Tag Archive for: Andescavage

Newborn baby in a crib

Pioneering research center aims to revolutionize prenatal and neonatal health

Catherine Limperopoulos, Ph.D., was drawn to understanding the developing brain, examining how early adverse environments for a mother can impact the baby at birth and extend throughout its entire lifetime. She has widened her lens – and expanded her team – to create the new Center for Prenatal, Neonatal & Maternal Health Research at Children’s National Hospital.

“Despite the obvious connection between mothers and babies, we know that conventional medicine often addresses the two beings separately. We want to change that,” said Dr. Limperopoulos, who also directs the Developing Brain Institute. “Given the current trajectory of medicine toward precision care and advanced imaging, we thought this was the right moment to channel our talent and resources into understanding this delicate and highly dynamic relationship.”

Moving the field forward

Since its establishment in July 2023, the new research center has gained recognition through high-impact scientific publications, featuring noteworthy studies exploring the early phases of human development.

Dr. Limperopoulos has been at the forefront of groundbreaking research, directing attention to the consequences of maternal stress on the unborn baby and the placenta. In addition, under the guidance of Kevin Cook, Ph.D., investigators published a pivotal study on the correlation between pain experienced by premature infants in the Neonatal Intensive Care Unit and the associated risks of autism and developmental delays.

Another area of research has focused on understanding the impact of congenital heart disease (CHD) on prenatal brain development, given the altered blood flow to the brain caused by these conditions during this period of rapid development. Led by Josepheen De Asis-Cruz, M.D., Ph.D., a research team uncovered variations in the functional connectivity of the brains of infants with CHD. In parallel, Nickie Andescavage, M.D., and her team employed advanced imaging techniques to identify potential biomarkers in infants with CHD, holding promise for guiding improved diagnostics and postnatal care. Separately, she is investigating the impact of COVID-19 on fetal brain development.

In the months ahead, the team plans to concentrate its efforts on these areas and several others, including the impact of infectious disease, social determinants of health and protecting developing brains from the negative impacts of maternal stress, pre-eclampsia and other conditions prevalent among expectant mothers.

Assembling a team

Given its robust research plan and opportunities for collaboration, the center pulled together expertise from across the hospital’s faculty and has attracted new talent from across the country, including several prominent faculty members:

  • Daniel Licht, M.D., has joined Children’s National to build a noninvasive optical device research group to better care for children with CHD. Dr. Licht brings decades of experience in pediatric neurology, psychiatry and critical care and is recognized internationally for his expertise in neurodevelopmental outcomes in babies with CHD.
  • Katherine L. Wisner, M.S., M.D., has accumulated extensive knowledge on the impact of maternal stress on babies throughout her career, and her deep background in psychiatry made her a natural addition to the center. While Dr. Wisner conducts research into the urgent need to prioritize maternal mental health, she will also be treating mothers as part of the DC Mother-Baby Wellness Initiative — a novel program based at Children’s National that allows mothers to more seamlessly get care for themselves and participate in mother-infant play groups timed to align with their clinical appointments.
  • Catherine J. Stoodley, B.S., M.S., D.Phil., brings extensive research into the role of the cerebellum in cognitive development. Dr. Stoodley uses clinical studies, neuroimaging, neuromodulation and behavioral testing to investigate the functional anatomy of the part of the brain responsible for cognition.
  • Katherine M. Ottolini, M.D., attending neonatologist, is developing NICU THRIVE – a research program studying the effects of tailored nutrition on the developing newborn brain, including the impact of fortifying human milk with protein, fat and carbohydrates. With a grant from the Gerber Foundation, Dr. Ottolini is working to understand how personalized fortification for high-risk babies could help them grow.

Early accolades

The new center brings together award-winning talent. This includes Yao Wu, Ph.D., who recently earned the American Heart Association’s Outstanding Research in Pediatric Cardiology award for her groundbreaking work in CHD, particularly for her research on the role of altered placental function and neurodevelopmental outcomes in toddlers with CHD. Dr. Wu became the third Children’s National faculty member to earn the distinction, joining an honor roll that includes Dr. Limperopoulos and David Wessel, M.D., executive vice president and chief medical officer.

Interim Chief Academic Officer Catherine Bollard, M.D., M.B.Ch.B., said the cross-disciplinary collaboration now underway at the new center has the potential to make a dramatic impact on the field of neonatology and early child development. “This group epitomizes the Team Science approach that we work tirelessly to foster at Children’s National,” Dr. Bollard said. “Given their energetic start, we know these scientists and physicians are poised to tackle some of the toughest questions in maternal-fetal medicine and beyond, which will improve outcomes for our most fragile patients.”

pregnant woman talking to doctor

Prenatal COVID exposure associated with changes in newborn brain

pregnant woman talking to doctor

The team found differences in the brains of both infants whose mothers were infected with COVID while pregnant, as well as those born to mothers who did not test positive for the virus.

Babies born during the COVID-19 pandemic have differences in the size of certain structures in the brain, compared to infants born before the pandemic, according to a new study led by researchers at Children’s National Hospital.

The team found differences in the brains of both infants whose mothers were infected with COVID while pregnant, as well as those born to mothers who did not test positive for the virus, according to the study published in Cerebral Cortex.

