Compressed primary‐to‐transmodal gradient is accompanied with subcortical alterations and linked to neurotransmitters and cellular signatures in major depressive disorder

Major depressive disorder (MDD) has been shown to involve widespread changes in low‐level sensorimotor and higher‐level cognitive functions. Recent research found that a primary‐to‐transmodal gradient could capture a cortical hierarchical organization ranging from perception and action to cognition in healthy subjects, but a prominent gradient dysfunction in MDD patients. However, whether and how this cortical gradient is linked to subcortical impairments and whether it is reflected in the microscale neurotransmitter systems and cell type‐specific transcriptional signatures remain largely unknown. Data were acquired from 323 MDD patients and 328 sex‐ and age‐matched healthy controls derived from the REST‐meta‐MDD project, and the human brain neurotransmitter systems density maps and gene expression data were drawn from two publicly available datasets. We investigated alterations of the primary‐to‐transmodal gradient in MDD patients and their correlations with clinical symptoms of depression and anxiety, as well as their paralleled subcortical impairments. The correlations between MDD‐related gradient alterations and densities of the neurotransmitter systems and gene expression information were assessed, respectively. The results demonstrated that MDD patients had a compressed primary‐to‐transmodal gradient accompanied by paralleled alterations in subcortical regions including the caudate, amygdala, and thalamus. The case–control gradient differences were spatially correlated with the densities of the neurotransmitter systems including the serotonin and dopamine receptors, and meanwhile with gene expression enriched in astrocytes, excitatory and inhibitory neuronal cells. These findings mapped the paralleled subcortical impairments in cortical hierarchical organization and also helped us understand the possible molecular and cellular substrates of the co‐occurrence of high‐level cognitive impairments with low‐level sensorimotor abnormalities in MDD.