illustration of brain showing cerebellum

Focusing on the “little brain” to rescue cognition

illustration of brain showing cerebellum

Research faculty at Children’s National in Washington, D.C., with colleagues recently published a review article in Nature Reviews Neuroscience that covers the latest research about how abnormal development of the cerebellum leads to a variety of neurodevelopmental disorders.

Cerebellum translates as “little brain” in Latin. This piece of anatomy – that appears almost separate from the rest of the brain, tucked under the two cerebral hemispheres – long has been known to play a pivotal role in voluntary motor functions, such as walking or reaching for objects, as well as involuntary ones, such as maintaining posture.

But more recently, says Aaron Sathyanesan, Ph.D., a postdoctoral research fellow at the Children’s Research Institute, the research arm of Children’s National  in Washington, D.C., researchers have discovered that the cerebellum is also critically important for a variety of non-motor functions, including cognition and emotion.

Sathyanesan, who studies this brain region in the laboratory of Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National and scientific director of the Children’s Research Institute, recently published a review article with colleagues in Nature Reviews Neuroscience covering the latest research about how altered development of the cerebellum contributes to a variety of neurodevelopmental disorders.

These disorders, he explains, are marked by problems in the nervous system that arise while it’s maturing, leading to effects on emotion, learning ability, self-control, or memory, or any combination of these. They include diagnoses as diverse as intellectual disability, autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder and Down syndrome.

“One reason why the cerebellum might be critically involved in each of these disorders,” Sathyanesan says, “is because its developmental trajectory takes so long.”

Unlike other brain structures, which have relatively short windows of development spanning weeks or months, the principal cells of the cerebellum – known as Purkinje cells – start to differentiate from stem cell precursors at the beginning of the seventh gestational week, with new cells continuing to appear until babies are nearly one year old.  In contrast, cells in the neocortex, a part of the brain involved in higher-order brain functions such as cognition, sensory perception and language is mostly finished forming while fetuses are still gestating in the womb.

This long window for maturation allows the cerebellum to make connections with other regions throughout the brain, such as extensive connections with the cerebral cortex, the outer layer of the cerebrum that plays a key role in perception, attention, awareness, thought, memory, language and consciousness. It also allows ample time for things to go wrong.

“Together,” Sathyanesan says, “these two characteristics are at the root of the cerebellum’s involvement in a host of neurodevelopmental disorders.”

For example, the review article notes, researchers have discovered both structural and functional abnormalities in the cerebellums of patients with ASD. Functional magnetic resonance imaging (MRI), an imaging technique that measures activity in different parts of the brain, suggests that significant differences exist between connectivity between the cerebellum and cortex in people with ASD compared with neurotypical individuals. Differences in cerebellar connectivity are also evident in resting-state functional connectivity MRI, an imaging technique that measures brain activity in subjects when they are not performing a specific task. Some of these differences appear to involve patterns of overconnectivity to different brain regions, explains Sathyanesan; other differences suggest that the cerebellums of patients with ASD don’t have enough connections to other brain regions.

These findings could clarify research from Children’s National and elsewhere that has shown that babies born prematurely often sustain cerebellar injuries due to multiple hits, including a lack of oxygen supplied by infants’ immature lungs, he adds. Besides having a sibling with ASD, premature birth is the most prevalent risk factor for an ASD diagnosis.

The review also notes that researchers have discovered structural changes in the cerebellums of patients with Down syndrome, who tend to have smaller cerebellar volumes than neurotypical individuals. Experimental models of this trisomy recapitulate this difference, along with abnormal connectivity to the cerebral cortex and other brain regions.

Although the cerebellum is a pivotal contributor toward these conditions, Sathyanesan says, learning more about this brain region helps make it an important target for treating these neurodevelopmental disorders. For example, he says, researchers are investigating whether problems with the cerebellum and abnormal connectivity could be lessened through a non-invasive form of brain stimulation called transcranial direct current stimulation or an invasive one known as deep brain stimulation. Similarly, a variety of existing pharmaceuticals or new ones in development could modify the cerebellum’s biochemistry and, consequently, its function.

“If we can rescue the cerebellum’s normal activity in these disorders, we may be able to alleviate the problems with cognition that pervade them all,” he says.

In addition to Sathyanesan and Senior Author Gallo, Children’s National study co-authors include Joseph Scafidi, D.O., neonatal neurologist; Joy Zhou and Roy V. Sillitoe, Baylor College of Medicine; and Detlef H. Heck, of University of Tennessee Health Science Center.

Financial support for research described in this post was provided by the National Institute of Neurological Disorders and Stroke under grant numbers 5R01NS099461, R01NS089664, R01NS100874, R01NS105138 and R37NS109478; the Hamill Foundation; the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center under grant number U54HD083092; the University of Tennessee Health Science Center (UTHSC) Neuroscience Institute; the UTHSC Cornet Award; the National Institute of Mental Health under grant number R01MH112143; and the District of Columbia Intellectual and Developmental Disabilities Research Center under grant number U54 HD090257.

Children’s National ranked No. 6 overall and No. 1 for newborn care by U.S. News

Children’s National in Washington, D.C., is the nation’s No. 6 children’s hospital and, for the third year in a row, its neonatology program is No.1 among all children’s hospitals providing newborn intensive care, according to the U.S. News Best Children’s Hospitals annual rankings for 2019-20.

This is also the third year in a row that Children’s National has been in the top 10 of these national rankings. It is the ninth straight year it has ranked in all 10 specialty services, with five specialty service areas ranked among the top 10.

“I’m proud that our rankings continue to cement our standing as among the best children’s hospitals in the nation,” says Kurt Newman, M.D., President and CEO for Children’s National. “In addition to these service lines, today’s recognition honors countless specialists and support staff who provide unparalleled, multidisciplinary patient care. Quality care is a function of every team member performing their role well, so I credit every member of the Children’s National team for this continued high performance.”

The annual rankings recognize the nation’s top 50 pediatric facilities based on a scoring system developed by U.S. News. The top 10 scorers are awarded a distinction called the Honor Roll.

“The top 10 pediatric centers on this year’s Best Children’s Hospitals Honor Roll deliver outstanding care across a range of specialties and deserve to be nationally recognized,” says Ben Harder, chief of health analysis at U.S. News. “According to our analysis, these Honor Roll hospitals provide state-of-the-art medical expertise to children with rare or complex conditions. Their rankings reflect U.S. News’ assessment of their commitment to providing high-quality, compassionate care to young patients and their families day in and day out.”

The bulk of the score for each specialty is based on quality and outcomes data. The process also includes a survey of relevant specialists across the country, who are asked to list hospitals they believe provide the best care for patients with challenging conditions.

Below are links to the five specialty services that U.S. News ranked in the top 10 nationally:

The other five specialties ranked among the top 50 were cardiology and heart surgery, diabetes and endocrinology, gastroenterology and gastro-intestinal surgery, orthopedics, and urology.

Jana and Stephen Monaco

Prenatal screening: the story of two siblings

Alex and Stephen Monaco

Stephen Monaco with his brother before a life-changing incident in 2001.

Jana and Tom Monaco have four children and two, Stephen and Caroline, were born with isovaleric acidemia (IVA) and secondary carnitine deficiency, a rare metabolic disorder. This genetic condition prevents the body from producing enzymes to break down the amino acid leucine, found in many proteins – from nuts and beans to chicken and fish. If undetected, the condition, which affects about one in 250,000 children, can be fatal. IVA can also lead to autism or severe brain damage. Fortunately, newborn screenings in every state now detect most IVA cases.

Eighteen years ago, a series of events happened with Stephen, age 3.5 at the time, which led to his diagnosis of having IVA and secondary carnitine deficiency. He celebrated his grandmother’s birthday with a family dinner on Memorial Day. The next day he woke up with symptoms of a stomach virus, which the family treated as such. The following morning he didn’t wake up at all. Jana went to his room to check on him and realized something was wrong. She called an ambulance and within 24 hours Stephen fell into a coma in her arms. He was immediately put on life support at a Virginia hospital.

Amy Lewanda, M.D., a geneticist, and Craig Futterman, M.D., an intensivist, both of whom now work at Children’s National Health System, delivered news about the condition: IVA is an inability for the IVD gene to create enzymes to break down protein. Within a 24- to 48-hour period, Stephen’s body flooded with isovaleric acid it couldn’t break down. Once the acid reached his brain he was paralyzed. Jana mentions you could find him in the emergency department of the hospital by following the odor: He reeked of ketones and isovaleric acid, which accumulated in his blood and body tissue. His blood glucose level was so low that he was practically in a diabetic coma.

Jana and Stephen Monaco

Jana and Stephen Monaco, at a charity golf tournament established in Stephen’s honor to raise awareness about and support for isovaleric acidemia (IVA).

If the Monaco family was able to get his blood checked locally at the hospital – which the clinicians did not yet have the ability to do because this condition is so rare – they may have been able to receive an early diagnosis, enabling them to intervene in infancy, as they did with their youngest daughter, Caroline.

After the diagnosis, in hindsight, Jana and Tom recognized Stephen’s symptoms as a toddler: picky eating, anemia, rejection of protein-rich foods, such as favoring jelly over peanut butter on a PB&J sandwich, opting for easy carbs, since they are easier for those with IVA to process, and breastfeeding longer, since breast milk is lower in protein. He had a peculiar odor trailing from his diaper, a common symptom of this condition. They also remembered he had a harder time recovering from a stomach virus, which left him weak and floppy, compared to one of his brothers, who had the same flu but bounced back faster. As parents, they did everything they could to promote healthy growth and development for their children – from properly installing  car seats to staying up-to-date on vaccines and enrolling everyone in activities, like Little League. They only wished they could have detected this condition earlier.

A second chance arrived six months after Stephen was diagnosed with IVA: Jana and Tom learned they were pregnant with Caroline. From studying Stephen’s condition, they knew Caroline had a 25 percent chance of having IVA and secondary carnitine deficiency. (Jana and Tom are recessive carriers for a mutated IVD gene, but remain asymptomatic.) They scheduled an amniocentesis, a prenatal test that provides information about a baby’s health from sample amniotic fluid, which can diagnose genetic defects and fetal infections. Caroline was just 16 weeks in utero, but abnormal metabolites from the amniotic fluid sample confirmed she had IVA and secondary carnitine deficiency.

Caroline Monaco

Caroline, a healthy teenager with IVA, is an example of the benefits of newborn screenings and early-life medical interventions.

Having advance knowledge about the condition enabled doctors and geneticists to create a plan for her delivery, which made a difference between her long-term prognosis and Stephen’s. After birth, she was transferred to the neonatal intensive care unit at Children’s National. She was fed a formula that prevented excess isovaleric acid build-up, part of an hour-by-hour protocol to ensure she stayed healthy. Caroline is now 16. She plays the viola in her school orchestra, rides horses and excels in school.