The findings suggest that exposure to the coronavirus and being pregnant during the pandemic could play a role in shaping infant brain development, said Nickie Andescavage, M.D., the first author of the paper and associate chief for the Developing Brain Institute at Children’s National.

The fine print

The study’s authors looked at three groups of infants: 108 born before the pandemic; 47 exposed to COVID before birth; and 55 unexposed infants. In all cases, researchers performed magnetic resonance imaging (MRI) scans of the newborns’ brains during the first few weeks of life. The MRI scans, which are non-invasive and do not expose patients to radiation, provided 3D images of the brain, allowing doctors to calculate the volume of different areas.

Researchers found several differences in the brains of babies exposed to COVID. They had larger volumes of the gray matter that makes up the brain’s outermost layer, compared to the two other groups. In contrast, an inner area of the brain, known as deep gray matter, was smaller than in unexposed babies. These are areas that contain large numbers of neurons that generate and process signals throughout the brain. “Their brains formed differently if they were exposed to COVID,” said Dr. Andescavage, adding that “those exposed to COVID had unique signatures” in the brain.

Doctors also measured the depths of the folds in the babies’ brains – a way to determine how the brain is maturing during early development. Babies born to mothers who had COVID in pregnancy had deeper grooves in the frontal lobe, while babies born during the pandemic – even without being exposed to COVID – had increased folds and grooves throughout the brain, compared to babies born before the pandemic. “There was something about being born during the pandemic that changed how the brain developed,” Dr. Andescavage said.

What’s ahead

The study authors can’t fully explain what caused the differences in brain development in these babies, Dr. Andescavage said. But other studies have linked maternal stress and depression to changes in the newborn brain. In a future study, Dr. Andescavage and her colleagues will examine the relationship between infant brain development and how stress and anxiety during the pandemic may have played a role in early development.

Because the babies in the study were just a few weeks old, researchers don’t know if their altered brain development will affect how they learn or behave. Researchers plan to follow the children until age 6, allowing them to observe whether pandemic-era babies hit key developmental milestones on time, such as walking, talking, holding a crayon and learning the alphabet.

Researchers have been worried about the effect of COVID on the fetus since the beginning of the pandemic. Studies show that babies exposed to COVID in the womb may experience developmental impacts, and research is underway to better understand long-term outcomes.

Although the coronavirus rarely crosses the placenta to infect the fetus directly, there are other ways maternal infection can influence the developing baby. Dr. Andescavage said inflammation is one potential harm to a developing baby. In addition, if a pregnant woman becomes so sick that the levels of oxygen in her blood fall significantly, that can deprive the fetus of oxygen, she added.

In recent decades, studies of large populations have found that maternal infections with influenza and other viruses increased the risk of serious problems in children even years later, including autism, attention deficit hyperactivity disorder and schizophrenia, although the reasons behind the association are not well understood. Technology may allow doctors to answer a number of questions about COVID and the infant brain.

“With advanced imaging and MRI, we’re in a position now to be able to understand how the babies are developing in ways we never previously could,” Dr. Andescavage said. “That will better allow us to identify the exposures that may be harmful, and at what times babies may be especially vulnerable, to better position us to promote maternal wellness. This, in turn, helps infant wellness.”

Catherine Limperopoulos

Imaging reveals altered brain chemistry of babies with CHD

Researchers at Children’s National Hospital used magnetic resonance spectroscopy to find new biomarkers that reveal how congenital heart disease (CHD) changes an unborn baby’s brain chemistry, providing early clues that could someday guide treatment decisions for babies facing lifelong health challenges.

Published in the Journal of the American College of Cardiology, the findings detail the ways that heart defects disrupt metabolic processes in the developing brain, especially during the third trimester of pregnancy when babies grow exponentially.

“Over the past decade, our team has been at the forefront of developing safe and sophisticated ways to measure and monitor fetal brain health in the womb,” said Catherine Limperopoulos, Ph.D., director of the Center for Prenatal, Neonatal and Maternal Health Research at Children’s National. “By tapping into the power of advanced imaging, we were able to measure certain maturational components of the brain to find early biomarkers for newborns who are going to struggle immediately after birth.”

The fine print

In one of the largest cohorts of CHD patients assembled to date, researchers at Children’s National studied the developing brains of 221 healthy unborn babies and 112 with CHD using magnetic resonance spectroscopy, a noninvasive diagnostic test that can examine chemical changes in the brain. They found:

  • Those with CHD had higher levels of choline and lower levels of N-Acetyl aspartate-to-choline ratios compared to healthy babies, potentially representing disrupted brain development.
  • Babies with more complex CHD also had higher levels of cerebral lactate compared to babies with two ventricle CHD. Lactate, in particular, is a worrying signal of oxygen deprivation.

Specifically, elevated lactate levels were notably increased in babies with two types of heart defects: transposition of the great arteries, a birth defect in which the two main arteries carrying blood from the heart are switched in position, and single ventricle CHD, a birth defect causing one chamber to be smaller, underdeveloped or missing a valve. These critical heart defects generally require babies to undergo heart surgery not long after birth. The elevated lactate levels also were associated with an increased risk of death, highlighting the urgency needed for timely and effective interventions.

The research suggests that this type of imaging can provide a roadmap for further investigation and hope that medicine will someday be able to better plan for the care of these children immediately after their delivery. “With important clues about how a fetus is growing and developing, we can provide better care to help these children not only survive, but thrive, in the newborn period and beyond,” said Nickie Andescavage, M.D., Children’s National neonatologist and first author on the paper.

