Major Depressive Disorder With Non‐Suicidal Self‐Injury in Adolescents: Altered Morphological Inverse Divergence Gradient in Brain Structure and Gene Expression Patterns

ABSTRACT

Adolescents with major depressive disorder (MDD) and non‐suicidal self‐injury (NSSI) face serious challenges to their mental and physical health. The development of this condition is influenced by genetic, environmental, and brain development factors. In this study, we used the Morphometric Inverse Divergence Gradient Network (MIND‐Gd) for the first time to explore brain structural network abnormalities and their transcriptional mechanisms in adolescents with MDD and NSSI. A total of 241 adolescents with MDD participated in this study. Among them, 134 had NSSI, while 107 did not. Using high‐resolution T1‐weighted magnetic resonance imaging (MRI), we constructed the principal MIND gradient network. This network reflects the similarity of cortical morphology between different brain regions. The results showed that adolescents with NSSI had higher MIND gradient values in the left caudal middle frontal gyrus and bilateral inferior temporal gyri. In contrast, lower values were observed in the left lingual gyrus and right superior parietal lobule. These structural changes were spatially correlated with functional alterations in the dorsal attention network. Further analysis revealed that these differences were linked to the distribution of nine types of neurotransmitter receptors, including 5‐HT1A, GABAa, glutamate, and dopamine. Partial least squares regression analysis (PLS) was also conducted. The first component (PLS1) explained 39.53% of the spatial variance in MIND‐Gd. This analysis identified key genes related to NSSI, such as GABRA5 and MGST1. Enrichment analysis showed that PLS1+ genes were involved in synaptic signaling, neurodevelopment, and mood disorder pathways. These genes were enriched in astrocytes and cortical layers I, II, and V. On the other hand, PLS1− genes were linked to chromatin regulation and cytoskeletal metabolism. These genes were mainly expressed in Cortical Layers III and IV. In conclusion, adolescents with MDD and NSSI show specific abnormalities in brain structural gradients. These abnormalities are closely related to neurotransmitter receptor distributions and gene expression patterns. The findings provide multi‐level evidence for understanding the neurobiological mechanisms of NSSI.