Tag Archive for: brain injury

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.

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.”

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.

boy with a chromosomal developmental disability.

NIH award will support intellectual and developmental disabilities research at Children’s National

boy with a chromosomal developmental disability.

Children’s National Hospital announces a $7 million award from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to support the DC Intellectual and Developmental Disabilities Research Center (DC-IDDRC).

Children’s National Hospital announces a $7 million award from the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) to support the DC Intellectual and Developmental Disabilities Research Center (DC-IDDRC). Through this award, the DC-IDDRC will enhance the recruitment and training of investigators, generate innovation and promote transdisciplinary research to facilitate the development, implementation and dissemination of new diagnostic and therapeutic advances for the care of individuals with intellectual and developmental disabilities.

The DC-IDDRC, led by Children’s National in partnership with George Washington University, Howard University and Georgetown University, is one of only 14 IDDRCs in the United States funded by NICHD. This long standing NICHD program supports researchers whose goals are to advance understanding of a variety of conditions and topics related to intellectual and developmental disabilities.

“Children’s National cares for one of the largest cohorts of children with developmental disabilities in the U.S. — which uniquely positions us to lead the way in both care and research of developmental disabilities in young children,” said Vittorio Gallo, Ph.D., interim chief academic officer and interim director of the Children’s National Research Institute, and principal investigator for the DC-IDDRC.

The research strategy for this period will address three key areas: neural development and neurodevelopmental disorders, fetal and neonatal brain injury and genetic disorders by leveraging the core facilities and core innovation — including the Genomics and Bioinformatics Core, Cell and Tissue Microscopy Core, Neuroimaging Core, Clinical Translational Core and Neurobehavioral Evaluation Core.

“In spite of tremendous advances in our understanding of how abnormalities in brain development cause neurodevelopmental disorders and developmental disabilities, integrated knowledge in all these areas of research is still lacking. In particular, it is still unknown how specific genetic defects and cellular abnormalities result in behavioral phenotypes,” said Gallo.

One in six children suffers from a chronic, complex neurodevelopmental disability — conditions such as intellectual disability, learning disability, attention deficit hyperactivity disorder, autism spectrum disorder, cerebral palsy and Down syndrome. For 20 years, the DC-IDDRC has been a home for researchers from different specialties and different institutions to discover new therapies and treatments for children with these types of neurodevelopmental disabilities.

“The DC-IDDRC promises to be a great vehicle to spawn new research and collaborative networks for D.C. area investigators,” said Chandan Vaidya, Ph.D., vice provost for faculty and professor at Georgetown University. “We will be examining whether a behavioral intervention to enhance self-regulation in adolescents with Autism changes how they learn and use computational modeling to understand learning strategy and identify associated changes in the brain using functional magnetic resonance imaging.”

The robust relationships and spirit of cooperation built over two decades of collaboration have laid a strong groundwork for the establishment of the expansive post-doctoral training program and continuous growth of the research programs within the DC-IDDRC. Gallo continues his efforts in expanding access to these programs and building a sustainable pipeline of young scholars from diverse backgrounds. The partnership between Children’s National and Howard University continues to play a crucial role in these goals.

The DC-IDDRC continues to work toward translating research findings into novel approaches and personalized treatments for people with developmental disabilities and their caregivers. This work will be amplified when the DC-IDDRC moves into the expanded facility at the Children’s National Research & Innovation Campus, which houses startup incubator programs and other support for device innovation.

PAS Logo

Children’s National participants share their expertise at PAS meeting

PAS Logo

The 2021 Pediatric Academic Societies (PAS) Virtual meeting hosted live-streamed events, on-demand sessions with live Q+A, a virtual exhibit hall, poster presentations and networking events that attracted pediatricians and healthcare providers worldwide. Among the physician-scientists, there were over 20 Children’s National Hospital-affiliated participants at this year’s meeting, adding to the conversation of pediatric research in specialty and sub-specialty areas.

Children’s National experts covered a range of topics, including heart disease, neurology, abnormal glycemia in newborns and antibiotic use in hospitalized children.

The “Neurological Implications of Abnormal Glycemia in Neonatal Encephalopathy and Prematurity” was a hot topic symposium presented by a panel of experts, including Sudeepta Basu, M.B.B.S., M.S., neonatologist at Children’s National.

