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Center for Neuroscience Research
Our Vision
To understand the development of the central nervous system, including the cellular and molecular mechanisms of brain dysfunction; to prevent or treat neurological and behavioral disorders in childhood.
Major Strategic Goals
- Develop a joint program on white matter diseases between Children’s clinical Center for Neuroscience and Behavioral Medicine and the Center for Genetic Medicine Research.
- Establish a joint research program with Yale Child Study Center on perinatal hypoxia and brain injury.
- Implement a translational research program in epilepsy.
- Continue to expand the neuroimaging program to include autism and traumatic brain injury.
- Launch research projects in animal models of perinatal hypoxia, Down syndrome, and fragile X syndrome/ autism.
Strategic Plan Accomplishments
- Initiate new scientific directions in epilepsy. Studies have expanded epilepsy research to include epidemiology and community intervention. The imaging program consists of a national and international imaging consortium. The tremendous growth of imaging studies now extends to other cognitive domains. Evidence for new mechanisms of disease are being pursued through the Pediatric Epilepsy Foundation for translational research and collaborative studies with NIH. Funding has been obtained to improve access to epilepsy care and effectively improve community health services research.
- Develop new basic/translational research components of the program in brain protection studies. The center is working with the Neonatal Intensive Care Unit (NICU) at Children’s National to conduct neuroprotection studies.
- Expand our neuroimaging program to include autism and traumatic brain injury. The center significantly expanded functional imaging initiatives in traumatic brain injury, autism, urea cycle disorders, and epilepsy by adding studies supported by the Singer Foundation, Medstar, the Gudulsky Foundation, and multiple internal awards.
- Recruit a mid-level investigator in epilepsy neurophysiology. Active search and negotiations are in progress.
Programmatic Areas
- Developmental Neurobiology
- Developmental Disabilities
Programmatic Areas
The Center for Neuroscience Research includes eight major programmatic areas of research to prevent or treat various neurological and behavioral disorders affecting children.
Developmental Neurobiology
Neural Stem Cells
Neural stem cells are present in both the embryonic and postnatal brain cells. These cells self-renew and are able to generate all the major cell types within the central nervous system.
David Panchision, PhD, continues to study the signals that direct stem cell amplification and specification in the embryonic central nervous system. He is interested in how oxygen levels regulate stem cell proliferation and cell specification into oligodendroyctes. His team determined that oxygen levels also regulate amplification of stem cells in brain tumors. This vital discovery has important implications for the development of targeted strategies aimed at developing therapeutic interventions for tumors of the central nervous system.
Tarik Haydar, PhD, continues his studies on neural stem cell development in the cerebral cortex and is developing new approaches to continuously express neural genes to alter the functional and physiological properties of specific populations of progenitors and neurons in the developing brain. Joshua Corbin, PhD, seeks to understand the relationship between amygdala progenitor cell specification and physiology, and maintains a very productive collaboration with Molly Huntsman at Georgetown University on this project. Vittorio Gallo, PhD, studies intrinsic and extrinsic signals that regulate the development of multipotential progenitors in the perinatal and adult brain. His laboratory is extending these studies to animal models of brain injury and disease, including demyelinating disorders of the white matter. Adan Aguirre, PhD, supported by an NIH, National Institute of Neurological Disorders and Stroke (NINDS) K99 Pathway to Independence Award, in collaboration with Vittorio Gallo, PhD, studies the generation of oligodendrocytes from their progenitors in the developing and adult brain and their potential to repair demyelinating lesions.
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Myelin and White Matter Development
Myelin formation during postnatal brain development represents one of the most crucial steps in the establishment of mature white matter and of fully functional connections between neurons.
Vittorio Gallo, PhD, and Li-Jin Chew, PhD, continue to study new molecular strategies that will promote oligodendrocyte maturation, myelination, and white matter development. Dr. Chew studies pathological signals that affect oligodendrocyte development in cultured cells and in transgenic mice. These studies focus on mechanisms that prevent oligodendrocyte progenitor proliferation and differentiation. Dr. Gallo and Dr. Haydar continue their collaboration utilizing advanced microscopic technology to study oligodendrocyte progenitor cell migration during normal development and during remyelination after injury. In collaboration with the Center for Genetic Medicine Research, Drs. Gallo and Chew are working on a larger molecular screening of novel oligodendrocyte regulatory genes by microarray analysis.
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Cerebral Cortex Development
It is widely accepted that proper cognitive development in humans is dependent upon appropriate interactions with one’s environment through sensorial exploration, didactic training, and social experience. However, evidence shows that cognitive ability also is specified by a genetic component. This is most readily seen in the increasing number of reports linking genetic abnormalities to various forms of intellectual disability. Cognitive performance depends in large part on proper prenatal development of the cerebral cortex. More specifically, cortical growth must proceed at a specific tempo and certain milestones must be achieved to enable proper connections between the cortex and other brain structures.