When Stephen was born, the state of Virginia, where the Monaco family lives, screened for eight prenatal conditions, such as PKU, a rare but more common condition. The state now screens for 31 conditions, thanks in part to Jana, Stephen and Caroline. The list grows as research evolves. Jana started advocating for these efforts in Richmond and on Capitol Hill when Caroline was 2. Her approach: Take Stephen and Caroline to her state capitol and to the U.S. Capitol to push for statewide newborn screenings – visually showing the same condition, but with two very different outcomes. How could anyone say no?

She worked with the Virginia Genetics Advisory Council and with the Health and Human Services Secretary Advisory Committee to pass the legislation, which helped detect other organic acidemias – inherited conditions that prevent babies from breaking down amino acids found in protein, creating potentially toxic situations, similar to Stephen’s. They advocated for adding other conditions to the panel, like severe combined immunodeficiency, commonly referred to as “bubble boy” syndrome. Stephan was the only newborn screening advocate in attendance with a disability. Now all 50 states have implemented these screenings.

Attendees of the charity golf event

The Monaco family raised $100,000 for the genetics division and ongoing IVA research at Children’s National Health System.

The family isn’t done yet. On Oct. 26, Stephen will celebrate his 22nd birthday and a fifth-annual golf tournament, created in his honor, to raise awareness about and support for IVA and similar conditions. The Monaco family started this tradition in 2015 on Stephen’s 18th birthday and have raised $100,000 for the genetics division at Children’s National. They hope Stephen’s legacy will leave others with a message they keep framed in their Virginia home: Learn from yesterday, live for today and hope for tomorrow.

They educate Caroline along the way, noting the annual golf tournament and their advocacy supports ongoing IVA research and care – ensuring that she and others with these rare metabolic conditions continue to live a long, healthy life, echoing their longstanding partnership with Children’s National to help children grow up stronger.

The Monaco family and Marshall Summar, M.D., director of the Rare Disease Institute, recently shared their story on Washington’s Fox 5.

Dr. Anitha John, third from right, director of the Washington Adult Congenital Heart Program, hosts the eighth-annual “Adult Congenital Heart Disease in the 21st Century” conference

CME spotlight: Treating adult congenital heart disease

Dr. Anitha John, third from right, director of the Washington Adult Congenital Heart Program, hosts the eighth-annual “Adult Congenital Heart Disease in the 21st Century” conference

Dr. Anitha John, third from right, director of the Washington Adult Congenital Heart Program, hosts the eighth-annual “Adult Congenital Heart Disease in the 21st Century” conference, which takes place Oct. 4-5, 2019.

A two-day continuing medical education (CME) conference for physicians and clinicians treating patients with adult congenital heart disease (ACHD) takes place Oct. 4-5, 2019, at the Bethesda Marriott in Bethesda, Maryland.

The eighth-annual conference, “Adult Congenital Heart Disease in the 21st Century,” hosted by Children’s National Health System and MedStar Washington Hospital Center provides a comprehensive review of the evaluation, diagnosis and management of ACHD, including guidelines to help ACHD patients manage a healthy pregnancy and clinical guidance about the progression of congenital heart disease (CHD) treatment from adolescence through adulthood.

Two tracks accommodate these themes, with the first focusing on a multidisciplinary approach clinicians can use to help ACHD patients assess risks for pregnancy complications, while planning and managing a healthy pregnancy, with input from cardiologists, anesthesiologists and maternal fetal medicine specialists. The second focuses on cardiac defects, starting with anatomical cardiac lessons with 3D heart models, then moves to imaging review, examining echocardiograms and MRI’s, and ends with clinical management review.

“This conference brings the best science and the most innovative approaches to treatment with questions doctors receive in the exam room,” says Anitha John, M.D., Ph.D., the conference organizer and director of the Washington Adult Congenital Heart program at Children’s National. “We’re inviting patients to join the afternoon of the second day of the CME conference again this year to support shared knowledge of these concepts, which supports lifelong treatment and education.”

Dr. John planned this year’s conference with the November 6 ACHD board exams in mind, integrating topics that will appear on the third ACHD certification exam issued by the American Board of Internal Medicine.

At this year’s CME conference, more than a dozen faculty members, including several physicians and nurses from Children’s National, will guide lectures to help attendees meet 13 objectives, from understanding the prevalence of congenital heart disease and its complications to learning about when surgical interventions and referrals to specialists are necessary.

Attendees will review new and innovative PAH therapies, mechanical support therapies, catheter-based interventional procedures and appraise the use of pacemaker and defibrillator therapy among adults with CHD.

Patients and families attending the patient sessions, held from 12:30 to 3:45 p.m. on Saturday, October 5, have a chance to participate in three sessions that support the medical and social needs of ACHD patients. Topics range from workshops that address the neurodevelopment and psychosocial factors of living with a congenital heart defect to sessions that focus on reproductive options for patients and personalized lifestyle recommendations, including fitness and exercise guidelines.

“To support cardiovascular health throughout the lifespan, it helps to educate patients about their heart’s structure and unique needs,” notes Dr. John. “We want to spark a dialogue now and have future conversations with patients, especially while they are young.”

The American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines updated ACHD treatment recommendations in August 2018, the first time in 10 years, and many of these guidelines manifest as panel discussions and interactive lectures presented at the 2019 Adult Congenital Heart Disease in the 21st Century conference.

Attendees can receive up to 12.5 credits from the Accreditation Council for Continuing Medical Education, the Accreditation Council for Pharmacy Education, the American Nurses Credentialing Center and the American Academy of PAs.

Those interested in starting their own ACHD program can attend an evening symposium, entitled “ACHD Program Building 101,” hosted by representatives from the Mid-Atlantic ACHD Regional Group. Topics in the six-session panel range from managing ACHD patients in a pediatric hospital setting to the role of clinical nurse coordinators in ACHD care.

To learn more about or to register for the conference, visit CE.MedStarHealth.org/ACHD.

preterm brain scans

Early lipids in micropreemies’ diets can boost brain growth

preterm brain scans

Segmentation of a preterm brain T2-weighted MRI image at 30 gestational weeks [green=cortical grey matter; blue=white matter; grey=deep grey matter; cyan=lateral ventricle; purple=cerebellum; orange=brainstem; red=hippocampus; yellow=cerebrospinal fluid].

Dietary lipids, already an important source of energy for tiny preemies, also provide a much-needed brain boost by significantly increasing global brain volume as well as increasing volume in regions involved in motor activities and memory, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

“Compared with macronutrients like carbohydrates and proteins, lipid intake during the first month of life is associated with increased overall and regional brain volume for micro-preemies,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and senior author. “Using non-invasive magnetic resonance imaging, we see increased volume in the cerebellum by 2 weeks of age. And at four weeks of life, lipids increase total brain volume and boost regional brain volume in the cerebellum, amygdala-hippocampus and brainstem.”

The cerebellum is involved in virtually all physical movement and enables coordination and balance. The amygdala processes and stores short-term memories. The hippocampus manages emotion and mood. And the brainstem acts like a router, passing messages from the brain to the rest of the body, as well as enabling essential functions like breathing, a steady heart rate and swallowing.

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. babies is born preterm, or before 37 weeks gestation. Regions of the brain that play vital roles in complex cognitive and motor activities experience exponential growth late in pregnancy, making the developing brains of preterm infants particularly vulnerable to injury and impaired growth.

Children’s research faculty examined the impact of lipid intake in the first month of life on brain volumes for very low birth weight infants, who weighed 1,500 grams or less at birth. These micro-preemies are especially vulnerable to growth failure and neurocognitive impairment after birth.

The team enrolled 68 micro-preemies who were 32 weeks gestational age and younger when they were admitted to Children’s neonatal intensive care unit during their first week of life. They measured cumulative macronutrients – carbohydrates, proteins, lipids and calories – consumed by these newborns at 2 and 4 weeks of life. Over years, Limperopoulos’ lab has amassed a large database of babies who were born full-term; this data provides unprecedented insights into normal brain development and will help to advance understanding of brain development in high-risk preterm infants.

“Even after controlling for average weight gain and other health conditions, lipid intake was positively associated with cerebellar and brainstem volumes in very low birthweight preterm infants,” adds Katherine M. Ottolini, the study’s lead author.

According to Limperopoulos, Children’s future research will examine the optimal timing and volume of lipids to boost neurodevelopment for micro-preemies.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Early lipid intake improves brain growth in premature infants.”
    • Saturday, April 27, 2019, 1:15-2:30 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.

Claire Marie Vacher

Placental function linked to brain injuries associated with autism

Claire Marie Vacher

“We saw long-term cerebellar white matter alterations in male experimental models, and behavioral testing revealed social impairments and increased repetitive behaviors, two hallmark features of ASD,” says Claire-Marie Vacher, Ph.D., lead study author.

Allopregnanolone (ALLO), a hormone made by the placenta late in pregnancy, is such a potent neurosteroid that disrupting its steady supply to the developing fetus can leave it vulnerable to brain injuries associated with autism spectrum disorder (ASD), according to Children’s research presented during the Pediatric Academic Societies 2019 Annual Meeting.

In order to more effectively treat vulnerable babies, the Children’s research team first had to tease out what goes wrong in the careful choreography that is pregnancy. According to the Centers for Disease Control and Prevention, about 1 in 10 babies is born preterm, before 37 weeks of gestation. Premature birth is a major risk factor for ASD.

The placenta is an essential and understudied organ that is shared by the developing fetus and the pregnant mother, delivering oxygen, glucose and nutrients and ferrying out waste products. The placenta also delivers ALLO, a progesterone derivative, needed to ready the developing fetal brain for life outside the womb.

ALLO ramps up late in gestation. When babies are born prematurely, their supply of ALLO stops abruptly. That occurs at the same time the cerebellum – a brain region essential for motor coordination, posture, balance and social cognition– typically undergoes a dramatic growth spurt.

“Our experimental model demonstrates that losing placental ALLO alters cerebellar development, including white matter development,” says Anna Penn, M.D., Ph.D., a neonatologist in the divisions of Neonatology and Fetal Medicine, and a developmental neuroscientist at Children’s National. “Cerebellar white matter development occurs primarily after babies are born, so connecting a change in placental function during pregnancy with lingering impacts on later brain development is a particularly striking result.”

The research team created a novel experimental model in which the gene encoding the enzyme responsible for producing ALLO is deleted in the placenta. They compared these preclinical models with a control group and performed whole brain imaging and RNAseq gene expression analyses for both groups.