The big picture

CHD is the most common birth defect in the United States, affecting about 1% of all children born or roughly 40,000 babies each year. While these defects can be fatal, babies who survive are known to be at significantly higher risk of lifelong neurological deficits, including lower cognitive function, poor social interaction, inattention and impulsivity. The impact can also be felt in other organ systems because their hearts did not pump blood efficiently to support development.

Yet researchers are only beginning to pinpoint the biomarkers that can provide information about which babies are going to struggle most and require higher levels of care. The National Institutes of Health (NIH) and the District of Columbia Intellectual and Developmental Disabilities Research Center supported the research at Children’s National to improve this understanding.

“For many years we have known that the brains of children with severe heart problems do not always develop normally, but new research shows that abnormal function occurs already in the fetus,” said Kathleen N. Fenton, M.D., M.S., chief of the Advanced Technologies and Surgery Branch in the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI). “Understanding how the development and function of the brain is already different before a baby with a heart defect is born will help us to intervene with personal treatment as early as possible, perhaps even prenatally, and improve outcomes.”

Note: This research and content are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The NIH provided support for this research through NHLBI grant R01HL116585 and the Eunice Kennedy Shriver National Institute of Child Health and Human Development grant P50HD105328.

doctor examining pregnant woman

Low parental socioeconomic status alters brain development in unborn babies

doctor examining pregnant woman

A first-of-its-kind study with 144 pregnant women finds that socioeconomic status (SES) has an impact in the womb, altering several key regions in the developing fetal brain as well as cortical features.

Maternal socioeconomic status impacts babies even before birth, emphasizing the need for policy interventions to support the wellbeing of pregnant women, according to newly published research from Children’s National Hospital.

A first-of-its-kind study with 144 pregnant women finds that socioeconomic status (SES) has an impact in the womb, altering several key regions in the developing fetal brain as well as cortical features. Parental occupation and education levels encompassing populations with lower SES hinder early brain development, potentially affecting neural, social-emotional and cognitive function later in the infant’s life.

Having a clear understanding of early brain development can also help policymakers identify intervention approaches such as educational assistance and occupational training to support and optimize the well-being of people with low SES since they face multiple psychological and physical stressors that can influence childhood brain development, Lu et al. note in the study published in JAMA Network Open.

“While there has been extensive research about the interplay between socioeconomic status and brain development, until now little has been known about the exact time when brain development is altered in people at high-risk for poor developmental outcomes,” said Catherine Limperopoulos, Ph.D., director of the Developing Brain Institute and senior author. “There are many reasons why these children can be vulnerable, including high rates of maternal prenatal depression and anxiety. Later in life, these children may experience conduct disorders and impaired neurocognitive functions needed to acquire knowledge, which is the base to thrive in school, work or life.”

The findings suggest that fetuses carried by women with low socioeconomic backgrounds had decreased regional brain growth and accelerated brain gyrification and surface folding patterns on the brain. This observation in lower SES populations may in part be explained by elevated parental stress and may be associated with neuropsychiatric disorders and mental illness later in life.

In contrast, fetuses carried by women with higher education levels, occupation and SES scores showed an increased white matter, cerebellar and brainstem volume during the prenatal period, and lower gyrification index and sulcal depth in the parietal, temporal and occipital lobes of the brain. These critical prenatal brain growth and development processes lay the foundation for normal brain function, which ready the infant for life outside the womb, enabling them to attain key developmental milestones after birth, including walking, talking, learning and social skills.

There is also a knowledge gap in the association between socioeconomic status and fetal cortical folding — when the brain undergoes structural changes to create sulcal and gyral regions. The study’s findings of accelerated gyrification in low SES adds to the scientific record, helping inform future research, Limperopoulos added.

The Children’s National research team gathered data from 144 healthy women at 24 to 40 weeks gestation with uncomplicated pregnancies. To establish the parameters for socioeconomic status, which included occupation and education in lieu of family income, parents completed a questionnaire at the time of each brain magnetic resonance imaging (MRI) visit. The researchers used MRI to measure fetal brain volumes, including cortical gray matter, white matter, deep gray matter, cerebellum and brain stem. Out of the 144 participants, the scientists scanned 40 brain fetuses twice during the pregnancy, and the rest were scanned once. The 3-dimensional computational brain models among healthy fetuses helped determine fetal brain cortical folding.

Potential proximal risk factors like maternal distress were also measured in the study using a questionnaire accounting for 60% of the participants but, according to the limited data available, there was no significant association with low and high socioeconomic status nor brain volume and cortical features.

Authors in the study from Children’s National include: Yuan-Chiao Lu, Ph.D., Kushal Kapse, M.S., Nicole Andersen, B.A., Jessica Quistorff, M.P.H., Catherine Lopez, M.S., Andrea Fry, B.S., Jenhao Cheng, Ph.D., Nickie Andescavage, M.D., Yao Wu, Ph.D., Kristina Espinosa, Psy.D., Gilbert Vezina, M.D., Adre du Plessis, M.D., and Catherine Limperopoulos, Ph.D.

