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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.

Preemie Baby

Brain food for preemies

Preemie Baby

Babies born prematurely – before 37 weeks of pregnancy – often have a lot of catching up to do. Not just in size. Preterm infants typically lag behind their term peers in a variety of areas as they grow up, including motor development, behavior and school performance.

New research suggests one way to combat this problem. The study, led by Children’s researchers and presented during the Pediatric Academic Societies 2018 annual meeting, suggests that the volume of carbohydrates, proteins, lipids and calories consumed by very vulnerable premature infants significantly contributes to increased brain volume and white matter development, even though additional research is needed to determine specific nutritional approaches that best support these infants’ developing brains.

During the final weeks of pregnancy, the fetal brain undergoes an unprecedented growth spurt, dramatically increasing in volume as well as structural complexity as the fetus approaches full term.

One in 10 infants born in the U.S. in 2016 was born before 37 weeks of gestation, according to the Centers for Disease Control and Prevention. Within this group, very low birthweight preemies are at significant risk for growth failure and neurocognitive impairment. Nutritional support in the neonatal intensive care unit (NICU) helps to encourage optimal brain development among preterm infants. However, their brain growth rates still lag behind those seen in full-term newborns.

“Few studies have investigated the impact of early macronutrient and caloric intake on microstructural brain development in vulnerable preterm infants,” says Katherine Ottolini, lead author of the Children’s-led study. “Advanced quantitative magnetic resonance imaging (MRI) techniques may help to fill that data gap in order to better direct targeted interventions to newborns who are most in need.”

The research team at Children’s National Health System enrolled 69 infants who were born younger than 32 gestational weeks and weighed less than 1,500 grams. The infants’ mean birth weight was 970 grams and their mean gestational age at birth was 27.6 weeks.

The newborns underwent MRI at their term-equivalent age, 40 weeks gestation. Parametric maps were generated for fractional anisotropy in regions of the cerebrum and cerebellum for diffusion tensor imaging analyses, which measures brain connectivity and white matter tract integrity. The research team also tracked nutritional data: Grams per kilogram of carbohydrates, proteins, lipids and overall caloric intake.

“We found a significantly negative association between fractional anisotropy and cumulative macronutrient/caloric intake,” says Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory and senior author of the research. “Curiously, we also find significantly negative association between macronutrient/caloric intake and regional brain volume in the cortical and deep gray matter, cerebellum and brainstem.”

Because the nutritional support does contribute to cerebral volumes and white matter microstructural development in very vulnerable newborns, Limperopoulos says the significant negative associations seen in this study may reflect the longer period of time these infants relied on nutritional support in the NICU.

In addition to Ottolini and Limperopoulos, study co-authors include Nickie Andescavage, M.D., Attending, Children’s Neonatal-Perinatal Medicine; and Kushal Kapse.

Pregnant-Mom

MRI opens new understanding of fetal growth restriction

Pregnant-Mom

Quantitative MRI can identify placental dysfunction complicated by fetal growth restriction earlier, creating the possibility for earlier intervention to minimize harm to the developing fetus.

A team of researchers has found that quantitative magnetic resonance imaging (MRI) can identify pregnancies where placental dysfunction results in fetal growth restriction (FGR), creating the possibility for earlier FGR detection and intervention to augment placental function and thus minimize harm to the fetal brain.

The study, published online in the Journal of Perinatology, reports for the first time that in vivo placental volume is tied to global and regional fetal brain volumes.

Placental insufficiency is a known risk factor for impaired fetal growth and neurodevelopment. It may cause the fetus to receive inadequate oxygen and nutrients, making it difficult to grow and thrive. The earlier placental insufficiency occurs in a pregnancy, the more serious it can be. But detecting a failing placenta before the fetus is harmed has been difficult.

One additional challenge is that a fetus may be small because the placenta is not providing adequate nourishment. Or the fetus simply may be genetically predisposed to be smaller. Being able to tell the difference early can have a lifelong impact on a baby. Infants affected by FGR can experience behavioral problems, learning difficulties, memory and attention deficits, and psychiatric issues as the child grows into adolescence and adulthood.

“Our study proved that MRI can more accurately determine which pregnancies are at greater risk for impaired fetal health or compromised placenta function,” says Nickie Andescavage, M.D., the study’s lead author and a specialist in neonatology and neonatal neurology and neonatal critical care at Children’s National Health System. “The earlier we can identify these pregnancies, the more thoughtful we can be in managing care.”

Dr. Andescavage’s research focus has been how fetal growth affects labor, delivery and postnatal complications.

Nickie-Andescavage-Niforatos

“Our study proved that MRI can more accurately determine which pregnancies are at greater risk for impaired fetal health or compromised placenta function,” says Nickie Andescavage, M.D., the study’s lead author.

“We don’t have a good understanding of why FGR happens, but we do know it’s hard to identify during pregnancy because often there are no signs,” says Dr. Andescavage. “Even when detected, it’s hard to follow. But if we’re aware of it, we can better address important questions, like when to deliver an at-risk fetus.”

