The age-related heterogeneity in major depressive disorder (MDD) has received significant attention. However, the neural mechanisms underlying such heterogeneity still need further investigation. This study aimed to explore the common and distinct functional brain abnormalities across different age groups of MDD patients from a large-sample, multicenter analysis.

The analyzed sample consisted of a total of 1238 individuals including 617 MDD patients (108 adolescents, 12–17 years old; 411 early-middle adults, 18–54 years old; and 98 late adults, > = 55 years old) and 621 demographically matched healthy controls (60 adolescents, 449 early-middle adults, and 112 late adults). MDD-related abnormalities in brain functional connectivity (FC) patterns were investigated in each age group separately and using the whole pooled sample, respectively.

We found shared FC reductions among the sensorimotor, visual, and auditory networks across all three age groups of MDD patients. Furthermore, adolescent patients uniquely exhibited increased sensorimotor-subcortical FC; early-middle adult patients uniquely exhibited decreased visual-subcortical FC; and late adult patients uniquely exhibited wide FC reductions within the subcortical, default-mode, cingulo-opercular, and attention networks. Analysis of covariance models using the whole pooled sample further revealed: (1) significant main effects of age group on FCs within most brain networks, suggesting that they are decreased with aging; and (2) a significant age group × MDD diagnosis interaction on FC within the default-mode network, which may be reflective of an accelerated aging-related decline in default-mode FCs.

To summarize, these findings may deepen our understanding of the age-related biological and clinical heterogeneity in MDD.

Childhood adversity is associated with abnormalities in brain structure, but this association has not been tested for childhood unpredictability, one form of adversity. We studied whether abnormalities in gray matter volume (GMV) could be a mechanism linking childhood unpredictability and psychopathology, over and above the effect of childhood trauma.

Participants were 158 right-handed healthy young adults (aged 17–28 years, M = 22.07, s.d. = 2.08; 66.46% female) who underwent structural magnetic resonance imaging measurements and provided retrospective reports of childhood unpredictability. The anxiety and depression subscales of the self-report Brief Symptom Inventory-53 were used to index psychopathology.

Whole-brain voxel-based morphometric analyses showed that after controlling for the effect of childhood trauma, childhood unpredictability was correlated with greater GMV in bilateral frontal pole, bilateral precuneus, bilateral postcentral gyrus, right hemisphere of fusiform, and lingual gyrus, and left hemisphere of ventrolateral prefrontal cortex as well as occipital gyrus. Greater GMV in bilateral frontal pole, bilateral precuneus, and bilateral postcentral gyrus mediated associations between unpredictability and symptoms of depression and anxiety.

The findings suggest that childhood unpredictability could exact unique effects on neural development, over and above the effect of childhood trauma. These findings are relevant for understanding the occurrence of psychopathology following childhood unpredictability and have implications for intervention.