glial cells

Future TBI treatments may hinge on understanding a new cell type

glial cells

Only recently have investigators begun to understand how a cell type – the NG2-glia – may respond to injuries, offering clues into the brain’s healing and regeneration.

Traumatic brain injury (TBI) afflicts 69 million people, including 630,000 children, worldwide each year. Yet only recently have investigators begun to understand how a cell type – the NG2-glia – may respond to injuries, offering clues into the brain’s healing and regeneration.

In a new paper published in GLIA, investigators from Children’s National Hospital reviewed 25 years of neuroscience research to lay out what’s known about the molecular response of these NG2-glia cells after TBI. Researchers said they see “a seductive possibility” that tapping into the regenerative potential of NG2-glia cells after neurotrauma could lead to therapies in the future. The impact could be profound, given that TBI is the leading cause of death among all people ages 1-44 and the global cost of this ‘silent epidemic’ is estimated to top $102 billion annually.

What they’re saying

“Our review lays out what’s known about these fascinating cells,” said Terry Dean, M.D., Ph.D., critical care specialist at Children’s National and investigator at the Center for Neuroscience Research (CNR). “NG2-glia are found throughout the brain, and we know that these cells undergo several dynamic changes in the hours, days and weeks after TBI. They are unique, and we want to understand their molecular characteristics to eventually enhance patients’ cellular recovery after TBI.”

Although only encompassing 4% to 8% of brain cells, these NG2-glia cells make up the largest population of regenerative cells in the adult central nervous system. In their article, Dean and Vittorio Gallo, Ph.D., Children’s National Research Institute interim director, lay out a number of unique features of these cells:

  • They proliferate, or multiply, and can form different cell types, especially after brain injuries.
  • They are structurally dynamic and can move and migrate throughout the cortex, including toward injury sites.
  • They appear to play a role in cell-to-cell signaling, which may prove vital after injuries.

The big picture

“As we study the brain after injuries, we hope our work will reveal the role these NG2-glia cells play in recovery, driving us to possible therapies,” Gallo said. “We believe the big answers will come through understanding the brain on a molecular level. This type of deep investigation is the foundation of our bench-to-bedside approach and positions researchers like Dr. Dean to find answers for our patients.”

Moving the field forward

Researchers have only begun to unlock how NG2-glia respond to injury, making this a fruitful area for research. Gallo, Dean and others at CNR hope to build on their knowledge about what happens to the brain immediately after an injury to learn more about what happens months after a debilitating impact. They are also considering new types of research models to expand their knowledge about cellular destruction, immune interaction and blood vessel compromise after different types of brain injuries.

“We look forward to the day when we have a truly targeted therapy for TBI patients,” Dean said. “Imagine the relief this could provide patients suffering from the persistent physical, cognitive and psychological disabilities that often accompany these brain injuries.”

Illustration of brain and brainwaves

Effective treatment for children with hemimegalencephaly

Illustration of brain and brainwaves

Anatomic or functional hemispherectomy are established neurosurgical treatment options and are recommended for effective seizure control and improved neurodevelopmental outcome in patients with HME.

Endovascular hemispherectomy can be safely used to provide definitive treatment of hemimegalencephaly (HME) related epilepsy in neonates and young infants when intraprocedural events are managed effectively, a new study finds.

The authors of the study, which published in the Journal of NeuroInterventional Surgery, add that this less invasive novel approach should be considered a feasible early alternative to surgical hemispherectomy.

Why it matters

Anatomic or functional hemispherectomy are established neurosurgical treatment options and are recommended for effective seizure control and improved neurodevelopmental outcome in patients with HME. Hemispherectomy in the neonate, however, is associated with high surgical risks and most neurosurgeons defer surgical hemispherectomy until the patient is at least 8 weeks old. This delay comes at a significant neurocognitive cost as the uncontrolled seizures during this time of deferred surgery have a deleterious effect on future neurocognitive outcome.

Why we’re excited

“The procedure we have developed, endovascular hemispherectomy by transarterial embolization, acutely stops seizures and this cessation of seizures has been sustained in each of the treated patients,” says Monica Pearl, M.D., director of the Neurointerventional Radiology Program at Children’s National Hospital and the study’s lead author.

This treatment option – performed early in life – provides hope and a better quality of life for these patients post procedure.

What’s been the hold-up in the field?

Currently, the only effective treatment option is hemispherectomy. With the patient population of neonates and young infants, hemispherectomy has a very high mortality and complication rate resulting in most neurosurgeons deferring treatment until at least 8 weeks. This leaves neonates and young infants without effective treatment options and on multiple antiseizure medications in an effort to control the seizures

How does this work move the field forward?

“Embolization provides a highly effective treatment option that acutely stops seizures during a time period of critical neurodevelopment and one in which traditional open neurosurgical procedures are not viable options,” Dr. Pearl says. “Specifically, we can consider and perform embolization in children as young as one or two weeks of age rather than waiting until at least 8 weeks of age. The impact of earlier intervention – acutely stopping the seizures, reducing the dose and number of antiseizure medications and avoiding more invasive surgical procedures (hemispherectomy, shunt placement) – appears to be dramatic in our recent series. We are conducting long term studies to assess this effect on neurodevelopmental outcome.”

How is Children’s National leading in this space?

Dr. Pearl and the late Taeung Chang, M.D., neurologist at Children’s National, pioneered this concept and treatment pathway. The multidisciplinary team is led by Dr. Pearl, who has performed all the embolization procedures (transarterial embolization/endovascular hemispherectomy) and Tayyba Anwar, M.D., Co-Director, Hemimegalencephaly Program at Children’s National Hospital. Our epilepsy team, neonatology team and neurosurgery team work collaboratively managing the patients before and after each procedure.

Sarah Mulkey

Exposure to Zika in utero may produce neurodevelopmental differences

Sarah Mulkey

“There are still many unanswered questions about the long-term impacts of Zika on children exposed in utero,” says Sarah Mulkey, M.D., Ph.D., a prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital.

Children who are exposed to the Zika virus while in the womb, but who are not subsequently diagnosed with Zika-related birth defects and congenital Zika syndrome (CZS), may still display differences in some aspects of cognitive development, mood and mobility compared to unexposed children, reports a study published in Pediatric Research. These findings suggest that Zika-exposed children may need some additional support and monitoring as they get older.

“There are still many unanswered questions about the long-term impacts of Zika on children exposed in utero,” says Sarah Mulkey, M.D., Ph.D., a prenatal-neonatal neurologist in the Prenatal Pediatrics Institute at Children’s National Hospital and the study’s first author. “These findings are another piece of the puzzle that provides insight into the long-term neurodevelopment of children with prenatal Zika virus exposure. Further evaluation is needed as these children get older.”

It has not been clear how children who were exposed to the Zika virus in the womb during the 2015–2017 epidemic, but who did not develop CZS and serious neurological complications, will develop as they get older.