In the study, the team measured placental and fetal brain growth in healthy, uncomplicated pregnancies and in pregnancies complicated by FGR. A total of 114 women participated, undergoing ultrasound, Doppler ultrasound and MRI imaging to measure placental volume and fetal brain volume.

An ultrasound test is often what detects FGR, but the measurements generated by ultrasound can be non-specific. In addition, reproducibility issues with 3D sonography limit its use as a standalone tool for placental assessment. Once FGR is detected via ultrasound, this study showed that complementary MRI provides more accurate structural measures of the fetal brain, as well as more detail and insight into placental growth and function.

“Our team has studied FGR for a few years, using imaging to see that’s happening with the fetus in real time,” says Dr. Andescavage. “The relationship of placental volume and fetal brain development had not been previously studied in utero.”

In pregnancies complicated by FGR, MRI showed markedly decreased placental and brain volumes. The team observed significantly smaller placental, total brain, cerebral and cerebellar volumes in these cases than in the healthy controls. The relationship between increasing placental volume and increasing total brain volume was similar in FGR and in normal pregnancies. However, the study authors write “the overall volumes were smaller and thus shifted downward in pregnancies with FGR.”

In addition, FGR-complicated pregnancies that also showed abnormalities in Doppler ultrasound imaging had even smaller placental, cerebral and cerebellar volumes than pregnancies complicated by FGR that did not have aberrations in Doppler imaging.

Since this study showed that quantitative fetal MRI can accurately detect decreased placental and brain volumes when FGR is present, Dr. Andescavage believes this imaging technique may give doctors important new insights into the timing and possibly the mechanisms of brain injury in FGR.  “Different pathways can lead to FGR. With this assessment strategy, we could potentially elucidate those,” she adds.

Using quantitative MRI to identify early deviations from normal growth may create opportunities for future interventions to protect the developing fetal brain. New treatments on the horizon promise to address placental health. MRI could be used to investigate these potential therapies in utero. When those therapies become available, it could allow doctors to monitor treatment effects in utero.

Study co-authors include Adré J. du Plessis, M.B.Ch.B., M.P.H., Director of Children’s Fetal Medicine Institute; Marina Metzler; Dorothy Bulas, M.D., FACR, FAIUM, FSRU, Chief of Children’s Division of Diagnostic Imaging and Radiology; L. Gilbert Vezina, M.D., Director of Children’s Neuroradiology Program; Marni Jacobs; Catherine Limperopoulos, Ph.D., Director of Children’s Developing Brain Research Laboratory and study senior author; Sabah N. Iqbal, MedStar Washington Hospital Center; and Ahmet Alexander Baschat, Johns Hopkins Center for Fetal Therapy.

Research reported in this post was supported by the Canadian Institutes of Health Research, MOP-81116; the National Institutes of Health under award numbers UL1TR000075 and KL2TR000076; and the Clinical and Translational Science Institute at Children’s National.

Sarah Mulkey

Fetal MRI plus ultrasound assess Zika-related brain changes

Sarah Mulkey

Magnetic resonance imaging and ultrasound provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero, says Sarah B. Mulkey, M.D., Ph.D.

For Zika-affected pregnancies, fetal magnetic resonance imaging (MRI) used in addition to standard ultrasound (US) imaging can better assess potential brain abnormalities in utero, according to research presented by Children’s National Health System during IDWeek 2017. In cases of abnormal brain structure, fetal MRI can reveal more extensive areas of damage to the developing brain than is seen with US.

“MRI and US provide complementary data needed to assess ongoing changes to the brains of fetuses exposed to Zika in utero,” says Sarah B. Mulkey, M.D., Ph.D., a fetal/neonatal neurologist at Children’s National Health System and lead author of the research paper. “In addition, our study found that relying on ultrasound alone would have given one mother the false assurance that her fetus’ brain was developing normally while the sharper MRI clearly pointed to brain abnormalities.”

As of Sept. 13, the Centers for Disease Control and Prevention (CDC) reported that 1,901 U.S. women were exposed to Zika at some point during their pregnancies but their infants appeared normal at birth. Another 98 U.S. women, however, gave birth to infants with Zika-related birth defects.  And eight more women had pregnancy losses with Zika-related birth defects, according to CDC registries.

The longitudinal neuroimaging study led by Children’s National enrolled 48 pregnant women exposed to the Zika virus in the first or second trimester whose infection was confirmed by reverse transcription polymerase chain reaction, which detects Zika viral fragments shortly after exposure, and/or Immunoglobulin M testing, which reveals antibodies the body produces to neutralize the virus. Forty-six of the study volunteers live in Barranquilla, Colombia, where Zika infection is endemic. Two women live in the Washington region and were exposed to Zika during travel elsewhere.