Tarik Haydar, PhD, investigates the molecular controls of neural stem cell development in the mammalian forebrain. Research in the Haydar lab is broadly classified into three areas:
- Molecular labeling of neural stem cells in utero is combined with laser scanning imaging to define the roles of different stem cells and progenitor cells during prenatal brain development. These studies use DNA probes and semiconductor nanocrystals (quantum dots) to label and track neural precursors in a dynamic fashion in their intact environment in the developing brain.
- Direct labeling and molecular perturbation of hippocampal neural stem cells is combined with electrophysiological studies on excitatory neurons during prenatal and postnatal development. These studies make use of a novel technique developed by the Haydar lab to specifically target hippocampal pyramidal neurons. This work will characterize the role(s) of membrane receptors and neurotrophic factors on development and maturation of the hippocampus and will have particular relevance to learning disabilities and epilepsy. This research is supported by a new NIH R21 award.
- Embryonic studies on the Ts65Dn mouse model of Down syndrome demonstrate that prenatal development of the cerebral cortex and hippocampus is delayed, resulting in fewer synaptic contacts in these forebrain areas after birth. The Haydar Lab found that certain types of inhibitory interneurons also are over-produced during prenatal Ts65Dn brain development and new evidence points to the role of two triplicated genes in this defect.
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Neural Tube Development
Neural tube defects are one of the most common developmental malformations in humans with poorly understood underlying causes. From studies in model organisms such as the mouse, we are beginning to gain significant insight into the pathways that are critical for proper neural tube closure.
Irene Zohn, PhD, was recruited to the Center for Neuroscience to establish a research program in this area. She obtained funding from both the March of Dimes and the Spina Bifida Foundation to study pathways regulating growth, patterning, and morphogenesis of not only the neural tissue, but the surrounding epithelium and mesenchyme. These tissues are essential for neural tube closure. While these studies have implicated many genes, it is clear that we only know the identity of a fraction of the candidate genes for human neural tube defects. Furthermore, detailed mechanisms of how mutation of these genes results in neural tube defects have been investigated for only a few of these candidates. These experiments promise to provide a greater understanding of the molecular pathways, which when disrupted, contribute to human birth defects.
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Amygdala Development
The mammalian basal telencephalic limbic system is comprised of a number of structures that are involved in the regulation of complex emotional and motivational behaviors. The two most prominent of these are the nucleus accumbens, which function in the regulation of positive reward stimuli, and the amygdala, which regulates specific aspects of emotional memory and conditioned responses to aversive stimuli.
Joshua Corbin, PhD, studies embryonic development of these structures. Dr. Corbin’s lab is interested in how different types of neural progenitor cells in the developing telencephalon contribute to neuronal cell diversity in the mature amygdala. He seeks to identify the genetic pathways involved in the specification and migration of amygdala neural progenitor cells. The ultimate goal of these studies is to understand the link between developmental events and the assembly of the mature amygdala at a genetic, cellular, structural, and functional level. These aim to not only elucidate the normal mechanisms of brain development, but also gain a greater understanding of the etiology of developmental disorders, such as autism, in which development of the amygdala is affected.
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Developmental Disabilities
Intellectual and Developmental Disabilities Research Center (IDDRC)
This Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) funded Center, directed by principal investigator Vittorio Gallo, PhD, supports five scientific core resources used by more than 90 NIH-funded investigators studying various aspects of brain development and function, as well as developmental disabilities at George Washington University, Georgetown University, and Children’s National. The activities of the IDDRC investigators are distributed among seven areas of research, corresponding to different intellectual and developmental disability-associated conditions: autism, brain tumors, epilepsy, neuromuscular disease, traumatic brain injury, urea cycle disorders, and white matter disorders. In each of these areas, genetic, translational neuroscience, and behavioral science programs are integrated to provide a multidisciplinary approach to each research theme. The seven areas of research are strongly supported by four scientific cores:
Each one of these cores continues to grow based on steady institutional investment in infrastructure, personnel, stateof- the-art equipment, and software. The Cellular Imaging, Neuroimaging, and Neurobehavioral Evaluation Cores are all part of the Center for Neuroscience Research, and are directed by Tarik Haydar, PhD, William Gaillard, MD, PhD, and Gerard Gioia, PhD, respectively.
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Brain Injury and Brain Protection
Traumatic brain injury (TBI) is the leading cause of acquired brain damage in children, producing persistent functional disability. The response to and recovery from TBI differs in adults and children. Brain damage from TBI is determined not only by direct mechanical injury to neural structures, but also by delayed axonal degeneration and neuronal apoptosis. The overall goal of this research project is to determine if fundamental differences in the molecular pathways that produce neuronal death are related to brain maturity.