Dr. Mulkey and colleagues examined the neurodevelopment of 55 children aged 3-5 years who were exposed to Zika in the womb in Sabanalarga, Colombia, and compared them to 70 control children aged 4-5 years who had not been exposed to Zika. Assessments occurred between December 2020 and February 2021. Health professionals tested the children’s motor skills (such as manual dexterity, aiming and catching, and balance) and their readiness for school (including knowledge of colors, letters, numbers and shapes). Parents completed three questionnaires providing information about their child’s cognitive function (such as memory and emotional control), behavioral and physical conditions (such as responsibility and mobility), and their parenting experience (including whether they felt distress).

Parents of Zika-exposed children reported significantly lower levels of mobility and responsibility compared to control children, although differences in cognitive function scores were not significant. Additionally, parents of 6 (11%) Zika-exposed children reported mood problems compared to 1 (1%) of control children, and Zika-exposed parents were significantly more likely to report parental distress.

Professional testing revealed no significant differences in the Zika-exposed children’s manual dexterity, such as their ability to catch an object or post a coin through a slot, compared to the control children. Both Zika-exposed and control children also scored lowly on readiness for school.

The authors highlight that parental responses may have been influenced by the Zika-exposed children’s parents’ perceptions or increased worry about the development of their child. Some differences in results may also have been caused by the age – and therefore developmental – differences between the groups of children.

The authors conclude that while these Zika-exposed children are making progress as they develop, they may need additional support as they prepare to start school.

Dr. Mulkey is committed to studying the long-term neurodevelopmental impacts that viruses like Zika and SARS-CoV-2 have on infants born to mothers who were infected during pregnancy through research with the Congenital Infection Program at Children’s National and in collaboration with colleagues in Colombia.

DNA molecule

NIH awards $1m grant to study visual system

DNA molecule

The team will focus its work on FXS, a genetic condition that causes changes in a gene called Fragile X Messenger Ribonucleoprotein 1 (FMR1).

Researchers at Children’s National Hospital received a $1 million grant from the National Institutes of Health (NIH) to study the neural mechanisms behind visual deficits in fragile X syndrome (FXS). The work will provide new insights into how the visual system develops.

With the award from the National Eye Institute, the Children’s National team – led by Jason Triplett, Ph.D., principal investigator at the Center for Neuroscience Research – will work to unravel the poorly understood relationship between sensory deficits and neurodevelopmental disorders (NDDs). The findings are expected to provide clues into possible non-invasive therapeutics that could someday be used to resolve visual deficits in children with FXS and other disorders.

“Deficits in sensory processing, including vision, are common in many NDDs, but how these deficits arise is poorly understood, hampering the development of therapies,” Triplett said. “Using a powerful combination of molecular, anatomic and electrophysiologic techniques, we are hoping to get a comprehensive understanding of visual circuit development – and its disruption in fragile X syndrome.”

The big picture

The team will focus its work on FXS, a genetic condition that causes changes in a gene called Fragile X Messenger Ribonucleoprotein 1 (FMR1). The gene normally makes a protein needed for brain development, including the highly complex visual system. However, people with FXS do not properly make the protein, leading to a spectrum of developmental and cognitive delays.

Triplett’s team theorizes that ameliorating sensory deficits could improve other features of the disorder. Research has shown that sensory processing is critical for communication and learning, which are central components of the behavioral therapies aimed at treating intellectual delays and social anxiety.

Yet little is known regarding the neural basis of sensory deficits in FXS. Understanding how neuronal circuits are disorganized and dysfunctional in the context of the disorder will be a critical first step to developing therapeutics. In addition, given the prevalence of sensory dysfunction across NDDs, the work could have broader applications.

Children’s National Hospital leads the way

This NIH-supported work builds on prior research in the Triplett Laboratory. The collaborative nature among investigators in the Center for Neuroscience Research combined with the technical resources supported by the DC-Intellectual and Developmental Disabilities Research Center create an environment that maximizes the experimental capabilities of the Triplett Lab.

“We are so excited to continue this work,” Triplett said. “It highlights the importance of supporting fundamental research at the bench. We started with basic biological questions about how circuits wire up, and now we are embarking on research that could set the stage for potentially life-changing therapies.”

Paper cutouts of silhouette

Successful autism and ADHD tools go digital

Paper cutouts of silhouette

A team is working to implement a successful, evidence-based online training and tele-support system for the Unstuck and On Target (UOT) program.

A team from Children’s National Hospital, Children’s Hospital Colorado and The Institute for Innovation and Implementation at the University of Maryland, Baltimore is working to implement a successful, evidence-based online training and tele-support system for the Unstuck and On Target (UOT) program. The program is now available for free to any parent or educator who needs it.

What is it?

Since 2020, this team has piloted UOT video training with 293 school-based staff across 230 elementary schools in Colorado and Virginia. The work follows a related PCORI-funded research project, Improving Classroom Behaviors Among Students with Symptoms of Autism Spectrum Disorder or Attention Deficit Hyperactivity Disorder, led by Children’s National and Children’s Colorado researchers. That project demonstrated the effectiveness of UOT at improving the executive functioning – or self-regulation skills including flexible thinking, planning and emotional-control – of school-aged children in Title 1 schools. The training focuses on the executive function of elementary school-aged children with autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD).

In addition to creating more accessible training for educators, the team created short, free videos highlighting executive functioning tips and tricks that parents can employ at home. These videos, evaluated by 100 parents and revised based on their input, are now available to parents nationwide.

The availability of this training is possible due to a $2 million contract awarded to Children’s Hospital Colorado’s (Children’s Colorado) Pediatric Mental Health Institute and Children’s National by the Patient-Centered Outcomes Research Institute (PCORI) in 2020.

Why it matters

There are many children, including those in low-income or rural settings, that don’t have access to clinics that offer services to support executive functioning skills, such as planning and flexibility, that they need. But all children have access to a school. Now, UOT training is online and accessible so any school with internet access can offer UOT where school staff (including special educators, teachers, paraprofessionals and counselors) can actively teach students how to plan, set goals and be flexible. The team’s next goal is to create a comparable video training for the high school version of UOT.

“These free, accessible and effective tools for improving children’s social-emotional development are building skills that are more important today than ever,” said Lauren Kenworthy, Ph.D., director of the Center for Autism Spectrum Disorders at Children’s National. “The vast majority (96%) of caregivers and educators found these tools useful and relevant. That feedback is a testament to our team’s efforts to make sure these resources were created and validated as usable, approachable and actionable for everyone who needs them.”

More information

For educators – Find resources on Unstuck and On Target, including links to the free trainings, tips and tricks and FAQs. Teachers can also receive continuing education credits (CEUs) for this training.

For schools – Add free Unstuck and On Target parent videos to your school district’s relevant websites, landing pages and newsletters.

illustration of the brain

How the circadian clock could help the brain recover after injury

illustration of the brain

A type of brain cell that can renew itself is regulated by circadian rhythms, providing significant insights into how the body’s internal clock may promote healing after traumatic brain injuries (TBI).

