficiency (RFE) remain unknown. This study aimed to investigate the abnormal RFE pattern and its neural correlates in MDD using a large, multi-site cohort. We calculated voxel-wise RFE from resting-state functional magnetic resonance imaging data of 1265 MDD patients and 1094 matched healthy controls (HCs). Raw RFE values were transformed into W-scores using a normative model and then compared between MDD and HC groups. We validated the reproducibility of the group differences through leave-one-site-out and subsample validation approaches. Additionally, we examined the associations between the abnormal RFE pattern and clinical features, as well as neurotransmitter receptor/transporter profiles derived from a public positron emission tomography-based atlas. Our results showed that MDD was associated with increased RFE in the cerebellum, thalamus, bilateral dorsolateral prefrontal cortex, and the middle and inferior frontal gyrus, while decreased RFE was observed in the posterior cingulate, precuneus, postcentral gyrus, and fusiform gyrus. This abnormal pattern demonstrated high spatial similarity with validation results, indicating reproducibility. Early-onset MDD patients exhibited reduced RFE in the bilateral ventromedial prefrontal cortex, bilateral insula, left putamen, right caudate, and angular gyrus, alongside increased RFE in the cerebellum anterior lobe, cuneus, and precuneus compared to middle-to-late onset patients. Furthermore, the abnormal RFE pattern in MDD showed significant associations with neurotransmitter receptor/transporter profiles, particularly GABA_a and mGluR₅, suggesting a molecular basis for these findings. These results highlight abnormal regional functional efficiency and its neural correlates in MDD.