Gerard Gioia, PhD, extends adaptation of cognitive rating scales established to assess adults following mild TBI (concussions) to young children.
Lauren Krivitsky, PhD, and her collaborators at National Rehabilitation Hospital (NRH) investigate the structural and functional consequences of mild TBI on brain structure and function with functional MRI (fMRI) and Diffusion Tensor Imaging (DTI).
Phillip Pearl, MD, completed a feasibility and pharmacokinetic study of leviteracitam, a new anti-epileptic drug (AED), in preventing epilepsy following mild TBI.
Richard Jonas, MD, continues his research program on neuroprotection during congenital heart surgery, including white matter injury prevention.
Vittorio Gallo, PhD, and Li-Jin Chew, PhD, study signals that induce reactive gliosis after injury.
Taeun Chang, MD, Tammy Tsuchida, MD, PhD, and Stephen Baumgart, MD, continue investigations of hypothermia to ameliorate hypoxic ischemic encephalopathy in neonates. They use an array of imaging and electrophysiological techniques to monitor and guide therapy.
Andrea Gropman, MD, uses magnetic resonance spectroscopy (MRS) to examine brain-based metabolic perturbations hypothesized to cause subcortical cognitive deficits in ornithine transcarbamylase (OTC) deficiency heterozygotes.
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Perinatal hypoxia and hyperoxia
Preterm birth is a major pediatric public health issue. Today, as many as 1 to 2 percent of all live births are preterm; the survival rate of these infants is between 85 and 90 percent; however children that survive preterm births have a high incidence of cerebral palsy, mental retardation, and other developmental disabilities. Circulatory disturbances and oxygen deprivation are the two major causes of neurodevelopmental impairments in these children.
Hypoxia, due to lung immaturity and respiratory disturbances, is an important mechanism underlying these neurological complications that occur at this critical time in development. The research program on perinatal hypoxia and brain injury is a collaborative effort between the research team of Vittorio Gallo, PhD, a group of investigators at Yale University, led by Flora Vaccarino, PhD, as well as the member of the Neurological Sciences Academic Development Award (NSADA) Program, directed by Roger Packer, MD, at Children’s National. Investigators use a clinically relevant mouse model of chronic sublethal hypoxic injury to the developing brain. This model reproduces the brain injury landmarks found in children, including cognitive behavioral abnormalities. These animal studies will be combined with clinical research on premature babies and studies of post-mortem human brain tissue. Thomas Schmitz, MD, is visiting the Center for Neuroscience Research from the Charité Pediatric Hospital (Berlin, Germany) to establish a project on the cellular effects of hyperoxia in white matter development.
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Epilepsy
Epilepsy affects 1 to 2 percent of all children, and 8 percent of all children will experience one seizure before adulthood.
The Comprehensive Pediatric Epilepsy Program is a multidisciplinary group that provides clinical care and conducts clinical research into the origins, impact, and treatment of epilepsy in children. This multidisciplinary team has active research in:
- Neuroimaging of seizure disorders
- Seizure predication and control
- Mood and anxiety disorders in epilepsy populations
- Identification and evaluation of recent onset epilepsy
- Medication trials and development of coping and socialization skills in children with epilepsy
Steven Weinstein, MD, continues his collaborative efforts with Steven Schiff, MD, PhD, at Penn State University. Their work focuses on seizure prediction and control in humans and in mouse and primate models of epilepsy.
Jay Salpekar, MD, explores mood and anxiety disorders in children with epilepsy. The study should lead to the development of new models for the interrelationship of epilepsy and mood/anxiety disorders, and eventually to new treatment and intervention strategies.
Sandra Cushner-Weinstein, MSW, examines the effect of a camp setting on functional adaptability in children with epilepsy, and expanded this model to neurofibromatosis, Tourette syndrome, and Asperger disorder.
Phillip Pearl, MD, continues his work on the GABAergic mechanisms of epileptogenicity in the inborn error of metabolism succinic semialdehyde dehydrogenase deficiency (SSADH). This research is a collaborative effort with William H. Theodore, MD, at NINDS, and Michael Gibson, PhD, at Oregon Health Sciences University.
Experimental therapeutics continues to play an important role in the epilepsy program. Joan Conry, MD, in addition to several new industry-sponsored trials, plays a leading role in a nationwide study to evaluate the efficacy and pharmacogenomics of ethosuximide, lamotrigine, and valproate, in childhood absence epilepsy.