“We saw long-term cerebellar white matter alterations in male experimental models, and behavioral testing revealed social impairments and increased repetitive behaviors, two hallmark features of ASD,” says Claire-Marie Vacher, Ph.D., lead study author. “These male-specific outcomes parallel the increased risk of brain injury and ASD we see in human babies born prematurely.”

ALLO binds to specific GABA receptors, which control most inhibitory signaling in the nervous system.

“Our findings provide a new way to frame poor placental function: Subtle but significant changes in utero may set in motion neurodevelopmental disorders that children experience later in life,” adds Dr. Penn, the study’s senior author. “Future directions for our research could include identifying new targets in the placenta or brain that could be amenable to hormone supplementation, opening the potential for earlier treatment for high-risk fetuses.”

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Placental allopregnanolone loss alters postnatal cerebellar development and function.”
    • Sunday, April 28, 2019, 5:15 p.m. to 5:30 p.m. (EST)

Claire-Marie Vacher, Ph.D., lead author; Jackie Salzbank, co-author; Helene Lacaille, co-author; Dana Bakalar, co-author; Jiaqi O’Reilly, co-author; and Anna Penn, M.D., Ph.D., a neonatologist in the divisions of Neonatology and Fetal Medicine, developmental neuroscientist and senior study author.

Catherine Limperopoulos

Breastfeeding boosts metabolites important for brain growth

Catherine Limperopoulos

“Proton magnetic resonance spectroscopy, a non-invasive imaging technique that describes the chemical composition of specific brain structures, enables us to measure metabolites that may play a critical role for growth and explain what makes breastfeeding beneficial for newborns’ developing brains,” says Catherine Limperopoulos, Ph.D.

Micro-preemies who primarily consume breast milk have significantly higher levels of metabolites important for brain growth and development, according to sophisticated imaging conducted by an interdisciplinary research team at Children’s National.

“Our previous research established that vulnerable preterm infants who are fed breast milk early in life have improved brain growth and neurodevelopmental outcomes. It was unclear what makes breastfeeding so beneficial for newborns’ developing brains,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National. “Proton magnetic resonance spectroscopy, a non-invasive imaging technique that describes the chemical composition of specific brain structures, enables us to measure metabolites essential for growth and answer that lingering question.”

According to the Centers for Disease Control and Prevention, about 1 in 10 U.S. infants is born preterm. The Children’s research team presented their findings during the Pediatric Academic Societies 2019 Annual Meeting.

The research-clinicians enrolled babies who were very low birthweight (less than 1,500 grams) and 32 weeks gestational age or younger at birth when they were admitted to Children’s neonatal intensive care unit in the first week of life. The team gathered data from the right frontal white matter and the cerebellum – a brain region that enables people to maintain balance and proper muscle coordination and that supports high-order cognitive functions.

Each chemical has its own a unique spectral fingerprint. The team generated light signatures for key metabolites and calculated the quantity of each metabolite. Of note:

  • Cerebral white matter spectra showed significantly greater levels of inositol (a molecule similar to glucose) for babies fed breast milk, compared with babies fed formula.
  • Cerebellar spectra had significantly greater creatine levels for breastfed babies compared with infants fed formula.
  • And the percentage of days infants were fed breast milk was associated with significantly greater levels of both creatine and choline, a water soluble nutrient.

“Key metabolite levels ramp up during the times babies’ brains experience exponential growth,” says Katherine M. Ottolini, the study’s lead author. “Creatine facilitates recycling of ATP, the cell’s energy currency. Seeing greater quantities of this metabolite denotes more rapid changes and higher cellular maturation. Choline is a marker of cell membrane turnover; when new cells are generated, we see choline levels rise.”

Already, Children’s National leverages an array of imaging options that describe normal brain growth, which makes it easier to spot when fetal or neonatal brain development goes awry, enabling earlier intervention and more effective treatment. “Proton magnetic resonance spectroscopy may serve as an important additional tool to advance our understanding of how breastfeeding boosts neurodevelopment for preterm infants,” Limperopoulos adds.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Improved cerebral and cerebellar metabolism in breast milk-fed VLBW infants.”
    • Monday, April 29, 2019, 3:30–3:45 p.m. (EST)

Katherine M. Ottolini, lead author; Nickie Andescavage, M.D., Attending, Neonatal-Perinatal Medicine and co-author; Kushal Kapse, research and development staff engineer and co-author; Sudeepta Basu, M.D., neonatologist and co-author; and Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain and senior author, all of Children’s National.

DNA Molecule

Decoding cellular signals linked to hypospadias

DNA Molecule

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” Daniel Casella, M.D. says.

Daniel Casella, M.D., a urologist at Children’s National, was honored with an AUA Mid-Atlantic Section William D. Steers, M.D. Award, which provides two years of dedicated research funding that he will use to better understand the genetic causes for hypospadias.

With over 7,000 new cases a year in the U.S., hypospadias is a common birth defect that occurs when the urethra, the tube that transports urine out of the body, does not form completely in males.

Dr. Casella has identified a unique subset of cells in the developing urethra that have stopped dividing but remain metabolically active and are thought to represent a novel signaling center. He likens them to doing the work of a construction foreman. “If you’re constructing a building, you need to make sure that everyone follows the blueprints.  We believe that these developmentally senescent cells are sending important signals that define how the urethra is formed,” he says.

His project also will help to standardize the characterization of hypospadias. Hypospadias is classically associated with a downward bend to the penis, a urethra that does not extend to the head of the penis and incomplete formation of the foreskin. Still, there is significant variability among patients’ anatomy and to date, no standardized method for documenting hypospadias anatomy.

“Some surgeons take measurements in the operating room, but without a standardized classification system, there is no definitive way to compare measurements among providers or standardize diagnoses from measurements that every surgeon makes,” he adds. “What one surgeon may call ‘distal’ may be called ‘midshaft’ by another.” (With distal hypospadias, the urethra opening is near the penis head; with midshaft hypospadias, the urethra opening occurs along the penis shaft.)

“By advancing our understanding of the genetic causes and the anatomic differences among patients, the real goal of this research is to generate knowledge that will allow us to take better care of children with hypospadias,” he says.

Parents worry about lingering social stigma, since some boys with hypospadias are unable to urinate while standing, and in older children the condition can be associated with difficulties having sex. Surgical correction of hypospadias traditionally is performed when children are between 6 months to 1 year old.

When reviewing treatment options with family, “discussing the surgery and postoperative care is straight forward. The hard part of our discussion is not having good answers to questions about long-term outcomes,” he says.

Dr. Casella’s study hopes to build the framework to enable that basic research to be done.

“Say we wanted to do a study to see how patients are doing 15-20 years after their surgery.  If we go to their charts now, often we can’t accurately describe their anatomy prior to surgery.  By establishing uniform measurement baselines, we can accurately track long-term outcomes since we’ll know what condition that child started with and where they ended up,” he says.

Dr. Casella’s research project will be conducted at Children’s National under the mentorship of Eric Vilain, M.D., Ph.D., an international expert in sex and genitalia development; Dolores J. Lamb, Ph.D., HCLD, an established leader in urology based at Weill Cornell Medicine; and Marius George Linguraru, DPhil, MA, MSc, an expert in image processing and artificial intelligence.

Mark Batshaw

40 years, 8 editions: Writing “Children With Disabilities”

Mark Batshaw

Forty years ago, Mark L. Batshaw, M.D., almost singlehandedly wrote a 23-chapter first edition that ran about 300 pages. Now Dr. Batshaw’s tome, “Children With Disabilities,” is in its eighth edition, and this new volume is almost 1,000 pages, with 42 chapters, two co-editors and over 35 authors from Children’s National.

Back in 1978, Mark L. Batshaw, M.D., was a junior faculty member at John’s Hopkins University School of Medicine. In the evenings he taught a course in the university’s School of Education  titled “The Medical and Physical Aspects of the Handicapped Child,” for Master’s level special education students. Because no textbook at that time focused on that specific topic, Batshaw developed his own slide set.

“At the end of the first year of teaching the course my students said ‘You really ought to consider writing a text book based on your slides to help us move forward,’ ” Dr. Batshaw recalls. The father of three carved out time by writing on weekends and at night, cutting back on sleep.

His first goal was to create a textbook that would serve as a curriculum for a series of courses that would be taught at universities to specialists who work with children with disabilities, including social workers, physical and occupational therapists, speech and language pathologists, special education teachers, nurses, doctors and dentists.

“I wanted to cover the whole range of disabilities and divided the book initially into a series of sections, including embryology, to help students understand what can go wrong in fetal development to lead to a developmental disability; and chapters on each developmental disability, including autism, attention-deficit/hyperactivity disorder (ADHD), cerebral palsy, learning disabilities and traumatic brain injury,” he says. “The third section was devoted to available treatments, including occupational and physical therapy, speech language therapy, nutrition and medications. The final section focused on outcomes.”

His second aim was for the book to serve as a reference text for professionals in the field. The 33-year-old contacted a brand-new new publisher, Paul H. Brookes Publishing Co., that focused on special education. “They took a chance on me, and I took a chance on them,” he says.

Forty years ago, he almost singlehandedly produced a 23-chapter first edition that ran about 300 pages. Now Dr. Batshaw’s tome is in its eighth edition, and this new volume is almost 1,000 pages. And, rather than being its sole author, Dr. Batshaw enlisted two co-editors and at least five dozen authors who contributed specialty expertise in genetic counseling, social work, physical and occupational therapy, medicine and nursing. His daughter, Elissa, a special education teacher and school psychologist, authored a chapter about special education services, and his son, Drew, an executive at a start-up company, contributed autobiographical letters about the effect ADHD has had on his life.

The book, “Children With Disabilities,” also includes:

  • A glossary of medical terms so that as the reader reviews patient reports they can easily look up an unfamiliar term
  • An appendix on commonly used drugs to treat children with disabilities in order to look up the medicine by name and see the range of doses
  • An appendix devoted to different syndromes children might have
  • A reference section with organizations and foundations that help children with disabilities
  • A web site with sections designed for students and other content designed for teachers with thought questions to guide practical use of information in each chapter and more than 450 customizable PowerPoint slides for download
  • Call-out boxes for interdisciplinary team members, such as genetic counselors, explaining the roles they serve and their educational background, and
  • Excerpts of recent research articles.

“The students say they don’t sell the book. Usually when students have a textbook, they try to sell it second hand after the course ends,” explains Dr. Batshaw, now Executive Vice President, Physician-in-Chief and Chief Academic Officer at Children’s National. “Instead, students keep it and use it as a practical reference as they become professionals in their field. It has had the impact I had hoped for both as a textbook and a reference book: They say they refer to it when they have patients with a particular disorder they’re not used to treating to read up on it.”

