Among all known birth defects, congenital heart disease (CHD) is the leading cause of death in infants. Fortunately, advances in surgical techniques and treatments are improving the outlook for these children, and more and more are reaching adulthood. However, because of this increased longevity, it has become increasingly clear that children born with CHD are at risk of developing life-long neurological deficits. Several risk factors for these neurodevelopmental abnormalities have been identified, but direct links between specific factors and neurological defects have yet to be established.
In a recent review article published in Circulation Research, a team from Children’s National Health System summarized what is currently known about how CHD affects brain maturation. Drawing from studies conducted at Children’s National as well as other research institutions, Paul D. Morton, Ph.D., Nobuyuki Ishibashi, M.D., and Richard A. Jonas, M.D., write that clinical findings in patients, improvements in imaging analysis, advances in neuromonitoring techniques and the development of animal models have greatly contributed to our understanding of the neurodevelopmental changes that occur with CHD.
Findings from Children’s National include:
The authors conclude that although there is ample clinical evidence of neurological damage associated with CHD, there is limited knowledge of the cellular events associated with these abnormalities. They offer perspectives about what can be done to improve our understanding of neurological deficits in CHD, and emphasize that ultimately, a multidisciplinary approach combining multiple fields and myriad technology will be essential to improve or prevent adverse neurodevelopmental outcomes in individuals with CHD.
Questions for future research
Q: What are the cellular events associated with each factor involved in neurodevelopmental delays?
Source: Norton, P.D., Ishibashi, N., Jonas, R.A. “Neurodevelopmental Abnormalities and Congenital Heart Disease: Insights Into Altered Brain Maturation,” Circulation Research (2017) 120:960-977.
Neurology & Neurosurgery
Researchers, doctors and parents of autistic children seem to all agree on one truth: If you’ve met one child with autism, you’ve met one child with autism. That fact helps to explain why every spring, researchers and clinicians from around the world gather for the International Meeting for Autism Research (IMFAR) – it’s a key opportunity to connect with some of the most respected investigators and stakeholder partners in the research community, and to understand the similarities as well as the differences between autistic populations around the world. Through three days of keynote and panel discussions as well as hundreds of poster presentations on a variety of topics, IMFAR aims to exchange and disseminate the latest scientific and clinical progress in Autism Spectrum Disorders (ASD) to this global audience of scientists and trainees.
This year, ten faculty members, staff and volunteers from the Center for Autism Spectrum Disorders (CASD) at Children’s National attended IMFAR, and presented on a variety of topics related to better understanding the complex challenges of ASD, especially in diverse patient populations such as Latinos and young adults with gender dysphoria.
Laura Anthony, Ph.D., clinical psychologist within CASD, led a panel session entitled, “Addressing Disparities through Interventions in Diverse Community Systems,” which highlighted four community based intervention projects aimed at tackling the vast disparities that exist in screening, diagnosis, acceptance, inclusion and access to evidence-based care, based on populations.
“Each of these studies takes place in very different community contexts,” says Dr. Anthony, “but they share common themes of addressing disparities, using intensive stakeholder input and community partnerships to increase successful adoption, and achieving sustainability through harnessing the existing community-based resources to administer the interventions.”
The panel presentations featured studies from Children’s National as well as other research institutions:
- Anthony’s co-investigation of the Sesame Workshop’s online tools called See Amazing in All Children and their effectiveness at providing useful education and resources for parents of children with ASD and at helping parents of non-ASD children feel more accepting of children on the spectrum.
- Lauren Kenworthy, Ph.D., presented findings from the first study comparing two school-based cognitive-behavioral interventions developed by Children’s National and Ivymount, a school for children with autism, ADHD and other special needs. The interventions target executive function/problem solving and increase children’s availability for learning at school. As the interventions are provided by school staff in the school setting, they hold promise to reach the many children who otherwise have no access to specialized clinical care for these disorders. As evidence of this, approximately half of the children in this large scale project in low-income public/charter schools had not received a diagnosis of ADHD or autism prior to the study.
- A study of the impacts of a stakeholder-informed primary care program to increase the rate of screening and referral for young Latino children (Georgetown University).
- An analysis of one program’s efforts to increase the use of evidence-based practices in publically-funded mental health centers (University of California, San Diego; University of California, Los Angeles; and University of Illinois).
Despite having vastly different designs, the panel also identified several common learned lessons from the studies. These include the amount of time required to build trusting relationships in previously neglected communities, and the need for creative and adaptive methodologies. Additionally, the importance of including individuals with ASD, their families and people in the community systems that serve them in stakeholder feedback sessions, and the need for specialized adaptations for each community’s unique needs.
Team members also presented ten research posters across a variety of specialty poster sessions, including Allison Ratto, Ph.D., a clinical psychologist at the CASD, who presented “Engaging Latino Families in ASD Treatment Research,” the first assessment of this type of effort to bring information and tools to Latino families in a way that makes them accessible.
“By developing an adaptive and flexible program, we were able to gain high levels of engagement from Latino families, who previously faced significant barriers to participation. The results show that if researchers take additional steps to build community trust and maintain stakeholder engagement, it is possible to recruit and retain study participants, and ultimately, meet the needs of underserved families.” Dr. Ratto concludes. Her poster was featured in a story in Spectrum News.
“IMFAR is definitely the premier opportunity to dialogue across disciplines and study methods,” says Dr. Kenworthy, who directs the CASD. “We hope that sharing our work at this prestigious meeting brings new understanding for our team and our colleagues in how to best meet the unique needs of psychologically, ethnically and economically diverse patients and families.”
It has been well established by researchers, including scientists at Children’s National Health System, that the Zika virus is responsible for a slew of birth defects – such as microcephaly, other brain malformations and retinal damage – in babies of infected mothers. But how the virus causes these often devastating effects, and who exactly is affected, has not been explained fully.
Also unknown is whether exposed babies that appear normal at birth are truly unaffected by the virus or have hidden problems that might surface later. The majority of babies born to Zika-infected mothers in the United States appear to have no evidence of Zika-caused birth defects, but that’s no guarantee that the virus has not caused lingering damage.
Recently, Sarah B. Mulkey, M.D., Ph.D., made a trip to Colombia, where Children’s National researchers are collaborating on a clinical study. There, she tested Zika-affected babies’ motor skills as they sat, stood and lay facing upward and downward. The international study aims to answer one of the most vexing questions about Zika: If babies’ brains appear “normal” at birth, have they survived Zika exposure in the womb with few neurological repercussions?
“We don’t know the long-term neurological consequences of having Zika if your brain looks normal,” says Dr. Mulkey, a fetal-neonatal neurologist who is a member of Children’s Congenital Zika Virus Program. “That is what’s so scary, the uncertainty about long-term outcomes.”