A type of brain cell that can renew itself is regulated by circadian rhythms, providing significant insights into how the body’s internal clock may promote healing after traumatic brain injuries (TBI), according to new research from Children’s National Hospital.

Released in the latest issue of eNeuro, the findings open new avenues of investigation for future TBI therapies. These injuries are currently managed only with supportive care and rehabilitation, rather than targeted drug treatment options. The findings also underscore the importance of addressing circadian disturbances to help injured brains heal.

Many of the body’s cells follow a 24-hour rhythm driven by their genes known as the circadian clock. The Children’s National research team found that a relatively newly discovered type of brain cell ­– known as NG2-glia, or oligodendrocyte precursor cells ­– also follow a circadian rhythm. This cell type is one of the few that continually self-renews throughout adulthood and is notably proliferative in the first week after brain injuries.

“We have found evidence for the role of this well-known molecular pathway – the molecular circadian clock – in regulating the ability for these NG2-glia to proliferate, both at rest and after injury,” said Terry Dean, M.D., Ph.D., critical care specialist at Children’s National and the lead author of the paper. “This will serve as a starting point to further investigate the pathways to controlling cellular regeneration and optimize recovery after injury.”

Sometimes called “the silent epidemic,” TBI afflicts an estimated 69 million people worldwide each year, with injuries ranging from mild concussions to severe injuries that cause mortality or lifelong disability. In the United States alone, approximately 2.8 million people sustain TBI annually, including 630,000 children. TBI is the leading cause of death in people under age 45, and those who survive are often left with persistent physical, cognitive and psychological disabilities.

Yet no targeted therapies exist for TBI, creating a critical need to uncover the mechanisms that could unlock the regeneration of these NG2-glia cells, which are the most common type of brain cell known to proliferate and self-renew in adult brains.

“It is essential for researchers to know that cell renewal is coordinated with the time of day,” said Vittorio Gallo, Ph.D., interim chief academic officer and interim director of the Children’s National Research Institute. “With this knowledge, we can dig deeper into the body’s genetic healing process to understand how cells regulate and regenerate themselves.”

Brain illustration

Paving the way toward better understanding and treatment of neonatal brain injuries

Brain illustration

The Gallo Lab’s latest research finds reduced expression of Sirt2 in the white matter of premature human infants and characterizes its role in white matter of the brain in normal conditions and during hypoxia.

Changes in myelination due to diffuse white matter injury are a common consequence of premature birth and hypoxic-ischemic injury due to asphyxia of sick term-born newborns. Hypoxic damage during the neonatal period can lead to motor disabilities and cognitive deficits with long-term consequences, including cerebral palsy, intellectual disability or epilepsy, which are often due to cellular and functional abnormalities.

The Gallo Lab, within the Center for Neuroscience Research at Children’s National Hospital, is focused on studying postnatal neural development and the impact of injury and disease on development and regeneration of neurons and glia. Their latest research, published in Nature Communications, finds reduced expression of Sirt2 in the white matter of premature human infants (born earlier than 32 weeks of gestation) and characterizes its role in white matter of the brain in normal conditions as well as during hypoxia.

What it means

The lab previously identified Sirt1 as important for the proliferative regenerative response of oligodendrocyte progenitor cells in response to chronic neonatal hypoxia. This new study characterizes the function of Sirt2 and finds that it acts as a critical promoter of oligodendrocyte differentiation during both normal brain development and after hypoxia.

It’s likely this reduced expression of Sirt2 contributes to the arrest in oligodendrocyte maturation and myelination failure seen in extremely low gestational age neonates. Therefore, targeting Sirt2 may be an opportunity to capture the early and small window of opportunity for therapeutic intervention.

How this moves the field forward

Sirtuins have been shown to play crucial therapeutic roles in various diseases, including aging, neurodegenerative disorders, cardiovascular disease and cancer. Identifying Sirt2 as a major regulator of white matter development and recovery and increasing the understanding of its protein and genomic interactions opens new avenues for Sirt2 as a therapeutic target for white matter injury in premature babies.

Why we’re excited

Interestingly, the team found that overexpression of Sirt2 in oligodendrocyte progenitor cells, but not mature oligodendrocytes, restores oligodendrocyte populations after hypoxia through enhanced proliferation and protection from apoptosis. This is exciting because:

  • It tells us that Sirt2 expression is very important for the transition from progenitor to differentiated oligodendrocyte.
  • It’s the first report, to the team’s knowledge, of Sirt2 regulating cell survival of oligodendrocytes.

Read more in Nature Communications

illustration of the brain

LIFU successfully delivers targeted therapies past the blood-brain barrier

illustration of the brain

LIFU offers doctors the first opportunity to open the blood-brain barrier and treat the entire malignant brain tumor.

Children’s National Hospital will leverage low-intensity focused ultrasound (LIFU) to deliver therapy directly to a child’s high-grade glioma. The approach offers doctors the first opportunity to open the blood-brain barrier and treat the entire malignant brain tumor.

Children’s National will be the first hospital in the U.S. to treat high-grade pediatric brain tumors with LIFU to disrupt the blood-brain barrier. Crossing it has been a major hurdle for effective therapy. The barrier, a network of blood vessels and tissue, prevents harmful substances from reaching the brain but also stops molecular targeted therapy and immunotherapy from getting into the tumor site and staying there.

“LIFU gives us a way to potentially transiently open up the barrier, so we can deliver novel therapy directly to the tumor and improve the likelihood of survival,” said Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National. “It is the greatest breakthrough we’ve potentially had in the past 50 years or more for the management of these tumors. We made great strides in our understanding of molecular genetics and the molecular drivers of tumors, but we have not yet translated that knowledge into better therapies; this may be our most effective mechanism to overcome the barrier.”

In 2020, Children’s National was recognized as the first worldwide Center of Excellence by the Focused Ultrasound Foundation.

Focused ultrasound (FUS) is a non-invasive therapeutic technology with the potential to transform the treatment of many medical disorders by using ultrasonic thermal energy to specifically target tissue deep in the body. The technology can treat without incisions or the need of radiation.

How it works

Doctors at Children’s National will be using LIFU in two different types of procedures:

  • 5-ALA: Doctors will give the patient 5-aminolevulinic acid (5-ALA) with the LIFU treatment. 5-ALA enters rapidly dividing cells and is activated by the ultrasound to a state where it kills the dividing cells of the tumor. The surrounding normal brain cells around the tumor are not dividing, so they do not take up the 5-ALA and are left unharmed after ultrasound therapy.
  • Microbubbles: While receiving different doses of LIFU over a one- to two-hour period, the patient is given “microbubbles,” which are widely used in medical imaging and as carriers for targeted drug delivery. These microbubbles bounce around against the walls like seltzer, opening the blood vessels and transiently opening that space.

