neurodevelopmental Archives

Yves d’Udekem, M.D., Ph.D., named Chief of Cardiac Surgery and Co-Director of the Children’s National Heart Institute

March 3, 2020

Children’s National Hospital announced that world-class surgeon Yves d’Udekem, M.D., Ph.D., will become the next Chief of Cardiac Surgery and Co-Director of the Children’s National Heart Institute this summer.

Dr. d’Udekem is Belgian-born with Canadian and Australian citizenship and received his early training in Belgium and Toronto. As an attending cardiac surgeon in Belgium, he operated on both adults and children with congenital heart disease. Dr. d’Udekem then worked with internationally recognized heart surgeon Marc de Laval, M.D., FRCS, and others in London to train in congenital heart surgery at the Great Ormond Street Hospital for Children.

From there, he was recruited to The Royal Children’s Hospital in Melbourne, Australia, an institution that has been a leader in advancing the field of congenital heart disease. In Melbourne, Dr. d’Udekem built an outstanding reputation for clinical excellence and an exceptional academic career. He has over 300 publications and is highly cited and respected. Dr. d’Udekem obtained more than $7 million in grant funding over the past five years as the creator and leader of the highly touted Fontan Registry.

The Children’s National Cardiology team and hospital leadership have built a framework for Dr. d’Udekem to succeed and advance the legacy that has been so successfully created in cardiac surgery by Richard Jonas, M.D. Dr. Jonas is a world leader in congenital heart surgery who made significant clinical and academic advances in the field and will continue his award-winning research career at Children’s National in the laboratory focusing on neurodevelopmental outcomes for children with heart disease.

Children’s National offers a comprehensive surgical program that includes a team of experienced surgeons performing the full range of procedures available for treatment of pediatric cardiac disease and congenital heart defects. The high volume program serves neonates through adults with congenital heart disease with particular attention to neurodevelopmental outcomes.

False negatives: Delayed Zika effects in babies who appeared normal at birth

January 6, 2020

Colombian infants exposed to Zika virus in the womb showed neurodevelopmental delays as toddlers, despite having “normal” brain imaging and head circumference at birth, a finding that underscores the importance of long-term neurodevelopmental follow-up for Zika-exposed infants.

Colombian infants exposed to Zika virus in the womb showed neurodevelopmental delays as toddlers, despite having “normal” brain imaging and head circumference at birth, a finding that underscores the importance of long-term neurodevelopmental follow-up for Zika-exposed infants, according to a cohort study published online Jan. 6, 2020, in JAMA Pediatrics.

“These infants had no evidence of Zika deficits or microcephaly at birth. Neurodevelopmental deficits, including declines in mobility and social cognition, emerged in their first year of life even as their head circumference remained normal,” says Sarah B. Mulkey, M.D. Ph.D., a fetal/neonatal neurologist at Children’s National Hospital and the study’s first author. “About one-third of these newborns who underwent postnatal head ultrasound had nonspecific imaging results, which we believe are the first published results finding a link between subtle brain injuries and impaired neuromotor development in Zika-exposed children.”

The multi-institutional research group led by Children’s National enrolled pregnant women in Atlántico Department, which hugs the Caribbean coast of Colombia, who had been exposed to Zika, and performed a series of fetal magnetic resonance images (MRI) and ultrasounds as their pregnancies progressed.

Even though their mothers had laboratory-confirmed Zika infections, 77 out of 82 of their offspring were born with no sign of congenital Zika syndrome, a constellation of birth defects that includes severe brain abnormalities, eye problems and congenital contractures, and 70 underwent additional testing of neurodevelopment during infancy. These apparently normal newborns were born between Aug. 1, 2016, and Nov. 30, 2017, at the height of the Zika epidemic, and had normal head circumference.