Associations Between Resting State Functional Connectivity and Behavior in the Fetal Brain

Maternal anxiety affects the fetal brain

Associations Between Resting State Functional Connectivity and Behavior in the Fetal Brain

Anxiety in gestating mothers appears to affect the course of brain development in their fetuses, changing neural connectivity in the womb, a new study suggests.

Anxiety in gestating mothers appears to affect the course of brain development in their fetuses, changing neural connectivity in the womb, a new study by Children’s National Hospital researchers suggests. The findings, published Dec. 7, 2020, in JAMA Network Open, could help explain longstanding links between maternal anxiety and neurodevelopmental disorders in their children and suggests an urgent need for interventions to diagnose and decrease maternal stress.

Researchers have shown that stress, anxiety or depression in pregnant mothers is associated not only with poor obstetric outcomes but also social, emotional and behavioral problems in their children. Although the care environment after birth complicates the search for causes, postnatal imaging showing significant differences in brain anatomy has suggested that these problems may originate during gestation. However, direct evidence for this phenomenon has been lacking, says Catherine Limperopoulos, Ph.D., director of the Developing Brain Institute at Children’s National.

To help determine where these neurological changes might get their start, Dr. Limperopoulos, along with staff scientist Josepheen De Asis-Cruz, M.D., Ph.D., and their Children’s National colleagues used a technique called resting-state functional magnetic resonance imaging (rs-fMRI) to probe developing neural circuitry in fetuses at different stages of development in the late second and third trimester.

The researchers recruited 50 healthy pregnant volunteers from low-risk prenatal clinics in the Washington, D.C. area who were serving as healthy “control” volunteers in a larger study on fetal brain development in complex congenital heart disease. These study participants, spanning between 24 and 39 weeks in their pregnancies, each filled out widely used and validated questionnaires to screen for stress, anxiety and depression. Then, each underwent brain scans of their fetuses that showed connections between discrete areas that form circuits.

After analyzing rs-fMRI results for their fetuses, the researchers found that those with higher scores for either form of anxiety were more likely to carry fetuses with stronger connections between the brainstem and sensorimotor areas, areas important for arousal and sensorimotor skills, than with lower anxiety scores. At the same time, fetuses of pregnant women with higher anxiety were more likely to have weaker connections between the parieto-frontal and occipital association cortices, areas involved in executive and higher cognitive functions.

“These findings are pretty much in keeping with previous studies that show disturbances in connections reported in the years and decades after birth of children born to women with anxiety,” says Dr. De Asis-Cruz. “That suggests a form of altered fetal programming, where brain networks are changed by this elevated anxiety even before babies are born.”

Whether these effects during gestation themselves linger or are influenced by postnatal care is still unclear, adds Dr. Limperopoulos. Further studies will be necessary to follow children with these fetal differences in neural connectivity to determine whether these variations in neural circuitry development can predict future problems. In addition, it’s unknown whether easing maternal stress and anxiety can avoid or reverse these brain differences. Dr. Limperopoulos and her colleagues are currently studying whether interventions that reduce stress could alter the trajectory of fetal neural development.

In the meantime, she says, these findings emphasize the importance of making sure pregnant women have support for mental health issues, which helps ensure current and future health for both mothers and babies.

“Mental health problems remain taboo, especially in the peripartum period where the expectation is that this is a wonderful time in a woman’s life. Many pregnant mothers aren’t getting the support they need,” Dr. Limperopoulos says. “Changes at the systems level will be necessary to chip away at this critical public health problem and make sure that both mothers and babies thrive in the short and long term.”

Other Children’s National researchers who contributed to this study include Dhineshvikram Krishnamurthy, M.S., software engineer; Li Zhao, Ph.D., research faculty; Kushal Kapse, M.S., staff engineer; Gilbert Vezina, M.D., neuroradiologist; Nickie Andescavage, M.D., neonatologist; Jessica Quistorff, M.P.H., clinical research program lead; and Catherine Lopez, M.S., clinical research program coordinator.

This study was funded by R01 HL116585-01 from the National Heart, Lung, and Blood Institute and U54HD090257 from the Intellectual and Developmental Disabilities Research Center.

doctor checking pregnant woman's belly

Novel approach to detect fetal growth restriction

doctor checking pregnant woman's belly

Morphometric and textural analyses of magnetic resonance imaging can point out subtle architectural deviations associated with fetal growth restriction during the second half of pregnancy, a first-time finding that has the promise to lead to earlier intervention.

Morphometric and textural analyses of magnetic resonance imaging (MRI) can point out subtle architectural deviations that are associated with fetal growth restriction (FGR) during the second half of pregnancy. The first-time finding hints at the potential to spot otherwise hidden placental woes earlier and intervene in a more timely fashion, a research team led by Children’s National Hospital faculty reports in Pediatric Research.

“We found reduced placental size, as expected, but also determined that the textural metrics are accelerated in FGR when factoring in gestational age, suggesting premature placental aging in FGR,” says Nickie Andescavage, M.D., a neonatologist at Children’s National and the study’s lead author. “While morphometric and textural features can discriminate placental differences between FGR cases with and without Doppler abnormalities, the pattern of affected features differs between these sub-groups. Of note, placental insufficiency with abnormal Doppler findings have significant differences in the signal-intensity metrics, perhaps related to differences of water content within the placenta.”