Now a bestseller, there are more than 200,000 copies in print, including Portuguese and Ukrainian translations. “It didn’t start that way. It grew organically,” he says.

In addition to Dr. Batshaw, Children’s contributors to “Children With Disabilities” include Nicholas Ah Mew, M.D., pediatric geneticist; Nickie N. Andescavage, M.D., neonatologist; Mackenzie E. Brown, D.O., fellow in Pediatric Rehabilitation Medicine; Justin M. Burton, M.D., chief, Division of Pediatric Rehabilitation Medicine; Gabrielle Sky Cardwell, BA, clinical research assistant; Catherine Larsen Coley, PT, DPT, PCS, physical therapist; Laurie S. Conklin, M.D., pediatric gastroenterologist; Denice Cora-Bramble, M.D., MBA, executive vice president and chief medical officer; Heather de Beaufort, M.D., pediatric ophthalmologist; Dewi Frances T. Depositario-Cabacar, M.D., pediatric neurologist; Lina Diaz-Calderon, M.D., fellow in Pediatric Gastroenterology; Olanrewaju O. Falusi, M.D., associate medical director of municipal and regional affairs, Child Health Advocacy Institute; Melissa Fleming, M.D., pediatric rehabilitation specialist; William Davis Gaillard, M.D., chief Division of Epilepsy, Neurophysiology and Critical Care; Satvika Garg, Ph.D., occupational therapist; Virginia C. Gebus, R.N., MSN, APN, CNSC, nutritionist; Monika K. Goyal, M.D., MSCE, assistant chief, Division of Emergency Medicine; Andrea Gropman, M.D., chief, Division of Neurodevelopmental Pediatrics and Neurogenetics, geneticist and Neurodevelopmental pediatrician; Mary A. Hadley, BS, senior executive assistant; Susan Keller, MLS., MS-HIT, research librarian; Lauren Kenworthy, Ph.D., director, Center for Autism Spectrum Disorders; Monisha S. Kisling, MS, CGC, genetic counselor; Eyby Leon, M.D., pediatric geneticist; Erin MacLeod, Ph.D., RD, LD, director, Metabolic Nutrition; Margaret B. Menzel, MS, CGC, genetic counselor; Shogo John Miyagi, Ph.D., PharmD, BCPPS, Pediatric Clinical Pharmacology fellow; Mitali Y. Patel, DDS, program director, Pediatric Dentistry; Deborah Potvin, Ph.D., neuropsychologist; Cara E. Pugliese, Ph.D., clinical psychologist; Khodayar Rais-Bahrami, M.D., neonatologist and director, Neonatal-Perinatal Medicine Fellowship Program; Allison B. Ratto, Ph.D., clinical psychologist; Adelaide S. Robb, M.D., chief, Division of Psychiatry and Behavioral Sciences; Joseph Scafidi, D.O., neonatal neurologist; Erik Scheifele, D.M.D., chief, Division of Oral Health; Rhonda L. Schonberg, MS, CGC, genetic counselor; Billie Lou Short, M.D., chief, Division of Neonatology; Kara L. Simpson, MS, CGC, genetic counselor; Anupama Rao Tate, D.M.D., MPH, pediatric dentist; Lisa Tuchman, M.D., chief, Division of Adolescent and Young Adult Medicine; Johannes N. van den Anker, M.D., Ph.D., FCP, chief, Division of Clinical Pharmacology, Vice Chair of Experimental Therapeutics; Miriam Weiss, CPNP-PC, nurse practitioner; and Tesfaye Getaneh Zelleke, M.D., pediatric neurologist.

Billie Lou Short and Kurt Newman at Research and Education Week

Research and Education Week honors innovative science

Billie Lou Short and Kurt Newman at Research and Education Week

Billie Lou Short, M.D., received the Ninth Annual Mentorship Award in Clinical Science.

People joke that Billie Lou Short, M.D., chief of Children’s Division of Neonatology, invented extracorporeal membrane oxygenation, known as ECMO for short. While Dr. Short did not invent ECMO, under her leadership Children’s National was the first pediatric hospital to use it. And over decades Children’s staff have perfected its use to save the lives of tiny, vulnerable newborns by temporarily taking over for their struggling hearts and lungs. For two consecutive years, Children’s neonatal intensive care unit has been named the nation’s No. 1 for newborns by U.S. News & World Report. “Despite all of these accomplishments, Dr. Short’s best legacy is what she has done as a mentor to countless trainees, nurses and faculty she’s touched during their careers. She touches every type of clinical staff member who has come through our neonatal intensive care unit,” says An Massaro, M.D., director of residency research.

For these achievements, Dr. Short received the Ninth Annual Mentorship Award in Clinical Science.

Anna Penn, M.D., Ph.D., has provided new insights into the central role that the placental hormone allopregnanolone plays in orderly fetal brain development, and her research team has created novel experimental models that mimic some of the brain injuries often seen in very preterm babies – an essential step that informs future neuroprotective strategies. Dr. Penn, a clinical neonatologist and developmental neuroscientist, “has been a primary adviser for 40 mentees throughout their careers and embodies Children’s core values of Compassion, Commitment and Connection,” says Claire-Marie Vacher, Ph.D.

For these achievements, Dr. Penn was selected to receive the Ninth Annual Mentorship Award in Basic and Translational Science.

The mentorship awards for Drs. Short and Penn were among dozens of honors given in conjunction with “Frontiers in Innovation,” the Ninth Annual Research and Education Week (REW) at Children’s National. In addition to seven keynote lectures, more than 350 posters were submitted from researchers – from high-school students to full-time faculty – about basic and translational science, clinical research, community-based research, education, training and quality improvement; five poster presenters were showcased via Facebook Live events hosted by Children’s Hospital Foundation.

Two faculty members won twice: Vicki Freedenberg, Ph.D., APRN, for research about mindfulness-based stress reduction and Adeline (Wei Li) Koay, MBBS, MSc, for research related to HIV. So many women at every stage of their research careers took to the stage to accept honors that Naomi L.C. Luban, M.D., Vice Chair of Academic Affairs, quipped that “this day is power to women.”

Here are the 2019 REW award winners:

2019 Elda Y. Arce Teaching Scholars Award
Barbara Jantausch, M.D.
Lowell Frank, M.D.

Suzanne Feetham, Ph.D., FAA, Nursing Research Support Award
Vicki Freedenberg, Ph.D., APRN, for “Psychosocial and biological effects of mindfulness-based stress reduction intervention in adolescents with CHD/CIEDs: a randomized control trial”
Renee’ Roberts Turner for “Peak and nadir experiences of mid-level nurse leaders”

2019-2020 Global Health Initiative Exploration in Global Health Awards
Nathalie Quion, M.D., for “Latino youth and families need assessment,” conducted in Washington
Sonia Voleti for “Handheld ultrasound machine task shifting,” conducted in Micronesia
Tania Ahluwalia, M.D., for “Simulation curriculum for emergency medicine,” conducted in India
Yvonne Yui for “Designated resuscitation teams in NICUs,” conducted in Ghana
Xiaoyan Song, Ph.D., MBBS, MSc, “Prevention of hospital-onset infections in PICUs,” conducted in China

Ninth Annual Research and Education Week Poster Session Awards

Basic and Translational Science
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Differences in the gut microbiome of HIV-infected versus HIV-exposed, uninfected infants”
Faculty: Hayk Barseghyan, Ph.D., for “Composite de novo Armenian human genome assembly and haplotyping via optical mapping and ultra-long read sequencing”
Staff: Damon K. McCullough, BS, for “Brain slicer: 3D-printed tissue processing tool for pediatric neuroscience research”
Staff: Antonio R. Porras, Ph.D., for “Integrated deep-learning method for genetic syndrome screening using facial photographs”
Post docs/fellows/residents: Lung Lau, M.D., for “A novel, sprayable and bio-absorbable sealant for wound dressings”
Post docs/fellows/residents:
Kelsey F. Sugrue, Ph.D., for “HECTD1 is required for growth of the myocardium secondary to placental insufficiency”
Graduate students:
Erin R. Bonner, BA, for “Comprehensive mutation profiling of pediatric diffuse midline gliomas using liquid biopsy”
High school/undergraduate students: Ali Sarhan for “Parental somato-gonadal mosaic genetic variants are a source of recurrent risk for de novo disorders and parental health concerns: a systematic review of the literature and meta-analysis”

Clinical Research
Faculty:
Amy Hont, M.D., for “Ex vivo expanded multi-tumor antigen specific T-cells for the treatment of solid tumors”
Faculty: Lauren McLaughlin, M.D., for “EBV/LMP-specific T-cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation”

Staff: Iman A. Abdikarim, BA, for “Timing of allergenic food introduction among African American and Caucasian children with food allergy in the FORWARD study”
Staff: Gelina M. Sani, BS, for “Quantifying hematopoietic stem cells towards in utero gene therapy for treatment of sickle cell disease in fetal cord blood”
Post docs/fellows/residents: Amy H. Jones, M.D., for “To trach or not trach: exploration of parental conflict, regret and impacts on quality of life in tracheostomy decision-making”
Graduate students: Alyssa Dewyer, BS, for “Telemedicine support of cardiac care in Northern Uganda: leveraging hand-held echocardiography and task-shifting”
Graduate students: Natalie Pudalov, BA, “Cortical thickness asymmetries in MRI-abnormal pediatric epilepsy patients: a potential metric for surgery outcome”
High school/undergraduate students:
Kia Yoshinaga for “Time to rhythm detection during pediatric cardiac arrest in a pediatric emergency department”

Community-Based Research
Faculty:
Adeline (Wei Li) Koay, MBBS, MSc, for “Recent trends in the prevention of mother-to-child transmission (PMTCT) of HIV in the Washington, D.C., metropolitan area”
Staff: Gia M. Badolato, MPH, for “STI screening in an urban ED based on chief complaint”
Post docs/fellows/residents:
Christina P. Ho, M.D., for “Pediatric urinary tract infection resistance patterns in the Washington, D.C., metropolitan area”
Graduate students:
Noushine Sadeghi, BS, “Racial/ethnic disparities in receipt of sexual health services among adolescent females”

Education, Training and Program Development
Faculty:
Cara Lichtenstein, M.D., MPH, for “Using a community bus trip to increase knowledge of health disparities”
Staff:
Iana Y. Clarence, MPH, for “TEACHing residents to address child poverty: an innovative multimodal curriculum”
Post docs/fellows/residents:
Johanna Kaufman, M.D., for “Inpatient consultation in pediatrics: a learning tool to improve communication”
High school/undergraduate students:
Brett E. Pearson for “Analysis of unanticipated problems in CNMC human subjects research studies and implications for process improvement”

Quality and Performance Improvement
Faculty:
Vicki Freedenberg, Ph.D., APRN, for “Implementing a mindfulness-based stress reduction curriculum in a congenital heart disease program”
Staff:
Caleb Griffith, MPH, for “Assessing the sustainability of point-of-care HIV screening of adolescents in pediatric emergency departments”
Post docs/fellows/residents:
Rebecca S. Zee, M.D., Ph.D., for “Implementation of the Accelerated Care of Torsion (ACT) pathway: a quality improvement initiative for testicular torsion”
Graduate students:
Alysia Wiener, BS, for “Latency period in image-guided needle bone biopsy in children: a single center experience”

View images from the REW2019 award ceremony.