Both studies are the first in the world for pediatric gliomas of the brain stem, allowing experts to treat patients 4-6 weeks after radiotherapy. The patient then receives medication orally or intravenously as it passes through the bloodstream. It does not go at high levels anywhere within the brain except where the blood-brain-barrier was opened, allowing oral medication or immune therapies to rush into the tumor.

The launch of this program comes a few months after the hospital successfully performed the first-ever high-intensity focused ultrasound surgery on a pediatric patient with neurofibromatosis.

Watch this video to learn more.

crawling baby

Gene-targeting may help prevent or recover neonatal brain injuries

crawling baby

The findings of a new pre-clinical study published in The Journal of Neuroscience are helping pave the way toward better understanding, prevention and recovery of neonatal brain injuries.

The findings of a new pre-clinical study published in The Journal of Neuroscience are helping pave the way toward better understanding, prevention and recovery of neonatal brain injuries. During pregnancy, the fetus normally grows in low oxygen conditions. When babies are born preterm, there is an abrupt change into a high oxygen environment which may be higher than the baby can tolerate. These preterm babies often need support to breathe because their lungs are immature. If the oxygen they receive is too high, oxygen-free radicals can form and cause cell death.

Premature infants have underdeveloped antioxidant defenses that prevent or delay some types of cell damage under normal conditions. In a high oxygen environment, these underdeveloped defenses cannot fully protect against oxidative stress, damaging different brain regions without available treatments or preventative measures.

“I am thrilled that we identified a defect in a specific cell population in the hippocampus for memory development,” said Vittorio Gallo, Ph.D., interim chief academic officer and interim director of the Children’s National Research Institute, and principal investigator for the District of Columbia Intellectual and Developmental Disabilities Research Center. “I did not think we would be able to do it at a refined level, identifying cell populations sensitive to oxidative stress and its underlying signaling pathway and molecular mechanism.”

Vittorio Gallo

“I am thrilled that we identified a defect in a specific cell population in the hippocampus for memory development,” said Vittorio Gallo, Ph.D.

Children’s National Hospital experts found that oxidative stress over-activates a glucose metabolism enzyme, GSK3β, altering hippocampal interneuron development and impairing learning and memory, according to the pre-clinical study. The researchers also inhibited GSK3β in hippocampal interneurons, reversing these cellular and cognitive deficits.

The role of oxidative stress in the developing hippocampus, as well as GSK3β involvement in oxidative stress-induced neurodevelopmental disorders and cognitive deficits, have both been unexplored until now. Goldstein et al. suggest the study paves the way for the field as a viable approach to maximize functional recovery after neonatal brain injury.

To better understand the mechanisms underlying neonatal brain injury, the researchers mimicked the brain injury by inducing high oxygen levels in a pre-clinical model for a short time. This quest led to unlocking the underpinnings of the cognitive deficits, including the pathophysiology and molecular mechanisms of oxidative damage in the developing hippocampus.

Once they identified what caused cellular damage, the researchers used a gene-targeted approach to reduce GSK3β levels in POMC-expressing cells or Gad2-expressing interneurons. By regulating the levels of GSK3β in interneurons ⁠— but not in POMC-expressing cells — inhibitory neurotransmission was significantly improved and memory deficits due to high oxygen levels were reversed.

caspase molecule

Caspases may link brain cell degeneration and cardiac surgery

caspase molecule

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

A review article in the journal Cell Press: Trends in Neuroscience outlines the wide variety of cellular signaling roles for caspase proteins — a type of cellular enzyme best known for its documented role in the natural process of cell death (apoptosis). The authors, including Nemanja Saric, Ph.D., Kazue Hashimoto-Torii, Ph.D., and Nobuyuki Ishibashi, M.D., all from Children’s National Research Institute, pay particular attention to what the scientific literature shows about caspases’ non-apoptotic roles in the neurons specifically. They also highlight research showing how, when activated during a cardiac surgery with anesthesia and cardiopulmonary bypass, these enzymes may contribute to the degeneration of brain cells seen in young children who undergo heart surgery for critical congenital heart defects (CHDs).

Why it matters

The review summarizes both the known physiological roles of caspases as well as some of the well-characterized neurotoxic effects of anesthetics in pre-clinical models.

The authors propose that these non-apoptotic activities of caspases may be behind some of the adverse effects on the developing brain related to cardiac surgery and anesthesia. Those adverse effects are known to increase risk of behavioral impairments in children with congenital heart disease who underwent cardiac surgery with both anesthesia and cardiopulmonary bypass at a very young age.

This work is the first to propose a possible link between developmental anesthesia neurotoxicity and caspase-dependent cellular responses.

The patient benefit

Better understanding of the time and dose-dependent effects of general anesthetics on the developing brain, particularly in children who have genetic predispositions to conditions such as CHDs, will help researchers understand their role (if any) in behavioral problems often encountered by these patients after surgery.

If found to be a contributing factor, perhaps new therapies to mitigate this caspase activity might be explored to alleviate some of these adverse effects on the developing brain.

What’s next?

The authors hope to stimulate more in-depth research into caspase signaling events, particularly related to how these signaling events change when an anesthetic is introduced. Deeper understanding of how anesthetics impact caspase activation in the developing brain will allow for better assessments of the risk for children who need major surgery early in life.

Children’s National leads the way

Children’s National Hospital leads studies funded by the U.S. Department of Defense to better understand how these other roles of caspases, which until now have not been well-documented, may contribute to brain cell degeneration when activated by prolonged anesthesia and cardiopulmonary bypass during cardiac surgery for congenital heart disease.

colorful strands of DNA

Paving the way to activate a single gene in Angelman syndrome

colorful strands of DNA

Angelman syndrome (AS) is a rare disorder that causes neurodevelopmental issues such as intellectual disability, impaired speech and motor skills, epilepsy and sleep disruptions. This single gene disorder is caused by mutations or deletions in the maternal copy of the UBE3A gene.

Angelman syndrome (AS) is a rare disorder that causes neurodevelopmental issues such as intellectual disability, impaired speech and motor skills, epilepsy and sleep disruptions. This single gene disorder is caused by mutations or deletions in the maternal copy of the UBE3A gene. To date, there is no treatment for AS.

It is easier to treat this syndrome when the disrupted gene is present but repressed. If experts can figure out how to activate it in clinical trials, they believe patients could receive a treatment that tackles the root of the problem. Children’s National Hospital experts support this vision and the AS community by helping establish appropriate biomarkers for current and future clinical trials.

While the field is trying to figure out the best scientific method to quantify progress in clinical trials for AS, the Sidorov Laboratory found that overnight sleep testing is not necessary for detecting Angelman syndrome electroencephalography (EEG) biomarkers, according to the study published in Autism Research. The data further suggests that while sleep EEGs do not provide additional benefit for detecting delta EEG rhythms, sleep itself represents a valuable AS biomarker.