When they were 4 to 8 months or 9 to 18 months of age, the infants’ neurodevelopment was evaluated using two validated tools, the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (a 50-item test of such skills as self-care, mobility, communication and social cognition) and the Alberta Infant Motor Scale (a motor examination of infants in prone, supine, sitting and standing positions). Some infants were assessed during each time point.

Women participating in the study were highly motivated, with 91% following up with appointments, even if it meant traveling hours by bus. In addition to Children’s National faculty traveling to Colombia to train staff how to administer the screening instruments, videotaped assessments, MRIs and ultrasounds were read, analyzed and scored at Children’s National. According to the study team, the U.S. scoring of Alberta Infant Motor Scale tests administered in Colombia is also unprecedented for a research study and offers the potential of remote scoring of infants’ motor skill maturity in regions of the world where pediatric specialists, like child neurologists, are lacking.

“Normally, neurodevelopment in infants and toddlers continues for years, building a sturdy neural network that they later use to carry out complex neurologic and cognitive functions as children enter school,” Dr. Mulkey adds. “Our findings underscore the recommendations by the Centers for Disease Control and Prevention (CDC) that all infants exposed to Zika in the womb undergo long-term follow-up, providing an opportunity to intervene earlier.”

An accompanying editorial by CDC staffers concurs, saying the study reported “intriguing data” that add “to the growing evidence of the need for long-term follow-up for all children with Zika virus exposure in utero to ensure they receive the recommended clinical evaluations even when no structural defects are identified at birth.”

In addition to Dr. Mulkey, study co-authors include Margarita Arroyave-Wessel, MPH, Dorothy I. Bulas, M.D., chief of Diagnostic Imaging and Radiology, JiJi Jiang, MS, Stephanie Russo, BS, Robert McCarter, ScD, research section head, design and biostatistics, Adré J. du Plessis, M.B.Ch.B., MPH, chief of the Division of Fetal and Transitional Medicine, and co-Senior Author, Roberta L. DeBiasi, MD, MS, chief of the Division of Pediatric Infectious Diseases, all of Children’s National; Colleen Peyton, PT, DPT, of Northwestern University; Yamil Fourzali, M.D., of Sabbag Radiologos, Barranquilla, Colombia; Michael E. Msall, M.D., of University of Chicago Comer Children’s Hospital; and co-Senior Author, Carlos Cure, M.D., BIOMELab, Barranquilla, Colombia.

Funding for the research described in this post was provided by the Thrasher Research Fund, the National Institutes of Health under award Nos. UL1TR001876 and KL2TR001877, and the Leadership Education in Neurodevelopmental and Related Disorders Training Program under grant HRSA/MCHB T73 MC11047.

Autism spectrum disorder risk linked to insufficient placental steroid

October 23, 2019

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.

Cardiac surgery chief recognized for studies of surgery’s impacts on neurodevelopment

October 9, 2019

Dr. Jonas and research collaborator Nobuyuki Ishibashi in the laboratory.

Richard Jonas, M.D., is this year’s recipient of the Newburger-Bellinger Cardiac Neurodevelopmental Award in recognition of his lifelong research into understanding the impact of cardiac surgery on the growth and development of the brain. The award was established in 2013 by the Cardiac Neurodevelopmental Outcome Collaborative (CNOC) to honor Jane Newburger and David Bellinger, pioneers in research designed to understand and improve neurodevelopmental outcomes for children with heart disease.

At Children’s National, Dr. Jonas’ laboratory studies of neuroprotection have been conducted in conjunction with Dr. Vittorio Gallo, director of neuroscience research at Children’s National, and Dr. Nobuyuki Ishibashi, director of the cardiac surgery research laboratory. Their NIH-supported studies have investigated the impact of congenital heart disease and cardiopulmonary bypass on the development of the brain, with particular focus on impacts to white matter, in people with congenital heart disease.