Beth Tarini

Getting to know SPR’s future President, Beth Tarini, M.D., MS

Beth Tarini

Quick. Name four pillar pediatric organizations on the vanguard of advancing pediatric research.

Most researchers and clinicians can rattle off the names of the Academic Pediatric Association, the American Academy of Pediatrics and the American Pediatric Society. But that fourth one, the Society for Pediatric Research (SPR), is a little trickier. While many know SPR, a lot of research-clinicians simply do not.

Over the next few years, Beth A. Tarini, M.D., MS, will make it her personal mission to ensure that more pediatric researchers get to know SPR and are so excited about the organization that they become active members. In May 2019 Dr. Tarini becomes Vice President of the society that aims to stitch together an international network of interdisciplinary researchers to improve kids’ health. Four-year SPR leadership terms begin with Vice President before transitioning to President-Elect, President and Past-President, each for one year.

Dr. Tarini says she looks forward to working with other SPR leaders to find ways to build more productive, collaborative professional networks among faculty, especially emerging junior faculty. “Facilitating ways to network for research and professional reasons across pediatric research is vital – albeit easier said than done. I have been told I’m a connector, so I hope to leverage that skill in this new role,” says Dr. Tarini, associate director for Children’s Center for Translational Research.

“I’m delighted that Dr. Tarini was elected to this leadership position, and I am impressed by her vision of improving SPR’s outreach efforts,” says Mark Batshaw, M.D., Executive Vice President, Chief Academic Officer and Physician-in-Chief at Children’s National. “Her goal of engaging potential members in networking through a variety of ways – face-to-face as well as leveraging digital platforms like Twitter, Facebook and LinkedIn – and her focus on engaging junior faculty will help strengthen SPR membership in the near term and long term.”

Dr. Tarini adds: “Success to me would be leaving after four years with more faculty – especially junior faculty – approaching membership in SPR with the knowledge and enthusiasm that they bring to membership in other pediatric societies.”

SPR requires that its members not simply conduct research, but move the needle in their chosen discipline. In her research, Dr. Tarini has focused on ensuring that population-based newborn screening programs function efficiently and effectively with fewer hiccups at any place along the process.

Thanks to a heel stick to draw blood, an oxygen measurement, and a hearing test, U.S. babies are screened for select inherited health conditions, expediting treatment for infants and reducing the chances they’ll experience long-term health consequences.

“The complexity of this program that is able to test nearly all 4 million babies in the U.S. each year is nothing short of astounding. You have to know the child is born – anywhere in the state – and then between 24 and 48 hours of birth you have to do testing onsite, obtain a specific type of blood sample, send the blood sample to an off-site lab quickly, test the sample, find the child if the test is out of range, get the child evaluated and tested for the condition, then send them for treatment. Given the time pressures as well as the coordination of numerous people and organizations, the fact that this happens routinely is amazing. And like any complex process, there is always room for improvement,” she says.

Dr. Tarini’s research efforts have focused on those process improvements.

As just one example, the Advisory Committee on Heritable Disorders in Newborns and Children, a federal advisory committee on which she serves, was discussing how to eliminate delays in specimen processing to provide speedier results to families. One possible solution floated was to open labs all seven days, rather than just five days a week. Dr. Tarini advocated for partnering with health care engineers who could help model ways to make the specimen transport process more efficient, just like airlines and mail delivery services. A more efficient and effective solution was to match the specimen pick-up and delivery times more closely with the lab’s operational times – which maximizes lab resources and shortens wait times for parents.

Conceptual modeling comes so easily for her that she often leaps out of her seat mid-sentence, underscoring a point by jotting thoughts on a white board, doing it so often that her pens have run dry.

“It’s like a bus schedule: You want to find a bus that not only takes you to your destination but gets you there on time,” she says.

Dr. Tarini’s current observational study looks for opportunities to improve how parents in Minnesota and Iowa are given out-of-range newborn screening test results – especially false positives – and how that experience might shake their confidence in their child’s health as well as heighten their own stress level.

“After a false positive test result, are there parents who walk away from newborn screening with lingering stress about their child’s health? Can we predict who those parents might be and help them?” she asks.

Among the challenges is the newborn screening occurs so quickly after delivery that some emotionally and physically exhausted parents may not remember it was done. Then they get a call from the state with ominous results. Another challenge is standardizing communication approaches across dozens of birthing centers and hospitals.

“We know parents are concerned after receiving a false positive result, and some worry their infant remains vulnerable,” she says. “Can we change how we communicate – not just what we say, but how we say it – to alleviate those concerns?”

Nickie Andescavage

To understand the preterm brain, start with the fetal brain

Nickie Andescavage

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

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

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

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

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

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

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

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

ACC19 attendees from Children's National

ACC.19: A focus on pediatric cardiology

ACC19 attendees from Children's National

Dr. Gerard Martin, center, accepts an award before delivering the 2019 Dan G. McNamara Keynote lecture at ACC.19.

“Innovation meets tradition,” is how many attendees and journalists described the American College of Cardiology’s 68th Scientific Sessions (ACC.19), which took place March 16-18, 2019 in New Orleans, La.

Gerard Martin, M.D., F.A.A.P., F.A.C.C., F.A.H.A., a pediatric cardiologist and the medical director of Global Services at Children’s National, supported this narrative by referencing both themes in his 2019 Dan G. McNamara keynote lecture, entitled “Improved Outcomes in Congenital Heart Disease through Advocacy and Collaboration.” Dr. Martin highlighted advancements in the field of pediatric cardiology that took place over the past 15 years, while touting modern advancements – such as pulse oximetry screenings for critical congenital heart disease – that were a result of physician-led advocacy and collaboration.

Dr. Martin’s message was to continue to invest in research and technology that leads to medical breakthroughs, but to remember the power of partnerships, such as those formed by the National Pediatric Cardiology Quality Improvement Collaborative. These alliances, which generated shared protocols and infrastructure among health systems, improved interstage mortality rates between surgeries for babies born with hypolastic left heart syndrome.

A dozen cardiologists and clinicians from the Children’s National Heart Institute also participated in CME panel discussions or delivered poster presentations to support future versions of this template, touching on early-stage innovations and multi-institution research collaborations. The themes among Children’s National Heart Institute faculty, presented to a diverse crowd of 12,000-plus professional attendees representing 108 countries, included:

Personalized guidelines:

  • Sarah Clauss, M.D., F.A.C.C., a cardiologist, presented “Unique Pediatric Differences from Adult Cholesterol Guidelines: Lipids and Preventive Cardiology,” before Charles Berul, M.D., division chief of cardiology and co-director of the Children’s National Heart Institute, presented “Unique Pediatric Differences from Adult Guidelines: Arrhythmias in Adults with Congenital Heart Disease,” in a joint symposium with the American Heart Association and the American College of Cardiology.
  • Berul, who specializes in electrophysiology, co-chaired a congenital heart disease pathway session, entitled “Rhythm and Blues: Electrophysiology Progress and Controversies in Congenital Heart Disease,” featuring components of pediatric electrophysiology, including heart block, surgical treatment of arrhythmias and sudden death risk.

Early detection:

  • Anita Krishnan, M.D., associate director of the echocardiography lab, presented “Identifying Socioeconomic and Geographic Barriers to Prenatal Detection of Hypoplastic Left Heart Syndrome and Transposition of the Great Arteries” as a moderated poster in Fetal Cardiology: Quickening Discoveries.
  • Jennifer Romanowicz, M.D., a cardiology fellow, and Russell Cross, M.D., director of cardiac MRI, presented the “Neonatal Supraventricular Tachycardia as a Presentation of Critical Aortic Coarctation” poster in FIT Clinical Decision Making: Congenital Heart Disease 2.
  • Pranava Sinha, M.D., a cardiac surgeon, presented the poster “Neuroprotective Effects of Vitamin D Supplementation in Children with Cyanotic Heart Defects: Insights from a Rodent Hypoxia Model” in Congenital Heart Disease: Therapy 2.

Coordinated care:

  • Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P., a cardiologist with a focus on hyperlipidemia and preventive cardiology, co-presented an update about BMI quality improvement (Q1) activity from the American College of Cardiology’s Adult Congenital and Pediatric Quality Network – BMI Q1 leadership panel.
  • Niti Dham, M.D., director of the cardio-oncology program, and Deepa Mokshagundam, M.D., cardiology fellow, presented the poster “Cardiac Changes in Pediatric Cancer Survivors” in Heart Failure and Cardiomyopathies: Clinical 3.
  • Nancy Klein, B.S.N., R.N., C.P.N., clinical program coordinator of the Washington Adult Congenital Heart program at Children’s National, presented the poster “Improving Completion of Advanced Directives in Adults with Congenital Heart Disease” in Risks and Rewards in Adult Congenital Heart Disease.

Innovation:

  • Jai Nahar, M.D., a cardiologist, moderated “Future Hub: Augmented Cardiovascular Practitioner: Giving Doctors and Patients a New Voice.” The session focused on technical aspects of artificial intelligence, such as language processing and conversational artificial intelligence, as well as how applications are used in patient-physician interactions.
  • Nahar also participated in a key event on the Heart-to-Heart stage, entitled “Rise of Intelligent Machines: The Potential of Artificial Intelligence in Cardiovascular Care.”

“While I enjoyed the significant representation of Children’s National faculty at the meeting and all of the presentations this year, one research finding that I found particularly compelling was Dr. Krishnan’s poster about geographical disparities in detecting congenital heart disease,” says Dr. Berul. “Her research finds obstetricians providing care to women in the lowest quartile of socioeconomic areas were twice as likely to miss a diagnosis for a critical congenital heart defect during a fetal ultrasound, compared to obstetricians providing care for women in the highest quartiles.”

Dr. Krishnan’s study was the collaborative effort of 21 centers in the United States and Canada, and investigated how socioeconomic and geographic factors affect prenatal detection of hypoplastic left heart syndrome and transposition of the great arteries.

“We studied over 1,800 patients, and chose these diseases because they require early stabilization by a specialized team at a tertiary care center,” says Dr. Krishnan, who led the research in conjunction with the Fetal Heart Society Research Collaborative. “We hope that by understanding what the barriers are, we can reduce disparities in care through education and community-based outreach.”

