Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8
Introduction
Previous studies have found structural changes throughout the brain in schizophrenia patients compared to non-psychiatric controls. Among these studies, increased ventricular size is the most well-replicated structural anomaly found in schizophrenia research (Gur et al., 2007, Wright et al., 2000). Decreases in whole brain volumes and temporolimbic regions also have been repeatedly found among schizophrenia patients (Gur et al., 2007, Wright et al., 2000). Further, studies of individuals who are in the prodrome of schizophrenia also have identified multiple structural brain changes, suggesting that brain disturbances associated with the disorder may have neurodevelopmental origins (Job et al., 2005, Pantelis et al., 2003). Despite these findings, few investigations have sought to determine the contributions of environmental risk factors to neuroanatomical changes found in schizophrenia.
Although genetic factors are believed to substantially contribute to the etiology of schizophrenia, concordance rates approximating 50% between monozygotic twins indicates the presence of substantial environmental influences (Cannon et al., 1998). Among the possible environmental contributors, maternal infections during pregnancy have been repeatedly linked to an increased risk for schizophrenia (Brown and Derkits, 2010). Nevertheless, many infections do not appear to cross the placenta; therefore the damaging influences to the fetal brain seem related to maternal antiviral responses to infection, such as increases in proinflammatory cytokines (Patterson, 2009). In a previous study using the birth cohort of the current investigation, increases in maternal levels of interleukin-8 (IL-8) during the second/third trimesters of pregnancy were associated with increased risk for schizophrenia among offspring (Brown et al., 2004).
Hence, we sought to examine whether fetal exposure to increases in maternal IL-8 during the second/third trimesters results in more pronounced structural brain alterations among individuals diagnosed with schizophrenia and other spectrum disorders (herein referred to as schizophrenia). Our primary hypothesis was that fetal exposure to IL-8 would result in increases in ventricular cerebrospinal fluid (CSF) volume among cases. In addition to the well-replicated association between increases in ventricular CSF and schizophrenia, this hypothesis was derived from animal studies indicating increased ventricular volumes following fetal exposure to immune activation (Patterson, 2009, Wright et al., 2000). Based on previous findings from studies of schizophrenia patients, prodromal research and animal studies, we also predicted that fetal exposure to increased maternal IL-8 would be associated with reduced volumes of temporal lobe regions, particularly in the hippocampus, parahippocampus, and the superior temporal gyrus, and reductions in basal ganglia volumes (Pantelis et al., 2003, Patterson, 2009, Wright et al., 2000). Exploratory analyses were conducted with control participants and on additional regions of interest (ROIs). Analyses of controls were conducted to obtain preliminary findings on whether there are differential vulnerabilities to fetal exposure to IL-8 among cases versus controls, as has been found in other studies (Cannon et al., 2008, Ellman et al., 2009).
Section snippets
Materials and methods
All subjects provided written informed consent and the study was approved by the Institutional Review Boards of the New York State Psychiatric Institute, the Kaiser Foundation Research Institute, and the University of California San Francisco VA Medical Center.
Results
There were no significant differences in age or sex between cases and controls (see Table 1). In addition, among several demographic variables examined, age (r = 0.0575, p = 0.785), (F = 0.35, df = 1, 24, p = 0.559), and medication status of cases (on antipsychotics or not; F = 0.01, df = 1, 24, p = 0.924) were not significantly related to IL-8 levels. Further, there were no differences in brain volumes between cases that were and were not taking antipsychotics at the time of the assessment (results available
Discussion
These results provide the first evidence that fetal exposure to increases in a maternal cytokine is associated with structural neuroanatomic alterations that have been consistently linked to schizophrenia (Wright et al., 2000). Among schizophrenia cases, increases in maternal IL-8 during the second/third trimesters of pregnancy were related to increases in ventricular CSF. In addition, we observed significant associations between maternal IL-8 and decreases in left entorhinal cortex and right
Role of funding source
This study was supported by research grants to Dr. Brown from the National Institute of Mental Health (R01MH060249, R01MH63264, and K02 MH065422-06) and a postdoctoral NIMH schizophrenia research fellowship to Dr. Ellman (5 T32 MH018870-20) and grants N01HD13334 and N01HD63258 from The Eunice Kennedy Shriver Institute of Child Health and Human Development. These funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and
Contributors
Dr. Ellman conducted all of the statistical analyses, contributed substantially to the conceptualization of the paper, study design, data interpretation, and was the main writer of the manuscript. Dr. Deicken supervised all of the imaging acquisition and imaging analyses for the study and contributed to writing of the manuscript. Drs Vinogradov, Kremen, and Poole contributed to the conceptual design, to data collection, data interpretation, and manuscript writing. Mr. Kern and Dr. Tsai aided in
Conflict of interest
The authors have no financial disclosures and/or conflicts to report.
Acknowledgments
This study was supported by research grants to Dr. Brown from the National Institute of Mental Health (R01MH060249, R01MH63264, and K02 MH065422-06) and a postdoctoral NIMH schizophrenia research fellowship to Dr. Ellman (5 T32 MH018870-20) and grants N01HD13334 and N01HD63258 from The Eunice Kennedy Shriver Institute of Child Health and Human Development. We also thank Theo van Erp, Ezra Susser, Michaeline Bresnahan, Barbara Cohn, Nashid Chaudhury, Aundrea Cook, Justin Penner, Nicole
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