William Gaillard, MD, in collaboration with Gerard Gioia, PhD, Chandan Vaidya, PhD, and Madison Berl, PhD, investigate the functional organization of language networks in children. The team completed the development of a child study population from ages 4 to 12 and will seek to provide evidence for developmental consolidation of language networks during childhood. Dr. Gaillard also leads an international and national consortium of pediatric epilepsy centers that use fMRI and other imaging modalities to evaluate children with refractory epilepsy and investigate factors that underlie plasticity of cognitive functions. He further works with Dr. Kroner (RTI International) on an epidemiological and quality of life epidemiological study in Washington, DC. Dr. Gaillard is the chair of the Pediatric Epilepsy Program for the American Epilepsy Society and is chair of the International League Against Epilepsy Diagnostic Commission.
Madison Berl, PhD, performs fMRI studies of working memory and language in children with epilepsy funded through an Avery Award.
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Neuro-oncology/Neurofibromatosis
Brain tumors are the most common solid tumor cancers of childhood. Roger Packer, MD, executive director of Children’s clinical Center for Neuroscience and Behavioral Medicine, continues to orchestrate national multidisciplinary neuro-oncological clinical research trials.
Children’s National is a lead institution of, and has been continuously funded by, the NIH Pediatric Brain Tumor Consortium (PBTC), and also is a member of the Children’s Oncology Group (COG). The neuro-oncology program pursues innovative translational research in childhood lowgrade gliomas, brain stem gliomas, medulloblastomas, ependymomas, and malignant glial tumors.
John Crawford, MD, is supported by a Neurological Sciences Academic Development Award (NSADA) for his investigations of viral contributions to the oncogenesis of gliomas.
Roger Packer, MD, continues his research activities in neurofibromatosis type 1 (NF-1), a neurogenetic disease that has a host of manifestations including malignant and pre-malignant entities and is group chair of the Neurofibromatosis Clinical Consortium, a cooperative group of institutions funded in 2007 by the Department of Defense to perform translational studies for children and adults with neurofibromatosis.
Maria Acosta, MD, continues collaborative work with Katherine North, MD (Sydney, Australia) as the site principal investigator for phenotyping of early cognitive profiles in NF-1 children as well as studies of their executive function. In collaboration with Dr. Packer and William Gaillard, MD, she opened the first trial evaluating the benefits of a biologic agent (Lovastatin), which interferes with RAS signaling. The specific aim is to reverse learning disabilities in children with NF-1 and to test the utility of fMRI to detect treatment-related brain alterations. This study is being extended to functional imaging studies of medication response.
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ADHD
Current estimates are that between 3 and 5 percent of all children have attention-deficit hyperactivity disorder. Studies within the Center for Neuroscience focus on early detection of ADHD, accurate assessment of the executive function of children with ADHD, and the effectiveness of medication and behavioral interventions to treat this disorder.
Gerard Gioia, MD, developed measures to assess executive function in young children—an extension of the Behavioral Rapid Inventory of Executive Functions (BRIEF) scale he previously developed.
Chandan J. Vaidya, MD, continues her work using functional neuroimaging to study working memory and attention in children with ADHD, and how these children respond to treatment related to genetic defects in the dopamine transporter.
Paramjit Joshi, MD, and Adelaide Robb, MD, are co-investigators in the multi-site National Institute of Mental Health (NIMH) funded study of the treatment of early age mania (TEAM). This project expanded to include an examination of developmental vulnerability to the toxic effects of treatment. Dr. Robb also conducts several therapeutic trials in children with depression, bipolar disorder, post-traumatic stress disorder, and schizophrenia.
Daniel Lewin, PhD, investigates the effects of sleep deprivation on sleep patterns in children with and without HIV.
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Autism
This past year Children’s National completed its fifth year of collaboration with the Kennedy Krieger Institute on the NIMH funded Studies to Advance Autism Research and Treatment (STAART) research grant (Rebecca Landa, PhD, principal investigator, William Gaillard, MD, co-principal investigator). Functional studies, directed by Dr. Gaillard, continue to be supported by a generous gift from the Fred and Elizabeth Singer Foundation. Angela Bollich, PhD, (Brown University) and Dr. Gaillard continue their collaborative work with Maximillian Reisenhuber, PhD (Georgetown University), investigating the neurobiology of face processing in adults with autism. These programs use functional imaging to elucidate the neurobiology of autism spectrum disorders (ASD).
Lauren Kenworthy, PhD, continues to pursue a study with Alex Martin, PhD, in the intramural NIMH program to examine emotional processing in older Asperger disorder patients, and has expanded studies to include genetic mecshanisms of the disease with Eric Hoffman, PhD. Ben Yerys, PhD, uses fMRI and diffusion tensor imaging (DTI) to investigate cognitive flexibility in children with autism. Adelaide Robb, PhD, investigates the effectiveness of new antipsychotics in ASD and with Dr. Hoffman is investigating the genetic predispositions to adverse effects of older generation anti-psychotic medications in at-risk children.
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