What this means

“It is encouraging to see that wake EEGs are sufficient, and perhaps ideal, for detecting delta waves in a clinical trial setting,” said Michael S. Sidorov, Ph.D., principal investigator with the Center for Neuroscience Research at Children’s National. “With this biomarker, researchers can measure how AS severity changes in children over the course of a clinical trial. This enables trials to test the efficacy of exciting new treatments.”

The hold-up in the field

In the past decade, the research community has focused on activating the dormant paternal copy of the UBE3A gene in pre-clinical models. Presently, there are three ongoing phase I clinical trials for AS in the U.S. These trials use antisense oligonucleotides (ASOs), which can modify gene expression to treat genetic disorders, and have been FDA approved for other disorders. These new compounds specifically target the gene activation to unleash the existing copy of UBE3A. However, there is a need for better and more accurate ways to know if the drug is working or not. The field has not reached a consensus yet on the appropriate biomarkers that can correctly measure success.

There are also challenges associated with performing overnight EEG studies in children with AS due to the severe sleeping problems, difficulty in tolerating the process and sample recruitment.

The patient benefit

Elizabeth R. Jalazo, M.D., assistant professor of pediatrics at the University of North Carolina in Chapel Hill, chief medical officer at the Angelman Syndrome Foundation, is also the parent of a child with Angelman syndrome. Dr. Jalazo, who was not part of the study, mentioned that her experience with a daughter with a rare disorder had brought challenges to their family over the last seven years. But, alas, she said the joy Evelyn has brought to their lives far outweighs the day-to-day challenges of special needs parenting.

“As a parent I’m thrilled that we can potentially capture as much meaningful EEG data in a short daytime EEG rather than subjecting our children to overnight EEG studies,” said Dr. Jalazo. “As a clinician this is equally exciting from a clinical trial feasibility standpoint.”

One of the greatest challenges facing Angelman syndrome and other neurodevelopmental disorder therapeutic development is the lack of appropriate endpoints to assess the efficacy of our interventions.

“I worry very much that without objective measures specific to Angelman syndrome, potentially beneficial therapeutics may fail to meet the mark and ultimately not reach the community,” she added.

The scientific community has transitioned from the hope of clinical trials to lessen those day-to-day challenges to witnessing first-in-human trials of potentially transformative therapeutics in just the last few years.

“It is a biomarker work like this that is critical as we delve into the exciting landscape of clinical trial design and advance therapeutics for Angelman syndrome,” said Dr. Jalazo.

You can read the full study “Evaluation of electroencephalography biomarkers for Angelman syndrome during overnight sleep” in Autism Research.

 

zika virus

Researcher to decipher how viruses affect the developing brain with nearly $1M NIH award

zika virus

Zika virus in blood with red blood cells, a virus which causes Zika fever found in Brazil and other tropical countries.

The National Institutes of Health (NIH) awarded Children’s National Hospital nearly $1M of research support toward uncovering the specific cellular response that happens inside a developing brain once it is infected with a virus, including how the neuron gets infected, and how it dies or survives. The research is expected to gather critical information that can inform prenatal neuro-precision therapies to prevent or attenuate the effects of endemic and pandemic viruses in the future.

“We need to use all of the information we have from ongoing and past pandemics to prevent tomorrow’s public health crisis,” said Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National. “There is still here a whole lot to learn and discover. We could eventually — and this is the vision that’s inspiring us — prevent neurodevelopmental disorders before a baby is born by understanding more about the interaction between the virus, mother, fetus, and environment, among other factors.”

Different viruses, including HIV, CMV, Zika and rubella, injure the developing brain in very similar ways. This line of work was fostered first by the clinical research team led by Adre du Plessis, M.B.Ch.B., and Sarah Mulkey, M.D., supported by Catherine Limperopoulos, Ph.D., chief and director of the Developing Brain Institute at Children’s National.

The clinical research findings then led to the NIH support, which then inspired more basic science research. Fast forward to now, Kousa will study how Zika affects the human brain and extrapolate what is learned and discovered for a broader understanding of neurovirology.

The research program is supported by senior scientists and advisors, including Tarik Haydar, Ph.D., and Eric Vilain, M.D., Ph.D., both at Children’s National and Avindra Nath, M.D., at NIH, as well as other leading researchers at various U.S. centers.

“This is a team effort;” added Kousa, “I’m thankful to have a group of pioneering and seasoned researchers engaged with me throughout this process to provide invaluable guidance.”

Many viruses can harm the developing brain when they replicate in the absence of host defenses, including the gene regulatory networks responsible for the neuronal response. As a result, viral infections can lead to brain injury and neurodevelopmental delays and disorders such as intellectual disability, seizures that are difficult to treat, and vision or hearing loss.

The big picture

Youssef Kousa

Youssef Kousa, MS, D.O., Ph.D., neonatal critical care neurologist and physician-scientist at Children’s National.

The translational research supported by NIH with this award synergistically complements nationally recognized clinical research programs and ongoing prospective cohort studies at Children’s National to identify the full spectrum of neurodevelopmental clinical outcomes after prenatal Zika and other viral infections led by Dr. Mulkey and Roberta DeBiasi, M.D., M.S..

The award also builds upon strengths at the Children’s National Research & Innovation Campus, which is in proximity to federal science agencies. Children’s National experts from the Center for Genetic Medicine Research, known for pediatric genomic and precision medicine, joined forces with the Center of Neuroscience Research and the NIH-NINDS intramural research program to focus on examining prenatal and childhood neurological disorders.

Kousa received this competitive career development award from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number K08NS119882. The research content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The hold-up in the field

Many neurodevelopmental disorders are caused by endemic viruses, such as CMV, and by viral pandemics, including rubella as seen in the 1960s and Zika since 2015. By studying Zika and other prenatal viral infections, Kousa and team hope to gain deeper biological understanding of the viral effects toward developing therapies for anticipating, treating and preventing virally induced prenatal brain injury in the long-term future.

To date, little is known about how viruses affect developing neurons and, as a result, prenatal brain injury is not yet treatable. To bridge the gap towards prenatal neuro-precision therapies, the research explores how genes regulate neuronal developmental and viral clearance by innovatively integrating three systems:

  • Cerebral organoids, which illuminate how a neuron reacts to a viral infection
  • Pre-clinical models that link prenatal brain injury to postnatal neurodevelopmental outcomes
  • Populational genomics to identify human genetic risk or protective factors for prenatal brain injury

Given the scope and complexity of this issue, the international Zika Genetics Consortium, founded in 2015 by Kousa and a team of leading investigators across the world, provides critical samples and resources for the third arm of the research by performing comprehensive genomic analyses using sequencing data collected from diverse human populations throughout Central and South America, which are not as heavily sequenced as Western populations. Through partnerships with the Centers for Disease Control and Prevention and NIH, the consortium’s database and biorepository houses thousands of patient records and biospecimens for research studies to better understand how viruses affect the developing human brain.