Kinsley and Dr. Timothy Kane

Case study: Diagnosing a choledochal cyst in utero

Kinsley and Dr. Timothy Kane

The Feigel family worked with Timothy Kane, M.D., the division chief of general and thoracic surgery at Children’s National, to ensure an accurate diagnosis, coordinate a corrective procedure and support a strong recovery for Kinsley, who just celebrated a 5-month milestone.

On Sept. 30, 2018, Elizabeth Feigel gave birth to a healthy baby girl, Kinsley Feigel. Thirty-two days later, Elizabeth and her husband, Steven Feigel, delighted in another hospital moment: Kinsley, who developed a choledochal cyst in utero, was recovering from a surgical procedure to remove an abnormal bile duct cyst, which also required the removal of her gallbladder.

While the series of events, interspersed with multiple hospital visits, would likely create uneasiness in new parents, the Feigel family worked with Vahe Badalyan, M.D., a gastroenterologist at Children’s National Health System, and with Timothy Kane, M.D., the division chief of general and thoracic surgery at Children’s National, to ensure an accurate diagnosis, coordinate a corrective procedure and support a strong recovery for Kinsley, who just celebrated a 5-month milestone.

One of the keys to Kinsley’s success was close communication between her parents and providers.

Dr. Badalyan and Dr. Kane listened to Elizabeth and Steven’s concerns, explained complex medical terms in lay language, and provided background about Kinsley’s presenting symptoms, risk factors and procedures. Instead of second-guessing the diagnosis, Elizabeth and Steven put their trust into and remained in contact with the medical team, sharing updates about Kinsley at home. This parent-physician partnership helped ensure an accurate diagnosis and tailored treatment for Kinsley.

Here is her story.

An early diagnosis

During a 12-week prenatal ultrasound, Elizabeth discovered that Kinsley had an intra-abdominal cyst. Before Elizabeth came to Children’s National for an MRI, she met with several fetal medicine specialists and had a variety of tests, including an amniocentesis to rule out chromosomal abnormalities, such as Down syndrome.

The team at Children’s National didn’t want to prematurely confirm Kinsley’s choledochal cyst in utero, but additional ultrasounds and an MRI helped narrow the diagnosis to a few conditions.

After Kinsley was born, and despite looking like a healthy, full-term baby, she was transported to the neonatal intensive care unit (NICU) at Children’s National. Dr. Badalyan and Dr. Kane analyzed Kinsley’s postnatal sonogram and found the cyst was bigger than they previously thought. Over a five-day period, the medical team kept Kinsley under their close watch, running additional tests, including an additional sonogram. They then followed up with Kinsley on an outpatient basis to better understand and diagnose her cyst.

Outpatient care

Over the next few weeks, Kinsley, Elizabeth and Steven returned to Children’s National to coordinate multiple exams, ranging from an MRI to a HIDA scan. During this period, Elizabeth and Steven remained in contact with Dr. Badalyan. They heard about Kinsley’s lab results and sent updates about her symptoms, including her stool, which helped the medical team monitor her status.

Meanwhile, Dr. Badalyan and Dr. Kane worked closely with the lab to measure Kinsley’s bilirubin levels. Her presenting symptoms and risk factors, she had jaundice and is a female baby of Asian descent, are associated with both choledochal cysts and biliary atresia.

Over time and with the help of Elizabeth, Steven and the pediatric radiologists, Dr. Badalyan and Dr. Kane confirmed Kinsley had a type 1 choledochal cyst, the most common. Originally, the plan was to operate at three to six months, but Dr. Kane needed to expedite the procedure and operate on Kinsley at one month due to a rise in her bilirubin, a sign of progressive liver disease.

Higher bilirubin levels are common in newborns and remain elevated at about 5 mg/dL after the first few days of birth, but Kinsley’s levels peaked and remained elevated. Instead of her bile flowing into her intestine, her choledochal cyst reduced the flow of bile, which accumulated and started to pour back into her liver. The timing of the surgery was as important as the procedure.

The surgery

On Oct. 31, Halloween, Kinsley had laparoscopic surgery to remove the choledochal cyst. Approximately five to seven patients per year undergo choledochal cyst removal at Children’s National. Smaller infants typically undergo removal of a choledochal cyst using a large incision (or open procedure). Kinsley was the smallest baby at Children’s National to have this type of surgery performed by minimally invasive laparoscopic surgery, which required a few 3-mm incisions – the size of coriander seeds.

Some hospitals use the da Vinci robot, which starts at 8-mm incisions, the size of a small pearl, to conduct this procedure on infants, but this method cannot effectively be done in very small infants. Instead, Dr. Kane prefers to stitch sutures by hand. This technique keeps the incisions small and is technically demanding, but Dr. Kane doesn’t mind (he views this as an advanced technical skill). The goal for this surgery was to cut out the abnormal piece of Kinsley’s common bile duct, comprised of the cyst, remove  this and then sew the bile duct to the small intestine (duodenum), creating a digestive pathway. The new digestive tube allows for bile to flow from her liver through the common hepatic duct, in place of the pathway where the cyst formed, and into her intestine.

Like other surgeries, Dr. Kane needed to adapt the procedure, especially with Kinsley’s size: Taking too much from the bile duct would create a tight space, and could create obstruction, blocking bile, while leaving too much room could create leakage and spilling of the bile, requiring a follow-up surgical procedure within a week or two of the original operation.

Dr. Kane had a few options in mind before he operated. He didn’t know which would be most suitable until the operation, but he remained open and prepared for all three. Adopting this mindset, instead of having one procedure in mind, has helped Dr. Kane with precise and tailored surgeries, which often result in the best procedure and a stronger recovery period for young patients.

After 4.5 hours, the surgery, a two-part procedure – removing the cyst and recreating a functional bile duct – was complete.

Kinsley moved into the recovery unit, where she rested and recovered under close medical supervision for five days. During the first few days, she didn’t have liquids or milk, but she did have two bedside nurses monitoring her status in addition to surgeons making regular rounds. Elizabeth and Steven were relieved: The diagnosis and surgery were over.

Managing risk factors

Before Kinsley left the hospital, Elizabeth and Steven scheduled a follow-up visit to ensure Kinsley was recovering well and avoided risk of infection, such as cholangitis, which can occur suddenly and become chronic.

Following Kinsley’s post-surgical bloodwork in early November, Dr. Badalyan noticed Kinsley’s white blood count was high, signaling infection, and he immediately brought the family back to the hospital. To help her body fight the infection, Kinsley received antibiotics and intravenous fluids. She stayed in the hospital for five days. Fortunately, cholangitis is easy to treat with antibiotics; the key is to detect it early.

Kinsley returned home in time for Thanksgiving. She came back to the hospital for biweekly visits. At this point, she was filling out, reaching a 2-month milestone and nearing a full recovery. She returned for follow-up visits in December and January – and has been healthy ever since. She will continue to make routine visits during her first year to ensure her white blood count remains in a healthy range.

Investing in youth resilience

Dr. Badalyan and Dr. Kane envision a healthy future for Kinsley. They don’t expect she’ll need additional operations. Her parents are also looking on the bright side: Since gallbladders aren’t essential for survival or long-term health outcomes, and since many people can easily live without them, Kinsley may be at an advantage. Elizabeth thinks Kinsley may be more cautious about lifestyle choices to support living without a gallbladder, which also support longevity.

Another perspective noted by Dr. Badalyan and Dr. Kane is Kinsley’s resilience factor. Having the surgery earlier brought unique challenges, but her age makes it easier for Kinsley to bounce back as her body rapidly develops. Her tissues were healthy, compared to adult patients undergoing surgery with chronic liver problems or heart disease, which puts her at an advantage for a faster healing process. Dr. Badalyan also mentions that while it’s good for her Kinsley and her family to continue to monitor risks for infections, she won’t have gallstones.

Elizabeth also started to notice something that Kinsley’s doctors likely wouldn’t pick up on: Her personality seems to be a result of her hospital experience and stay. Kinsley’s an easy baby. She eats well and sleeps well, which Elizabeth credits to being around clinicians and to learning the art of self-soothing, a skill she likely acquired while recovering from surgery.

This month, Kinsley has another adventure. She’ll travel with her parents to visit extended family in Seattle, Napa Valley, Calif. and West Virginia. She has several relatives and family friends, all of whom are looking forward to meeting her.

toddler nursing

Newborns with suspected food allergies breastfed significantly longer

toddler nursing

Mothers whose newborns had suspected food allergies reported breastfeeding them significantly longer than women whose infants had no adverse reactions after food exposure, according to preliminary research led by Karen A. Robbins, M.D., and presented during the American Academy of Allergy, Asthma & Immunology 2019 Annual Meeting.

According to the Centers for Disease Control and Prevention (CDC), food allergies affect 4 to 6 percent of U.S. children, making such allergies a growing public health concern. Researchers are attempting to learn more about the interplay between food allergies and what, when and how children eat to inform allergy-prevention efforts. Little is known about the association between perceived food allergies, intolerance or hypersensitivity among babies eating their first bites of solid food and how long they’re breastfed.

Dr. Robbins and colleagues analyzed data gathered through a longitudinal study led by the Food and Drug Administration (FDA) and the CDC from 2005 to 2007. The Infant Feeding Practices Study II tracked diet and feeding practices of about 2,000 women late in their pregnancies and followed their babies’ diets through the first year of life.

Some 2,586 breastfeeding mothers in the study completed surveys when their infants were 4, 9 and 12 months old. The women were asked whether there were problems caused by food, such as an allergic reaction, sensitivity or intolerance. The majority of these infants (84.6 percent) had no suspected allergic reaction to either food they ate on their own or to food they were exposed to via breastmilk. The mothers reported that nearly 11 percent of infants reacted to something they ate; 2.4 percent reacted to food products they were exposed to via breastmilk; and 2.4 percent reacted to both food they consumed directly or were exposed to via breastfeeding. They also found:

  • Infants with suspected food allergies after exposure to food their mothers ate were breastfed a mean of 45.8 weeks.
  • Infants with food intolerance after both exposure to food their mother consumed and food they ate themselves were breastfed a mean of 40.2 weeks.

That contrasts with infants with no concern for food reactions, who were breastfed a mean of 32 weeks.

“Breastfeeding a newborn for the first few months of life helps their developing immune system become more robust, may affect the microbiome, and could influence or prevent development of allergy later in life,” says Dr. Robbins, an allergist at Children’s National Health System and lead author of the research. “However, mothers’ perceptions of their newborns’ adverse reactions to food appears to factor into how long they breastfeed.”

