Neural Correlates of Peripheral Inflammation in Major Depressive Disorder and Their Transcriptomic Architecture, Neurochemical Basis, and Behavioral Relevance

Hum Brain Mapp. 2025 Oct 1;46(14):e70371. doi: 10.1002/hbm.70371.

ABSTRACT

The role of inflammation in the neuropathology of major depressive disorder (MDD) is evident. However, the neural correlates of peripheral inflammation in MDD and their transcriptomic architecture, neurochemical basis, and behavioral relevance have not been systematically investigated. We adopted functional and diffusion magnetic resonance imaging to assess gray matter function and white matter integrity, whose associations with serum C-reactive protein (CRP) levels were explored in a large sample of MDD patients. Further, we examined the spatial relationships of the identified neural correlates of CRP with transcriptome, neurotransmitter, and behavioral domain atlases. Higher serum CRP levels were associated with local gray matter function alterations and widespread white matter integrity changes in MDD patients, but not HC. Moreover, the gray matter functional correlates of CRP in MDD were spatially correlated with functional gene categories involving inflammatory signaling pathways (macrophage activation, NF-κB signaling, and JUN kinase activity), specific neurotransmitters (serotonin, GABA, and glutamate), and diverse behavioral domains (sensorimotor, cognition, emotion, and sleep). In addition, some neural correlates of CRP (anterior cingulate cortex function and superior corona radiata integrity) mediated the relationships of serum CRP with sustained attention and sleep structure in MDD patients. Our findings may not only confirm the role of inflammation in the neuropathology of MDD, but also inform a novel conceptualization of targeting inflammatory processes to treat this disorder.

PMID:41014304 | DOI:10.1002/hbm.70371