The Developing Brain Research Laboratory, directed by Catherine Limperopoulos, PhD, is housed in the Division of Diagnostic Imaging and Radiology and affiliated with the Fetal and Transitional Medicine Program at Children’s National Health System. Our research focuses on the developing brain, both in utero and in the newborn stages of life. We are developing advanced MRI (magnetic resonance imaging) techniques to examine the structure, connectivity, and metabolism of the brain in ways that cannot be done with conventional MRI studies. It is our long-term goal to be able to identify babies with impaired brain growth as soon as possible, so that the proper interventions and clinical planning can take place.
Fetal Brain Study: Healthy Starts for Tiny Hearts
Recent advances in the management of congenital heart disease (CHD) have markedly reduced mortality. However, brain injury remains a major impediment to high quality of life in survivors. A growing body of literature suggests that a substantial component of this neurologic morbidity may be prenatal in origin. Our studies in CHD fetuses showed for the first time that impaired brain development occurs predominantly in the third trimester and is associated with evidence of impaired brain perfusion and anaerobic metabolism.
Quantifying Brain Development with MRI
The mechanism by which CHD disrupts fetal brain development remains unclear. We have developed and validated methods to safely and reliably quantify brain development and metabolism in the living fetus and newborn using advanced magnetic resonance imaging (MRI) techniques. In the current proposal, we plan to apply echocardiographic measures of the fetal circulation (as well as quantitative MRI methods) to identify the earliest biomarkers for impaired brain development in the fetus with CHD.
We will accomplish this by addressing the following specific aims:
- To determine whether abnormalities in cortical development and brain metabolism (by quantitative MRI and Magnetic Resonance Spectroscopy) are an early marker for risk of impaired volumetric brain growth in the fetus with CHD compared to control fetuses
- To determine whether systemic and cerebral hemodynamic perfusion abnormalities (by echocardiography/Doppler ultrasound) predict impaired brain growth and/or elevated cerebral lactate in the fetus with CHD versus controls
- To examine the early and long-term neurodevelopmental significance of fetal biomarkers for impaired brain development identified in aims 1 and 2
Our goal is to develop the capacity to reliably and non-invasively identify fetuses with CHD at risk for early brain injury. This, in turn, will begin to open windows for the development of therapeutic interventions aimed at preventing or limiting impaired brain development in these high-risk fetuses.
In Vivo fMRI
Until now, congenital heart disease (CHD) in the fetus and its relationship to placental function has been unknown. But the advanced fetal imaging study has shown for the first time that abnormal growth in the fetus with CHD relates to impaired placental growth over the third trimester of pregnancy.
Catherine Limperopoulos, Ph.D., Director of the Children’s National Developing Brain Research Laboratory in the Division of Diagnostic Imaging and Radiology, is the senior author of the study published in the September 2015 issue of the journal Placenta, “3-D Volumetric MRI Evaluation of the Placenta in Fetuses with Complex Heart Disease.” Specifically, the decreased 3-D volumetric MRI measurements of pregnant women reported in this study suggest placental insufficiency related to CHD. The placenta nourishes and maintains the fetus, through the delivery of food and oxygen. Its volume and weight can determine fetal growth and birth weight.
Abnormality in placental development may contribute to significant morbidity in this high-risk population. This study shows impaired placental growth in CHD fetuses is associated with the length of the pregnancy and weight at birth. Nearly 1 in every 100 babies is born in the United States with a congenital heart defect
Advanced MRI is needed to identify early markers of impaired placental structure and function in the high-risk pregnancy.
Developing the capacity to examine the placenta non-invasively using advanced MRI is needed to identify early markers of impaired placental structure and function in the high-risk pregnancy. “This is a critical first step towards developing strategies for improved fetal monitoring and management,” Dr. Limperopoulos says.
“We are trying to develop the earliest and most reliable indicators of placental health and disease in high-risk pregnancies. Our goal is to bring these early biomarkers into clinical practice and improve our ability to identify placental dysfunction,” Dr. Limperopoulos said. “If we can develop the capacity to reliably identify when things begin to veer off-course, we then have a window of opportunity to develop therapies to restore function.”
The study used in vivo 3-D MRI studies and explored placental development and its relationship to neonatal outcomes by comparing placental volumetric growth in healthy pregnancies and pregnancies complicated by CHD. While mortality rates continue to decrease steadily in newborns diagnosed with complex CHD, long-term neurodevelopmental impairments are recognized with increasing frequency in surviving infants, Dr. Limperopoulos said. “Our goal is to better support the developing fetus with CHD. We can best accomplish this if we develop technology that can allow us to safely and effectively monitor the fetal-placental unit as a whole throughout pregnancy,” Dr. Limperopoulos said. “This is the new frontier, not only to ensure survival but to safeguard the fetus and to ensure the best possible quality of life,” she said.
Preemie Study: Cerebellar Development in the Preterm Infant (CRIB)
This research study seeks to better understand brain development in premature babies. We are particularly interested in an area of the brain called the cerebellum. The cerebellum is responsible for motor coordination of the body and also plays a role in higher functions such as attention, cognition and language.
