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Inflammation in Pregnant Moms Linked to Child’s Brain Development

Effects on connectivity, wiring, memory, impulse control may predispose for disorders

Science Update

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NIMH-funded researchers are connecting the dots between inflammation in a pregnant human mother and possible effects on her young child’s developing brain. So far, they have linked high levels of maternal inflammation during pregnancy to reduced brain circuit communications and altered long-distance brain wiring at birth, poorer cognitive function at one year – and to reduced impulse control and working memory at two years.

Inflammation and mental illness

Inflammation is part of the body’s normal defense against environmental insults, such as infections. In addition, the body can mount inflammatory responses to a host of factors, including obesity, diet, drugs (e.g., smoking), maternal depression, poverty, and stress.

Such exposures don’t necessarily cause harm, but inflammation in pregnant mothers has been linked to mental disorders in their children. For example, studies suggest that the child of a pregnant mother who catches the flu may run an estimated 4-fold higher risk for developing bipolar disorder and a 3 to 7-fold higher risk for developing schizophrenia. Evidence suggests that the prenatal brain isn’t directly affected by the microorganisms, but rather by the mother’s own inflammatory response to the infection. Research shows maternal inflammation is  also implicated in some cases of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).

Clues from Neuroimaging

Yet, few human studies have explored effects on the developing brain that could boost risk for disorders. Now, the first major trove of such evidence is emerging from brain imaging studies.  The researchers measured blood levels of an inflammatory messenger chemical, IL-6 (interleukin-6), in 84 pregnant mothers – and followed-up with neuroimaging and behavioral assessments of their children. Claudia Buss, Ph.D., of Charité University Medicine Berlin and University of California Irvine, Damien Fair, P.A.-C., Ph.D., of Oregon Health Sciences University (OHSU), and colleagues, reported their latest findings in three recent journal articles (see References below).

“By examining the brain shortly after birth, we were able to distinguish between the influences of prenatal and post-natal environmental factors on the brain’s development,” said Buss.

The researchers first related pregnant human mothers’ IL-6 levels to measures of their newborn’s brain to get a snapshot of how inflammation might affect prenatal development. Buss’s team scanned their brains at rest using magnetic resonance imaging (MRI). Such resting state scans of brain activity have emerged as an index of how effectively brain networks are talking with each other – levels of functional connectivity. The scans also gauged the anatomical maturity of a key long-distance wiring pathway connecting the executive hub and deeper emotion processing regions.

Inflammation, circuit connectivity, working memory

The researchers reported in Nature Neuroscience that higher maternal IL-6 levels were linked to poorer circuit connectivity in newborns and to reduced working memory at age two. Deficient working memory – the ability to hold thoughts mind – marks several mental disorders and is thought to be key to other “executive functions,” such as inhibition and impulse control. Working memory also depends on the same circuits that showed reduced functional connectivity.  

Using artificial intelligence/machine learning technology, the researchers incorporated these findings into a model that makes it possible to infer from a newborn’s MRI scans the mother’s inflammatory state during pregnancy – and, potentially, a forecast of her child’s future working memory ability.

“Measures of the brain at birth can serve as a reliable marker of the earlier environment and a predictor of later function,” explained Julia Zehr, Ph.D., of the NIMH Division of Translational Research. “With better identification of early inflammation markers, we may be able to develop interventions targeted to those individuals who will most benefit.”

Inflammation, “catch-up growth,” cognition

The researchers reported in Neuroimage that higher IL-6 levels in mothers  were associated with sped-up growth in the long-distance wiring pathway during the first year of life.  Evidence suggested that this may reflect a compensatory response to relatively stunted prenatal growth.  Notably, this “catch-up growth” predicted poorer cognitive performance at age one. A similar pattern is often seen in people with ASD, noted the researchers.

Impulse control, emotion center growth

In Biological Psychiatry, Buss and colleagues revealed that maternal IL-6 levels relationship to newborns’ brain function and structure predicted children’s performance on a test of impulse control at age two. Children of mothers with higher IL-6 levels during pregnancy tended to have an anatomically larger and more functionally connected amygdala – an emotion-processing area deep in the brain – which was linked to poorer impulse control at age two.

“IL-6 is critically important for normal brain development, so we definitely wouldn’t want to block it,” noted Buss. “We still need to learn much more about what levels are associated with adverse outcomes. Until then, the focus should be on targeting those conditions in the mother that have been shown to elevate IL-6 concentrations during pregnancy.” 

For More Information, see OHSU press release:
Study confirms that inflammation during pregnancy is linked to baby’s brain

References

Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. Rudolph MD, Graham AM, Feczko E, Miranda-Dominguez O, Rasmussen JM, Nardos R, Entringer S, Wadhwa PD, Buss C, Fair DA. Nat Neurosci. 2018 May;21(5):765-772. doi: 10.1038/s41593-018-0128-y. Epub 2018 Apr 9. PMID: 29632361

Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life. Rasmussen JM, Graham AM, Entringer S, Gilmore JH, Styner M, Fair DA, Wadhwa PD, Buss C. Neuroimage. 2018 Apr 11. pii: S1053-8119(18)30316-1. doi: 10.1016/j.neuroimage.2018.04.020. [Epub ahead of print] Review. PMID:29654875

Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age. Graham AM, Rasmussen JM, Rudolph MD, Heim CM, Gilmore JH, Styner M, Potkin SG, Entringer S, Wadhwa PD, Fair DA, Buss C. Biol Psychiatry. 2018 Jan 15;83(2):109-119. doi: 10.1016/j.biopsych.2017.05.027. Epub 2017 Jun 19. PMID:28754515

Baby brains reflect maternal inflammation. Rosenberg MD. Nat Neurosci. 2018 May;21(5):651-653. doi: 10.1038/s41593-018-0134-0. No abstract available. PMID: 29632358

Grants

MH091351, MH105538, MH096773, MH091238, MH111805, MH105283