Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8

Lauren M. Ellman; Raymond F. Deicken; Sophia Vinogradov; William S. Kremen; John H. Poole; David M. Kern; Wei Yann Tsai; Catherine A. Schaefer; Alan S. Brown

doi:10.1016/j.schres.2010.05.014

Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8

Lauren M. Ellman, Raymond F. Deicken, Sophia Vinogradov, William S. Kremen, John H. Poole, David M. Kern, Wei Yann Tsai, Catherine A. Schaefer, Alan S. Brown

Psychiatry & Behavioral Sciences

Research output: Contribution to journal › Article › peer-review

199 Scopus citations

Abstract

Background: Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. Methods: Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. Results: Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. Conclusion: Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

Original language	English (US)
Pages (from-to)	46-54
Number of pages	9
Journal	Schizophrenia Research
Volume	121
Issue number	1-3
DOIs	https://doi.org/10.1016/j.schres.2010.05.014
State	Published - Aug 2010

Bibliographical note

Funding Information:
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 Stephenson, Dawn Schpak and the study teams of the CHDS, the PDS, and the DIBS for their contributions to data collection and preparation of this manuscript. The authors also wish to acknowledge Larry Kegeles, M.D. for his helpful comments.

Funding Information:
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 in the decision to submit the paper for publication.

Keywords

Infection
Obstetric complications
Pregnancy
Proinflammatory cytokines
Schizophrenia
Structural MRI

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.schres.2010.05.014

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@article{737c5f54db8a4dc7b314f7c4da9b5c3e,

title = "Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8",

abstract = "Background: Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. Methods: Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. Results: Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. Conclusion: Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.",

keywords = "Infection, Obstetric complications, Pregnancy, Proinflammatory cytokines, Schizophrenia, Structural MRI",

author = "Ellman, {Lauren M.} and Deicken, {Raymond F.} and Sophia Vinogradov and Kremen, {William S.} and Poole, {John H.} and Kern, {David M.} and Tsai, {Wei Yann} and Schaefer, {Catherine A.} and Brown, {Alan S.}",

note = "Funding Information: 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 Stephenson, Dawn Schpak and the study teams of the CHDS, the PDS, and the DIBS for their contributions to data collection and preparation of this manuscript. The authors also wish to acknowledge Larry Kegeles, M.D. for his helpful comments. Funding Information: 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 in the decision to submit the paper for publication. ",

year = "2010",

month = aug,

doi = "10.1016/j.schres.2010.05.014",

language = "English (US)",

volume = "121",

pages = "46--54",

journal = "Schizophrenia Research",

issn = "0920-9964",

publisher = "Elsevier B.V.",

number = "1-3",

}

TY - JOUR

T1 - Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8

AU - Ellman, Lauren M.

AU - Deicken, Raymond F.

AU - Vinogradov, Sophia

AU - Kremen, William S.

AU - Poole, John H.

AU - Kern, David M.

AU - Tsai, Wei Yann

AU - Schaefer, Catherine A.

AU - Brown, Alan S.

N1 - Funding Information: 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 Stephenson, Dawn Schpak and the study teams of the CHDS, the PDS, and the DIBS for their contributions to data collection and preparation of this manuscript. The authors also wish to acknowledge Larry Kegeles, M.D. for his helpful comments. Funding Information: 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 in the decision to submit the paper for publication.

PY - 2010/8

Y1 - 2010/8

N2 - Background: Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. Methods: Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. Results: Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. Conclusion: Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

AB - Background: Maternal infection during pregnancy has been repeatedly associated with increased risk for schizophrenia. Nevertheless, most viruses do not cross the placenta; therefore, the damaging effects to the fetus appear to be related to maternal antiviral responses to infection (e.g. proinflammatory cytokines). Fetal exposure to the proinflammatory cytokine interleukin-8 (IL-8) has been significantly associated with risk of schizophrenia in offspring. This study sought to determine the association between fetal exposure to IL-8 and structural brain changes among schizophrenia cases and controls. Methods: Subjects were 17 cases diagnosed with schizophrenia from the Developmental Insult and Brain Anomaly in Schizophrenia (DIBS) study. Psychiatric diagnoses were determined among offspring with semi-structured interviews and medical records review. IL-8 was determined from assays in archived prenatal sera and volumetric analyses of neuroanatomical regions were obtained from T1-weighted magnetic resonance imaging in adulthood. Eight controls were included for exploratory purposes. Results: Among cases, fetal exposure to increases in IL-8 was associated with significant increases in ventricular cerebrospinal fluid, significant decreases in left entorhinal cortex volumes and significant decreases in right posterior cingulate volumes. Decreases that approached significance also were found in volumes of the right caudate, the putamen (bilaterally), and the right superior temporal gyrus. No significant associations were observed among controls. Conclusion: Fetal exposure to elevations in maternal IL-8 led to structural neuroanatomic alterations among cases in regions of the brain consistently implicated in schizophrenia research. In utero exposure to elevations in IL-8 may partially account for brain disturbances commonly found in schizophrenia.

KW - Infection

KW - Obstetric complications

KW - Pregnancy

KW - Proinflammatory cytokines

KW - Schizophrenia

KW - Structural MRI

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U2 - 10.1016/j.schres.2010.05.014

DO - 10.1016/j.schres.2010.05.014

M3 - Article

C2 - 20553865

AN - SCOPUS:77955057052

SN - 0920-9964

VL - 121

SP - 46

EP - 54

JO - Schizophrenia Research

JF - Schizophrenia Research

IS - 1-3

ER -

Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8

Abstract

Bibliographical note

Keywords

UN SDGs

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