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T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation

Maternal mental health alters structure and biochemistry of developing fetal brain

Even when pregnant women have uncomplicated pregnancies and high socioeconomic status, when they experience elevated anxiety, stress or depression these prenatal stressors can alter the structure of the developing fetal brain and disrupt its biochemistry, according to Children’s National Hospital research published online Jan. 29, 2020, in JAMA Network Open.

The Children’s National research findings “have enormous scientific, clinical and public health implications,” Charles A. Nelson III, Ph.D.,  Boston Children’s Hospital, writes in a companion editorial.

“Previously we found that 65% of pregnant women who received a diagnosis of fetal congenital heart disease had elevated levels of stress. It’s concerning but not surprising that pregnant women who wonder if their baby will need open heart surgery would feel stress,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s senior author. “In this latest study, we ran the same panel of questionnaires and were surprised to find a high proportion of otherwise healthy pregnant women whose unborn babies are doing well also report high levels of stress.”

Anxiety and depression are the most common mental health problems during pregnancy. To learn more about the implications for the developing fetal brain, the Children’s National research team recruited 119 healthy volunteers with low-risk pregnancies from obstetric clinics in Washington, D.C., from Jan. 1, 2016, to April 17, 2019. The women’s mean age was 34.4 years old. All were high school graduates, 83% were college graduates, and 84% reported professional employment.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation.

T2-Weighted Magnetic Resonance (MR) Imaging Brain Segmentation. Segmentation results of total brain (orange), cortical gray matter (green), white matter (blue), deep gray matter (brown), brainstem (yellow), cerebellum (light blue), left hippocampus (purple) and right hippocampus (red) on a 3-Dimensional reconstructed T2-weighted MR image of a fetus at 26.4 gestational weeks. The hippocampus plays a central role in memory and behavioral inhibition and contains high concentrations of corticosteroid receptors and, thus, this brain region is sensitive to stress. Credit: JAMA Network Open.

The team performed 193 fetal brain magnetic resonance imaging (MRI) sessions between 24-40 weeks gestation and measured the volume of the total fetal brain as well as the cortical gray matter, white matter, deep gray matter, cerebellum, brainstem and hippocampus volumes. On the same day as their MRI visit, the pregnant women completed validated questionnaires to measure maternal stress, anxiety and depression, answering questions such as “how do you feel right now,” “how do you generally feel” as well as the degree of stressful feelings they experienced the month prior.

Of the pregnant women in the study:

  • 27% tested positive for stress
  • 26% tested positive for anxiety
  • 11% tested positive for depression
  • Maternal anxiety and stress were associated with increased fetal cortical gyrification
  • Elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain
  • Maternal stress scores decreased with increasing gestational age, while anxiety and depression did not

“We report for the first time that maternal psychological distress may be associated with increased fetal local gyrification index in the frontal and temporal lobes,” says Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author. “We also found an association with left fetal hippocampal volume, with maternal psychological distress selectively stunting the left hippocampal volumetric growth more than the right. And elevated maternal depression was associated with decreased creatine and choline levels in the fetal brain,” Wu adds.

Late in pregnancy – at the time these women were recruited into the cohort study – the fetal brain grows exponentially and key metabolite levels also rise. Creatine facilitates recycling of adenosine triphosphate, the cell’s energy currency. Typically, levels of this metabolite rise, denoting rapid changes and higher cellular maturation; creatine also is known to support cognitive function. Choline levels also typically rise, marking cell membrane turnover as new cells are generated and support memory, mental focus and concentration.

“These women were healthy, and of high socioeconomic status and educational level, leading us to conclude that the prevalence of prenatal maternal psychological distress may be underestimated,” Limperopoulos adds. “While stress is an everyday reality for most of us, this is different because elevated stress during pregnancy can alter fetal brain programming. Our findings underscore the critical need to universally screen all pregnant women for prenatal psychological distress, even young mothers whose pregnancies wouldn’t otherwise raise red flags.”

In addition to Limperopoulos and Wu, Children’s National study co-authors include Yuan-Chiao Lu, Ph.D., research associate; Marni Jacobs, Ph.D., biostatistician; Subechhya Pradhan, Ph.D., research faculty; Kushal Kapse, MS, staff engineer; Li Zhao, Ph.D., research faculty; Nickie Niforatos-Andescavage, M.D., neonatologist; Gilbert Vezina, M.D., director of the neuroradiology program; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Research coordinators Catherine Lopez, MS, Kathryn Lee Bannantine, BSN, and Jessica Lynn Quistorff, MPH, assisted with subject recruitment.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. RO1 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

Journal Reference:
Yao Wu, Yuan-Chiao Lu, Marni Jacobs, Subechhya Pradhan, Kushal Kapse, Li Zhao, Nickie Niforatos-Andescavage, Gilbert Vezina, Adré J. du Plessis, Catherine Limperopoulos. “Association of prenatal maternal psychological distress with fetal brain growth, metabolism and cortical maturation,” JAMA Network Open, 3(1): e1919940, 2020

Catherine Limperopoulos

Stressful pregnancies can leave fingerprint on fetal brain

Catherine Limperopoulos

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author.