The placenta, an organ shared by the pregnant woman and the developing fetus, delivers oxygen and nutrients to the developing fetus and ferries away waste products. Placental insufficiency is characterized by a placenta that develops poorly or is damaged, impairing blood flow, and can result in still birth or death shortly after birth. Surviving infants may be born preterm or suffer early brain injury; later in life, they may experience cardiovascular, metabolic or neuropsychiatric problems.

Because there are no available tools to help clinicians identify small but critical changes in placental architecture during pregnancy, placental insufficiency often is found after some damage is already done. Typically, it is discovered when FGR is diagnosed, when a fetus weighs less than 9 of 10 fetuses of the same gestational age.

“There is a growing appreciation for the prenatal origin of some neuropsychiatric disorders that manifest years to decades later. Those nine months of gestation very much define the breath of who we later become as adults,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and the study’s senior author. “By identifying better biomarkers of fetal distress at an earlier stage in pregnancy and refining our imaging toolkit to detect them, we set the stage to be able to intervene earlier and improve children’s overall outcomes.”

The research team studied 32 healthy pregnancies and compared them with 34 pregnancies complicated by FGR. These women underwent up to two MRIs between 20 weeks to 40 weeks gestation. They also had abdominal circumference, fetal head circumference and fetal femur length measured as well as fetal weight estimated.

In pregnancies complicated by FGR, placentas were smaller, thinner and shorter than uncomplicated pregnancies and had decreased placental volume. Ten of 13 textural and morphometric features that differed between the two groups were associated with absolute birth weight.

“Interestingly, when FGR is diagnosed in the second trimester, placental volume, elongation and thickness are significantly reduced compared with healthy pregnancies, whereas the late-onset of FGR only affects placental volume,” Limperopoulos adds. “We believe with early-onset FGR there is a more significant reduction in the developing placental units that is detected by gross measures of size and shape. By the third trimester, the overall shape of the placenta seems to have been well defined so that primarily volume is affected in late-onset FGR.”

In addition to Dr. Andescavage and Limperopoulos, study co-authors include Sonia Dahdouh, Sayali Yewale, Dorothy Bulas, M.D., chief of the Division of Diagnostic Imaging and Radiology, and Biostatistician, Marni Jacobs, Ph.D., MPH, all of Children’s National; Sara Iqbal, of MedStar Washington Hospital Center; and Ahmet Baschat, of Johns Hopkins Center for Fetal Therapy.

Financial support for research described in this post was provided by the National Institutes of Health under award number 1U54HD090257, R01-HL116585, UL1TR000075 and KL2TR000076, and the Clinical-Translational Science Institute-Children’s National.

Nickie Andescavage

To understand the preterm brain, start with the fetal brain

Nickie Andescavage

“My best advice to future clinician-scientists is to stay curious and open-minded; I doubt I could have predicted my current research interest or described the path between the study of early oligodendrocyte maturation to in vivo placental development, but each experience along the way – both academic and clinical – has led me to where I am today,” Nickie Andescavage, M.D., writes.

Too often, medical institutions erect an artificial boundary between caring for the developing fetus inside the womb and caring for the newborn whose critical brain development continues outside the womb.

“To improve neonatal outcomes, we must transform our current clinical paradigms to begin treatment in the intrauterine period and continue care through the perinatal transition through strong collaborations with obstetricians and fetal-medicine specialists,” writes Nickie Andescavage, M.D., an attending in Neonatal-Perinatal Medicine at Children’s National.

Dr. Andescavage’s commentary was published online March 25, 2019, in Pediatrics Research and accompanies recently published Children’s research about differences in placental development in the setting of placental insufficiency. Her commentary is part of a new effort by Nature Publishing Group to spotlight research contributions from early career investigators.

The placenta, an organ shared by a pregnant woman and the developing fetus, plays a critical but underappreciated role in the infant’s overall health. Under the mentorship of Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain, and Adré J. du Plessis, M.B.Ch.B., MPH, chief of the Division of Fetal and Transitional Medicine, Dr. Andescavage works with interdisciplinary research teams at Children’s National to help expand that evidence base. She has contributed to myriad published works, including:

While attending Cornell University as an undergraduate, Dr. Andescavage had an early interest in neuroscience and neurobehavior. As she continued her education by attending medical school at Columbia University, she corroborated an early instinct to work in pediatrics.

It wasn’t until the New Jersey native began pediatric residency at Children’s National that those complementary interests coalesced into a focus on brain autoregulation and autonomic function in full-term and preterm infants and imaging the brains of both groups. In normal, healthy babies the autonomic nervous system regulates heart rate, blood pressure, digestion, breathing and other involuntary activities. When these essential controls go awry, babies can struggle to survive and thrive.

“My best advice to future clinician-scientists is to stay curious and open-minded; I doubt I could have predicted my current research interest or described the path between the study of early oligodendrocyte maturation to in vivo placental development, but each experience along the way – both academic and clinical – has led me to where I am today,” Dr. Andescavage writes in the commentary.

Breastfeeding Mom

Breast milk helps white matter in preemies

Breastfeeding Mom

Critical white matter structures in the brains of babies born prematurely at low birth weight develop more robustly when their mothers breast-feed them, compared with preemies fed formula.