One potential concern is that extended breastfeeding can impact solid food introduction practices.

“Gradually transitioning to solid food gives infants an opportunity to sample an array of foods, nibble by nibble, including food allergens like peanut and eggs. We know from previously published research that introducing high-risk babies to a food allergen like peanuts early in life appropriately primes their immune system and dramatically decreases how often these children actually develop peanut allergies,” Dr. Robbins adds. “The relationship between breastfeeding and allergy development is complex, so understanding mothers’ practices is important. We also do not know how often these early reactions result in true food allergy, compared with transient food intolerance.”

American Academy of Allergy, Asthma & Immunology 2019 Annual Meeting presentation

  • “Perceived food allergy, sensitivity or intolerance and its impact on breastfeeding practices.”

Monday, Feb. 25, 2019, 9:45-10:45 a.m. (PST)

Karen A. Robbins M.D., lead author; Marni Jacobs, Ph.D., co-author; Ashley Ramos Ph.D., co-author; Daniel V. DiGiacomo, M.D., co-author; Katherine M. Balas BS, co-author; and Linda Herbert, Ph.D., director of Children’s Division of Allergy and Immunology’s psychosocial clinical program and senior author.

Breastfeeding Mom

Exclusive breastfeeding lowers odds of some schoolchildren having eczema

Breastfeeding Mom

Children exclusively breastfed for the first three months of life had significantly lower odds of having eczema at age 6 compared with peers who were not breastfed or were breastfed for less time, according to preliminary research presented during the American Academy of Allergy, Asthma & Immunology 2019 Annual Meeting.

Eczema is a chronic condition characterized by extremely itchy skin that, when scratched, becomes inflamed and covered with blisters that crack easily. While genes and the environment are implicated in this inflammatory disease, many questions remain unanswered, such as how best to prevent it. According to the Centers for Disease Control and Prevention (CDC), breastfed infants have reduced risks for developing many chronic conditions, including asthma and obesity.

“The evidence that being exclusively breastfed protects children from developing eczema later in life remains mixed,” says Katherine M. Balas, BS, BA, a clinical research assistant at Children’s National and the study’s lead author. “Our research team is trying to help fill that data gap.”

Balas and colleagues tapped data collected in Infant Feeding Practices Study II, a longitudinal study co-led by the CDC and the Food and Drug Administration (FDA) from 2005 to 2007, as well as the agencies’ 2012 follow-up examination of that study cohort. This study first tracked the diets of about 2,000 pregnant women from their third trimester and examined feeding practices through their babies’ first year of life. Their follow-up inquiry looked at the health, development and dietary patterns for 1,520 of these children at 6 years of age.

About 300 of the children had been diagnosed with eczema at some point in their lives, and 58.5 percent of the 6-year-olds had eczema at the time of the CDC/FDA Year Six Follow-Up. Children with higher socioeconomic status or a family history of food allergies had higher odds of being diagnosed with eczema.

“Children who were exclusively breastfed for three months or longer were significantly less likely (adjusted odds ratio: 0.477) to have continued eczema at age 6, compared with peers who were never breastfed or who were breastfed for less than three months,” Balas adds. “While exclusive breastfeeding may not prevent kids from getting eczema, it may protect them from experiencing extended flare-ups.”

American Academy of Allergy, Asthma & Immunology 2019 Annual Meeting presentation

  • “Exclusive breastfeeding in infancy and eczema diagnosis at 6 years of age.”

Sunday, Feb. 24, 2019, 9:45 a.m. (PST)

Katherine M. Balas BS, BA, lead author; Karen A. Robbins M.D., co-author; Marni Jacobs, Ph.D., co-author; Ashley Ramos Ph.D., co-author; Daniel V. DiGiacomo, M.D., co-author; and Linda Herbert, Ph.D., director of Children’s Division of Allergy and Immunology’s psychosocial clinical program and senior author.

Dr. Anna Penn uses a microscope

New model mimics persistent interneuron loss seen in prematurity

Dr. Anna Penn uses a microscope

Children’s research-clinicians created a novel preclinical model that mimics the persistent interneuron loss seen in preterm human infants, identifying interneuron subtypes that could become future therapeutic targets to prevent or lessen neurodevelopmental risks.

Research-clinicians at Children’s National Health System have created a novel preclinical model that mimics the persistent interneuron loss seen in preterm human infants, identifying interneuron subtypes that could become future therapeutic targets to prevent or lessen neurodevelopmental risks, the team reports Jan. 31, 2019, in eNeuro. The open access journal for Society for Neuroscience recognized the team’s paper as its “featured” article.

In the prefrontal cortex (PFC) of infants born preterm, there are decreased somatostatin and calbindin interneurons seen in upper cortical layers in infants who survived for a few months after preterm birth. This neuronal damage was mimicked in an experimental model of preterm brain injury in the PFC, but only when the newborn experimental models had first experienced a combination of prenatal maternal immune activation and postnatal chronic sublethal hypoxia. Neither neuronal insult on its own produced the pattern of interneuron loss in the upper cortical layers observed in humans, the research team finds.

“These combined insults lead to long-term neurobehavioral deficits that mimic what we see in human infants who are born extremely preterm,” says Anna Penn, M.D., Ph.D., a neonatologist in the Division of Neonatology and the Fetal Medicine Institute and a developmental neuroscientist at Children’s National Health System, and senior study author. “Future success in preventing neuronal damage in newborns relies on having accurate experimental models of preterm brain injury and well-defined outcome measures that can be examined in young infants and experimental models of the same developmental stage.”

According to the Centers for Disease Control and Prevention 1 in 10 infants is born preterm, before the 37th week of pregnancy. Many of these preterm births result from infection or inflammation in utero. After delivery, many infants experience other health challenges, like respiratory failure. These multi-hits can exacerbate brain damage.

Prematurity is associated with significantly increased risk of neurobehavioral pathologies, including autism spectrum disorder and schizophrenia. In both psychiatric disorders, the prefrontal cortex inhibitory circuit is disrupted due to alterations of gamma-aminobutyric acid (GABA) interneurons in a brain region involved in working memory and social cognition.

Cortical interneurons are created and migrate late in pregnancy and early infancy. That timing leaves them particularly vulnerable to insults, such as preterm birth.

In order to investigate the effects of perinatal insults on GABAergic interneuron development, the Children’s research team, led by Helene Lacaille, Ph.D., in Dr. Penn’s laboratory, subjected the new preterm encephalopathy experimental model to a battery of neurobehavioral tests, including working memory, cognitive flexibility and social cognition.

“This translational study, which examined the prefrontal cortex in age-matched term and preterm babies supports our hypothesis that specific cellular alterations seen in preterm encephalopathy can be linked with a heightened risk of children experiencing neuropsychiatric disorders later in life,” Dr. Penn adds. “Specific interneuron subtypes may provide specific therapeutic targets for medicines that hold the promise of preventing or lessening these neurodevelopmental risks.”

In addition to Dr. Penn and Lead Author Lacaille, Children’s co-authors include Claire-Marie Vacher; Dana Bakalar, Jiaqi J. O’Reilly and Jacquelyn Salzbank, all of Children’s Center for Neuroscience Research.

Financial support for research described in this post was provided by the National Institutes of Health under award R01HD092593, District of Columbia Intellectual Developmental Disabilities Research Center under award U54HD090257, Cerebral Palsy Alliance Research Foundation, Children’s National Board of Visitors, Children’s Research Institute and Fetal Medicine Institute.

Vittorio Gallo

Neurodevelopmental disorders: Developing medical treatments

Vittorio Gallo

Vittorio Gallo, Ph.D., Chief Research Officer, participates in the world’s largest general scientific gathering, leading panelists in a timely conversation about progress made so far with neurodevelopmental disorders and challenges that lie ahead.

The human brain is the body’s operating system. Imagine if rogue code worked its way into its hardware and software, delaying some processes, disrupting others, wreaking general havoc.

Neurodevelopmental disorders are like that errant code. They can occur early in life and impact brain development for the rest of the person’s life. Not only can fundamental brain development go awry, processes that refine the brain also can become abnormal, creating a double neural hit.  Adding to those complications, children with neurodevelopmental disorders like autism spectrum disorder (ASD) and Fragile X syndrome often contend with multiple, overlapping cognitive impairments and learning disabilities.

The multiple layers of complexities for these disorders can make developing effective medical treatments particularly challenging, says Vittorio Gallo, Ph.D., Chief Research Officer at Children’s National Health System and recipient of a coveted Senator Jacob Javits Award in the Neurosciences.

During the Feb. 16, 2019, “Neurodevelopmental Disorders: Developing Medical Treatments” symposium, Gallo will guide esteemed panelists in a timely conversation about progress made so far and challenges that lie ahead during the AAAS Annual Meeting in Washington, the world’s largest general scientific gathering.

“This is a very important symposium; we’re going to put all of the open questions on the table,” says Gallo. “We’re going to present a snapshot of where the field is right now: We’ve made incredible advances in developmental neuroscience, neonatology, neurology, diagnostic imaging and other related fields. The essential building blocks are in place. Where are we now in developing therapeutics for these complex disorders?”

For select disorders, many genes have been identified, and each new gene has the potential to become a target for improved therapies. However, for other neurodevelopmental disorders, like ASD, an array of new genes continue to be discovered, leaving an unfinished picture of which genetic networks are of most importance.

Gallo says the assembled experts also plan to explore major research questions that remain unanswered as well as how to learn from past experiences to make future studies more powerful and insightful.

“One topic up for discussion will be new preclinical models that have the potential to help in identifying specific mechanisms that cause these disorders. A combination of genetic, biological, psychosocial and environmental risk factors are being combined in these preclinical models,” Gallo says.

“Our studies of the future need to move beyond describing and observing in order to transform into studies that establish causality between the aberrant developmental processes and these constellations of neurodevelopmental disorders.”

little girl with spina bifida

Oral clefts may stem from a shared genetic cause as neural tube defects

little girl with spina bifida

Research by an international team that includes Children’s National faculty, published online Jan. 25, 2019 in Human Molecular Genetics, suggests that genetic mutations that cause cleft lip and palate also may contribute to neural tube defects, such as spina bifida.

Oral clefts are some of the most common birth defects worldwide, affecting about one in every 700 births. In the U.S., more than 4,000 babies are born each year with cleft lip, with or without cleft palate.

This defect isn’t simply a cosmetic manner: Oral clefts can severely affect feeding, speech and hearing, and they cause about 3,300 deaths annually worldwide.

To better understand these conditions, researchers have isolated a number of genetic mutations that appear to play contributing roles. These include those in a gene known as Interferon Regulatory Factor 6. New research by an international team that includes Children’s National faculty, published online Jan. 25, 2019 in Human Molecular Genetics, suggests that these mutations also may contribute to neural tube defects such as spina bifida.

