Neural correlates of peripheral inflammation in individuals with first-episode schizophrenia

Abstract

Elevated pro-inflammatory markers have been reported in schizophrenia, and inflammation has been found to modulate brain functional connectivity. This paper provides novel evidence on the association between striatal connectivity and inflammation in first-episode schizophrenia (FES) and its relationship with negative symptoms and cognitive performance. We included 132 individuals with FES who underwent resting-state functional MRI (fMRI) as part of the Benefit of Minocycline on negative symptoms of schizophrenia (BeneMin) trial. We applied a previously estimated semi-supervised machine learning clustering solution on inflammatory patterns to assign individuals with FES to an inflammation group at baseline and at 12-month follow-up. A seed-based functional connectivity analysis was conducted using bilateral basal ganglia as seed regions. Symptoms of psychosis were evaluated using the Positive and Negative Syndrome Scale (PANSS). The Digit Symbol Substitution Test (DSST) was used as a proxy for cognitive function. At baseline, FES individuals in the elevated CRP group (High-CRP) presented higher functional connectivity between the right nucleus accumbens and the left middle frontal gyrus and between the right pallidum and the left middle frontal gyrus/precentral gyrus, compared with individuals in the low inflammation group (Low-Inf). These differences were also evident at follow-up, although they did not reach statistical significance. We found a greater correlation between right nucleus accumbens—left superior and middle frontal gyri functional connectivity and PANSS negative symptom subscale scores in the High-CRP group compared with the Low-Inf group. Our findings suggest that inflammation is associated with differences in fronto-striatal connectivity early in schizophrenia, which could, in turn, be associated with more severe negative symptoms. Greater fronto-striatal connectivity may represent a distinct neural signature associated with greater inflammation. Interventions aiming at reducing inflammation may represent novel strategies for modulating striatal connectivity and ameliorating negative symptoms.