PMID- 29487127 OWN - NLM STAT- MEDLINE DCOM- 20190705 LR - 20190705 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 38 IP - 11 DP - 2018 Mar 14 TI - Maternal Immune Activation During the Third Trimester Is Associated with Neonatal Functional Connectivity of the Salience Network and Fetal to Toddler Behavior. PG - 2877-2886 LID - 10.1523/JNEUROSCI.2272-17.2018 [doi] AB - Prenatal maternal immune activation (MIA) is associated with altered brain development and risk of psychiatric disorders in offspring. Translational human studies of MIA are few in number. Alterations of the salience network have been implicated in the pathogenesis of the same psychiatric disorders associated with MIA. If MIA is pathogenic, then associated abnormalities in the salience network should be detectable in neonates immediately after birth. We tested the hypothesis that third trimester MIA of adolescent women who are at risk for high stress and inflammation is associated with the strength of functional connectivity in the salience network of their neonate. Thirty-six women underwent blood draws to measure interleukin-6 (IL-6) and C-reactive protein (CRP) and electrocardiograms to measure fetal heart rate variability (FHRV) at 34-37 weeks gestation. Resting-state imaging data were acquired in the infants at 40-44 weeks postmenstrual age (PMA). Functional connectivity was measured from seeds placed in the anterior cingulate cortex and insula. Measures of cognitive development were obtained at 14 months PMA using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Both sexes were studied. Regions in which the strength of the salience network correlated with maternal IL-6 or CRP levels included the medial prefrontal cortex, temporoparietal junction, and basal ganglia. Maternal CRP level correlated inversely with FHRV acquired at the same gestational age. Maternal CRP and IL-6 levels correlated positively with measures of cognitive development on the BSID-III. These results suggest that MIA is associated with short- and long-term influences on offspring brain and behavior.SIGNIFICANCE STATEMENT Preclinical studies in rodents and nonhuman primates and epidemiological studies in humans suggest that maternal immune activation (MIA) alters the development of brain circuitry and associated behaviors, placing offspring at risk for psychiatric illness. Consistent with preclinical findings, we show that maternal third trimester interleukin-6 and C-reactive protein levels are associated with neonatal functional connectivity and with both fetal and toddler behavior. MIA-related functional connectivity was localized to the salience, default mode, and frontoparietal networks, which have been implicated in the pathogenesis of psychiatric disorders. Our results suggest that MIA alters functional connectivity in the neonatal brain, that those alterations have consequences for cognition, and that these findings may provide pathogenetic links between preclinical and epidemiological studies associating MIA with psychiatric risk in offspring. CI - Copyright (c) 2018 the authors 0270-6474/18/382877-10$15.00/0. FAU - Spann, Marisa N AU - Spann MN AD - Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032. FAU - Monk, Catherine AU - Monk C AD - Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York 10032. AD - New York State Psychiatric Institute, New York, New York 10032. FAU - Scheinost, Dustin AU - Scheinost D AUID- ORCID: 0000-0002-6301-1167 AD - Radiology and Biomedical Imaging and in the Child Study Center, Yale University School of Medicine, New Haven, Connecticut 06520. FAU - Peterson, Bradley S AU - Peterson BS AD - Institute for the Developing Mind, Children's Hospital Los Angeles, Los Angeles, California 90027, and bpeterson@chla.usc.edu. AD - Department of Psychiatry, Keck School of Medicine, University of Southern California, Los Angeles, California 90033. LA - eng GR - KL2 TR001874/TR/NCATS NIH HHS/United States GR - R01 MH093677/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20180227 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (IL6 protein, human) RN - 0 (Interleukin-6) RN - 9007-41-4 (C-Reactive Protein) SB - IM MH - Adolescent MH - Basal Ganglia/growth & development/physiology MH - C-Reactive Protein/analysis MH - Cerebral Cortex/growth & development/physiology MH - Child Development/*physiology MH - Cognition/physiology MH - Electrocardiography MH - Female MH - Fetus/physiology MH - Heart Rate, Fetal MH - Humans MH - Infant MH - Infant Behavior/*physiology MH - Infant, Newborn MH - Interleukin-6/blood MH - Male MH - Nerve Net/growth & development/*immunology/*physiology MH - Neuropsychological Tests MH - Pregnancy MH - Pregnancy Trimester, Third/*immunology MH - Young Adult PMC - PMC5852665 OTO - NOTNLM OT - cognition OT - maternal C-reactive protein OT - maternal immune activation OT - maternal interleukin 6 OT - neonatal functional connectivity OT - salience network EDAT- 2018/03/01 06:00 MHDA- 2019/07/06 06:00 PMCR- 2018/09/14 CRDT- 2018/03/01 06:00 PHST- 2017/08/10 00:00 [received] PHST- 2018/01/06 00:00 [revised] PHST- 2018/01/22 00:00 [accepted] PHST- 2018/03/01 06:00 [pubmed] PHST- 2019/07/06 06:00 [medline] PHST- 2018/03/01 06:00 [entrez] PHST- 2018/09/14 00:00 [pmc-release] AID - JNEUROSCI.2272-17.2018 [pii] AID - 2272-17 [pii] AID - 10.1523/JNEUROSCI.2272-17.2018 [doi] PST - ppublish SO - J Neurosci. 2018 Mar 14;38(11):2877-2886. doi: 10.1523/JNEUROSCI.2272-17.2018. Epub 2018 Feb 27.