According to the Centers for Disease Control and Prevention (CDC), one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection results in birth defects in the fetus or infant. For the lion’s share of Zika-affected pregnancies, then, babies’ long-term prospects remain a mystery.
“This is a huge number of children to be impacted and the impact, as we understand, has the potential to be pretty significant,” Dr. Mulkey adds.
Dr. Mulkey, the lead author, presented the research group’s preliminary findings during the 2017 annual meeting of the Pediatric Academic Societies (PAS). The presentation was one of several that focused on the Zika virus. Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases at Children’s National, organized two invited symposia devoted to the topic of Zika: Clinical perspectives and knowledge gaps; and the science of Zika, including experimental models of disease and vaccines. Dr. DeBiasi’s presentation included an overview of the 68 Zika-exposed or infected women and infants seen thus far by Children’s multidisciplinary Congenital Zika Virus Program.
“As the world’s largest pediatric research meeting, PAS2017 is an ideal setting for panelists to provide comprehensive epidemiologic and clinical updates about the emergence of Congenital Zika Syndrome and to review the pathogenesis of infection as it relates to the fetal brain,” Dr. DeBiasi says. “With temperatures already rising to levels that support spread of the Aedes mosquito, it is imperative for pediatricians around the world to share the latest research findings to identify the most effective interventions.”
As one example, Dr. Mulkey’s research sought to evaluate the utility of using magnetic resonance imaging (MRI) to evaluate fetal brain abnormalities in 48 babies whose mothers had confirmed Zika infection during pregnancy. Forty-six of the women/infant pairs enrolled in the prospective study are Colombian, and two are Washington, D.C. women who were exposed during travel to a Zika hot zone.
The women were infected with Zika during all three trimesters and experienced symptoms at a mean gestational age of 8.4 weeks. The first fetal MRIs were performed as early as 18 weeks’ gestation. Depending upon the gestational age when they were enrolled in the study, the participants had at least one fetal MRI as well as serial ultrasounds. Thirty-six fetuses had a second fetal MRI at about 31.1 gestational weeks. An experienced pediatric neuroradiologist evaluated the images.
Among the 48 study participants, 45 had “normal” fetal MRIs.
Three fetuses exposed to Zika in the first or second trimester had abnormal fetal MRIs:
- One had heterotopia and an early, abnormal fold on the surface of the brain, indications that neurons did not migrate to their anticipated destination during brain development. This pregnancy was terminated at 23.9 gestational weeks.
- One had parietal encephalocele, a rare birth defect that results in a sac-like protrusion of the brain through an opening in the skull. According to the CDC, this defect affects one in 12,200 births, or 340 babies, per year. It is not known if this rare finding is related to Zika infection.
- One had a thin corpus callosum, dysplastic brainstem, heterotopias, significant ventriculomegaly and generalized cerebral/cerebellar atrophy.
“Fetal brain MRI detected early structural brain changes in fetuses exposed to the Zika virus in the first and second trimester,” Dr. Mulkey says. “The vast majority of fetuses exposed to Zika in our study had normal fetal MRI, however. Our ongoing study, underwritten by the Thrasher Research Fund, will evaluate their long-term neurodevelopment.”
Adré J. du Plessis, MB.Ch.B., M.P.H., director of the Fetal Medicine Institute and senior author of the paper, notes that this group “is a very important cohort to follow as long as Dr. Mulkey’s funding permits. We know that microcephaly is among the more devastating side effects caused by Zika exposure in utero. Unanswered questions remain about Zika’s impact on hearing, vision and cognition for a larger group of infants. Definitive answers only will come with long-term follow-up.”
Many of the Colombian families live in Sabanalarga, a relatively rural, impoverished area with frequent rain, leaving pockets of fresh water puddles that the mosquito that spreads Zika prefers, Dr. Mulkey adds. Families rode buses for hours for access to fetal MRI technology, which is not common in Colombia.
“The mothers are worried about their babies. They want to know if their babies are doing OK,” she says.
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.
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.”
When the brain is exposed to an environmental stressor all is not immediately lost. Brain cells have mechanisms that protect them against the ravages of alcohol and other toxic substances. One of these is a protein the cells make, known as Heat Shock Factor 1 (Hsf1), which helps to shield them from damage. The fetal brain also can make Hsf1, which protects its particularly vulnerable cells from environmental stressors that pregnant mothers are exposed to during gestation.
However, a new study suggests that this system is not perfect. Research led by Children’s National Health System scientists suggests that when too much Hsf1 is produced, it actually can impair the brain during development. While this finding was made in a preclinical model, it raises questions about neural risks for human infants if their mothers drink alcohol in the first or second trimester of pregnancy.
When fetuses are chronically exposed to harmful agents such as alcohol, ethanol or methyl mercury in utero, the experience can negatively affect fetal brain development in unpredictable ways. Some fetal brains show little or no damage, while others suffer severe damage. By looking at the earliest moments of embryonic brain development, an international research team that includes five Children’s National authors sought to explain the molecular and cellular bases for complex congenital brain disorders that can result from exposure to such harmful agents.
“From a public health perspective, there is ongoing debate about whether there is any level of drinking by pregnant women that is ‘safe,’ ” says Kazue Hashimoto-Torii, Ph.D., principal investigator in the Center for Neuroscience Research at Children’s National and senior author of the paper published May 2 in Nature Communications. “We gave ethanol to pregnant preclinical models and found their offspring’s neural cells experienced widely differing responses to this environmental stress. It remains unclear which precise threshold of stress exposure represents the tipping point, transforming what should be a neuroprotective response into a damaging response. Even at lower levels of alcohol exposure, however, the risk for fetal neural cells is not zero,” Hashimoto-Torii adds.
The cerebral cortex – the thin outer layer of the cerebrum and cerebellum that enables the brain to process information – is particularly vulnerable to disturbances in the womb, the study authors write. To fend off insult, neural cells employ a number of self-preservation strategies, including launching the protective Hsf1-Heat shock protein (Hsp) signaling pathway that is used by a wide range of organisms, from single-cell microbes to humans. Developing fetuses activate Hsf1-Hsp signaling upon exposure to environmental stressors, some to no avail.
To help unravel the neurological mystery, the researchers used a method that allows a single molecule to fluoresce during stress exposure. They tapped specific environmental stressors, such as ethanol, hydrogen peroxide and methyl mercury – each of which are known to produce oxidative stress at defined concentrations. And, using an experimental model, they examined the Hsf1 activation pattern in the developing cerebral cortex by creating a marker, an encoding gene tagged with a type of fluorescent protein that makes it glow bright red.
“Our results suggest that heterogeneous events of abnormal brain development may occur probabilistically – which explains patterns of cortical malformations that vary with each individual, even when these individuals are exposed to similar levels of environmental stressors,” Hashimoto-Torii adds.