When a diagnosis of fetal congenital heart disease causes pregnant moms to test positive for stress, anxiety and depression, powerful imaging can detect impaired development in key fetal brain regions, according to Children’s National Hospital research published online Jan. 13, 2020, in JAMA Pediatrics.

While additional research is needed, the Children’s National study authors say their unprecedented findings underscore the need for universal screening for psychological distress as a routine part of prenatal care and taking other steps to support stressed-out pregnant women and safeguard their newborns’ developing brains.

“We were alarmed by the high percentage of pregnant women with a diagnosis of a major fetal heart problem who tested positive for stress, anxiety and depression,” says Catherine Limperopoulos, Ph.D., director of the Center for the Developing Brain at Children’s National and the study’s corresponding author. “Equally concerning is how prevalent psychological distress is among pregnant women generally. We report for the first time that this challenging prenatal environment impairs regions of the fetal brain that play a major role in learning, memory, coordination, and social and behavioral development, making it all the more important for us to identify these women early during pregnancy to intervene,” Limperopoulos adds.

Congenital heart disease (CHD), structural problems with the heart, is the most common birth defect. Still, it remains unclear how exposure to maternal stress impacts brain development in fetuses with CHD.

The multidisciplinary study team enrolled 48 women whose unborn fetuses had been diagnosed with CHD and 92 healthy women with uncomplicated pregnancies. Using validated screening tools, they found:

  • 65% of pregnant women expecting a baby with CHD tested positive for stress
  • 27% of women with uncomplicated pregnancies tested positive for stress
  • 44% of pregnant women expecting a baby with CHD tested positive for anxiety
  • 26% of women with uncomplicated pregnancies tested positive for anxiety
  • 29% of pregnant women expecting a baby with CHD tested positive for depression and
  • 9% women with uncomplicated pregnancies tested positive for depression

All told, they performed 223 fetal magnetic resonance imaging sessions for these 140 fetuses between 21 and 40 weeks of gestation. They measured brain volume in cubic centimeters for the total brain as well as volumetric measurements for key regions such as the cerebrum, cerebellum, brainstem, and left and right hippocampus.

Maternal stress and anxiety in the second trimester were associated with smaller left hippocampi and smaller cerebellums only in pregnancies affected by fetal CHD. What’s more, specific regions — the hippocampus head and body and the left cerebellar lobe – were more susceptible to stunted growth. The hippocampus is key to memory and learning, while the cerebellum controls motor coordination and plays a role in social and behavioral development.

The hippocampus is a brain structure that is known to be very sensitive to stress. The timing of the CHD diagnosis may have occurred at a particularly vulnerable time for the developing fetal cerebellum, which grows faster than any other brain structure in the second half of gestation, particularly in the third trimester.

“None of these women had been screened for prenatal depression or anxiety. None of them were taking medications. And none of them had received mental health interventions. In the group of women contending with fetal CHD, 81% had attended college and 75% had professional educations, so this does not appear to be an issue of insufficient resources,” Limperopoulos adds. “It’s critical that we routinely to do these screenings and provide pregnant women with access to interventions to lower their stress levels. Working with our community partners, Children’s National is doing just that to help reduce toxic prenatal stress for both the health of the mother and for the future newborns. We hope this becomes standard practice elsewhere.”

Adds Yao Wu, Ph.D., a research associate working with Limperopoulos at Children’s National and the study’s lead author: “Our next goal is exploring effective prenatal cognitive behavioral interventions to reduce psychological distress felt by pregnant women and improve neurodevelopment in babies with CHD.”

In addition to Limperopoulos and Wu , Children’s National study co-authors include Kushal Kapse, MS, staff engineer; Marni Jacobs, Ph.D., biostatistician; Nickie Niforatos-Andescavage, M.D., neonatologist; Mary T. Donofrio, M.D., director, Fetal Heart Program; Anita Krishnan, M.D., associate director, echocardiography; Gilbert Vezina, M.D., director, Neuroradiology Program; David Wessel, M.D., Executive Vice President and Chief Medical Officer; and Adré  J. du Plessis, M.B.Ch.B., director, Fetal Medicine Institute. Jessica Lynn Quistorff, MPH, Catherine Lopez, MS, and Kathryn Lee Bannantine, BSN, assisted with subject recruitment and study coordination.

Financial support for the research described in this post was provided by the National Institutes of Health under grant No. R01 HL116585-01 and the Thrasher Research Fund under Early Career award No. 14764.

zika virus

Neuroimaging essential for Zika cases

zika virus

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero.

Seventy-one of 110 Brazilian infants at the highest risk for experiencing problems due to exposure to the Zika virus in the womb experienced a wide spectrum of brain abnormalities, including calcifications and malformations in cortical development, according to a study published July 31, 2019 in JAMA Network Open.

The infants were born at the height of Brazil’s Zika epidemic, a few months after the nation declared a national public health emergency. Already, many of the infants had been classified as having the severe form of congenital Zika syndrome, and many had microcephaly, fetal brain disruption sequence, arthrogryposis and abnormal neurologic exams at birth.