The experts addressed the importance of recognizing early blood glucose disturbances in newborns with encephalopathy following birth asphyxia and its likely impact on brain injury and long-term outcomes. Although whole body cooling for newborns with encephalopathy after birth asphyxia is now standard of care in most advanced centers like Children’s National, many newborns still die or have neurological impairments. Dr. Basu emphasized on the need of continued advances in newer therapies and optimizing intensive care support for these vulnerable newborns immediately after birth. Dr. Basu’s presentation focused on the association of not only low blood glucose (hypoglycemia) but also high blood glucose (hyperglycemia) with abnormal motor, visual and intellectual outcomes in surviving newborns.

“Recognizing the problem is the first step for further advancement,” Dr. Basu said. “The scientific community needs to recognize the importance of early glucose status as an early marker for disease severity and risk of brain injury.” To sum up, Dr. Basu drew attention to recent newborn resuscitation guidelines from the International Liaison Committee on Resuscitation (ILCOR), which recommends close monitoring of blood glucose levels and optimizing supportive care to maintain it within normal range. Dedicated clinical trials are the need of the hour to guide what are “normal” glucose levels in newborns with encephalopathy and what treatment options are most beneficial.

Rana F. Hamdy, M.D., M.P.H., M.S.C.E., director of the Children’s National Antimicrobial Stewardship Program, delved into the increased number of children receiving care for acute conditions – like acute respiratory tract infections – from urgent care centers and direct-to-consumer (DTC) telemedicine companies during her session “Implementing Antibiotic Stewardship in Telemedicine and Urgent Care Settings.”

Telemedicine, in this case, refers to DTC telemedicine companies—not to be confused with the telemedicine established with primary care providers, like the services provided by Children’s National.

There has been little research focused on promoting good antibiotic stewardship in urgent care settings that tend to overprescribe antibiotics compared to a primary care setting. In addition to her work focusing on improving antimicrobial use within Children’s National, Dr. Hamdy has led collaborative quality improvement work nationally in both the pediatric urgent care and DTC telemedicine settings.

“What we’ve learned from our work with the DTC telemedicine setting is that leadership commitment coming from the company is a necessary core element,” Dr. Hamdy said. “There may be unique opportunities in the telemedicine setting to employ the home-grown computer systems for antimicrobial stewardship interventions, for example, incorporating clinical decision support or feedback reports into the electronic health record systems or displaying a commitment letter in the virtual waiting room.”

In the urgent care setting, Dr. Hamdy’s team recruited approximately 150 pediatric urgent care providers to participate in the national quality improvement initiative. Communication training modules for pediatric urgent care providers with scripted language for target infectious conditions — acute otitis media, pharyngitis and otitis media with effusion — were among the successful intervention approaches that led to improved appropriate antibiotic prescribing practices, according to her team’s findings.

“Understanding the prescribing practices in the urgent care setting is important to knowing where and how to focus on target conditions and to be able to support with education and resources,” Dr. Hamdy said. “And understanding the perceived barriers to judicious antibiotic prescribing can help to identify the highest yield interventions.”

This also reflects the approach taken by the outpatient antibiotic stewardship team at the Children’s National Goldberg Center, led by Ariella Slovin, M.D., primary care pediatrics provider at Children’s National Hospital. Dr. Slovin’s oral abstract entitled “Antibiotic Prescribing Via Telemedicine in the Time of COVID-19,” examined the effect that a shift to telemedicine due to the COVID-19 pandemic had on antibiotic use for acute respiratory tract infections. Overall, her team found a decrease in the proportion of acute respiratory tract infections prescribed antibiotics and concluded that the shift to telemedicine did not adversely affect judicious antibiotic prescribing for acute respiratory tract infections.

Other participants from Children’s National included: Taeun Chang, M.D.; Yuan-Chiao Lu, Ph.D.; Chidiogo Anyigbo, M.D., M.P.H.; Panagiotis Kratimenos, M.D.; Sudeepta Basu, M.B.B.S., M.S.; Ashraf Harahsheh, M.D., F.A.C.C., F.A.A.P.; Rana F. Hamdy, M.D., M.P.H., M.S.C.E.; John Idso, M.D.; Michael Shoykhet, M.D., Ph.D.; Monika Goyal, M.D.; Ioannis Koutroulis, M.D., Ph.D., M.B.A.; Josepheen De Asis-Cruz, M.D., Ph.D.; Asad Bandealy, M.D., M.P.H.; Priti Bhansali, M.D.; Sabah Iqbal, M.D.; Kavita Parikh, M.D.; Shilpa Patel, M.D.; Cara Lichtenstein, M.D.

