Inflammation in schizophrenia: Peripheral interleukin-6-related disease-specific functional activity abnormalities

Abstract Background Peripheral inflammation is implicated in the pathophysiology of schizophrenia, but how inflammatory signals map onto the large-scale brain organization remains incompletely understood. Methods We applied a supervised multimodal fusion approach guided by interleukin-6 (IL-6) to gray matter volume (GMV) and resting-state regional homogeneity (ReHo) from a population-based discovery cohort in the UK Biobank. Brain components related to IL-6 were identified and then projected onto an independent schizophrenia cohort to examine their relevance to the disease. Imaging-transcriptomic analyses using the Allen Human Brain Atlas characterize the molecular substrates underlying the disease-relevant pattern. Results Two ReHo components were significantly associated with plasma IL-6, while no GMV components showed robust IL-6 correlations. One of the components (ReHo IC4) exhibited a conserved functional pattern characterized by enhanced visual synchrony and reduced synchrony in the medial prefrontal cortex. This pattern remained unchanged in both the healthy controls and patients. In contrast, another component (ReHo IC8) showed increased synchrony in the default mode network and reduced synchrony in sensorimotor networks, and its loadings were significantly elevated in patients with schizophrenia. Imaging-transcriptomic analysis revealed the molecular architecture of this disease-amplified pattern. The default mode region was enriched in synaptic signaling pathways, while the sensorimotor region was linked to mitochondrial bioenergetic processes; both patterns significantly enriched with gene sets related to schizophrenia. Conclusions This study identified an IL-6-associated functional brain pattern that is amplified in schizophrenia, linking peripheral inflammation to disease-specific network dysregulation. The findings provide a systems-level framework for understanding how peripheral inflammation interacts with large-scale brain network activities in schizophrenia.