Among the more striking findings, neural cells with excessively high levels of Hsf1-Hsp activation due to ethanol exposure experience disruptions to normal development, with delayed migration by immature cortical neurons. For the fetal brain to develop normally, neurons need to migrate to precise places in the brain at just the right time to enable robust neural connections. When neurons fail to arrive at their destinations or get there too late, there can be gaps in the neural network, compromising efficient and effective communication across the brain’s various regions.
“Even a short period of Hsf1 overactivation during prenatal development causes critical neuronal migration deficiency. The severity of deficiency depends on the duration of Hsf1 overactivation,” Hashimoto-Torii says. “Expression patterns vary, however, across various tissues. Stochastic response within individual cells may be largely responsible for variability seen within tissue and organs.”
The research team found one bright spot: Cortical neurons that stalled due to lack of the microtubule-associated molecule Dcx were able to regain their ability to migrate properly when the gene was replenished after birth. A reduction in Hsf1 activity after birth, however, did not show the same ability to trigger the “reset” button on neural development.
“The finding suggests that genes other than microtubule-associated genes may play pivotal roles in ensuring that migrating neurons reach their assigned destinations in the brain at the right time – despite the added challenge of excessive Hsf1 activation,” according to Hashimoto-Torii.
The first pregnant patient with worries about a possible Zika virus infection arrived at the Children’s National Health System Fetal Medicine Institute on Jan. 26, 2016, shortly after returning from international travel.
Sixteen months ago, the world was just beginning to learn how devastating the mosquito-borne illness could be to fetuses developing in utero. As the epidemic spread, a growing number of sun-splashed regions that harbor mosquitoes that efficiently spread the virus experienced a ballooning number of Zika-affected pregnancies and began to record sobering birth defects.
The Washington, D.C. patient’s concerns were well-founded. Exposure to Zika virus early in her pregnancy led to significant fetal brain abnormalities, and Zika virus lingered in the woman’s bloodstream months after the initial exposure — longer than the Centers for Disease Control and Prevention (CDC) then thought was possible.
The research paper describing the woman’s lengthy Zika infection, published by The New England Journal of Medicine, was selected as one of the most impactful research papers written by Children’s National authors in 2016.
In the intervening months, a multidisciplinary team at Children National has consulted on 66 pregnancies and infants with confirmed or suspected Zika exposure. Thirty-five of the Zika-related evaluations were prenatal, and 31 postnatal evaluations assessed the impact of in utero Zika exposure after the babies were born.
The continuum of Zika-related injuries includes tragedies, such as a 28-year-old pregnant woman who was referred to Children’s National after imaging hinted at microcephaly. Follow-up with sharper magnetic resonance imaging (MRI) identified severe diffuse thinning of the cerebral cortical mantle, evidence of parenchymal cysts in the white matter and multiple contractures of upper and lower extremities with muscular atrophy.
According to a registry of Zika-affected pregnancies maintained by the CDC, one in 10 pregnancies across the United States with laboratory-confirmed Zika virus infection has resulted in birth defects in the fetus or infant.
“More surprising than that percentage is the fact that just 25 percent of infants underwent neuroimaging after birth – despite the CDC’s recommendation that all Zika-exposed infants undergo postnatal imaging,” says Roberta L. DeBiasi, M.D., M.S., chief of the Division of Pediatric Infectious Diseases and co-director of the Congenital Zika Virus Program at Children’s National. “Clinicians should follow the CDC’s guidance to the letter, asking women about possible exposure to Zika and providing multidisciplinary care to babies after birth. Imaging is an essential tool to accurately monitor the growing baby’s brain development.”
Adré du Plessis, M.B.Ch.B., M.P.H., director of the Fetal Medicine Institute and Congenital Zika Virus Program co-leader, explains the challenges: ”When it comes to understanding the long-term consequences for fetuses exposed to the Zika virus, we are still on the steepest part of the learning curve. Identifying those children at risk for adverse outcomes will require a sustained and concerted multidisciplinary effort from conception well beyond childhood.”
In addition to counseling families in the greater Washington, D.C. region, the Children’s research team is collaborating with international colleagues to conduct a clinical trial that has been recruiting Zika-infected women and their babies in Colombia. Pediatric Resident Youssef A. Kousa, D.O., Ph.D., M.S., and Neurologist Sarah B. Mulkey, M.D., Ph.D., will present preliminary findings during Research and Education Week 2017.
In Colombia as well as the District of Columbia, a growing challenge continues to be assessing Zika’s more subtle effects on pregnancies, developing fetuses and infants, says Radiologist Dorothy Bulas, M.D., another member of Children’s multidisciplinary Congenital Zika Virus Program.
The most severe cases from Brazil were characterized by interrupted fetal brain development, smaller-than-normal infant head circumference, brain calcifications, enlarged ventricles, seizures and limbs folded at odd angles. In the United States and many other Zika-affected regions, Zika-affected cases with such severe birth defects are outnumbered by infants who were exposed to Zika in utero but have imaging that appears normal.
In a darkened room, Dr. Bulas pores over magnified images of the brains of Zika-infected babies, looking for subtle differences in structure that may portend future problems.
“There are some questions we have answered in the past year, but a number of questions remain unanswered,” Dr. Bulas says. “For neonates, that whole area needs assessment. As the fetal brain is developing, the Zika virus seems to affect the progenitor cells. They’re getting hit quite early on. While we may not detect brain damage during the prenatal period, it may appear in postnatal images. And mild side effects that may not be as obvious early on still have the potential to be devastating.”
In 2016, clinicians and research scientists working at Children’s National Health System published more than 1,100 articles in high-impact journals about a wide array of topics. A Children’s Research Institute review group selected the top articles for the calendar year considering, among other factors, work published in top-tier journals with impact factors of 9.5 and higher.
“Conducting world-class research and publishing the results in prestigious journals represents the pinnacle of many research scientists’ careers. I am pleased to see Children’s National staff continue this essential tradition,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “While it was difficult for us to winnow the field of worthy contenders to this select group, these papers not only inform the field broadly, they epitomize the multidisciplinary nature of our research,” Dr. Batshaw adds.
The published papers explain research that includes discoveries made at the genetic and cellular levels, clinical insights and a robotic innovation that promises to revolutionize surgery:
- Outcomes from supervised autonomous procedures are superior to surgery performed by expert surgeons
- The Zika virus can cause substantial fetal brain abnormalities in utero, without microcephaly or intracranial calcifications
- Mortality among injured adolescents was lower among patients treated at pediatric trauma centers, compared with adolescents treated at other trauma center types
- Hydroxycarbamide can substitute for chronic transfusions to maintain transcranial Doppler flow velocities for high-risk children with sickle cell anemia
- There is convincing evidence of the efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease
- Sirt1 is an essential regulator of oligodendrocyte progenitor cell proliferation and oligodendrocyte regeneration after neonatal brain injury
Read the complete list.
Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2017 at Children’s National, a weeklong event that begins April 24. This year’s theme, “Collaboration Leads to Innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.
Hypoxia, or a lack of oxygen, is a major cause of diffuse white matter injury (DWMI). This condition leads to permanent developmental disabilities in prematurely born infants. The long-term abnormalities of the brain’s white matter that characterize DWMI are caused by the loss of a specific type of cells known as oligodendrocytes, which support nerve cells and produce myelin, a lipid and protein sheath that electrically insulates nerve cells. Oligodendrocytes are produced by a population of immature cells known as oligodendrocyte progenitor cells (OPCs). Previous research has shown that hypoxia can trigger OPCs to proliferate and presumably produce new oligodendrocytes. The molecular pathways that hypoxia triggers to make new OPCs remain unclear.
A team of researchers led by Vittorio Gallo, Ph.D., director of the Center for Neuroscience Research and the Intellectual and Developmental Disabilities Research Center at Children’s National Health System, investigated the molecular mechanisms behind what prompts OPCs to proliferate in a preclinical model of neonatal hypoxia. The researchers found that a molecule known as Sirt1 acts as a major regulator of OPC proliferation and regeneration. Sirt1 is a sirtuin, a class of molecules that has attracted interest over the past several years for its role in stem cells, aging and inflammation. Hypoxia appears to induce Sirt1 formation. When the researchers prevented brain tissues in petri dishes from making Sirt1 or removed this molecule in preclinical models, these actions prevented OPC proliferation. What’s more, preventing Sirt1 production also inhibited OPCs from making oligodendrocytes. These findings suggest that Sirt1 is essential for replacing oligodendrocytes to repair DWMI after hypoxia. Additionally, finding ways to enhance Sirt1 activity eventually could provide a novel way to help infants recover after hypoxia and prevent DWMI.
Questions for future research
Q: How can Sirt1 activity be enhanced in preclinical models and humans?
Source: “Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury.” Jablonska, M., M. Gierdalski, L. Chew, T. Hawley, M. Catron, A. Lichauco, J. Cabrera-Luque, T. Yuen, D. Rowitch and V. Gallo. Published by Nature Communications on Dec. 19, 2016.
The Children’s National Health System Center for Neuroscience and Behavioral Medicine is proud to host the 27th Annual Pediatric Neurology Update course.
This year’s course will be focused on the new understandings, molecular biology and novel treatments of childhood movement disorders ranging from Tourette’s syndrome to incapacitating neuro-genetic and auto-immune conditions.
We invite you to join us for presentations from renowned experts in the field in this full-day, CME accredited event on April 19, 2017 at the Children’s National main campus in Washington, D.C.
When fetuses are exposed to environmental stressors, such as maternal smoking or alcohol consumption, radiation or too little oxygen, some of these cells can die. A portion of those that survive often have lingering damage and remain more susceptible to further environmental insults than healthy cells; however, researchers haven’t had a way to identify these weakened cells. This lack of knowledge has made it difficult to discover the mechanisms behind pathological brain development thought to arise from these very early environmental exposures, as well as ways to prevent or treat it.
A team led by Kazue Hashimoto-Torii, Ph.D., a principal investigator in the Center for Neuroscience Research at Children’s National Health System, developed a marker that makes a protein known as Heat Shock Factor 1 glow red. This protein is produced in cells that become stressed through exposure to a variety of environmental insults. Gestation is a particularly vulnerable time for rapidly dividing nerve cells in the fetal brain. Tests showed that this marker worked not just on cells in petri dishes but also in an experimental model to detect brain cells that were damaged and remained vulnerable after exposure to a variety of different stressors. Tweaks to the system allowed the researchers to follow the progeny of cells that were affected by the initial stressor and track them as they divided and spread throughout the brain. By identifying which neurons are vulnerable, the study authors say, researchers eventually might be able to develop interventions that could slow or stop damage before symptoms arise.
Questions for future research
Q: How do different environmental insults damage brain cells during gestation?
Source: Torii, M., S. Masanori, Y.W. Chang, S. Ishii, S.G. Waxman, J.D. Kocsis, P. Rakic and K. Hashimoto-Torii. “Detection of vulnerable neurons damaged by environmental insults in utero.” Published Dec. 22, 2016 by Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.1620641114
When 4-year-old Henry Lapham died in his sleep just weeks after being diagnosed with epilepsy in 2009, it was a shock to everyone — even his pediatrician and neurologist. Henry’s cause of death was sudden unexpected (or unexplained) death in epilepsy persons (SUDEP), a condition that causes sudden death in about 1 of every 1,000 otherwise healthy patients with epilepsy. Neither health care professional had mentioned this as a possibility, as remote as it was.
“I was desperate to make sense out of our tragedy,” writes Henry’s mother, Gardiner Lapham, R.N., M.P.H., in “Increasing awareness of sudden death in pediatric epilepsy together,” an article published in the February 2017 issue of Pediatrics. After her son’s death, by working with a group called Citizens United for Epilepsy Research, Lapham connected with other families affected by the same heartbreak. “I have met many bereaved family members,” she adds, “and the most consistent thing I hear is that they wish they had known about SUDEP.”
Now, a new collaboration with Children’s National Health System, where Henry received care, University of Virginia Medical Center (UVA) and other academic medical centers is helping to expand awareness of SUDEP among patients, families and caregivers alike. Known as Childhood Epilepsy Risks and Impact on Outcomes (CHERIO), the multiyear effort aims to develop approaches to increase knowledge about SUDEP and other conditions that can accompany epilepsy, such as attention deficit hyperactivity disorder, autism, anxiety, depression and sleep issues, according to co-authors of the Pediatrics article.
CHERIO got its start in 2014 at the American Epilepsy Society annual meeting. There, Lapham met Madison M. Berl, Ph.D., director of research, Division of Pediatric Neuropsychology at Children’s National, who studies epilepsy comorbidities. When Lapham asked what she could do to help raise awareness of SUDEP at Children’s National, she and Berl, along with William Davis Gaillard, M.D., Henry’s neurologist, hatched a plan.
Working with multiple disciplines and stakeholders, including neuropsychologists, psychiatrists, neurologists, epidemiologists, basic scientists, nurses and parent advocates at both Children’s National and UVA, CHERIO plans to assess the level of knowledge about SUDEP and other epilepsy comorbidities among medical providers and parents and to implement ways to increase knowledge. The first item on the agenda, Berl explains, was to conduct a survey to see just how much doctors knew about SUDEP.
“Although many neurologists are aware of this condition, ours was the first to survey pediatricians, and the majority was not aware of SUDEP – despite having children with epilepsy in their practice,” Dr. Gaillard says. “We know that many neurologists do not discuss SUDEP with patients and the reasons for not talking about SUDEP are varied. Thus, CHERIO felt that in addition to educating neurologists about the need to discuss the risk of death associated with epilepsy, increasing pediatricians’ awareness of SUDEP is one approach that could open more opportunities for families to have this discussion.”