To view the PAS phase I mini session list and the various areas of expertise at Children’s National, visit: https://innovationdistrict.childrensnational.org/childrens-national-hospital-at-the-2021-pediatric-academic-societies-meeting/

Purkinje cell

Premature birth disrupts Purkinje cell function, resulting in locomotor learning deficits

Purkinje cell

Children’s National Hospital researchers explored how preterm birth disrupts Purkinje cell function, resulting in locomotor learning deficits.

As the care of preterm babies continues to improve, neonatologists face new challenges to ensure babies are protected from injury during critical development of the cerebellum during birth and immediately after birth. How does this early injury affect locomotor function, and to what extent are clinicians able to protect the brain of preterm babies?

A new peer-reviewed study by Aaron Sathyanesan, Ph.D., Panagiotis Kratimenos, M.D., Ph.D., and Vittorio Gallo, Ph.D., published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), explores exactly what neural circuitry of the cerebellum is affected due to complications that occur around the time of birth causing these learning deficits, and finds a specific type of neurons — Purkinje cells — to play a central role.

Up until now, there has been a sparsity of techniques available to measure neuronal activity during locomotor learning tasks that engage the cerebellum. To surmount this challenge, Children’s National used a multidisciplinary approach, bringing together a team of neuroscientists with neonatologists who leveraged their joint expertise to devise a novel and unique way to measure real-time Purkinje cell activity in a pre-clinical model with clinical relevance to humans.

Researchers measured neural circuit function by pairing GCaMP6f fiber photometry, used to measure neuronal activity in the brain of a free moving subject, with an ErasmusLadder, in which it needs to travel from point A to point B on a horizontal ladder with touch-sensitive rungs that register the type and length of steps. By introducing a sudden obstacle to movement, researchers observed how the subject coped and learned accordingly to avoid this obstacle. By playing a high-pitch tone just before the obstacle was introduced, researchers were able to measure how quickly the subjects were able to anticipate the obstacle and adjust their steps accordingly. Subjects with neonatal brain injury and normal models were run through a series of learning trials while simultaneously monitoring brain activity. In this way, the team was able to quantify cerebellum-dependent locomotor learning and adaptive behavior, unlocking a functional and mechanistic understanding of behavioral pathology that was previously unseen in this field.

In addition to showing that normal Purkinje cells are highly active during movement on the ErasmusLadder, the team explored the question of whether Purkinje cells of injured pre-clinical models were generally non-responsive to any kind of stimuli. They found that while Purkinje cells in injured subjects responded to puffs of air, which generally cue the subject to start moving on the ErasmusLadder, dysfunction in these cells was specific to the period of adaptive learning. Lastly, through chemogenetic inhibition, which specifically silences neonatal Purkinje cell activity, the team was able to mimic the effects of perinatal cerebellar injury, further solidifying the role of these cells in learning deficits.

The study results have implications for clinical practice. As the care of premature babies continues to improve, neonatologists face new challenges to ensure that babies not only survive but thrive. They need to find ways to prevent against the lifelong impacts that preterm birth would otherwise have on the cerebellum and developing brain.

Read the full press release here.

Read the full journal article here.

MRI of the patient's head close-up

Early versus late MRI in newborn brain injury

MRI of the patient's head close-up

A single magnetic resonance imaging (MRI) performed in the first week after birth is adequate to assess brain injury and offer prognostic information in newborn infants with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia, according to a new study published in The Journal of Pediatrics.

A collaborative team of neonatology, neurology and neuroradiology experts from Children’s National Hospital that included Gilbert Vezina, M.D., Taeun Chang, M.D., and An N. Massaro, M.D., came together to evaluate the agreement in brain injury findings between early and late MRI in newborn infants with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia. The team then compared the ability of early versus late MRI to predict early neurodevelopmental outcomes.

This was a prospective longitudinal study of 49 patients with HIE who underwent therapeutic hypothermia and had MRI performed at both <7 and ≥7 days of age. MRIs were reviewed by an experienced neuroradiologist and assigned brain injury severity scores according to established systems. Scores for early and late MRIs were assessed for agreement using the kappa statistic. The ability of early and late MRI scores to predict death or developmental delay at 15-30 months of age was assessed by logistic regression analyses.

