Inflammatory Cytokines Mediate Brain Dysconnectivity and Cognitive Deficits Across Major Psychiatric Disorders

Abstract

Background: Cognitive impairment influenced by brain dysconnectivity and inflammatory cytokines has consistently been the most prominent feature across major psychiatric disorders (MPDs) including schizophrenia, bipolar disorder, and major depressive disorder. The commonalities call upon a trans-diagnostic and dimensional approach in delineating the neural mechanisms underlying the relationship between brain connectivity, cognition, and inflammation among MPDs. Methods: 1543 participants, including 1058 with MPDs and 485 healthy controls, from a single site were enrolled in this study. Participants underwent diffusion tensor imaging and resting-state functional magnetic resonance imaging, with the majority of participants (n = 1169, 765 participants with MPDs and 404 healthy controls) also completing the Wisconsin Card Sorting Test (WCST). Blood samples were obtained from 325 participants within 24 h of imaging. Fractional anisotropy (FA) and regional functional connectivity (FC) were used to measure structural and functional connectivity, respectively. Findings: Differences in inflammatory cytokine indices were assessed using IL-1β, IL-6 and TNF-α. WCST deficits were associated with decreased FA; increased regional FC; and elevated IL-1β, IL-6 and TNF-α among MPDs. Overlapping structural and functional dysconnectivity within the frontolimbic-striatal regions contributed to cognitive deficits among MPDs. Mediation analyses revealed that IL-1β mediated the association between FA and WCST and that IL-6 mediated the relationship between regional FC and WCST. Interpretation: Our findings implicate an intriguing mechanism for the effects of inflammation on cognitive function through different molecular-brain-cognition pathways among MPDs. Specific cytokine influences allow for more targeted studies and potentially more targeted interventions that may improve cognition in MPDs. Funding Statement: This study was funded by National Science Fund for Distinguished Young Scholars (81725005 to F.W.), National Natural Science Foundation of China (81571311 to Y.T., 81571331 to F.W.), National Key Research and Development Program (2018YFC1311604 to Y.T., 2016YFC1306900 to Y.T., 2016YFC0904300 to F.W.), National High Tech Development Plan (863) (2015AA020513 to F.W.), Liaoning Science and Technology Project (2015225018 to Y.T.), Liaoning Education Foundation (Pandeng Scholar to F.W.), Innovation Team Support Plan of Higher Education of Liaoning Provience (LT2017007 to F.W.), and Major Special Construction plan of China Medical University (3110117059 to F.W.). Declaration of Interests: The authors report no biomedical financial interests or potential conflicts of interest. Ethics Approval Statement: The study was approved by the Institutional Review Board of China Medical University and was performed in accordance with the Declaration of Helsinki. All experiments and methods were performed in accordance with approved guidelines and regulations. All subjects provided written informed consent.