To help make it easier to talk about this risk, the CHERIO team is developing strategies for doctors to start the conversation with patients and their families by framing SUDEP in the context of more common epilepsy comorbidities.
“Clinicians walk a fine line in giving information at the right time to make people more aware,” Berl adds, “but also being realistic and giving information that fits with what’s going on in a particular child’s case. By discussing SUDEP along with other, more common epilepsy risks, it brings context to a family so that they’re not unduly concerned about death – which also can paralyze a family and create unnecessary alarm.” The risk of death in most children with epilepsy is very low, slightly higher than the risks faced by healthy children. But parents of children with complicated epilepsy who have more risk factors for sudden death should be especially aware , she says.
Another way to help facilitate discussion may be through a simple tweak in the medical record, Berl adds. The team is currently developing a checklist that pops up annually in a patient’s medical record to remind clinicians of important points to discuss with patients and their families, including SUDEP.
Additionally, they are working on ways that can help families become more empowered to start the discussion themselves. Materials for the waiting room or questionnaires to fill out before appointments could trigger conversations with care providers, Berl says.
Last, the team also is collaborating with a medical device company that is working on a nighttime monitoring system that could provide an alert if patients with epilepsy experience nighttime seizures, a risk factor for SUDEP. Such technologies have not been proven to prevent SUDEP. Yet, it may help caregivers get help more quickly than if they did not receive the alert.
For each of these efforts, Berl notes, having Lapham as a partner has been key. “She’s part of our meetings and has input into the direction of each project,” Berl explains. “When you have a partner who is so close to the daily work you’re doing, it just heightens those efforts and brings to the forefront the simple message of why this is important.”
Unraveling one of the greatest mysteries of Sarah B. Mulkey’s research career started with a single child.
At the time, Mulkey, M.D., Ph.D., a fetal-neonatal neurologist in the Division of Fetal and Transitional Medicine at Children’s National Health System, was working at the University of Arkansas for Medical Sciences. Rounding one morning at the neonatal intensive care unit (NICU), she met a new patient: A newborn girl with an unusual set of symptoms. The baby was difficult to wake and rarely opened her eyes. Results from her electroencephalogram (EEG), a test of brain waves, showed a pattern typical of a severe brain disorder. She had an extreme startle response, jumping and twitching any time she was disturbed or touched, that was not related to seizures. She also had trouble breathing and required respiratory support.
Dr. Mulkey did not know what to make of her new patient: She was unlike any baby she had ever cared for before. “She didn’t fit anything I knew,” Dr. Mulkey remembers, “so I had to get to the bottom of what made this one child so different.”
Suspecting that her young patient’s symptoms stemmed from a genetic abnormality, Dr. Mulkey ran a targeted gene panel, a blood test that looks for known genetic mutations that might cause seizures or abnormal movements. The test had a hit: One of the baby’s genes, called KCNQ2, had a glitch. But the finding deepened the mystery even further. Other babies with a mutation in this specific gene have a distinctly different set of symptoms, including characteristic seizures that many patients eventually outgrow.
Dr. Mulkey knew that she needed to dig deeper, but she also knew that she could not do it alone. So, she reached out first to Boston Children’s Hospital Neurologist Philip Pearl, M.D., an expert on rare neurometabolic diseases, who in turn put her in touch with Maria Roberto Cilio, M.D., Ph.D., of the University of California, San Francisco and Edward Cooper, M.D., Ph.D., of Baylor College of Medicine. Drs. Cilio, Cooper and Pearl study KCNQ2 gene variants, which are responsible for causing seizures in newborns.
Typically, mutations in this gene cause a “loss of function,” causing the potassium channel to remain too closed to do its essential job properly. But the exact mutation that affected KCNQ2 in Dr. Mulkey’s patient was distinct from others reported in the literature. It must be doing something different, the doctors reasoned.
Indeed, a research colleague of Drs. Cooper, Cilio and Pearl in Italy — Maurizio Taglialatela, M.D., Ph.D., of the University of Naples Federico II and the University of Molise — had recently discovered in cell-based work that this particular mutation appeared to cause a “gain of function,” leaving the potassium channel in the brain too open.
Wondering whether other patients with this same type of mutation had the same unusual constellation of symptoms as hers, Dr. Mulkey and colleagues took advantage of a database that Dr. Cooper had started years earlier in which doctors who cared for patients with KCNQ2 mutations could record information about symptoms, lab tests and other clinical findings. They selected only those patients with the rare genetic mutation shared by her patient and a second rare KCNQ2 mutation also found to cause gain of function — a total of 10 patients out of the hundreds entered into the database. The researchers began contacting the doctors who had cared for these patients and, in some cases, the patients’ parents. They were scattered across the world, including Europe, Australia and the Middle East.
Dr. Mulkey and colleagues sent the doctors and families surveys, asking whether these patients had similar symptoms to her patient when they were newborns: What were their EEG results? How was their respiratory function? Did they have the same unusual startle response?
She is lead author of the study, published online Jan. 31, 2017 in Epilepsia, that revealed a brand-new syndrome that stems from specific mutations to KCNQ2. Unlike the vast majority of others with mutations in this gene, Dr. Mulkey and her international collaborators say, these gain-of-function mutations cause a distinctly different set of problems for patients.
Dr. Mulkey notes that with a growing focus on precision medicine, scientists and doctors are becoming increasingly aware that knowing about the specific mutation matters as much as identifying the defective gene. With the ability to test for more and more mutations, she says, researchers likely will discover more cases like this one: Symptoms that differ from those that usually strike when a gene is mutated because the particular mutation differs from the norm.
Such cases offer important opportunities for researchers to come together to share their collective expertise, she adds. “With such a rare diagnosis,” Dr. Mulkey says, “it’s important for physicians to reach out to others with knowledge in these areas around the world. We can learn much more collectively than by ourselves.”
The Doppler image on the oversized computer screen shows the path taken by blood as it flows through the newborn’s brain, with bright blue distinguishing blood moving through the middle cerebral artery toward the frontal lobe and bright red depicting blood coursing away. Pitch black zones indicate ventricles, cavities through which cerebrospinal fluid usually flows and where hydrocephalus can get its start.
The buildup of excess cerebrospinal fluid in the brain can begin in the womb and can be detected by fetal magnetic resonance imaging. Hydrocephalus also can crop up after birth due to trauma to the head, an infection, a brain tumor or bleeding in the brain, according to the National Institutes of Health. An estimated 1 to 2 per 1,000 newborns have hydrocephalus at birth.
When parents learn of the hydrocephalus diagnosis, their first question tends to be “Is my child going to be OK?” says Suresh Magge, M.D., a pediatric neurosurgeon at Children’s National Health System.