The results of the study found agreement between the early and late MRI was substantial to near perfect (k>0.75, p<0.001) across MRI scoring systems. In cases of discrepant scoring, early MRI was more likely to identify severe injury when compared with late MRI. Early MRI scores were more consistently predictive of adverse outcomes compared with late MRI.

Read the full study in The Journal of Pediatrics.

doctor checking pregnant woman's belly

Novel approach to detect fetal growth restriction

doctor checking pregnant woman's belly

Morphometric and textural analyses of magnetic resonance imaging can point out subtle architectural deviations associated with fetal growth restriction during the second half of pregnancy, a first-time finding that has the promise to lead to earlier intervention.

Morphometric and textural analyses of magnetic resonance imaging (MRI) can point out subtle architectural deviations that are associated with fetal growth restriction (FGR) during the second half of pregnancy. The first-time finding hints at the potential to spot otherwise hidden placental woes earlier and intervene in a more timely fashion, a research team led by Children’s National Hospital faculty reports in Pediatric Research.

“We found reduced placental size, as expected, but also determined that the textural metrics are accelerated in FGR when factoring in gestational age, suggesting premature placental aging in FGR,” says Nickie Andescavage, M.D., a neonatologist at Children’s National and the study’s lead author. “While morphometric and textural features can discriminate placental differences between FGR cases with and without Doppler abnormalities, the pattern of affected features differs between these sub-groups. Of note, placental insufficiency with abnormal Doppler findings have significant differences in the signal-intensity metrics, perhaps related to differences of water content within the placenta.”

The placenta, an organ shared by the pregnant woman and the developing fetus, delivers oxygen and nutrients to the developing fetus and ferries away waste products. Placental insufficiency is characterized by a placenta that develops poorly or is damaged, impairing blood flow, and can result in still birth or death shortly after birth. Surviving infants may be born preterm or suffer early brain injury; later in life, they may experience cardiovascular, metabolic or neuropsychiatric problems.

Because there are no available tools to help clinicians identify small but critical changes in placental architecture during pregnancy, placental insufficiency often is found after some damage is already done. Typically, it is discovered when FGR is diagnosed, when a fetus weighs less than 9 of 10 fetuses of the same gestational age.

“There is a growing appreciation for the prenatal origin of some neuropsychiatric disorders that manifest years to decades later. Those nine months of gestation very much define the breath of who we later become as adults,” says Catherine Limperopoulos, Ph.D., director of MRI Research of the Developing Brain at Children’s National and the study’s senior author. “By identifying better biomarkers of fetal distress at an earlier stage in pregnancy and refining our imaging toolkit to detect them, we set the stage to be able to intervene earlier and improve children’s overall outcomes.”

The research team studied 32 healthy pregnancies and compared them with 34 pregnancies complicated by FGR. These women underwent up to two MRIs between 20 weeks to 40 weeks gestation. They also had abdominal circumference, fetal head circumference and fetal femur length measured as well as fetal weight estimated.

In pregnancies complicated by FGR, placentas were smaller, thinner and shorter than uncomplicated pregnancies and had decreased placental volume. Ten of 13 textural and morphometric features that differed between the two groups were associated with absolute birth weight.

“Interestingly, when FGR is diagnosed in the second trimester, placental volume, elongation and thickness are significantly reduced compared with healthy pregnancies, whereas the late-onset of FGR only affects placental volume,” Limperopoulos adds. “We believe with early-onset FGR there is a more significant reduction in the developing placental units that is detected by gross measures of size and shape. By the third trimester, the overall shape of the placenta seems to have been well defined so that primarily volume is affected in late-onset FGR.”

In addition to Dr. Andescavage and Limperopoulos, study co-authors include Sonia Dahdouh, Sayali Yewale, Dorothy Bulas, M.D., chief of the Division of Diagnostic Imaging and Radiology, and Biostatistician, Marni Jacobs, Ph.D., MPH, all of Children’s National; Sara Iqbal, of MedStar Washington Hospital Center; and Ahmet Baschat, of Johns Hopkins Center for Fetal Therapy.

Financial support for research described in this post was provided by the National Institutes of Health under award number 1U54HD090257, R01-HL116585, UL1TR000075 and KL2TR000076, and the Clinical-Translational Science Institute-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.

An-Massaro

Looking for ‘help’ signals in the blood of newborns with HIE

An Massaro

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” says An N. Massaro, M.D.