“It is inspiring to imagine that, in the longer term, we could recognize early on the level of brain-injury risk faced by a developing fetus and have the tools to mitigate ensuing complications,” said Kousa. “What is driving this research is the vision that one day, brain injury could be prevented from happening before a baby is born.”

illustration of brain tumor

International initiative aims to find rare brain tumor treatments

illustration of brain tumor

Rare brain tumors are not as well characterized due to the paucity of biological and clinical data available.

Certain brain tumors can be hard to diagnose. And as such, that makes it complicated to find a treatment.

In an effort to identify and tailor treatments to patients with rare brain tumors, Children’s National is launching a rare brain tumor initiative. The hospital is collaborating with other hospitals in North America, South America and Europe to compile a registry of children diagnosed with rare brain tumors. The registry will collect biospecimens, clinical and radiological data from patients diagnosed with certain rare brain tumors.

The goal is to find a correlation between the molecular findings and the clinical findings to categorize them. This will help doctors get different prognosticators or different treatment approaches.

Here, Adriana Fonseca Sheridan, M.D., pediatric neuro-oncologist at Children’s National Hospital, tells us more about this international initiative.

What’s been the hold-up in the field?

The recent incorporation of molecular features as part of the diagnostic criteria and classification of brain tumors highlighted a high biological and molecular heterogeneity within previously histologically defined entities. The improvement in our diagnostic capabilities have been incredibly useful to stratify patients into different disease-specific risk groups and tailor therapeutic approaches accordingly in the most common brain tumors. In contrast, rare brain tumors are not as well characterized due to the paucity of biological and clinical data available. Additionally, newly molecularly defined entities lack specific clinical and therapeutic data and represent a major challenge to patients and doctors alike.

How does this work move the field forward?

The overarching objective of the international rare brain tumor registry is to deepen our understanding of the biological underpinnings of rare brain tumors. The registry also seeks to create infrastructure that allows for development of rational and personalized treatment strategies for children with rare entities.

What are you hoping to discover?

We hope to characterize the clinicopathological features and identify risk factors for survival and optimal therapeutic approaches of:

  • CNS sarcomas
  • BCOR-ITD tumors
  • Astroblastoma/MN1 altered tumors
  • Histologically ambiguous/unclassifiable brain tumors

How unique is this work?

Children’s National will spearhead the development of this initiative and lead an effort to prospectively collect biological specimens, radiological and clinical data that allow us to better understand the biologic mechanisms and therapeutic susceptibilities of these rare diseases.

We know that the best way to lead the advancement of the field in rare diseases is through collaboration. Therefore, we will synchronize efforts and collaborate with our European colleagues. They will be running a similar initiative. Our goal is to generate meaningful and robust data that will allow us to better understand how to successfully treat patients with these rare brain tumors across the globe.

mitochondria

Grant funds study of two maternally inherited mitochondrial diseases

mitochondria

The National Institutes of Health awarded George Washington University and Children’s National Hospital a grant to study two maternally inherited mitochondrial diseases.

The National Institutes of Health awarded George Washington University and Children’s National Hospital a grant to study two maternally inherited mitochondrial diseases. Andrea Gropman, M.D., division chief of Neurodevelopmental Pediatrics and Neurogenetics at Children’s National, along with her co-investigator, Anne Chiaramello, M.D., from the George Washington University School of Medicine, will lead the study.

The proposed studies focus on two ultra-rare maternally inherited mitochondrial diseases:

  • Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes (MELAS); and
  • Leber’s Hereditary Optic Neuropathy-Plus (LHON-Plus).

Both diseases are among those studied by the Rare Diseases Clinical Research Network.

“We are really pleased to be able to change the landscape for MELAS and LHON, two mitochondrial disorders with relentless progression and no treatment,” Dr. Gropman said. “This grant represents the fruition of an eight-year collaboration with my colleague Dr. Chiaramello and we are fortunate to be able to deliver this at Children’s National and serve our patients and community.”

Because patients currently do not have access to effective therapeutic intervention, this results in significant disability, morbidity and premature death. The UG3 phase of the study will focus on translational MELAS and LHON-Plus studies and submission of an IND protocol to the Food and Drug Administration. The UH3 phase will focus on a basket clinical trial with MELAS and LHON-Plus to:

  • Provide proof-of-concept that the basket design can be applied to divergent ultra-rare diseases.
  • Advance the dataset for safety and pharmacokinetics/pharmacodynamics of our lead compound for a larger number of patients than in a conventional clinical trial setting.
  • Gather outcomes and practical information for optimizing the design of future basket clinical trial.

“Dr. Gropman is dedicated to giving children with MELAS the very best care,” said Elizabeth Wells, M.D., vice president of Neuroscience and Behavioral Medicine Center at Children’s National. “This new research funding is exciting and means more patients can benefit from the expertise she has developed at Children’s National.”

brain network illustration

Changing the surgical evaluation of epilepsy

brain network illustrationThe choice between stereoelectroencephalography (SEEG) and subdural evaluation is not mutually exclusive, according to a new opinion piece published in JAMA Neurology.

In their article, Chima Oluigbo, M.D., pediatric epilepsy neurosurgeon, William D. Gaillard, M.D., division chief of Epilepsy and Neurophysiology and Neurology, both at Children’s National Hospital, and Mohamad Z. Koubeissi, M.D., M.A., from The George Washington University Hospital, discuss how the practicing epileptologist requires a profound understanding of the roles of different technologies. It also looks at how to integrate both traditional and emerging paradigms to optimize seizure control. This issue is particularly relevant to choosing the best method of invasive intracranial electroencephalography monitoring in individual cases.

Noting that despite the dramatic increase in SEEG use in recent years, the authors talk about how many patients still benefit from invasive monitoring using subdural grids. Therefore, it is important to define the considerations that should guide decision-making on the choice of SEEG versus subdural monitoring in each patient. The authors expand on their statement explaining that it is critical to define the roles of SEEG vs subdural grid investigation in each patient as subdural grid evaluations are still indicated in specific circumstances.

Additionally combined hybrid deployment of both techniques may be indicated in specific situations. Accommodation should be made to allow customization of the technique chosen to available technical expertise and equipment as well as patient preference.

2021 neurology infographic

2021 at a glance: Neurology and Neurosurgery at Children’s National

2021 neurology infographic

MRI Room

Children’s National uses HIFU to perform first ever non-invasive brain tumor procedure

MRI Room

Children’s National Hospital successfully performed the first-ever high-intensity focused ultrasound (HIFU) procedure on a pediatric patient with neurofibromatosis (NF). This is the youngest patient to undergo HIFU treatment in the world. Image provided by Insightec.