All of the women underwent at least one diagnostic imaging session while pregnant, receiving an initial MRI or US at 25.1 weeks’ gestational age. Thirty-six women underwent a second MRI/US imaging pair at roughly 31 weeks’ gestation. Children’s National radiologists read every image.

Three of 48 pregnancies, or 6 percent, were marked by abnormal fetal MRIs:

  • One fetus had heterotopias (clumps of grey matter located at the wrong place) and abnormal cortical indent (a deformation at the outer layer of the cerebrum, a brain region involved in consciousness). The US taken at the same gestational age for this fetus showed its brain was developing normally.
  • Another fetus had parietal encephalocele (an uncommon skull defect) and Chiari malformation Type II (a life-threatening structural defect at the base of the skull and the cerebellum, the part of the brain that controls balance). The US for this fetus also detected these brain abnormalities.
  • The third fetus had a thin corpus callosum (bundle of nerves that connects the brain’s left and right hemispheres), an abnormally developed brain stem, temporal cysts, subependymal heterotopias and general cerebral/cerebellar atrophy. This fetal US showed significant ventriculomegaly (fluid-filled structures in the brain that are too large) and a fetal head circumference that decreased sharply from the 32nd to 36th gestational week, a hallmark of microcephaly.

After they were born, infants underwent a follow-up MRI without sedation and US. For nine infants, these ultrasounds revealed cysts in the choroid plexus (cells that produce cerebrospinal fluid) or germinal matrix (the source for neurons and glial cells that migrate during brain development). And one infant’s US after birth showed lenticulostriate vasculopathy (brain lesions).

“Because a number of factors can trigger brain abnormalities, further studies are needed to determine whether the cystic changes to these infants’ brains are attributable to Zika exposure in the womb or whether some other insult caused these troubling results,” Dr. Mulkey says.

Catherine Limperopoulous

Brain impairment in newborns with CHD prior to surgery

Catherine Limperopoulous

Children’s National researchers led by Catherine Limperopoulos, Ph.D., demonstrate for the first time that the brains of high-risk infants show signs of functional impairment before they undergo corrective cardiac surgery.

Newborns with congenital heart disease (CHD) requiring open-heart surgery face a higher risk for neurodevelopmental disabilities, yet prior studies had not examined whether functional brain connectivity is altered in these infants before surgery.

Findings from a Children’s National Health System study of this question suggest the presence of brain dysfunction early in the lives of infants with CHD that may be associated with neurodevelopmental impairments years later.

Using a novel imaging technique, Children’s National researchers demonstrated for the first time that the brains of these high-risk infants already show signs of functional impairment even before they undergo corrective open heart surgery. Looking at the newborns’ entire brain topography, the team found intact global organization – efficient and effective small world networks – yet reduced functional connectivity between key brain regions.

“A robust neural network is critical for neurons to travel to their intended destinations and for the body to carry out nerve cells’ instructions. In this study, we found the density of connections among rich club nodes was diminished, and there was reduced connectivity between critical brain hubs,” says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and senior author of the study published online Sept. 28, 2017 in NeuroImage: Clinical. “CHD disrupts how oxygenated blood flows throughout the body, including to the brain. Despite disturbed hemodynamics, infants with CHD still are able to efficiently transfer neural information among neighboring areas of the brain and across distant regions.”

The research team led by Josepheen De Asis-Cruz, M.D., Ph.D., compared whole brain functional connectivity in 82 healthy, full-term newborns and 30 newborns with CHD prior to corrective heart surgery. Conventional imaging had detected no brain injuries in either group. The team used resting state functional connectivity magnetic resonance imaging (rs-fcMRI), a imaging technique that characterizes fluctuating blood oxygen level dependent signals from different regions of the brain, to map the effect of CHD on newborns’ developing brains.

The newborns with CHD had lower birth weights and lower APGAR scores (a gauge of how well brand-new babies fare outside the womb) at one and five minutes after birth. Before the scan, the infants were fed, wrapped snugly in warm blankets, securely positioned using vacuum pillows, and their ears were protected with ear plugs and ear muffs.

While the infants with CHD had intact global network topology, a close examination of specific brain regions revealed functional disturbances in a subnetwork of nodes in newborns with cardiac disease. The subcortical regions were involved in most of those affected connections. The team also found weaker functional connectivity between right and left thalamus (the region that processes and transmits sensory information) and between the right thalamus and the left supplementary motor area (the section of the cerebral cortex that helps to control movement). The regions with reduced functional connectivity depicted by rs-fcMRI match up with regional brain anomalies described in imaging studies powered by conventional MRI and diffusion tensor imaging.

“Global network organization is preserved, despite CHD, and small world brain networks in newborns show a remarkable ability to withstand brain injury early in life,” Limperopoulos adds. “These intact, efficient small world networks bode well for targeting early therapy and rehabilitative interventions to lower the newborns’ risk of developing long-term neurological deficits that can contribute to problems with executive function, motor function, learning and social behavior.”