Dr. Jonas’s focus on neurodevelopment after cardiac surgery has spanned his entire career in medicine, starting with early studies in the Harvard psychology department where he developed models of ischemic brain injury. He subsequently undertook a series of highly productive pre-clinical cardiopulmonary bypass studies at the National Magnet Laboratory at MIT. These studies suggested that some of the bypass techniques used at the time were suboptimal. The findings helped spur a series of retrospective clinical studies and subsequently several prospective randomized clinical trials at Boston Children’s Hospital examining the neurodevelopmental consequences of various bypass techniques. These studies were conducted by Dr. Jonas and others, in collaboration with Dr. Jane Newburger and Dr. David Bellinger, for whom this award is named.

Dr. Jonas has been the chief of cardiac surgery and co-director of the Children’s National Heart Institute since 2004. He previously spent 20 years on staff at Children’s Hospital Boston including 10 years as department chief and as the William E. Ladd Chair of Surgery at Harvard Medical School.

As the recipient of the 2019 award, Dr. Jonas will deliver a keynote address at the 8^th Annual Scientific Sessions of the Cardiac Neurodevelopmental Outcome Collaborative in Toronto, Ontario, October 11-13, 2019.

Paradoxical outcomes for Zika-exposed tots

August 2, 2019

In the midst of an unprecedented Zika crisis in Brazil, there were a few flickers of hope: Some babies appeared to be normal at birth, free of devastating birth defects that affected other Brazilian children exposed to the virus in utero.

In the midst of an unprecedented Zika crisis in Brazil, there were a few flickers of hope: Some babies appeared to be normal at birth, free of devastating birth defects that affected other Brazilian children exposed to the virus in utero. But according to a study published online July 8, 2019, in Nature Medicine and an accompanying commentary co-written by a Children’s National clinician-researcher, the reality for Zika-exposed infants is much more complicated.

Study authors led by Karin Nielsen-Saines at David Geffen UCLA School of Medicine followed 216 infants in Rio de Janeiro who had been exposed to the Zika virus during pregnancy, performing neurodevelopmental testing when the babies ranged in age from 7 to 32 months. These infants’ mothers had had Zika-related symptoms themselves, including rash.

Although many children had normal assessments, 29% scored below average in at least one domain of neurological development, including cognitive performance, fine and gross motor skills and expressive language, Sarah B. Mulkey, M.D., Ph.D., and a colleague write in a companion commentary published online by Nature Medicine July 29, 2019.

The study authors found progressively higher risks for developmental, hearing and eye abnormality depending on how early the pregnancy was at the time the infants were exposed. Because Zika virus has an affinity for immature neurons, even babies who were not born with microcephaly remained at continued risk for suffering abnormalities.

Of note, 24 of 49 (49%) infants who had abnormalities at birth went on to have normal test results in the second or third year of life. By contrast, 17 of 68 infants (25%) who had normal assessments at birth had below-average developmental testing or had abnormalities in hearing or vision by age 32 months.

“This work follows babies who were born in 2015 and 2016. It’s heartening that some babies born with abnormalities tested in the normal range later in life, though it’s unclear whether any specific interventions help to deliver these positive findings,” says Dr. Mulkey, a fetal–neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National in Washington, D.C. “And it’s quite sobering that babies who appeared normal at birth went on to develop abnormalities due to that early Zika exposure.”

It’s unclear how closely the findings apply to the vast majority of U.S. women whose Zika infections were asymptomatic.

“This study adds to the growing body of research that argues in favor of ongoing follow-up for Zika-exposed children, even if their neurologic exams were reassuring at birth,” Dr. Mulkey adds. “As Zika-exposed children approach school age, it’s critical to better characterize the potential implications for the education system and public health.”

In addition to Dr. Mulkey, the perspective’s senior author, William J. Muller, Northwestern University, was the commentary’s lead author.

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

July 30, 2019

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 fetal–neonatal 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.

Coming together as a team for the good of the baby

March 12, 2019

Children’s National has a new program to care for children who have severe bronchopulmonary dysplasia, a serious complication of preterm birth.