Breast-feeding offers a slew of benefits to infants, including protection against common childhood infections and potentially reducing the risk of chronic health conditions such as asthma, obesity and type 2 diabetes. These benefits are especially important for infants born prematurely, or before 37 weeks gestation – a condition that affects 1 in 10 babies born in the United States, according to the Centers for Disease Control and Prevention. Prematurely born infants are particularly vulnerable to infections and other health problems.

Along with the challenges premature infants face, there is a heightened risk for neurodevelopmental disabilities that often do not fully emerge until the children enter school. A new study by Children’s National Health System researchers shows that breast-feeding might help with this problem. The findings, presented at the 2017 annual meeting of the Pediatric Academic Societies, show that critical white matter structures in the brains of babies born so early that they weigh less than 1,500 grams develop more robustly when their mothers breast-feed them, compared with preemie peers who are fed formula.

The Children’s National research team used sophisticated imaging tools to examine brain development in very low birth weight preemies, who weighed about 3 pounds at birth.

They enrolled 37 babies who were no more than 32 weeks gestational age at birth and were admitted to Children’s neonatal intensive care unit within the first 48 hours of life. Twenty-two of the preemies received formula specifically designed to meet the nutritional needs of infants born preterm, while 15 infants were fed breast milk. The researchers leveraged diffusion tensor imaging – which measures organization of the developing white matter of the brain – and 3-D volumetric magnetic resonance imaging (MRI) to calculate brain volume by region, structure and tissue type, such as cortical gray matter, white matter, deep gray matter and cerebellum.

“We did not find significant differences in the global and regional brain volumes when we conducted MRIs at 40 weeks gestation in both groups of prematurely born infants,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory and senior author of the paper. “There are striking differences in white matter microstructural organization, however, with greater fractional anisotropy in the left posterior limb of internal capsule and middle cerebellar peduncle, and lower mean diffusivity in the superior cerebellar peduncle.”

White matter lies under the gray matter cortex, makes up about half of the brain’s volume, and is a critical player in human development as well as in neurological disorders. The increased white matter microstructural organization in the cerebral and cerebellar white matter suggests more robust fiber tracts and microarchitecture of the developing white matter which may predict better neurologic outcomes in preterm infants. These critical structures that begin to form in the womb are used for the rest of the person’s life when, for instance, they attempt to master a new skill.

“Previous research has linked early breast milk feeding with increased volumetric brain growth and improved cognitive and behavioral outcomes,” she says. “These very vulnerable preemies already experience a high incidence rate of neurocognitive dysfunction – even if they do not have detectable structural brain injury. Providing them with breast milk early in life holds the potential to lessen those risks.”

The American Academy of Pediatrics endorses breast-feeding because it lowers infants’ chances of suffering from ear infections and diarrhea in the near term and decreases their risks of being obese as children. Limperopoulos says additional studies are needed in a larger group of patients as well as longer-term follow up as growing infants babble, scamper and color to gauge whether there are differences in motor skills, cognition and writing ability between the two groups.

Catherine Limperopoulous

The brain’s fluid-filled spaces during growth

Catherine Limperopoulous

Catherine Limperopoulous, Ph.D., and her colleagues used volumetric MRIs to assess how the ventricles, cerebrospinal fluid and the rest of the fetal brain normally change over time.

The human brain is not one solid mass. Buried within its gray and white matter are a series of four interconnected chambers, called ventricles, which produce cerebrospinal fluid. These ventricles are readily apparent on the fetal ultrasounds that have become the standard of prenatal care in the United States and most developed countries around the world. Abnormalities in the ventricles’ size or shape – or both – can give doctors an early warning that fetal brain development might be going awry.

But what is abnormal? It is not always clear, says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National Health System. Limperopoulos explains that despite having many variations in fetal ventricles, some infants have completely normal neurodevelopmental outcomes later. On the other hand, some extremely subtle variations in shape and size can signal problems.

On top of these complications are the tools clinicians typically use to assess the ventricles. Limperopoulos explains that most early indications of ventricle abnormalities come from ultrasounds, but the finer resolution of magnetic resonance imaging (MRI) can provide a more accurate assessment of fetal brain development. Still, both standard MRI and ultrasound provide only two-dimensional pictures, making it difficult to quantify slight differences in the volume of structures.

To help solve these problems, Limperopoulos and her colleagues recently published a paper in Developmental Neuroscience that takes a different tack. The team performed volumetric MRIs – a technique that provides a precise three-dimensional measure of structural volumes – on the brains of healthy fetuses to assess how the ventricles, cerebrospinal fluid and the rest of the brain normally change over time. Limperopoulos’ team recently performed a similar study to assess normal volumetric development in the brain’s solid tissues.

Previous studies published on comparable topics typically used information gathered from subjects who initially had clinical concerns but eventually were dismissed from these studies for not having worrisome diagnoses in the end. This might not truly reflect a typical population of pregnant women, Limperopoulos says.

Working with 166 pregnant women with healthy pregnancies spanning from 18 to 40 weeks gestation, the researchers performed volumetric MRIs on their singleton fetuses that covered every week of this second half of pregnancy. This technique allowed them to precisely calculate the volumes of structures within the fetal brain and get an idea of how these volumes changed over time within the group.

Their results show that over the second and third trimester:

  • The lateral ventricles, the largest ventricles found in the cerebrum with one for each brain hemisphere, grew about two-fold;
  • The third ventricle, found in the forebrain, grew about 23-fold;
  • The fourth ventricle, found in the hindbrain, grew about eight-fold;
  • And the extra-axial cerebrospinal fluid, found under the lining of the brain, increased about 11-fold.

