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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.

Andrea Gropman

$5M in federal funding to help patients with urea cycle disorders

Andrea Gropman

Andrea L. Gropman, M.D.: We have collected many years of longitudinal clinical data, but with this new funding now we can answer questions about these diseases that are meaningful on a day-to-day basis for patients with urea cycle disorders.

An international research consortium co-led by Andrea L. Gropman, M.D., at Children’s National Hospital has received $5 million in federal funding as part of an overall effort to better understand rare diseases and accelerate potential treatments to patients.

Urea cycle disorder, one such rare disease, is a hiccup in a series of biochemical reactions that transform nitrogen into a non-toxic compound, urea. The six enzymes and two carrier/transport molecules that accomplish this essential task reside primarily in the liver and, to a lesser degree, in other organs.

The majority of patients have the recessive form of the disorder, meaning it has skipped a generation. These kids inherit one copy of an abnormal gene from each parent, while the parents themselves were not affected, says Dr. Gropman, chief of the Division of Neurodevelopmental Pediatrics and Neurogenetics at Children’s National. Another more common version of the disease is carried on the X chromosome and affects boys more seriously that girls, given that boys have only one X chromosome.

Regardless of the type of urea cycle disorder, when the urea cycle breaks down, nitrogen converts into toxic ammonia that builds up in the body (hyperammonemia), particularly in the brain. As a result, the person may feel lethargic; if the ammonia in the bloodstream reaches the brain in high concentrations, the person can experience seizures, behavior changes and lapse into a coma.

Improvements in clinical care and the advent of effective medicines have transformed this once deadly disease into a more manageable chronic ailment.

“It’s gratifying that patients diagnosed with urea cycle disorder now are surviving, growing up, becoming young adults and starting families themselves. Twenty to 30 years ago, this never would have seemed conceivable,” Dr. Gropman says. “We have collected many years of longitudinal clinical data, but with this new funding now we can answer questions about these diseases that are meaningful on a day-to-day basis for patients with urea cycle disorders.”

In early October 2019, the National Institutes of Health (NIH) awarded the Urea Cycle Disorders Consortium for which Dr. Gropman is co-principal investigator a five-year grant. This is the fourth time that the international Consortium of physicians, scientists, neuropsychologists, nurses, genetic counselors and researchers has received NIH funding to study this group of conditions.

Dr. Gropman says the current urea cycle research program builds on a sturdy foundation built by previous principal investigators Mendel Tuchman, M.D., and Mark Batshaw, M.D., also funded by the NIH. While previous rounds of NIH funding powered research about patients’ long-term survival prospects and cognitive dysfunction, this next phase of research will explore patients’ long-term health.

Among the topics they will study:

Long-term organ damage. Magnetic resonance elastrography (MRE) is a state-of-the-art imaging technique that combines the sharp images from MRI with a visual map that shows body tissue stiffness. The research team will use MRE to look for early changes in the liver – before patients show any symptoms – that could be associated with long-term health impacts. Their aim is spot the earliest signs of potential liver dysfunction in order to intervene before the patient develops liver fibrosis.

Academic achievement. The research team will examine gaps in academic achievement for patients who appear to be underperforming to determine what is triggering the discrepancy between their potential and actual scholastics. If they uncover issues such as learning difficulties or mental health concerns like anxiety, there are opportunities to intervene to boost academic achievement.

“And if we find many of the patients meet the criteria for depression or anxiety disorders, there are potential opportunities to intervene.  It’s tricky: We need to balance their existing medications with any new ones to ensure that we don’t increase their hyperammonemia risk,” Dr. Gropman explains.

Neurologic complications. The researchers will tap continuous, bedside electroencephalogram, which measures the brain’s electrical activity, to detect silent seizures and otherwise undetectable changes in the brain in an effort to stave off epilepsy, a brain disorder that causes seizures.

“This is really the first time we will examine babies’ brains,” she adds. “Our previous imaging studies looked at kids and adults who were 6 years and older. Now, we’re lowering that age range down to infants. By tracking such images over time, the field has described the trajectory of what normal brain development should look like. We can use that as a background and comparison point.”

In the future, newborns may be screened for urea cycle disorder shortly after birth. Because it is not possible to diagnose it in the womb in cases where there is no family history, the team aims to better counsel families contemplating pregnancy about their possible risks.

Research described in this post was underwritten by the NIH through its Rare Diseases Clinical Research Network.

allopregnanolone molecule

Autism spectrum disorder risk linked to insufficient placental steroid

allopregnanolone molecule

A study led by Children’s National Hospital and presented during Neuroscience 2019 finds that loss of allopregnanolone, a key hormone supplied by the placenta, leads to long-term structural alterations of the cerebellum – a brain region essential for smooth motor coordination, balance and social cognition – and increases the risk of developing autism.

An experimental model study suggests that allopregnanolone, one of many hormones produced by the placenta during pregnancy, is so essential to normal fetal brain development that when provision of that hormone decreases – as occurs with premature birth – offspring are more likely to develop autism-like behaviors, a Children’s National Hospital research team reports at the Neuroscience 2019 annual meeting.