“We have a number of ways to treat hydrocephalus. It is one of the most common conditions that pediatric neurosurgeons treat,” Dr. Magge adds.
Unlike fluid build-up elsewhere in the body where there are escape routes, with hydrocephalus spinal fluid becomes trapped in the brain. To remove it, surgeons typically implant a flexible tube called a shunt that drains excess fluid into the abdomen, an interim stop before it is flushed away. Another surgical technique, called an endoscopic third ventriculostomy has the ability to drain excess fluid without inserting a shunt, but it only works for select types of hydrocephalus, Dr. Magge adds.
For the third year, Dr. Magge is helping to organize the Hydrocephalus Education Day on Feb. 25, a free event that offers parents an opportunity to learn more about the condition.
Reflective of the myriad symptoms and complications that can accompany hydrocephalus, such as epilepsy, cerebral palsy, cortical vision impairment and global delays, a multidisciplinary team at Children’s National works with patients and families for much of childhood.
Neuropsychologist Yael Granader, Ph.D., works with children ages 4 and older who have a variety of developmental and medical conditions. Granader is most likely to see children and adolescents with hydrocephalus once they become medically stable in order to assist in devising a plan for school support services and therapeutic interventions. Her assessments can last an entire day as she administers a variety of tasks that evaluate how the child thinks and learns, such as discerning patterns, assembling puzzles, defining words, and listening to and remembering information.
Neuropsychologists work with schools in order to help create the most successful academic environment for the child. For example, some children may struggle to visually track across a page accurately while reading; providing a bookmark to follow beneath the line is a helpful and simple accommodation to put in place. Support for physical limitations also are discussed with schools in order to incorporate adaptive physical education or to allow use of an elevator in school.
“Every child affected by hydrocephalus is so different. Every parent should know that their child can learn,” Granader says. “We’re going to find the best, most supportive environment for them. We are with them on their journey and, every few years, things will change. We want to be there to help with emerging concerns.”
Another team member, Justin Burton, M.D., a pediatric rehabilitation specialist, says rehabilitation medicine’s “piece of the puzzle is doing whatever I can to help the kids function better.” That means dressing, going to the bathroom, eating and walking independently. With babies who have stiff, tight muscles, that can mean helping them through stretches, braces and medicine management to move muscles smoothly in just the way their growing bodies want. Personalized care plans for toddlers can include maintaining a regular sleep-wake cycle, increasing attention span and strengthening such developmental skills as walking, running and climbing stairs. For kids 5 and older, the focus shifts more to academic readiness, since those youths’ “full-time job” is to become great students, Dr. Burton says.
The area of the hospital where children work on rehabilitation is an explosion of color and sounds, including oversized balance balls of varying dimensions in bright primary colors, portable basketball hoops with flexible rims at multiple heights, a set of foam stairs, parallel bars, a climbing device that looks like the entry to playground monkey bars and a chatterbox toy that lets a patient know when she has opened and closed the toy’s doors correctly.
“We end up taking care of these kids for years and years,” he adds. “I always love seeing the kids get back to walking and talking and getting back to school. If we can get them back out in the world and they’re doing things just like every other kid, that’s success.”
Meanwhile, Dr. Magge says research continues to expand the range of interventions and to improve outcomes for patients with hydrocephalus, including:
- Fluid dynamics of cerebrospinal fluid
- Optimal ways to drain excess fluid
- Improving understanding of why shunts block
- Definitively characterizing post-hemorrhagic ventricular dilation.
Unlike spina bifida, which sometimes can be corrected in utero at some health institutions, hydrocephalus cannot be corrected in the womb. “While we have come a long way in treating hydrocephalus, there is still a lot of work to be done. We continue to learn more about hydrocephalus with the aim of continually improving treatments,” Dr. Magge says.
During a recent office visit, 5-year-old Abagail’s head circumference had measured ¼ centimeter of growth, an encouraging trend, Robert Keating, M.D., Children’s Chief of Neurosurgery, tells the girl’s mother, Melissa J. Kopolow McCall. According to Kopolow McCall, who co-chairs the Hydrocephalus Association DC Community Network, it is “hugely” important that Children’s National infuses its clinical care with the latest research insights. “I have to have hope that she is not going to be facing a lifetime of brain surgery, and the research is what gives me the hope.”
Michael J. Bell, M.D., will join Children’s National as Chief of the Division of Critical Care Medicine, in April 2017.
Dr. Bell is a nationally known expert in the field of pediatric neurocritical care, and established the pediatric neurocritical care program at the Children’s Hospital of UPMC in Pittsburgh.
He is a founding member of the Pediatric Neurocritical Care Research Group, an international consortia of 40 institutions dedicated to advancing clinical research for children with critical neurological illnesses. Prior to joining the University of Pittsburgh, Dr. Bell served on the faculty at Children’s National and simultaneously conducted research on the impact of inflammation on the developing brain at the National Institute of Neurological Disorders and Stroke (NINDS), within the laboratory of the Chief of the NINDS Stroke Branch.
Dr. Bell also leads the largest study to date evaluating the impact of interventions on the outcomes of infants and children with severe traumatic brain injury (TBI) and analyzing findings to improve clinical practice across the world. The Approaches and Decisions for Acute Pediatric Traumatic Brain Injury (ADAPT) Trial, funded by NINDS, has enrolled 1,000 children through 50 clinical sites across eight countries and compiled an unmatched database, which will be used to develop new guidelines for clinical care and research on TBIs. Dr. Bell is currently working on expanding the scope and continuing the trial for at least the next 5 years.
In his time at Children’s National, he played a critical role in building one of the first clinical pediatric neuro-critical care consult services in the country, which established common protocols between Children’s Divisions of Critical Care Medicine, Neurology, and Neurosurgery aimed at improving clinical care of children with brain injuries. Dr. Bell’s current research interests include: barriers to implementation of traumatic brain injury guidelines, the effect of hypothermia on various brain injuries and applications for neurological markers in a clinical setting.
The Children’s National Division of Critical Care Medicine is a national leader in the care of critically ill and injured infants and children, with clinical outcomes and safety measures among the best in the country across the pediatric, cardiac, and neuro critical care units.
Javad Nazarian, Ph.D., has been named scientific director of the Brain Tumor Institute of the Children’s National Health System. Since 2006, Dr. Nazarian has been an active member of the Brain Tumor Institute, contributing to the advancement in understanding pediatric brain tumors.
He has been instrumental in his role as a Principal Investigator in the Center for Cancer and Immunology Research where his laboratory actively investigates the molecular mechanisms of diffuse intrinsic pontine gilomas (DIPGs) and establishes preclinical models of pediatric brain tumors.