The total brain volume increased 64-fold over this time, with the parenchyma – the solid brain tissue that encompasses gray and white matter – growing significantly faster than the cerebrospinal fluid-filled spaces.

Limperopoulos points out that the ability to measure the growth of the brain’s fluid-filled spaces relative to the surrounding brain tissue can provide critical information to clinicians caring for developing fetuses. In most cases, knowing what is normal allows doctors to reassure pregnant women that their fetus’ growth is on track. Abnormalities in these ratios can provide some of the first signals to alert doctors to blockages in cerebrospinal fluid flow, abnormal development, or the loss of brain tissue to damage or disease. Although the neurodevelopmental outcomes from each of these conditions can vary significantly, traditional ultrasounds or MRIs might not be able to distinguish these possibilities from each other. Being able to differentiate why cerebrospinal fluid spaces have abnormal shapes or sizes might allow doctors to better counsel parents, predict neurological outcomes, or potentially intervene before or after birth to mitigate brain damage.

“By developing a better understanding of what’s normal,” Limperopoulos says, “we can eventually identify reliable biomarkers of risk and guide interventions to minimize risks for vulnerable fetuses.”

Setting a baseline for healthy brain development

Catherine Limperopoulos, Ph.D., and colleagues performed the largest magnetic resonance imaging study of normal fetal brains in the second and third trimesters of pregnancy.

Starting as a speck barely visible to the naked eye and ending the in utero phase of its journey at an average weight of 7.5 pounds, the growth of the human fetus is one of the most amazing events in biology. Of all the organs, the fetal brain undergoes one of the most rapid growth trajectories, expanding over 40 weeks from zero to 100 billion neurons — about as many brain cells as there are stars in the Milky Way Galaxy.

This exponential growth is part of what gives humans our unique abilities to use language or have abstract thoughts, among many other cognitive skills. It also leaves the brain extremely vulnerable should disruptions occur during fetal development. Any veering off the developmental plan can lead to a cascade of results that have long-lasting repercussions. For example, studies have shown that placental insufficiency, or the inability of the placenta to supply the fetus with oxygen and nutrients in utero, is associated with attention deficit hyperactivity disorder, autism, and schizophrenia.

Recent research has identified differences in the brains of people with these disorders compared with those without. Despite the almost certain start of these conditions within the womb, they have remained impossible to diagnose until children begin to show clinical symptoms. If only researchers could spot the beginnings of these problems early in development, says Children’s National Health System researcher Catherine Limperopoulos, Ph.D., they might someday be able to develop interventions that could turn the fetal brain back toward a healthy developmental trajectory.

“Conventional tools like ultrasound and magnetic resonance imaging (MRI) can identify structural brain abnormalities connected to these problems, but by the time these differences become apparent, the damage already has been done,” Limperopoulos says. “Our goal is to be able to pick up very early deviations from normal in the high-risk pregnancy before an injury to the fetus might become permanent.”

Before scientists can recognize abnormal, she adds, they first need to understand what normal looks like.

In a new study published in Cerebral Cortex, Limperopoulos and colleagues begin to tackle this question through the largest MRI study of normal fetal brains in the second and third trimesters of pregnancy. While other studies have attempted to track normal fetal brain growth, that research has not involved nearly as many subjects and typically relied on data collected when fetuses were referred for MRIs for a suspected problem. When the suspected abnormality was ruled out by the scan, these “quasi-controls” were considered “normal” — even though they may be at risk for problems later in life, Limperopoulos explains.

By contrast, the study she led recruited 166 healthy pregnant women from nearby low-risk obstetrics practices. Each woman had an unremarkable singleton pregnancy and ended up having a normal full-term delivery, with no evidence of problems affecting either the mother or fetus over the course of 40 weeks.

At least one time between 18 and 39 gestational weeks, the fetuses carried by these women underwent an MRI scan of their brains. The research team developed complex algorithms to account for movement (since neither the mothers nor their fetuses were sedated during scans) and to convert the two-dimensional images into three dimensions. They used the information from these scans to measure the increasing volumes of the cerebellum, an area of the brain connected to motor control and known to mediate cognitive skills; as well as regions of the cerebrum, the bulk of the brain, that is pivotal for movement, sensory processing, olfaction, language, and learning and memory.

Their results in uncomplicated, full-term pregnancies show that over 21 weeks in the second half of pregnancy, the cerebellum undergoes an astounding 34-fold increase in size. In the cerebrum, the fetal white matter, which connects various brain regions, grows 22-fold. The cortical gray matter, key to many of cerebrum’s functions, grows 21-fold. And the deep subcortical structures (thalamus and basal ganglia), important for relaying sensory information and coordination of movement and behavior, grow 10-fold. Additional examination showed that the left hemisphere has a larger volume than the right hemisphere early in development, but sizes of the left and right brain halves were equal by birth.

By developing similar datasets on high-risk pregnancies or births—for example, those in which fetuses are diagnosed with a problem in utero, mothers experience a significant health problem during pregnancy, babies are born prematurely, or fetuses have a sibling diagnosed with a health problem with genetic risk, such as autism—Limperopoulos says that researchers might be able to spot differences during gestation and post-natal development that lead to conditions such as schizophrenia, attention deficit hyperactivity disorder and autism spectrum disorder.