Children’s National Hospital successfully performed the first-ever high-intensity focused ultrasound (HIFU) procedure on a pediatric patient with neurofibromatosis (NF). This is the youngest patient to undergo HIFU treatment in the world. The advancement of children’s medical devices in the U.S. continues to significantly lag behind adult devices. This is why this milestone marks a significant advance in making pediatric surgery more precise and less invasive.

The hospital is offering this treatment to patients under an ongoing research clinical trial. Children’s National is one of the first pediatric hospitals in the nation to use HIFU for neuro-oncology patients. It’s also the first hospital in the world to use it to treat a pediatric patient with NF. NF is a condition that occurs in approximately 1 in 3,500 births and causes tumors to form in the brain, spinal cord and nerves.

“Using HIFU to treat our pediatric patients is a quantum leap towards non-invasive surgery for kids,” said Robert Keating, M.D., division chief of Neurosurgery and co-director of the HIFU program at Children’s National. “It’s exciting because the future is now here and it’s significantly better for our kids, in terms of non-invasive surgery with lower risk of complications and no exposure to radiation.”

Focused ultrasound (FUS) is a non-invasive therapeutic technology with the potential to transform the treatment of many medical disorders by using ultrasonic thermal energy to specifically target tissue deep in the body. The technology can treat without incisions or the need of radiation.

FUS, which has been used for adult clinical trials for many decades, can be delivered through high- or low-intensity focused ultrasound (LIFU). HIFU uses non-invasive therapy that uses focused ultrasound waves to thermally ablate a focal area of tissue. Children’s National will now use HIFU to treat low-grade type tumors located in difficult locations of the brain, such as hypothalamic hamartomas and pilocytic astrocytoma, as well as for movement disorders and epilepsy.

An alternative approach, LIFU uses lower levels of energy to disrupt the blood-brain barrier. Unlike medications, which often have difficulty crossing the blood-brain barrier, LIFU can transiently open the blood-brain barrier to chemotherapy. This may allow more effective treatment of tumors and offer opportunities to treat, for the first time, the entire extent of a malignant brain tumor.

“Having focused ultrasound technology as a tool and conducting clinical trials will allow our neurologists and oncologists to offer a non-invasive treatment option to many patients who suffer from neurological conditions,” said Hasan Syed, M.D., co-director of the HIFU program at Children’s National. “The milestone of performing this first HIFU procedure will lead the way to better understanding of the effect of this technology and provide patients with more options.”

At Children’s National, the HIFU program is being led by Dr. Keating and a multidisciplinary team, including clinicians and investigators from the Sheik Zayed Institute for Pediatric Innovation, radiology, oncology, surgery and orthopedics. In an effort to collaborate with the region’s adult hospitals, Children’s National will also treat adult patients on a selective basis who have movement disorders such as essential tremor and Parkinson’s. There is a scarcity of similar resources in the metro region. Many adult patients face one-year wait periods for treatment of their movement disorders, requiring many to travel out of state for treatment.

The LIFU program is scheduled to be operational in 2022. It will likely be the first in the U.S. to treat high-grade pediatric brain tumors with disruption of the blood-brain barrier and provide more effective routes for chemotherapy as well as potential immunotherapy and molecular approaches.

“The use of LIFU with microbubbles to open up the blood-brain barrier is an exciting, potentially game-changing approach for children with these tumors,” said Roger Packer, M.D., senior vice president of the Center for Neurosciences and Behavioral Medicine at Children’s National. “It should safely allow the blood-brain barrier to open and allow delivery of potentially life-saving personalized therapy to the tumor and spare the rest of the brain. It is the most exciting, new development in brain tumor therapy for these malignant midline tumors in the past 50 years.”

Children’s National continues to be a leader in pediatric HIFU use. In 2015, Children’s National doctors became the first in the U.S. to use MR-HIFU to treat pediatric osteoid osteoma – a benign, but painful bone tumor. Successful clinical trial results led to FDA approval in early 2021 for the use of the technology for this treatment. In 2020, the Focused Ultrasound Foundation also designated Children’s National as the first global pediatric Center of Excellence for using this technology to help patients with specific types of childhood tumors.

girl with down syndrome

Study finds delayed oligodendrocyte progenitor maturation in Down syndrome

girl with down syndrome

People with Down syndrome (DS) can have moderate to severe intellectual disability, which is thought to be associated with changes in early brain development.

People with Down syndrome (DS) can have moderate to severe intellectual disability, which is thought to be associated with changes in early brain development. Children’s National Hospital experts discovered delayed maturation in oligodendrocyte progenitors in DS. Oligodendrocytes produce the white matter which insulates neural pathways and ensures speedy electrical communication in the brain. The researchers identified these delays by measuring gene expression at key steps in cell development, according to a new study published in Frontiers in Cellular Neuroscience.

The findings further suggest that brain and spinal cord oligodendrocytes differ in their developmental trajectories and that “brain-like” oligodendrocyte progenitors were most different from control cells, indicating that oligodendrocytes in the brains of people with DS are not equally affected by the trisomy 21.

“This is one of the critical steps towards identifying the key stages and molecular players in the DS white matter deficits,” said Tarik Haydar, Ph.D., director of the Center for Neuroscience Research. “With this knowledge, and with further work in this direction, we envision future therapies that may improve nerve cell communication in the brains of people with Down syndrome.”

The hold-up in the field

The mechanisms that lead to the reduction of white matter in the brains of people with DS are unknown. To better understand early neural precursors, they used isogenic pluripotent stem cell lines derived from two individuals with Down syndrome to study the brain development and spinal cord oligodendrocytes.

“I was excited that we discovered another example of how important it is not to generalize when studying DS brain development,” said Haydar. “This is one of several papers, from our group and others, that demonstrate how important it is to be very specific about the brain area and the developmental stage when investigating the causes of DS brain dysfunction.”

What’s next

Dysmaturation of oligodendrocyte cells are a relatively new discovery by the Haydar Lab, one of the preeminent labs in DS research. These results isolate specific steps that are affected in human cells with trisomy 21. They are using these results to develop a drug screening platform that may prevent altered generation of oligodendrocytes in the future.

You can read the full study “Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21” in Frontiers in Cellular Neuroscience.

DNA moleucle

Multidisciplinary team seeks to reverse epigenetic changes associated with fetal alcohol syndrome disorder

DNA moleucle

The team hopes to optimize and develop treatments that can reverse epigenetic changes in clinical trials, paving the way to make significant progress in the field — something that is lacking to date.

A clinical team joined forces with a research team at Children’s National Hospital to help advance treatments that can improve a child’s development caused by fetal alcohol syndrome disorder (FASDs), which is a group of conditions that can occur in a person who was exposed to alcohol before birth. This boost in collaboration between the bench and clinical hopes to optimize and develop treatments that can reverse epigenetic changes in clinical trials, paving the way to make significant progress in the field — something that is lacking to date.