Investigating the Development of the Cerebellum
This study investigates the development of the cerebellum in premature babies, and its relationship with early development.
Our research focuses on the developing brain, both in utero and in the newborn stages of life.
We are developing advanced MRI (magnetic resonance imaging) techniques to examine the structure, connectivity and metabolism of the brain in ways that cannot be done with conventional MRI studies. It is our long-term goal to be able to identify babies with impaired brain growth as soon as possible, so that the proper interventions and clinical planning can take place.
ONESIE Study: Vulnerable Preterm Cerebellum
In this research study, we plan to leverage our large fetal normative database to compare in utero fetal and ex-utero preterm cerebellar growth trajectories.
These findings will inform specific targets, interventions and timing of future neuroprotective strategies, advance clinical practices and improve neurodevelopmental outcomes.
Premature birth is a major public health problem, associated with a personal, familial and societal burden of enormous proportions.
The potentially lifelong cognitive, learning and affective-behavioral consequences have become the major determinant of life quality in prematurity survivors, with up to 50 percent of very premature infants experiencing dysfunction in these domains by school age. Impaired cerebellar development has been recently implicated in this dysfunction.
The onset and underlying mechanisms and consequences of prematurity-related cerebellar developmental impairment (CDI) remain poorly understood, which in turn have complicated the search for potential therapeutic interventions. We have described a clinically important, previously under-recognized form of prematurity-related cerebellar parenchymal injury in up to 20 percent of extremely preterm infants. Recently, our observations have extended beyond the role of parenchymal cerebellar injury to a broader and more prevalent spectrum of cerebellar developmental impairments. We have shown that cerebellar development is markedly accelerated during the third trimester, but significantly impeded after premature birth, even in the absence of direct cerebellar injury. Complementing this intriguing set of structural observations are our findings of a distinctive long-term neuropsychological profile of cognitive, language, affective and social deficiency, which we have termed the developmental cerebellar cognitive affective disorder. The onset and underlying mechanisms and consequences of prematurity-related CDI remain poorly understood, which in turn have complicated the search for potential therapeutic interventions. We propose to utilize serial, advanced MRI techniques to elucidate the timing, evolution, mechanisms and risk factors of CDI in preterm infants born ≤32 weeks gestational age. Our overarching goal is to identify early MR imaging biomarkers of prematurity-related CDI and the associated clinical factors that lead to specific development disabilities.
MAGIC Study: Preterm Brain Studies In Vivo
Preterm infants are vulnerable to brain injury. Gamma-aminobutyric acid (GABA) is a vital neurotransmitter that has an important developmental role and can potentially be altered due to brain injury in the preterm infant. MAGIC study (Magnetic Resonance for GABA In Preterm Brain and Cerebellum) is a pilot study investigating feasibility and reliability of novel magnetic resonance spectroscopy (MRS) techniques to quantify GABA concentrations in the developing brain in very low birth weight (<1500 grams) preterm infants.
The study includes both preterm imaging (<37 weeks corrected age) as well as follow up studies at term equivalent age (TEA), investigating any trends in regional and temporal concentrations of GABA between the two scans and its association with postnatal events during the extrauterine third trimester duration before reaching term corrected age. This prospective study is currently in progress and supported by funding from CTSI-CN at CNHS.
GABAergic means "pertaining to or affecting the neurotransmitter GABA". A synapse is GABAergic if it uses GABA as its neurotransmitter. A GABAergic neuron produces GABA. A substance is GABAergic if it produces its effects via interactions with the GABA system, such as by stimulating or blocking neurotransmission. A GABAergic or GABAergic agent is any chemical that modifies the effects of GABA in the body or brain. Some different classes of GABAergic drugs include the following: GABA receptor agonists, GABA receptor antagonists, and GABA reuptake inhibitors. Examples of types include gabapentinoids and GABA analogues.
GABAergic neurons play an inhibitory role and synaptically release the neurotransmitter GABA in order to regulate the firing rate of target neurons.
Cerebellar development in the preterm infant
This research study seeks to better understand brain development in premature babies. We are particularly interested in an area of the brain called the cerebellum. The cerebellum is responsible for motor coordination of the body and also plays a role in higher functions such as attention, cognition and language. This study investigates the development of the cerebellum in premature babies, and its relationship with early development.
Brain development in the fetus with congenital heart disease – The ABC Study
The ABC Study – or Antenatal Brain Cardiac study – Seeks to better understand brain development in babies with congenital heart defects. Although infants with a heart problem are at greater risk for problems with brain development, the precise effect, if any, of the heart problem on the development of the brain remains poorly understood. We study the brain as it is developing during pregnancy, through a technique called fetal MRI. Enrolled babies have also an MRI scan shortly after birth to look at the brain in the newborn period. We also aim to evaluate the relationship between brain development and cognitive and social-behavioral development in this population.