Eventually, researchers may be able to develop fixes so that babies grow up without life-long developmental issues.

“Understanding ‘normal’ is really opening up opportunities for us to begin to precisely pinpoint when things start to veer off track,” Limperopolous says. “Once we do that, opportunities that have been inaccessible will start to present themselves.”

Using 3-D MRI for fetal brain imaging during high-risk pregnancies

3DMRI

What’s Known
The placenta plays an essential role in the growth of a healthy fetus and, among other critical tasks, it ferries in oxygen and nutrients. During pregnancies complicated by fetal growth restriction (FGR), the failing placenta cannot support the developing fetus adequately. FGR is a major cause of stillbirth and death, and newborns who do survive face numerous risks for multiple types of ailments throughout their lives. In fact, studies have shown that nutrient depravation during gestation can have lasting consequences that may manifest themselves years or decades later in life. These risks can also cross generations, affecting future pregnancies.

What’s New
A team of researchers applied an advanced imaging technique, three-dimensional (3-D) MRI, to study brain development in these high-risk pregnancies. They are the first to report regional, tissue-specific volume delays for the developing fetal brain in FGR-affected pregnancies. The team compared overall fetal brain volume as well as regional brain volumes for a control group of healthy young pregnant women with a group of young women whose pregnancies were complicated by FGR. While fetuses in both groups grew exponentially as pregnancies progressed, the researchers began to see dramatic differences when they compared the volumes of specific regions of the brain, including the cerebellum, which coordinates balance and smooth movement; the deep gray matter, which also is involved in complex functions, such as memory and emotion; and the white matter, which is made up of millions of nerve fibers that connect to neurons in different regions. Because there are no biomarkers to spot early brain failure, 3-D MRI imaging may fill this knowledge gap.

Questions for Future Research
Q: Certain regions of the brains of FGR-affected infants show accelerated volume. Are these differences regional or global?
Q: Is accelerated brain volume in FGR-affected infants a result of heightened stress that these fetuses experience in the womb?
Q: How do differences in regional brain volume relate to later neurodevelopmental impairment that some FGR-affected infants experience?

Source: “Impaired Global and Tissue-Specific Brain Development in the Growth-Restricted Fetus.N. Andescavage, J. Cruz, M. Metzler, A. du Plessis, and C. Limperopoulos. Presented during the 2016 Pediatric Academic Societies Annual Meeting, Baltimore, MD. May 2, 2016.

Catherine Limperopoulos

Connection between abnormal placenta and impaired growth of fetuses discovered

CLimperopoulous

A team of researchers used 3-D volumetric magnetic resonance imaging (MRI) in an innovative study that reported that when the placenta fails to grow adequately in a fetus with congenital heart disease (CHD), it contributes to impaired fetal growth and premature birth. Fetal CHD involves an abnormality of the heart and is associated with increased risk for neurodevelopmental morbidity.Until now, CHD in the fetus and its relationship to placental function has been unknown. But the advanced fetal imaging study has shown for the first time that abnormal growth in the fetus with CHD relates to impaired placental growth over the third trimester of pregnancy. Catherine Limperopoulos, PhD, Director of Children’s National Developing Brain Research Laboratory in the Division of Diagnostic Imaging and Radiology, is the senior author of the study published in the September 2015 issue of the journal Placenta, “3-D Volumetric MRI Evaluation of the Placenta in Fetuses With Complex Heart Disease.”

Specifically, the decreased 3-D volumetric MRI measurements of pregnant women reported in this study suggest placental insufficiency related to CHD. The placenta nourishes and maintains the fetus, through the delivery of food and oxygen. Its volume and weight can determine fetal growth and birth weight.

Abnormality in placental development may contribute to significant morbidity in this high risk-population. This study shows impaired placental growth in CHD fetuses is associated with the length of the pregnancy and weight at birth. Nearly 1 in every 100 babies is born in the United States with a congenital heart defect.

Developing the capacity to examine the placenta non-invasively using advanced MRI is needed to identify early markers of impaired placental structure and function in the high-risk pregnancy. This is a critical first step towards developing strategies for improved fetal monitoring and management, Dr. Limperopoulos says.

“We are trying to develop the earliest and most reliable indicators of placental health and disease in high-risk pregnancies. Our goal is to bring these early biomarkers into clinical practice and improve our ability to identify placental dysfunction,” Dr. Limperopoulos says. “If we can develop the capacity to reliably identify when things begin to veer off course, we then have a window of opportunity to develop therapies to restore function.”

The study used in-vivo 3-D MRI studies and explored placental development and its relationship to neonatal outcomes by comparing placental volumetric growth in healthy pregnancies and pregnancies complicated by CHD.

While mortality rates continue to decrease steadily in newborns diagnosed with complex CHD, long-term neurodevelopmental impairments are recognized with increasing frequency in surviving infants, Dr. Limperopoulos says.

“Our goal is to better support the developing fetus with CHD. We can best accomplish this if we develop technology that can allow us to safely and effectively monitor the fetal-placental unit as a whole throughout pregnancy,” Dr. Limperopoulos says.

“This is the new frontier, not only to ensure survival but to safeguard the fetus and to ensure the best possible quality of life,” she says.