Brain morphology is differentially impacted by peripheral cytokines in schizophrenia-spectrum disorder

Deficits in brain morphology are one of the most widely replicated neuropathological features in schizophreniaspectrum disorder (SSD), although their biological underpinnings remain unclear. Despite the existence of hypotheses by which peripheral inflammation may impact brain structure, few studies have examined this relationship in SSD. This study aimed to establish the relationship between peripheral markers of inflammation and brain morphology and determine whether such relationships differed across healthy controls and individuals with first episode psychosis (FEP) and chronic schizophrenia. A panel of 13 pro- and anti-inflammatory cytokines were quantified from serum in 175 participants [n = 84 Healthy Controls (HC), n = 40 FEP, n = 51 Chronic SCZ]. We first performed a series of permutation tests to identify the cytokines most consistently associated with brain structural regions. Using moderation analysis, we then determined the extent to which individual variation in select cytokines, and their interaction with diagnostic status, predicted variation in brain structure. We found significant interactions between cytokine level and diagnosis on brain structure. Diagnostic status significantly moderated the relationship of IFN gamma, IL4, IL5 and IL13 with frontal thickness, and of IFN gamma and IL5 and total cortical volume. Specifically, frontal thickness was positively associated with IFN gamma, IL4, IL5 and IL13 cytokine levels in the healthy control group, whereas pro-inflammatory cytokines IFN gamma and IL5 were associated with lower total cortical volume in the FEP group. Our findings suggest that while there were no relationships detected in chronic schizophrenia, the relationship between peripheral inflammatory markers and select brain regions are differentially impacted in FEP and healthy controls. Longitudinal investigations are required to determine whether the relationship between brain structure and peripheral inflammation changes over time.

Automated summary

The study found differential relationships between peripheral inflammatory markers and select brain regions in first-episode psychosis (FEP) and healthy controls, although no relationships were detected in chronic schizophrenia. Specifically, frontal thickness was positively associated with certain cytokine levels in the healthy control group, while pro-inflammatory cytokines were associated with lower total cortical volume in the FEP group. Longitudinal investigations are needed to determine how the relationship between brain structure and peripheral inflammation may change over time.