Measuring a number of biomarkers over time that are produced as the body responds to inflammation and injury may help to pinpoint newborns who are more vulnerable to suffering lasting brain injury due to disrupted oxygen delivery and blood flow, according to research presented during the Pediatric Academic Societies 2019 Annual Meeting.

Hypoxic-ischemic encephalopathy (HIE) happens when blood and oxygen flow are disrupted around the time of birth and is a serious birth complication for full-term infants. To lessen the chance of these newborns suffering permanent brain injury, affected infants undergo therapeutic cooling, which temporarily lowers their body temperatures.

“Several candidate blood biomarkers have been investigated in HIE but we still don’t have one in clinical use.  We need to understand how these markers change over time before we can use them to direct care in patients,” says An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program at Children’s National and the study’s senior author. “The newborns’ bodies sent out different ‘help’ signals that we detected in their bloodstream, and the markers had strikingly different time courses. A panel of plasma biomarkers has the potential to help us identify infants most in need of additional interventions, and to help us understand the most optimal timing for those interventions.”

Past research has keyed in on inflammatory cytokines and Tau protein as potential biomarkers of brain injury for infants with HIE who are undergoing therapeutic cooling. The research team led by Children’s faculty wanted to gauge which time periods to measure such biomarkers circulating in newborns’ bloodstreams. They enrolled 85 infants with moderate or severe HIE and tapped unused blood specimens that had been collected as cooling began, as well as 12, 24, 72 and 96 hours later. The infants’ mean gestational age was 38.7 weeks, their mean birth weight was about 7 pounds (3.2 kilograms), and 19% had severe brain disease (encephalopathy).

Cytokines – chemicals like Interleukin (IL) 6, 8 and 10 that regulate how the body responds to infection, inflammation and trauma – peaked in the first 24 hours of cooling for most of the newborns. However, the highest measure of Tau protein for the majority of newborns was during or after the baby’s temperature was restored to normal.

“After adjusting for clinical severity of encephalopathy and five-minute Apgar scores, IL-6, IL-8 and IL-10 predicted adverse outcomes, like severe brain injury or death, as therapeutic hypothermia began. By contrast, Tau protein measurements predicted adverse outcomes during and after the infants were rewarmed,” Dr. Massaro says.

IL-6 and IL-8 proteins are pro-inflammatory cytokines while IL-10 is considered anti-inflammatory.  These chemicals are released as a part of the immune response to brain injury. Tau proteins are abundant in nerve cells and stabilize microtubules.

“This data support our hypothesis that a panel of biomarkers – not a one-time test for a single biomarker – is needed to adequately determine the risk and timing of brain injury for babies with HIE,” she adds.

Pediatric Academic Societies 2019 Annual Meeting presentation

  • “Serial plasma biomarkers of brain injury in infants with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH).”
    • Saturday, April 27, 2019, 6 p.m. (EST)

Meaghan McGowan, lead author; Alexandra C. O’Kane, co-author; Gilbert Vezina, M.D.,  director, Neuroradiology Program and co-author; Tae Chang, M.D., director, Neonatal Neurology Program and co-author; and An N. Massaro, M.D., co-director of the Neonatal Neurocritical Care Program and senior author; all of Children’s National; and co-author Allen Everett, of Johns Hopkins School of Medicine.

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.

An-Massaro

Keeping an eye on autonomic function for infants with HIE

An-Massaro

“By including heart rate variability measurements and other markers of autonomic function in our current predictive armamentarium,” says An Massaro, M.D., “we may be able to offer new hope for infants with HIE.”

In about two to three in every 1,000 full-term births, babies develop a neurological condition called hypoxic ischemic encephalopathy (HIE) when their brains receive insufficient oxygen. HIE can be a devastating condition, leading to severe developmental or cognitive delays or motor impairments that become more evident as the child grows older. Despite improvements in care – including therapeutic hypothermia, a whole-body cooling method administered shortly after birth that can slow brain damage – about half of children with this condition die from neurological complications by age 2.

Finding ways to identify children with the most severe HIE could help researchers focus their efforts and provide even more intense neuroprotective care, explains An Massaro, M.D., a neonatologist at Children’s National Health System. But thus far, it’s been unclear which symptoms reflect the extent of HIE-induced brain damage.

That’s why Dr. Massaro and colleagues embarked on a study published in the May 2018 issue of Journal of Pediatrics. The team sought to determine whether dysfunction of the autonomic nervous system (ANS) – the auto-pilot part of the nervous system responsible for unconscious bodily functions, such as breathing and digestion – reflected in routine care events can be used as a marker for brain injury severity.