So far, Children’s National experts have published various pre-clinical studies that identified epigenetic changes caused by alcohol exposure during pregnancy. These changes observed in the pre-clinical models created neuropsychiatric problems like patients with fetal alcohol syndrome disorder. Now, they want to bring such potential treatments effective in pre-clinical models to the bedside.

“As a first step, we are going to test whether the epigenetic changes that were observed in pre-clinical models of FASD are also true in human patients,” said Kazue Hashimoto-Torii, Ph.D., principal investigator of the Center for Neuroscience Research at Children’s National. “We hope a small amount of blood donated by patients with FASD reveal the changes. Meanwhile, my group has also been optimizing drug candidates that reverse the epigenetic changes toward clinical trials.”

Advances in genetics and genomics have led to discoveries about the timing of exposure and developmental outcomes and genetic and epigenetic signatures that may be protective or harmful in terms of how in utero alcohol exposure affects developmental outcomes.

The hold-up in the field

While the exact number of people with FASDs is unknown, the National Institutes of Health estimates that 1% to 5% of the population have FASDs. FASDs has a spectrum of diagnoses that represent a broad range of effects that can be manifested in an individual whose mother drank alcohol during pregnancy. These conditions can affect everyone in different ways and range from mild to severe. Individuals with mild conditions may go undiagnosed. The more affected individuals have comorbid attention-deficit/hyperactivity disorder (ADHD) and behavioral problems that become the focus of clinical encounters. The individual’s health care provider may not recognize the core features as part of FASD.

“Because there is a stigma associated with drinking while pregnant, many providers fail to get this history, and women may be reluctant to offer this information,” said Andrea Gropman, M.D., division chief of Neurodevelopmental Pediatrics and Neurogenetics at Children’s National. “There are subtle and more obvious facial dysmorphology that may help with suspicion or identification, but many individuals do not have these findings.”

The core features may be nonspecific, such as intellectual disabilities and problems with behavior and learning, difficulties with math, memory, attention, judgment and poor impulse control, which are frequent findings in ADHD, autism, learning disorders and other conditions.

“Unless history is taken and FASD is in the differential diagnosis, the diagnosis may not be made,” said Dr. Gropman. “Individuals with FASD may feel stigmatized and opt not to participate in clinical trials.”

As mentioned by Dr. Gropman, stigma can make a patient family be reluctant to seek treatment, and thus the development of treatment for FASD cannot make significant progress to date, Hashimoto-Torii added.

Children’s National Hospital leads the way in an IRB approved study

Researchers at Children’s National have identified a potential drug candidate that reverse the epigenetic changes and may lead to clinical trials. The team is seeking people to participate in an IRB approved study. The study will involve cognitive testing, filling out surveys about current functioning and cheek swab and blood sample to determine if these changes are seen in patients. To participate, subjects must be

  • Children between the ages 5-12 with prenatal alcohol exposure.
  • Mother of child recruited above.

For participation, please contact Grace Johnson, research coordinator at to screen for eligibility at 202-476-6034 or gjohnson3@childrensnational.org

Meet the multidisciplinary team with different yet complementary skills in different fields, such as basic science, medical, social sciences, neurology and developmental disabilities, and development, who are working tirelessly to address the complex health problem.

Gropman lab:

Andrea Gropman, M.D., received her medical doctorate degree from the University of Massachusetts Medical School and specializes in neurogenetics, with a focus on mitochondrial disorders and Smith Magenis syndrome. Her latest research focuses on atypical patterns of inheritance, childhood mitochondrial disorders and other inborn errors of metabolism presenting with white matter disease.

Meira Meltzer, M.A., M.S., C.G.C., genetic counselor with a demonstrated history of working in the hospital and healthcare industry. Also skilled in molecular biology, clinical research and medical education. Strong healthcare services professional with a M.S. focused on genetic counseling from Brandeis University.

Cathy Scheiner, M.D., developmental behavioral pediatrician with a special interest in attention-deficit / hyperactivity disorder (ADHD), cerebral palsy and premature infant.

Grace Johnson, research assistant.

Hashimoto-Torii Lab:

Kazue Hashimoto-Torii, Ph.D., received her postdoctoral training in the Pasko Rakic laboratory at Yale University. Her research focuses on neurobehavior problems of children that stem from their environment during development, such as prenatal exposure to alcohol, drug and high-level glucose. A few drug candidates that her lab discovered have been patented and her lab is currently working hard to bring those medicines to bedside.

Satoshi Yamashita, M.D., Ph.D., postdoctoral research fellow skilled in developmental neurobiology. He is a pediatrician with Japanese medical license and received his Ph.D. with iPS cell research for STXBP1 encephalopathy in Japan.

Chiho Yamashita, B.N., research assistant passionate about child disease research. She is a nurse with a Japanese nursing license and worked in the pediatric department in Japan.

Representative OFF and DIFF spectra

GABA and glutamate in the preterm neonatal brain

Preterm and sick newborns are at high risk of brain injury that can lead to cognitive delays and behavioral disorders including autism and ADHD. Gamma-aminobutyric acid (GABA) and glutamate system disruptions may underlie these neonatal brain injuries and hence it is important to describe their normative profile in the developing neonatal brain.

In a study led by Sudeepta Basu, M.D., neonatologist at Children’s National Hospital and Assistant Professor of Pediatrics at George Washington University School of Medicine and Health Sciences, specialized GABA editing spectroscopy (MEGA-PRESS) was acquired on a 3Tesla MRI scanner. Although MEGA-PRESS has been used in older subjects, there are challenges in the newborn population that have limited investigations with only a few institutions worldwide. Under the leadership of Catherine Limperopoulos, Ph.D., in the Developing Brain Institute (DBI) at Children’s National, a team of scientists (in particular, Dr. Subechhya Pradhan) have diligently overcome the technical challenges to enable use of this cutting-edge technology for research at the institute.

With this unique capability, Dr. Basu’s team prospectively enrolled 58 healthy newborns to describe the normal GABA and glutamate concentrations in different regions of the developing brain. In a recent article published in the American Journal of Neuroradiology, Dr. Basu reports that GABA and glutamate concentrations were highest in the cerebellum, slightly lower in the basal ganglia, but significantly lower in the frontal lobe.

“Our ability to reliably describe the normal metabolic-neurotransmitter milieu of the developing newborn brain is the first step in filling a critical gap in knowledge,” says Dr. Basu. “We hope to identify early bio-markers of brain injury of cognitive delays and autism and ADHD risk which remains a major challenge until clinical symptoms manifest later in childhood.”

Under the direction of Dr. Limperopoulos, advanced multi-modal high precision MRI protocols have been developed for use in research studies at Children’s National that allows the scientists to identify subtle signs of delayed growth and development of the newborn brain. With the optimization of MEGA-PRESS for newborns, Children’s National is one of a few institutions worldwide capable of investigating the newborn brain neurotransmitters in future research studies.

Read the full article in American Journal of Neuroradiology.

Representative OFF and DIFF spectra

Representative OFF and DIFF spectra.