“To our knowledge, no other research team has studied how placental allopregnanolone (ALLO) contributes to brain development and long-term behaviors,” says Claire-Marie Vacher, Ph.D., lead author. “Our study finds that targeted loss of ALLO in the womb leads to long-term structural alterations of the cerebellum – a brain region that is essential for motor coordination, balance and social cognition ­– and increases the risk of developing autism,” Vacher says.

According to the Centers for Disease Control and Prevention, about 1 in 10 infants is born preterm, before 37 weeks gestation; and 1 in 59 children has autism spectrum disorder.

In addition to presenting the abstract, on Monday, Oct. 21, Anna Penn, M.D., Ph.D., the abstract’s senior author, will discuss the research with reporters during a Neuroscience 2019 news conference. This Children’s National abstract is among 14,000 abstracts submitted for the meeting, the world’s largest source of emerging news about brain science and health.

ALLO production by the placenta rises in the second trimester of pregnancy, and levels of the neurosteroid peak as fetuses approach full term.

To investigate what happens when ALLO supplies are disrupted, a research team led by Children’s National created a novel transgenic preclinical model in which they deleted a gene essential in ALLO synthesis. When production of ALLO in the placentas of these experimental models declines, offspring had permanent neurodevelopmental changes in a sex- and region-specific manner.

“From a structural perspective, the most pronounced cerebellar abnormalities appeared in the cerebellum’s white matter,” Vacher adds. “We found increased thickness of the myelin, a lipid-rich insulating layer that protects nerve fibers. From a behavioral perspective, male offspring whose ALLO supply was abruptly reduced exhibited increased repetitive behavior and sociability deficits – two hallmarks in humans of autism spectrum disorder.”

On a positive note, providing a single ALLO injection during pregnancy was enough to avert both the cerebellar abnormalities and the aberrant social behaviors.

The research team is now launching a new area of research focus they call “neuroplacentology” to better understand the role of placenta function on fetal and newborn brain development.

“Our team’s data provide exciting new evidence that underscores the importance of placental hormones on shaping and programming the developing fetal brain,” Vacher notes.

  • Neuroscience 2019 presentation
    Sunday, Oct. 20, 9:30 a.m. (CDT)
    “Preterm ASD risk linked to cerebellar white matter changes”
    Claire-Marie Vacher, lead author; Sonia Sebaoui, co-author; Helene Lacaille, co-author; Jackie Salzbank, co-author; Jiaqi O’Reilly, co-author; Diana Bakalar, co-author; Panagiotis Kratimenos, M.D., neonatologist and co-author; and Anna Penn, M.D., clinical neonatologist and developmental neuroscientist and senior author.

Autonomic nervous system appears to function well regardless of mode of childbirth

Late in pregnancy, the human body carefully prepares fetuses for the rigors of life outside the protection of the womb. Levels of cortisol, a stress hormone, ramp up and spike during labor. Catecholamines, another stress hormone, also rise at birth, helping to kick start the necessary functions that the baby will need to regulate breathing, heartbeat, blood pressure and energy metabolism levels at delivery. Oxytocin surges, promoting contractions for the mother during labor and stimulating milk production after the infant is born.

These processes also can play a role in preparing the fetal brain during the transition to life outside the womb by readying the autonomic nervous system and adapting its cerebral connections. The autonomic nervous system acts like the body’s autopilot, taking in information it needs to ensure that internal organs run steadily without willful action, such as ensuring the heart beats and eyelids blink at steady intervals. Its yin, the sympathetic division, stimulates body processes while its yang, the parasympathetic division, inhibits them.

Infants born preterm have reduced autonomic function compared with their full-term peers and also face possible serious neurodevelopmental impairment later in life. But is there a difference in autonomic nervous system function for full-term babies after undergoing labor compared with infants delivered via cesarean section (C-section)?

A team from the Children’s National Inova Collaborative Research Program (CNICA) – a research collaboration between Children’s National in Washington, D.C., and Inova Women’s and Children’s Hospital in Virginia – set out to answer that question in a paper published online July 30, 2019, in Scientific Reports.

They enrolled newborns who had experienced normal, full-term pregnancies and recorded their brain function and heart performance when they were about 2 days old. Infants whose conditions were fragile enough to require observation in the neonatal intensive care unit were excluded from the study. Of 167 infants recruited for the prospective cohort study, 118 newborns had sufficiently robust data to include them in the research.  Of these newborns:

  • 62 (52.5%) were born by vaginal delivery
  • 22 (18.6%) started out with vaginal delivery but ultimately switched to C-section based on failure to progress, failed labor induction or fetal intolerance to labor
  • And 34 (28.8%) were born by elective C-section.

The CNICA research team swaddled infants for comfort and slipped electrode nets over their tiny heads to simultaneously measure heart rate variability and electrocortical function through non-invasive techniques. The team hypothesized that infants who had been exposed to labor would have enhanced autonomic tone and higher cortical electroencephalogram (EEG) power than babies born via C-section.

“In a low-risk group of babies born full-term, the autonomic nervous system and cortical systems appear to function well regardless of whether infants were exposed to labor prior to birth,” says Sarah B. Mulkey, M.D., Ph.D., a fetalneonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National and the study’s lead author.