Dr. Nazarian has also contributed to the expansion of the comprehensive biorepository at Children’s National, growing from 12 samples six years ago to more than 3,000 specimens donated by more than 900 patients with all types of pediatric brain tumors, including DIPG. Recently he was appointed Scientific Co-chair of the Children’s Brain Tumor Tissue Consortium.
Disruptions in cerebral oxygen supply caused by congenital heart disease have significant impact on cortical growth, according to a research led by Children’s National Health System. The findings of the research team, which include co-authors from the National Institutes of Health, Boston Children’s Hospital and Johns Hopkins School of Medicine, appear on the cover of Science Translational Medicine. The subventricular zone (SVZ) in normal newborns’ brains is home to the largest stockpile of neural stem/progenitor cells, with newly generated neurons migrating from this zone to specific regions of the frontal cortex and differentiating into interneurons. When newborns experience disruptions in cerebral oxygen supply due to congenital heart disease, essential cellular processes go awry and this contributes to reduced cortical growth.
The preliminary findings point to the importance of restoring these cells’ neurogenic potential, possibly through therapeutics, to lessen children’s long-term neurological deficits.
“We know that congenital heart disease (CHD) reduces cerebral oxygen at a time when the developing fetal brain most needs oxygen. Now, we are beginning to understand the mechanisms of CHD-induced brain injuries at a cellular level, and we have identified a robust supply of cells that have the ability to travel directly to the site of injury and potentially provide help by replacing lost or damaged neurons,” says Nobuyuki Ishibashi, M.D., Director of the Cardiac Surgery Research Laboratory at Children’s National, and co-senior study author.
The third trimester of pregnancy is a time of dramatic growth for the fetal brain, which expands in volume and develops complex structures and network connections that growing children rely on throughout adulthood. According to the National Heart, Lung, and Blood Institute, congenital heart defects are the most common major birth defect, affecting 8 in 1,000 newborns. Infants born with CHD can experience myriad neurological deficits, including behavioral, cognitive, social, motor and attention disorders, the research team adds.
Cardiologists have tapped noninvasive imaging to monitor fetal hearts during gestation in high-risk pregnancies and can then perform corrective surgery in the first weeks of life to fix damaged hearts. Long term neurological deficits due to immature cortical development also have emerged as major challenges in pregnancies complicated by CHD.
“I think this is an enormously important paper for surgeons and for children and families who are affected by CHD. Surgeons have been worried for years that the things we do during corrective heart surgery have the potential to affect the development of the brain. And we’ve learned to improve how we do heart surgery so that the procedure causes minimal damage to the brain. But we still see some kids who have behavioral problems and learning delays,” says Richard A. Jonas, M.D., Chief of the Division of Cardiac Surgery at Children’s National, and co-senior study author. “We’re beginning to understand that there are things about CHD that affect the development of the brain before a baby is even born. What this paper shows is that the low oxygen level that sometimes results from a congenital heart problem might contribute to that and can slow down the growth of the brain. The good news is that it should be possible to reverse that problem using the cells that continue to develop in the neonate’s brain after birth.”
Among preclinical models, the spatiotemporal progression of brain growth in this particular model most closely parallels that of humans. Likewise, the SVZ cytoarchitecture of the neonatal preclinical model exposed to hypoxia mimics that of humans in utero and shortly after birth. The research team leveraged CellTracker Green to follow the path traveled by SVZ derived cells and to illuminate their fate, with postnatal SVZ supplying the developing cortex with newly generated neurons. SVZ derived cells were primarily neuroblasts. Superparamagnetic iron oxide nanoparticles supplied answers about long term SVZ migration, with SVZ derived cells making their way to the prefrontal cortex and the somatosensory cortex of the brain.
“We demonstrated that in the postnatal period, newly generated neurons migrate from the SVZ to specific cortices, with the majority migrating to the prefrontal cortex,” says Vittorio Gallo, Ph.D., Director of the Center for Neuroscience Research at Children’s National, and co-senior study author. “Of note, we revealed that the anterior SVZ is a critical source of newborn neurons destined to populate the upper layers of the cortex. We challenged this process through chronic hypoxia exposure, which severely impaired neurogenesis within the SVZ, depleting this critical source of interneurons.”
In the preclinical model of hypoxia as well as in humans, brains were smaller, weighed significantly less and had a significant reduction in cortical gray matter volume. In the prefrontal cortex, there was a significant reduction in white matter neuroblasts. Taken as a whole, according to the study authors, the findings suggest that impaired neurogenesis within the SVZ represents a cellular mechanism underlying hypoxia induced, region specific reduction in immature neurons in the cortex. The prefrontal cortex, the region of the brain that enables such functions as judgment, decision making and problem solving, is most impacted. Impairments in higher order cognitive functions involving the prefrontal cortex are common in patients with CHD.
Eight of every 1,000 children born each year have congenital heart disease (CHD). Although recent advances have greatly improved the survival of these children, up to 55 percent will be left with injury to their brain’s white matter – an area that is critical for aiding connection and communication between various regions in the brain. The resulting spectrum of neurological deficits can have significant costs for the individual, their family and society. Although studies have demonstrated that white matter injuries due to CHD have many contributing factors, including abnormal blood flow to the fetal brain, many questions remain about the mechanisms that cause these injuries and the best interventions.
A Children’s National Health System research team combed existing literature, reviewing studies from Children’s as well as other research groups, to develop an article detailing the current state of knowledge on CHD and white matter injury. The scientists write that advances in neuroimaging – including magnetic resonance imaging, magnetic resonance spectroscopy, Doppler ultrasound and diffusion tensor imaging – have provided a wealth of knowledge about brain development in patients who have CHD. Unfortunately, these techniques alone are unable to provide pivotal insights into how CHD affects cells and molecules in the brain. However, by integrating animal models with findings in human subjects and in postmortem human tissue, the scientists believe that it will be possible to find novel therapeutic targets and new standards of care to prevent developmental delay associated with cardiac abnormalities.
For example, using a porcine model, the Children’s team was able to define a strategy for white matter protection in congenital heart surgery through cellular and developmental analysis of different white matter regions. Another study from Children’s combined rodent hypoxia with a brain slice model to replicate the unique brain conditions in neonates with severe and complex congenital heart disease. This innovative animal model provided novel insights into the possible additive effect of preoperative hypoxia on brain insults due to cardiopulmonary bypass and deep hypothermic circulatory arrest.
The Children’s research team also recently published an additional review article describing the key windows of development during which the immature brain is most vulnerable to CHD-related injury.
Questions for future research
Q: Can we create an animal model that recapitulates the morphogenic and developmental aspects of CHD without directly affecting other organs or developmental processes?
Source: Reprinted from Trends in Neurosciences, Vol. 38/Ed. 6, Paul D. Morton, Nobuyuki Ishibashi, Richard A. Jonas and Vittorio Gallo, “Congenital cardiac anomalies and white matter injury,” pp. 353-363, Copyright 2015, with permission from Elsevier.