The researchers collected data from 25 infants who were treated for HIE with therapeutic hypothermia at Children’s National. Thanks to multi-modal monitoring, these babies’ medical records hold a treasure trove of information, explains Rathinaswamy B. Govindan, Ph.D., a staff scientist in Children’s Advanced Physiological Signals Processing Lab.

In addition to including continuous heart rate tracings and blood pressure readings that are standard for many infants in the neonatal intensive care unit (NICU), they also recorded cerebral near infrared spectroscopy, a monitor that measures brain tissue oxygen levels. The investigators performed detailed analyses to evaluate how these monitor readings change in response to a variety of routine care events, such as diaper changes, heel sticks, endotracheal tube manipulations and pupil examinations.

The researchers stratified these infants based on how dysfunctional their ANS behaved by using heart rate variability as a marker: The fewer natural fluctuations in heart rate, the more damaged their ANS was thought to be. And they also used non-invasive brain magnetic resonance imaging (MRI) to determine brain damage. They then compared this information with the babies’ physiological responses during each care event.

Their findings show that infants with impaired ANS, based on depressed heart rate variability before the care event, had significantly different responses to these care events compared with babies with intact ANS.

  • For stimulating interventions, such as diaper changes and heel sticks, both heart rate and blood pressure increased in babies with intact ANS but decreased in babies with impaired ones.
  • Shining a light in their pupils led to an expected decreased heart rate with stable blood pressure in ANS-intact infants, but in ANS-impaired infants, there was no responsive change in heart rate and, additionally, a decrease in blood pressure was observed.
  • Responses were similar between the two groups during breathing tube manipulations, except for a slight increase in heart rate a few minutes later in the ANS-impaired group.

These results, Govindan explains, suggest that a real-time, continuous way to assess ANS function may offer insights into the expected physiological response for a given infant during routine NICU care.

“This is exactly the type of additional information that intensivists need to pinpoint infants who may benefit from additional neuroprotective support,” he says. “Right now, it is standard practice to monitor brain activity continuously using electroencephalogram and to check the status of the brain using MRI to assess the response to therapeutic cooling. Neither of these assessments can be readily used by neonatologists at the bedside in real-time to make clinical decisions.”

Assessing ANS function in real-time can help guide neuroprotective care in high-risk newborns by providing insight into the evolving nature of brain damage in these infants, Dr. Massaro adds.

Beyond simply serving as a biomarker into brain injury, poor ANS function also could contribute to the development of secondary injury in newborns with HIE by stymieing the normal changes in heart rate and blood pressure that help oxygenate and heal injured brains. The researchers found that the cumulative duration of autonomic impairment was significantly correlated with the severity of brain injury visible by MRI in this group of infants.

“By including heart rate variability measurements and other markers of autonomic function in our current predictive armamentarium,” says Dr. Massaro, “we may be able to offer new hope for infants with HIE.”

In addition to Dr. Massaro, the Senior Author, study co-authors include Lead Author, Heather Campbell, M.D.; Rathinaswamy B. Govindan, Ph.D., Children’s Advanced Physiological Signals Processing Lab; Srinivas Kota, Ph.D.; Tareq Al-Shargabi, M.S.; Marina Metzler, B.S.; Nickie Andescavage, M.D., Children’s neonatalogist; Taeun Chang, M.D., Children’s neonatal and fetal neurologist; L. Gilbert Vezina, M.D., attending in Children’s Division of Diagnostic Imaging and Radiology; and Adré J. du Plessis, M.B.Ch.B., M.P.H., chief of Children’s Division of Fetal and Transitional Medicine.

This research was supported by the Clinical and Translational Science Institute at Children’s National under awards UL1TR000075 and 1KL2RR031987-01 and the Intellectual and Developmental Disabilities Research Consortium within the National Institutes of Health under award P30HD040677.

Sudeepta Basu

GABA concentration in pre-term brain increases with gestational age

Sudeepta Basu

“A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury,” says Sudeepta K. Basu, M.D.

The major neurotransmitters gamma-aminobutyric acid (GABA) and glutamate are pivotal to fetal and newborn brain development and influence evolution of brain injury and repair following preterm birth. Magnetic resonance spectroscopy (MRS) enables in vivo measurement of brain metabolites. However, GABA and glutamate are found in the developing brain in low concentrations, and their weak signal can be swamped by the stronger signal of more dominant metabolites.