However, infants born by C-section following a period of labor had significantly increased accelerations in their heart rates. And the infants born by C-section during labor had significantly lower relative gamma frequency EEG at 25.2 hours old compared with the other two groups studied.

“Together these findings point to a possible increased stress response and arousal difference in infants who started with vaginal delivery and finished delivery with C-section,” Dr. Mulkey says. “There is so little published research about the neurologic impacts of the mode of delivery, so our work helps to provide a normal reference point for future studies looking at high-risk infants, including babies born preterm.”

Because the research team saw little differences in autonomic tone or other EEG frequencies when the infants were 1 day old, future research will explore these measures at different points in the newborns’ early life as well as the role of the sleep-wake cycle on heart rate variability.

In addition to Dr. Mulkey, study co-authors include Srinivas Kota, Ph.D., Rathinaswamy B. Govindan, Ph.D., Tareq Al-Shargabi, MSc, Christopher B. Swisher, BS, Laura Hitchings, BScM, Stephanie Russo, BS, Nicole Herrera, MPH, Robert McCarter, ScD, and Senior Author Adré  J. du Plessis, M.B.Ch.B., MPH, all of Children’s National; and Augustine Eze Jr., MS, G. Larry Maxwell, M.D., and Robin Baker, M.D., all of Inova Women’s and Children’s Hospital.

Financial support for research described in this post was provided by the National Institutes of Health National Center for Advancing Translational Sciences under award numbers UL1TR001876 and KL2TR001877.

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.

newborn in incubator

In HIE lower heart rate variability signals stressed newborns

newborn in incubator

In newborns with hypoxic-ischemic encephalopathy (HIE), lower heart rate variability correlates with autonomic manifestations of stress shortly after birth, underscoring the value of this biomarker, according to Children’s research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Tethered to an array of machines that keep their bodies nourished, warm and alive, newborns with health issues can’t speak. But Children’s research teams are tapping into what the machinery itself says, looking for insights into which vulnerable infants are most in need of earlier intervention.

Heart rate variability – or the variation between heartbeats – is a sign of health. Our autonomic nervous system constantly sends signals to adjust our heart rate under normal conditions. We can measure heart rate variability non-invasively, providing a way to detect potential problems with the autonomic nervous system as a sensitive marker of health in critically ill newborns,” says An N. Massaro, M.D., co-Director of Research for the Division of Neonatology at Children’s National, and the study’s senior author. “We’re looking for validated markers of brain injury in babies with HIE, and our study helps to support heart rate variability as one such valuable physiological biomarker.”

In most newborns, the autonomic nervous system reliably and automatically receives information about the body and the outside world and, in response, controls essential functions like blood pressure, body temperature, how quickly the baby breathes and how rapidly the newborn’s heart beats. The sympathetic part stimulates body processes, while the parasympathetic part inhibits body processes. When the nervous system’s internal auto-pilot falters, babies can suffer.

The Children’s team enrolled infants with HIE in the prospective, observational study. (HIE is brain damage that occurs with full-term babies who experience insufficient blood and oxygen flow to the brain around the time they are born.) Fifteen percent had severe encephalopathy. Mean age of babies in the observational study was 38.9 weeks gestation. Their median Apgar score at five minutes was 3; the 0-9 Apgar range indicates how ready newborns are for the rigors of life outside the womb.

The team analyzed heart rate variability metrics for three time periods:

  • The first 24 to 27 hours of life
  • The first three hours after babies undergoing therapeutic cooling were rewarmed and
  • The first three hours after babies’ body temperature had returned to normal.

They correlated the relationship between heart rate variability for 68 infants during at least one of these time periods with the stress z-score from the NICU Network Neurobehavioral Scale. The scale is a standardized assessment of newborn’s neurobehavioral integrity. The stress summary score indicates a newborn’s overall stress response, and six test items specifically relate to autonomic function.

“Alpha exponent and root mean square in short timescales, root mean square in long timescales, as well as low and high frequency powers positively correlated with stress scores and, even after adjusting for covariates, remained independently associated at 24 hours,” says Allie Townsend, the study’s lead author.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Heart rate variability (HRV) measures of autonomic nervous system (ANS) function relates to neonatal neurobehavioral manifestations of stress in newborn with hypoxic-ischemic encephalopathy (HIE).”
    • Monday, April 29, 2019, 5:45 p.m. (EST)

Allie Townsend, lead author; Rathinaswamy B. Govindan, Ph.D., staff scientist, Advanced Physiological Signals Processing Lab and co-author; Penny Glass, Ph.D., director, Child Development Program and co-author; Judy Brown, co-author; Tareq Al-Shargabi, M.S., co-author; Taeun Chang, M.D., director, Neonatal Neurology and Neonatal Neurocritical Care Program and co-author; Adré J. du Plessis, M.B.Ch.B., MPH, chief of the Division of Fetal and Transitional Medicine and co-author; An N. Massaro, M.D., co-Director of Research for the Division of Neonatology and senior author, all of Children’s National.