The Thrasher Research Fund will fund a Children’s National Health System project, “Defining a new parameter for post-hemorrhagic ventricular dilation in premature infants,” as part of its Early Career Award Program, an initiative designed to support the successful training and mentoring of the next generation of pediatric researchers.
The proposal was submitted by Rawad Obeid, M.D., a neonatal neurology clinical research fellow at Children’s National who will serve as the project’s principal investigator. The competition for one-year Thrasher Research Fund awards is highly competitive with just two dozen granted across the nation. Research clinicians at Children’s National received two awards this funding cycle, with another awarded to support a neurologic outcomes study about Zika-affected pregnancies led by Fetal-Neonatal Neurologist Sarah B. Mulkey, M.D., Ph.D.
“Preterm infants born earlier than the 29th gestational week are at high risk for developing cerebral palsy and other brain injuries,” Dr. Obeid says. “Infants with intraventricular hemorrhage (IVH) followed by hydrocephalus (post-hemorrhagic hydrocephalus) face the highest risks of such brain injuries.”
Dr. Obeid hypothesizes that measuring distinct frontal and temporal horn ratio trajectories in extremely premature infants with and without IVH will help to definitively characterize post-hemorrhagic ventricular dilation (PHVD). Right now, experts disagree about the degree of PHVD that should trigger treatment to avoid life-long impairment.
He will be mentored by Anna A. Penn, M.D., Ph.D., Director, Translational Research for Hospital-Based Services & Board of Visitors Cerebral Palsy Prevention Program; Taeun Chang, M.D., Director of the Neonatal Neurology Program within the Division of Neurophysiology, Epilepsy & Critical Care; and Dorothy Bulas, M.D., F.A.C.R., F.A.I.U.M., F.S.R.U., Vice Chief of Academic Affairs.
In the award nomination letter, Dr. Penn noted that in “clinical settings and in the laboratory, I have supervised many trainees, but a trainee like Dr. Obeid is rare. He has pursued his research interests with great commitment. Before coming to Children’s National, he already had multiple job offers, but chose further training to enhance his research skills. While I have worked with many accomplished students, residents and fellows, Dr. Obeid stands out not only for his strong clinical skills, but also for his eagerness to learn and his dedication to both his patients and his research.”
A new three-year, multi-million dollar research and education collaboration in maternal, fetal and neonatal medicine aims to improve the health of pregnant women and their children. The partnership between Children’s National Health System and Inova will yield a major, nationally competitive research and academic program in these areas that will leverage the strengths of both health care facilities and enhance the quality of care available for these vulnerable populations.
The collaboration will streamline completion of retrospective and prospective research studies, shedding light on a number of conditions that complicate pregnancies. It is one of several alliances between the two institutions aimed at improving the health and well-being of children in Northern Virginia and throughout the region.
“The Washington/Northern Virginia region has long had the capability to support a major, nationally competitive research and academic program in maternal and fetal medicine,” says Adre du Plessis, M.B.Ch.B., Director of the Fetal Medicine Institute at Children’s National and a co-Principal Investigator for this partnership. “The Children’s National/Inova maternal-fetal-neonatal research education program will fill this critical void.
“This new partnership will help to establish a closer joint education program between the two centers, working with the OB/Gyn residents at Inova and ensuring their involvement in Children’s National educational programs and weekly fetal case review meetings,” Dr. du Plessis adds.
Larry Maxwell, M.D., Chairman of Obstetrics and Gynecology at Inova Fairfax Medical Campus and a co-Principal Investigator for the collaboration, further emphasizes that “Inova’s experience in caring for women and children — combined with genomics- and proteomics-based research — will synergize with Children National’s leadership in neonatal pediatrics, placental biology and fetal magnetic resonance imaging (MRI) to create an unprecedented research consortium. This will set the stage for developing clinically actionable interventions for mothers and babies in metropolitan District of Columbia.”
Children’s National, ranked No. 3 nationally in neonatology, has expertise in pediatric neurology, fetal and neonatal neurology, fetal and pediatric cardiology, infectious diseases, genetics, neurodevelopment and dozens of additional pediatric medical subspecialties. Its clinicians are national leaders in next-generation imaging techniques, such as MRI. Eighteen specialties and 50 consultants evaluate more than 700 cases per year through its Fetal Medicine Institute. In mid-2016, Children’s National created a Congenital Zika Virus Program to serve as a dedicated resource for referring clinicians and pregnant women. The hospital performs deliveries in very high-risk, complex situations, but does not offer a routine labor and delivery program.
Inova Fairfax Medical Campus is home to both Inova Women’s Hospital and Inova Children’s Hospital. Inova Women’s Hospital is the region’s most comprehensive and highest-volume women’s hospital — delivering more than 10,000 babies in 2016. Inova Children’s Hospital serves as Northern Virginia’s children’s hospital —providing expert care in pediatric and fetal cardiology, cardiac surgery, genetics, complex general surgery, neurology, neurosurgery and other medical and surgical specialties. Its 108-bed Level IV neonatal intensive care unit is one of the largest and most comprehensive in the nation. Inova’s Translational Medicine Institute includes a genomics lab, as well as a research Institute focused on studies designed to build genetic models that help answer questions about individual disease. Each of these specialties is integrated into the Inova Fetal Care Center — which serves as a connection point between Inova Women’s and Children’s Hospitals. The Inova Fetal Care Center provides complex care coordination for women expecting infants with congenital anomalies or with other fetal concerns. Because Inova Women’s Hospital and Inova Children’s Hospital are co-located, women are able to deliver their babies in the same building where their children will receive care.
The research collaboration will support research assistants; tissue technicians; a placental biologist; as well as support for biomedical engineering, fetal-neonatal imaging, telemedicine, regulatory affairs and database management. The joint research projects that will take place under its auspices include:
- Fetal growth restriction (FGR), which occurs when the failing placenta cannot support the developing fetus adequately. FGR is a major cause of stillbirth and death, and newborns who survive face numerous risks for multiple types of ailments throughout their lives. A planned study will use quantitative MRI to identify signs of abnormal brain development in pregnancies complicated by FGR.
- Placental abnormalities, including placenta accreta. A planned study will combine quantitative MRI studies on the placenta during the third trimester and other points in time with formal histopathology to identify MRI signals of placenta health and disease.
- Microcephaly, a condition that is characterized by babies having a much smaller head size than expected due to such factors as interrupted brain development or brain damage during pregnancy. While the global Zika virus epidemic has heightened awareness of severe microcephaly cases, dozens of pregnancies in the region in recent years have been complicated by the birth defect for reasons other than Zika infection. A planned study will examine the interplay between MRI within the womb and head circumference and weight at birth to examine whether brain volume at birth correlates with the baby’s developmental outcomes.