Prenatal chronic inflammation impacts fetal brain functional connectivity
Poster No:
1777
Submission Type:
Abstract Submission
Authors:
Iris Menu1, Lanxin Ji1, Amyn Majbri2, Mark Duffy1, Christopher Trentacosta3, Adam Eggebrecht4, Muriah Wheelock5, Suzanne Jacques3, Faisal Qureshi3, Moriah Thomason6
Institutions:
1NYU Langone Health, New York, NY, 2New York University Medical Center, New York, NY, 3Wayne State University School of Medicine, Detroit, MI, 4Washington University School of Medicine, St. Louis, MO, 5Washington University in St. Louis, St. Louis, MO, 6NYU Langone Medical Center, New York, NY
First Author:
Co-Author(s):
Introduction:
Strong evidence suggests that prenatal inflammation significantly increases the risk of neurodevelopmental or psychotic disorders in offspring (Brown et al., 2004; Werenberg Dreier et al., 2016). The belief is that inflammation during pregnancy can disrupt fetal brain development, leading to long-term impacts on the health and development of the offspring. Prior studies have shown that newborns born to mothers with elevated levels of prenatal interleukin-6 and C-reactive protein, biological indicators of maternal inflammation, exhibit differences in functional connectivity in salience, dorsal attention, medial temporal, and subcortical networks (Graham et al., 2018; Rudolph et al., 2018; Spann et al., 2018). However, to date, if and how prenatal inflammation is related to the fetal brain is still unknown.The current study aims to fill this gap.
Methods:
Pregnant mothers (N = 102; 89% racial/ethnic minority) were recruited during the second and third trimester of pregnancy. Instead of measuring a single cytokine at one time point in maternal blood, we assessed chronic inflammation based on placental histology. Expert pathologists examined the placental tissues and scored them for chronic placental inflammatory lesions, including chronic chorioamnionitis, villitis of unknown etiology, and chronic deciduitis. Resting-state imaging data were acquired in fetuses between 24.14 and 37.86 weeks of gestation using two sets of Multi-Echo Functional Magnetic Resonance Imaging (ME-fMRI). Each set comprised of a 12-minute ME-fMRI scan (360 volumes) and the scanning parameters were as follows: for dataset a) TR = 2000ms; TE = 18, 31.07, 44.14ms (3 echoes); flip angle: 83 degrees; voxel size: 3.5 x 3.5 x 3.5 mm³, and for dataset b) TR = 2000ms; TE = 18, 34, 50ms (3 echoes); flip angle: 83 degrees; voxel size: 3.487 x 3.487 x 3.5 mm³.
We first applied a consensus procedure (infomap) to develop an optimal model consisting of 15 distinct fetal networks distributed across cortical and subcortical regions of interest (Figure 1). Once networks defined, we conducted an enrichment analysis (Eggebrecht et al., 2017) to examine differences associated with chronic inflammation in each within- and between-network pair. We used the Kendall-tau rank correlation, followed by enrichment permutation Wilcoxon tests (10,000 permutations), to determine if the number of significant connections (edges) affected by prenatal inflammation within each network pair exceeded what would be expected by chance.
We first applied a consensus procedure (infomap) to develop an optimal model consisting of 15 distinct fetal networks distributed across cortical and subcortical regions of interest (Figure 1). Once networks defined, we conducted an enrichment analysis (Eggebrecht et al., 2017) to examine differences associated with chronic inflammation in each within- and between-network pair. We used the Kendall-tau rank correlation, followed by enrichment permutation Wilcoxon tests (10,000 permutations), to determine if the number of significant connections (edges) affected by prenatal inflammation within each network pair exceeded what would be expected by chance.
Results:
Our findings revealed that prenatal chronic inflammation disrupted connectivity in frontal, visual, motor, and subcortical networks (Figure 1). Specifically, chronic inflammation led to reduced connectivity within the prefrontal network (network 5, in cyan) and between the fronto-parietal (network 6, in yellow) and subcortical networks (network 13, in light pink) (Figure 2).
·Figure 1: Chronic-inflammation differences in neural connectivity between and across networks.
·Figure 2: Higher chronic inflammation scores lead to a decrease in connectivity within the prefrontal network and between the fronto-parietal and subcortical networks.
Conclusions:
These results support the idea that the neural regions most susceptible to prenatal chronic inflammation are those associated with behavioral impairments based on existing literature (Morgan et al., 2020; Rudolph et al., 2018). Overall, this suggests that the heightened risk of developmental disorders in children exposed to chronic inflammation before birth may be a result of neuroinflammatory events that occur while they are still in the womb.
Lifespan Development:
Normal Brain Development: Fetus to Adolescence 2
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling 1
Keywords:
Development
FUNCTIONAL MRI
Other - Fetal imaging; Prenatal chronic inflammation
1|2Indicates the priority used for review
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Eggebrecht, A. T., et al. (2017). Joint Attention and Brain Functional Connectivity in Infants and Toddlers. Cerebral Cortex (New York, N.Y.: 1991), 27(3), 1709–1720. https://doi.org/10.1093/cercor/bhw403
Graham, A. M., et al. (2018). Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age. Biological Psychiatry, 83(2), 109–119. https://doi.org/10.1016/j.biopsych.2017.05.027
Morgan, J. E., et al. (2020). Prenatal maternal C-reactive protein prospectively predicts child executive functioning at ages 4–6 years. Developmental Psychobiology, 62(8), 1111–1123. https://doi.org/10.1002/dev.21982
Rudolph, M. D., et al. (2018). Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. Nature Neuroscience, 21(5), 765–772. https://doi.org/10.1038/s41593-018-0128-y
Spann, M. N., et al. (2018). Maternal Immune Activation During the Third Trimester Is Associated with Neonatal Functional Connectivity of the Salience Network and Fetal to Toddler Behavior. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 38(11), 2877–2886. https://doi.org/10.1523/JNEUROSCI.2272-17.2018
Werenberg Dreier, J., et al. (2016). Fever and infections in pregnancy and risk of attention deficit/hyperactivity disorder in the offspring. Journal of Child Psychology