These 110 infants “represented a group of ZIKV-exposed infants who would be expected to have a high burden of neuroimaging abnormalities, which is a difference from other reported cohorts,” Sarah B. Mulkey, M.D., Ph.D., writes in an invited commentary published in JAMA Network Open that accompanies the Rio de Janeiro study. “Fortunately, many ZIKV-exposed infants do not have abnormal brain findings or a clinical phenotype associated with congenital Zika syndrome,” adds Dr. Mulkey, a fetalneonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National in Washington, D.C.

Indeed, a retrospective cohort of 82 women exposed to Zika during their pregnancies led by a research team at Children’s National found only three pregnancies were complicated by severe fetal brain abnormalities. Compared with the 65% abnormal computed tomography (CT) or magnetic resonance imaging (MRI) findings in the new Brazilian study, about 1 in 10 (10%) of babies born to women living in the continental U.S. with confirmed Zika infections during pregnancy had Zika-associated birth defects, according to the Centers for Disease Control and Prevention.

“There appears to be a spectrum of brain imaging abnormalities in ZIKV-exposed infants, including mild, nonspecific changes seen at cranial US [ultrasound], such as lenticulostriate vasculopathy and germinolytic cysts, to more significant brain abnormalities, such as subcortical calcifications, ventriculomegaly and, in its most severe form, thin cortical mantle and fetal brain disruption sequence,” Dr. Mulkey writes.

About three years ago, Zika virus emerged as a newly recognized congenital infection, and a growing body of research indicates the damage it causes differs from other infections that occur in utero. Unlike congenital cytomegalovirus infection, cerebral calcifications associated with Zika are typically subcortical, Dr. Mulkey indicates. What’s more, fetal brain disruption sequence seen in Zika-exposed infants is unusual for other infections that can cause microcephaly.

“Centered on the findings of Pool, et al, and others, early neuroimaging remains one of the most valuable investigations of the Zika-exposed infant,” Dr. Mulkey writes, including infants who are not diagnosed with congenital Zika syndrome.  She recommends:

  • Cranial ultrasound as the first-line imaging option for infants, if available, combined with neurologic and ophthalmologic exams, and brainstem auditory evoked potentials
  • Zika-exposed infants with normal cranial ultrasounds do not need additional imaging unless they experience a developmental disturbance
  • Zika-exposed infants with abnormal cranial ultrasounds should undergo further neuroimaging with low-dose cranial CT or brain MRI.
preterm brain scans

Early lipids in micropreemies’ diets can boost brain growth

preterm brain scans

Segmentation of a preterm brain T2-weighted MRI image at 30 gestational weeks [green=cortical grey matter; blue=white matter; grey=deep grey matter; cyan=lateral ventricle; purple=cerebellum; orange=brainstem; red=hippocampus; yellow=cerebrospinal fluid].

Dietary lipids, already an important source of energy for tiny preemies, also provide a much-needed brain boost by significantly increasing global brain volume as well as increasing volume in regions involved in motor activities and memory, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

“Compared with macronutrients like carbohydrates and proteins, lipid intake during the first month of life is associated with increased overall and regional brain volume for micro-preemies,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and senior author. “Using non-invasive magnetic resonance imaging, we see increased volume in the cerebellum by 2 weeks of age. And at four weeks of life, lipids increase total brain volume and boost regional brain volume in the cerebellum, amygdala-hippocampus and brainstem.”

The cerebellum is involved in virtually all physical movement and enables coordination and balance. The amygdala processes and stores short-term memories. The hippocampus manages emotion and mood. And the brainstem acts like a router, passing messages from the brain to the rest of the body, as well as enabling essential functions like breathing, a steady heart rate and swallowing.

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. babies is born preterm, or before 37 weeks gestation. Regions of the brain that play vital roles in complex cognitive and motor activities experience exponential growth late in pregnancy, making the developing brains of preterm infants particularly vulnerable to injury and impaired growth.

Children’s research faculty examined the impact of lipid intake in the first month of life on brain volumes for very low birth weight infants, who weighed 1,500 grams or less at birth. These micro-preemies are especially vulnerable to growth failure and neurocognitive impairment after birth.

The team enrolled 68 micro-preemies who were 32 weeks gestational age and younger when they were admitted to Children’s neonatal intensive care unit during their first week of life. They measured cumulative macronutrients – carbohydrates, proteins, lipids and calories – consumed by these newborns at 2 and 4 weeks of life. Over years, Limperopoulos’ lab has amassed a large database of babies who were born full-term; this data provides unprecedented insights into normal brain development and will help to advance understanding of brain development in high-risk preterm infants.

“Even after controlling for average weight gain and other health conditions, lipid intake was positively associated with cerebellar and brainstem volumes in very low birthweight preterm infants,” adds Katherine M. Ottolini, the study’s lead author.

According to Limperopoulos, Children’s future research will examine the optimal timing and volume of lipids to boost neurodevelopment for micro-preemies.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Early lipid intake improves brain growth in premature infants.”
    • Saturday, April 27, 2019, 1:15-2:30 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.