A Children’s research team reports findings from a pilot study utilizing an innovative technique of MRS to reliably measure in vivo GABA in the developing preterm brain. The groundbreaking research done by the team that includes Principal Investigator Sudeepta K. Basu, M.D., neonatology attending at Children’s National Health System, is very unique and original since there are no existing data of in vivo GABA concentrations in the developing cerebellum. Under the mentorship of Catherine Limperopoulos, Ph.D., director of Children’s Developing Brain Research Laboratory, the team of multi-disciplinary specialists is pursuing cutting-edge technologies in advanced MRI neuroimaging to explore brain development and injury in preterm infants.

The research, presented at the Eastern Society for Pediatric Research (ESPR) annual meeting by Dr. Basu, was honored with the “2018 Meritorious Poster Award.” The research titled “Distinct temporal trends of GABA and glutamate in the cerebellum and frontal cortex of preterm infants” reports, for the first time, positive temporal trends in the specific regions of the developing brain intricately involved in cognitive and motor functions. This work lays the foundation for developing novel ways to diagnose, monitor and investigative brain protective therapies for vulnerable prematurely born infants.

The Children’s team performed non-sedated MRS in 44 preterm infants whose mean gestational age at birth was 26.5 weeks, placing voxels at the middle of the cerebellum and the right frontal cortex. GABA and GIx (glutamate combined with glutamine) were positively correlated with post-menstrual age in the frontal cortex, but not the cerebellum.  At the ESPR meeting, the team also presented for the first time that caffeine, a neuroprotective agent in preemies, leads to increased in vivo GABA concentration in the developing frontal cortex.

“Open questions include whether these findings reflect varying paces of maturation and vulnerability to injury among specific regions of the brain. Also, the relationship between clinical factors and medication exposure and changes in the concentration of these neurotransmitters may guide brain protective therapies in future,” Dr. Basu says. “A more complete understanding of the diagnostic and prognostic importance of GABA and glutamate in the preterm brain will help us to direct treatment strategies for the most vulnerable preterm infants at risk of brain injury.”

Children’s senior fellows from Division of Neonatology made four platform presentations during the ESPR conference:

  • “Caffeine increases GABA/Cr ratio in frontal cortex of preterm infants on spectroscopy.” Aditi Gupta; Sudeepta K. Basu, M.D.; Mariam Said, M.D.; Subechhya Pradhan, Linda White; Kushal Kapse; Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.
  • “Impact of early nutrition on microstructural brain development in VLBW Infants.” Katherine M. Ottolini, Nickie Andescavage, M.D.; Kushal Kapse; and Catherine Limperopoulos, Ph.D.
  • “Direct measurement of neonatal cardiac output utilizing the CO status monitor.” Simranjeet S. Sran, Mariam Said, M.D.; and Khodayar Rais-Bahrami, M.D.
  • “Cerebro-cerebellar diaschisis in preterm infants following unilateral cerebral parenchymal injury.” Huma Mirza, Yao Wu, Kushal Kapse, Jonathan Murnick, M.D., Ph.D.; Taeun Chang, M.D.; and Catherine Limperopoulos, Ph.D.
nurse holding newborn baby

Continuous EEG monitoring better predicts HIE outcomes

nurse holding newborn baby

For newborns who experience a serious complication that deprives their brain of oxygen, continuously monitoring brain activity and examining how the electrical signals evolve may be a more reliable way to identify infants most at risk for brain injury.

For newborns who experience a serious complication that deprives their brain of oxygen, continuously monitoring brain activity and examining how the electrical signals evolve may be a more reliable way to identify infants most at risk for brain injury, compared with doing evaluations at discreet intervals, according to a prospective cohort study led by Children’s National Health System research-clinicians.

Amplitude-integrated electroencephalogram (aEEG) is a bedside tool that permits clinicians to monitor the complex electrical activity of the child’s brain over time. It’s a positive sign when an aEEG shows babies beginning to sleep and wake normally by the time they are 3 days old. Conversely, severely abnormal aEEG readings in the first days of life predict poor outcomes.

The Children’s team used aEEG with infants born with hypoxic-ischemic encephalopathy (HIE), one of the most severe complications that can affect full-term infants. During pregnancy, birth or shortly after birth, a hypoxic-ischemic event can occur that impedes blood flow and oxygen delivery to the brain, resulting in destruction of brain tissue. Cooling (therapeutic hypothermia) is now standard for newborns with HIE in order to stave off life-long consequences, but deaths and neurodevelopmental disability still can occur.

