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

Background 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. This study aimed to explore brain structural network abnormalities and their transcriptional mechanisms in adolescents with MDD and NSSI using the Morphometric Inverse Divergence Gradient Network for the first time. Methods A total of 241 adolescents with MDD participated in this study, including 134 individuals with a history of non-suicidal self-injury and 107 without. Using high-resolution T1-weighted magnetic resonance imaging, we constructed the principal morphometric gradient network, which reflects the similarity of cortical morphology between different brain regions. Partial least squares regression analysis was conducted to link imaging findings with neurotransmitter receptor distributions and gene expression patterns. Results Adolescents with NSSI showed higher morphometric gradient values in the left caudal middle frontal gyrus and bilateral inferior temporal gyri, and lower values in the left lingual gyrus and right superior parietal lobule. These structural changes were slightly associated with functional alterations in the dorsal attention network. Further analysis revealed associations with the distribution of nine neurotransmitter receptor types, including serotonin 5-HT1A, GABAa, glutamate, and dopamine receptors. The first component of partial least squares regression analysis explained 39.53% of the spatial variance in the morphometric gradient and identified key genes related to NSSI, such as GABRA5 and MGST1. Enrichment analysis showed that positively correlated genes were involved in synaptic signaling, neurodevelopment, and mood disorder pathways, and were enriched in astrocytes and cortical layers I, II, and V. Negatively correlated genes were linked to chromatin regulation and cytoskeletal metabolism, and were mainly expressed in cortical layers III and IV. Conclusions Adolescents with MDD and non-suicidal self-injury display specific abnormalities in brain structural gradients that are closely associated with neurotransmitter receptor distributions and gene expression profiles. These findings provide multi-level evidence for understanding the neurobiological mechanisms underlying non-suicidal self-injury.