Around the 1-year-old’s crib is a tight circle of smiling adults, and at the foot of his bed is a menagerie of plush animals, each a different color and texture and shape to spark his curiosity and sharpen his intellect.

Gone are the days a newborn with extremely complex medical needs like Elijah would transfer from the neonatal intensive care unit (NICU) to the pediatric intensive care unit and transition through a couple of other hospital units by the time he was discharged. Gone are the days when he’d see a variety of new physician faces at every stop. And gone are the days he’d be confined to his room, divorced from the sights and sounds and scents of the outside world, stimulation that helps little baby’s neural networks grow stronger.

Children’s National has a new program designed to meet the unique needs of children like Elijah who have severe bronchopulmonary dysplasia (BPD), a common complication of preterm birth.

“It’s more forward-thinking – and I mean thinking for the future of each individual baby, and it’s allowing the baby to have one team and one location to take advantage of a deep knowledge of and relationship with that baby and family,” says Robin Steinhorn, M.D. Dr. Steinhorn is senior vice president of the Center for Hospital-Based Specialties and one of Children’s multidisciplinary team members who visited Elijah’s bed twice weekly during his lengthy hospitalization and who continues to see him regularly during outpatient visits.

“The pulmonologist, the neonatologist, the respiratory therapist, the physical therapist, the dietitian, the cardiologist – we all come as a team to work together for the good of the baby,” Dr. Steinhorn adds. “We stick with these babies through thick and thin. We will stick with that baby with this team and this location until they are ready to go home – and beyond.”

BPD, a serious lung condition, mostly affects extremely low birthweight preterm babies whose lungs were designed to continue developing inside the womb until the pregnancy reaches full term. Often born months before their due dates, these extremely vulnerable newborns have immature organs, including the lungs, which are not ready for the task of breathing air. Children’s program targets infants who experience respiratory failure from BPD. The respiratory support required for these infants ranges from oxygen delivered through a nasal cannula to mechanical ventilators.

“It’s more forward-thinking – and I mean thinking for the future of each individual baby, and it’s allowing the baby to have one team and one location to take advantage of a deep knowledge of and relationship with that baby and family,” says Robin Steinhorn, M.D.

About 1 percent of all preterm births are extremely low birthweight, or less than 1,500 grams. Within that group, up to 40 percent will develop BPD. While they represent a small percentage of overall births, these very sick babies need comprehensive, focused care for the first few years of their lives. And some infants with severe BPD also have pulmonary hypertension which, at Children’s National, is co-managed by cardiology and pulmonary specialists.

Children’s BPD team not only focuses on the child’s survival and medical care, they focus on the neurodevelopmental and social care that a baby needs to thrive. From enhanced nutrition to occupational and physical therapy to a regular sleep cycle, the goal is to help these babies achieve their full potential.

“These babies are at tremendous risk for long-term developmental issues. Everything we do is geared to alleviate that,” adds John T. Berger III, M.D., director of Children’s Pulmonary Hypertension Program.

“Our NICU care is more focused, comprehensive and consistent,” agrees Mariam Said, M.D., a neonatologist on the team. “We’re also optimizing the timing of care and diagnostic testing that will directly impact health outcomes.”

Leaving no detail overlooked, the team also ensures that infants have age-appropriate developmental stimuli, like toys, and push for early mobility by getting children up and out of bed and into a chair or riding in a wagon.

“The standard approach is to keep the baby in a room with limited physical or occupational therapy and a lack of appropriate stimulation,” says Geovanny Perez, M.D., a pulmonologist on the team. “A normal baby interacts with their environment inside the home and outside the home. We aim to mimic that within the hospital environment.”

Dr. Steinhorn, who had long dreamed of creating this comprehensive team care approach adds that “it’s been so gratifying to see it adopted and embraced so quickly by Children’s NICU caregivers.”

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