“We know whole-body cooling – or lowering the body’s temperature by about 3 degrees Celsius – can help vulnerable newborns survive and can protect their brains from suffering profound injuries,” says An N. Massaro, M.D., a Children’s National neonatologist and senior author of the study published online Sept. 28, 2017 in the American Journal of Perinatology.  “What we were trying to determine with this study is whether evaluating the pattern of evolution of the aEEG as a whole provides more information compared with looking at snapshots in time.”

Eighty infants undergoing therapeutic cooling who met the inclusion criteria were enrolled in the five-year study, one of the largest such studies to date. The babies weighed more than 1,800 grams and were older than 35 weeks’ gestational age at birth, and either needed prolonged resuscitation after birth or had low APGAR scores – a measure of how well newborns fare outside the womb. Continuous recordings of EEG data occurred from the time of admission up to 12 hours after the infants’ temperatures were raised to normal and aEEG tracings were calculated.

After the therapeutic cooling blankets were removed, the infants underwent at least one magnetic resonance imaging (MRI) scan prior to discharge. During the routine follow-up check at about 18 months of age, the HIE survivors’ cognitive and motor skills were assessed using validated instruments.

Fifty-six of the infants in the study had favorable outcomes. Twenty-four infants had adverse outcomes, including 15 with severe brain injury detected by MRI and nine infants who died. These children had lower APGAR scores at five minutes, and were more likely to have severe HIE and to have experienced more frequent seizures.

“Infants whose aEEG abnormalities do not improve were at increased risk: Infants who do not reach a discontinuous background pattern by 15.5 hours of life, achieve cycling by 45.5 hours after birth and who fail to achieve continuous normal voltage by 78 hours after birth are most at risk for adverse outcomes,” Dr. Massaro says. “In addition to defining worrisome trends, we found that overall assessment of continuous aEEG readings through the course of hypothermia treatment provide the most meaningful predictive power. This means we can speak with families at the bedside with more confidence about their child’s outcomes after the infant undergoes cooling therapy.”

Related Resources

Altered blood flow may contribute to preemie brain injuries

A Children’s National research team for the first time mapped abnormalities in blood flow that may contribute to brain injury suffered by preterm infants.

Advanced noninvasive imaging permitted Children’s National Health System researchers to measure the lasting impact of abnormalities in blood flow on the immature brains of premature babies. Blood flow to the brain, or perfusion, has been studied previously to understand its role in other health conditions, but this is the first time a research team has mapped how these changes may contribute to brain injury suffered by babies born before 32 weeks’ gestation.

Preterm birth is a major risk factor for brain injury. The prospective study examined infants weighing less than 1,500 grams who were born prior to 32 gestational weeks.

Of 78 infants studied, 47 had structural brain injuries categorized as either mild or moderate to severe, and 31 had no brain injury. While global cerebral blood flow decreased with advancing postnatal age, the blood flow decreased more significantly among preterm infants with brain injury, says Eman S. Mahdi, M.D., M.B.Ch.B. Dr. Mahdi is a pediatric radiology fellow at Children’s National and lead author of the abstract.

“In addition to differences in global brain blood flow, we saw a marked decrease in regional blood flow to the thalamus and the pons, regions known to be metabolically active during this time,” Dr. Mahdi says. The thalamus helps to process information from the senses and relays it elsewhere within the brain. Located at the base of the brain, the pons is part of the central nervous system and also is a critical relay of information between the cerebrum and cerebellum. “These regional variations in blood flow reflect vulnerability of the cerebral-cerebellar circuitry,” she adds.

The Radiological Society of North America (RSNA) recognized Dr. Mahdi with its Trainee Research Prize. She presented the work, “Cerebral Perfusion Is Perturbed by Preterm Birth and Brain Injury,” during the RSNA Scientific Assembly and Annual Meeting, held from Nov. 27 to Dec. 2.

The findings point to the need for additional research to explore how cerebral blood flow trends evolve as preemies grow older and whether abnormal blood flow is linked to differences in health outcomes. In addition, the technique used by the research team, arterial spin labeling perfusion imaging – a type of magnetic resonance imaging – represents a useful and non-invasive technology for identifying early cerebral perfusion abnormalities in preterm infants, says Catherine Limperopoulos, Ph.D., director of the Developing Brain Research Laboratory at Children’s National and abstract senior author.