In the first weeks of fetal development, the neural plate curves, creating a neural tube that, once fused shut, becomes the fetal brain and fetal spinal cord. Neural tube defects, which can range from mild to severe, are characterized by incomplete development of the brain, spinal cord or meninges. These defects can potentially result in paralysis or even fetal or neonatal demise. According to the National Institutes of Health, spina bifida, which affects the spinal cord, is the most common neural tube defect in the U.S., affecting up to 2,000 infants each year.

“Despite its high frequency, spina bifida remains among the least understood structural birth defects,” says Brian C. Schutte, an associate professor of Microbiology and Molecular Genetics, Pediatrics and Human Development at Michigan State University and the study’s senior author. “There is strong evidence that genetic factors are a leading cause of such structural birth defects, but in most cases, the cause is unknown. Our team’s study is the first published research to demonstrate that DNA variants in the gene IRF6 can cause spina bifida,” Schutte says.

What’s more, the research team identified a mechanism to explain how altering IRF6 leads to neural tube defects. This mechanism links IRF6 function to two other genes – known as transcription Factor AP2A (TFAP2A) and Grainyhead Like 3 (GRHL3) – that are also known to be required for the development of the neural tube, lip and palate.

“We’re all on the hunt for the reasons when, how and why birth defects happen,” adds Youssef A. Kousa, MS, D.O., Ph.D., a clinical fellow in the Division of Child Neurology at Children’s National Health System and the study’s lead author. “Our main goal is prevention. This paper is a significant development because our team has identified a group of genes that can potentially contribute to very common types of birth defects: craniofacial as well as neural tube defects.”

The scientific odyssey is a wonderful example of serendipity. Kousa, then working in Schutte’s lab, was studying the effects of a new mutant experimental model strain on development of the palate. But one day, he walked into Schutte’s office holding a deformed preclinical embryo and said: “Brian, look at this!”

“Weird things happen in biology,” Schutte replied and counseled him to return if it happened again. Less than two weeks later, Kousa was back with several more of the deformed preclinical embryos, saying: “OK, Brian. It happened again.”

Within hours Kousa had unearthed recently published research that included an image of a similarly affected preclinical embryo. The pair then sketched out possible intersecting genetic pathways, as they brainstormed the myriad ways to end up with that specific phenotype. Initially, they tested their hypotheses in experimental models and eventually corroborated findings through human genetic studies.

The human studies could only be performed by collaborations. Schutte shared their initial observations with human genetics researchers scattered across the country. Those labs then generously agreed to test whether DNA variants in IRF6 were associated with neural tube defects in samples from patients that they had collected over decades of research.

The team found that Tfap2aIrf6 and Grhl3 are components of a gene regulatory network required for neurulation, a folding process that results in the neural tube bending and then fusing to become the basis of the embryo’s nervous system, from brain to spinal cord.

“Since this network is also required for formation of the lip, palate, limbs and epidermis, which develop at different times and places during embryogenesis, we suggest that the Tfap2aIrf6Grhl3 network is a fundamental pathway for multiple morphogenetic processes,” the researchers write.

Interferon Regulatory Factor 6 functions best when there is neither too much expression nor too little. Overexpression of Irf6 suppresses Transcription Factor Activation Protein 2A and Grainyhead Like 3, causing exencephaly, a neural tube defect characterized by the brain being located outside of the skull. Counterintuitively, experimental models that had too little Irf6 also ended up with reduced levels of Tfap2a and Grhl3 that led to a structural birth defect, but at the opposite end of the neural tube.

To test whether the experimental model findings held true in humans, they sequenced samples from people who had spina bifida and anencephaly – the rare birth defect that Kousa spotted in the experimental models – and found IRF6 function was conserved in people. Because of the genetic complexity of these birth defects, and the challenges inherent in collecting samples from cases of severe birth defects, many research teams were invited to participate in the study.

As testament to their collegiality, researchers from Stanford University, University of Texas at Austin, University of Iowa, University of Texas at Houston and Duke University agreed to share precious samples from the California Birth Defects Monitoring Program, from the Hereditary Basis of Neural Tube Defects study and from their own institutional sample collections.

“As we get better at personalized medicine, we could use this information to one day help to counsel families about their own risk and protective factors,” Kousa adds. “If we can identify the genetic pathway, we might also be able to modify it to prevent a birth defect. For example, prenatal supplementation with folic acid has led to a decrease in babies born with neural tube defects, but not all neural tube defects are sensitive to folic acid. This knowledge will help us develop individual-based interventions.”

Financial support for the research covered in this post was provided by the National Institutes of Health under grants DE13513, F31DE022696, DE025060, P01HD067244 and GM072859; startup funding from Michigan State University and the UT-Health School of Dentistry in Houston; and the Centers for Disease Control and Prevention under award number 5U01DD001033.

In addition to Kousa and Schutte, study co-authors include Huiping Zhu, Yunping Lei and Richard H. Finnell, University of Texas at Austin; Walid D. Fakhouri, University of Texas Health Science Center at Houston; Akira Kinoshita, Nagasaki University; Raeuf R. Roushangar, Nicole K. Patel, Tamer Mansour, Arianna L. Smith, and Dhruv B. Sharma, Michigan State University; A.J. Agopian and Laura E. Mitchell, University of Texas School of Public Health; Wei Yang and Gary M. Shaw, Stanford University School of Medicine; Elizabeth J. Leslie, Emory University; Xiao Li, Tamara D. Busch, Alexander G. Bassuk and Brad A. Amendt, University of Iowa; Edward B. Li and Eric C. Liao, Massachusetts General Hospital; Trevor J. Williams, University of Colorado Denver at Anschutz Medical Campus; Yang Chai, University of Southern California; and Simon Gregory and Allison Ashley-Koch, Duke University Medical Center.

Nobuyuki Ishibashi

Cortical dysmaturation in congenital heart disease

Nobuyuki Ishibashi

On Jan. 4, 2019, Nobuyuki Ishibashi, M.D., the director of the Cardiac Surgery Research Laboratory and an investigator with the Center for Neuroscience Research at Children’s National Health System, published a review in Trends in Neurosciences about the mechanisms of cortical dysmaturation, or disturbances in cortical development, that can occur in children born with congenital heart disease (CHD). By understanding the early-life impact and relationship between cardiac abnormalities and cortical neuronal development, Dr. Ishibashi and the study authors hope to influence strategies for neonatal neuroprotection, mitigating the risk for developmental delays among CHD patients.

Dr. Ishibashi answers questions about this review and CHD-neurodevelopmental research:

  1. Tell us more about your research. Why did you choose to study these interactions in this patient population?

My research focuses on studying how CHD and neonatal cardiac surgery affect the rapidly-developing brain. Many children with CHD, particularly the most complex anomalies, suffer from important behavioral anomalies and neurodevelopmental delays after cardiac surgery. As a surgeon scientist, I want to optimize treatment strategy and develop a new standard of care that will reduce neurodevelopmental impairment in our patients.

  1. How does this study fit into your larger body of work? What are a few take-home messages from this paper?

Our team and other laboratories have recently identified a persistent perinatal neurogenesis that targets the frontal cortex – the brain area responsible for higher-order cognitive functions. The main message from this article is that further understanding of the cellular and molecular mechanisms underlying cortical development and dysmaturation will likely help to identify novel strategies to treat and improve outcomes in our patients suffering from intellectual and behavioral disabilities.

  1. What do you want pediatricians and researchers to know about this study? Why is it important right now?

Although the hospital mortality risk is greatly reduced, children with complex CHD frequently display subsequent neurological disabilities affecting intellectual function, memory, executive function, speech and language, gross and fine motor skills and visuospatial functions. In addition to the impact of the neurological morbidity on the patients themselves, the toll on families and society is immense. Therefore it is crucial to determine the causes of altered brain maturation in CHD.

  1. How do you envision this research influencing future studies and pediatric health outcomes? As a researcher, how will you proceed?

In this article we placed special emphasis on the need for well-designed preclinical studies to define disturbances in cortical neurogenesis due to perinatal brain injury. I believe that further study of the impact of hypoxemia on brain development is of broad relevance — not just for children with congenital heart disease, but for other populations where intellectual and behavioral dysfunctions are a source of chronic morbidity, such as survivors of premature birth.

  1. What discoveries do you envision being at the forefront of this field?

One of the important questions is: During which developmental period, prenatal or postnatal, is the brain most sensitive to developmental and behavioral disabilities associated with hypoxemia? Future experimental models will help us study key effects of congenital cortical development anomalies on brain development in children with CHD.

  1. What impact could this research make? What’s the most striking finding and how do you think it will influence the field?

Although cortical neurogenesis at fetal and adult stages has been widely studied, the development of the human frontal cortex during the perinatal period has only recently received greater attention as a result of new identification of ongoing postnatal neurogenesis in the region responsible for important intellectual and behavioral functions. Children’s National is very excited with the discoveries because it has opened new opportunities that may lead to regeneration and repair of the dysmature cortex. If researchers identify ways to restore endogenous neurogenic abilities after birth, the risk of neurodevelopment disabilities and limitations could be greatly reduced.

  1. Is there anything else you would like to add that we didn’t ask you about? What excites you about this research?

In this article we highlight an urgent need to create a truly translational area of research in CHD-induced brain injury through further exploration and integration of preclinical models. I’m very excited about the highly productive partnerships we developed within the Center for Neuroscience Research at Children’s National, led by an internationally-renowned developmental neuroscientist, Vittorio Gallo, Ph.D., who is a co-senior author of this article. Because of our collaboration, my team has successfully utilized sophisticated and cutting-edge neuroscience techniques to study brain development in children born with CHD. To determine the causes of altered brain maturation in congenital heart disease and ultimately improve neurological function, we believe that a strong unity between cardiovascular and neuroscience research must be established.

Additional study authors include Camille Leonetti, Ph.D., a postdoctoral research fellow with the Center for Neuroscience Research and Children’s National Heart Institute, and Stephen Back, M.D., Ph.D., a professor of pediatrics at Oregon Health and Science University.

The research was supported by multiple grants and awards from the National Institutes of Health, inclusive of the National Heart Lung and Blood Institute (RO1HL139712), the National Institute of Neurological Disorders and Stroke (1RO1NS054044, R37NS045737, R37NS109478), the National Institute on Aging (1RO1AG031892-01) and the National Institute of Child Health and Human Development (U54HD090257).

Additional support for this review was awarded by the American Heart Association (17GRNT33370058) and the District of Columbia Intellectual and Developmental Disabilities Research Center, which is supported through the Eunice Kennedy Shriver National Institute of Child Health and Human Development program grant 1U54HD090257.