Current and Past Grantees
2022 PERF™ Shields Research Grant Recipient
Angela L. Hewitt, MD, PhD
University of Rochester Medical Center
Identifying Neurophysiological Biomarkers to Optimize Deep Brain Stimulation for Dystonia
Dr. Angela Hewitt’s project “Identifying Neurophysiological Biomarkers To Optimize Deep Brain Stimulation (DBS) For Dystonia” will chronically record local field potential (LFP), EEG, and EMG data from subjects before and during DBS therapy. Dystonia symptoms may take weeks to months to respond to DBS, which makes optimizing stimulation settings for individual patients challenging. We also have limited understanding of why DBS effectively treats some types of childhood-onset dystonia, but provides only modest benefit for others. Prior investigations have been limited to short-term LFP recordings over hours to days, which may not adequately capture changes in dystonia symptoms. Our research project is unique in that we will simultaneously record electrophysiology data over months after DBS therapy is initiated, so that we can evaluate long-term neural dynamics at multiple sensorimotor network nodes. Identifying biomarkers that correlate with dystonia severity and progressively change with treatment could facilitate selecting optimal stimulation settings, quantifying therapy response, and predicting who will respond favorably to DBS. Dr. Hewitt will be mentored by Dr. Jonathan Mink and Dr. Karlo Lizarraga for this project.
2021 PERF™ Shields Research Grant Recipient
Nathan T. Cohen, MD, FAAP
George Washington University School of Medicine
Defining pharmacoresistant epileptic networks in pediatric focal cortical dysplasia
Nathan T. Cohen, MD, FAAP, is an Assistant Professor of Neurology and Pediatrics at The George Washington University School of Medicine and attending epileptologist and child neurologist at Children’s National Hospital in Washington, DC. Dr. Cohen earned an ScB in neuroscience from Brown University, where he was elected to Sigma Xi. He obtained his MD from the University of Virginia School of Medicine. Dr. Cohen performed all of his postgraduate medical training at Children’s National including internship and residency in general pediatrics, and fellowships in child neurology and epilepsy. He also spent a year as an attending pediatrician in the Children’s National Emergency Department. He is board-certified in General Pediatrics, Neurology with Special Qualification in Child Neurology, and Epilepsy.
Dr. Cohen’s clinical focus is on the management of refractory epilepsy. He is particularly interested in the surgical management of epilepsy and the nascent field of neurostimulation. His research interests include using functional imaging to study epileptic networks, surgical epileptology, malformations of cortical development, the pharmacologic treatment of epilepsy, and the study and treatment of status epilepticus. He was the recipient of the 2020 John M. Pellock Award from the American Epilepsy Society for a project detailing the natural history of epilepsy in pediatric focal cortical dysplasia.
He will use the 2021 CNF-PERF™ Shields Award to study network properties of pharmacoresistance in pediatric focal cortical dysplasia-related epilepsy using structural and functional imaging techniques. This study will test the hypothesis that there is an association between FCD co-localization to one of seven distributed cortical neural networks and development of pharmacoresistant epilepsy. This study aims to alter clinical practice by identifying children who will be candidates for early resective surgery to cure FCD pharmacoresistant epilepsy and will provide the basis for further study of FCD epileptogenesis mechanisms based on network connectivity analytic methods.
2020 PERF™ Shields Research Grant Recipient
Youssef A. Kousa, MS, DO, PhD
Children’s National Hospital
Identifying Genetic Risk Factors in Congenital Zika Syndrome
Youssef A. Kousa, MS, D.O., Ph.D., is a physician-scientist specializing in neonatal neurology at Children’s National Hospital in Washington, DC. During pediatric internship, he founded an international, trans-disciplinary research team, the Zika Genetics Consortium, to study the 2015 Zika virus pandemic and model human genetic modifiers in neuroinfectious diseases and neurodevelopmental disorders. Dr. Kousa is the Principal Investigator of the Consortium, which now includes 19 co-investigators representing 13 different institutions. Partnering with the National Institutes of Health and Centers for Disease Control and Prevention, the Consortium is bringing together mother-infant dyad cohorts with 12,000 participants throughout the Western Hemisphere. Their goal is disease prevention by integrating and leveraging team science, systems biology, and genomics.
Dr. Kousa completed a combined pediatrics and child neurology residency at Children’s National Hospital and the DO-PhD Physician Scientist Training Program at Michigan State University. Through graduate and post-graduate research training, he has focused on human genetics, genetic engineering, developmental biology, immunology, and virology. His accomplishments include creation of an adenovirus-based malaria vaccine, discovery of a conserved gene regulatory network in craniofacial and neural tube development, 30 peer-reviewed publications, and multiple national and international invited research presentations. His awards and honors span academic, research, service, and leadership roles, including the highest honors possible at Michigan State University for a graduate and medical student. Dr. Kousa directs the Perinatal Neuroinfections Clinic at Children’s National Hospital and is an Instructor in Neurology, Pediatrics, & Genomics, and Precision Medicine at George Washington University School of Medicine, Washington, DC.
2019 PERF™ Shields Research Grant Recipient
Alexander Li Cohen, MD, PhD
Boston Children’s Hospital
Using clinical cohorts and functional connectivity to identify the neuroanatomical basis of atypical face processing in autism spectrum disorders
Autism spectrum disorder (ASD) affects 1 in 59 children and is often associated with a heterogeneous mix of disabling and treatment resistant symptoms, yet there remains a paucity of new therapeutic approaches. If we can identify the specific regions and networks in the brain that produce specific symptoms, novel individualized therapies such as transcranial magnetic stimulation or fMRI-based neurofeedback might be possible.
While atypical social communication and difficulty with joint attention are hallmark features of ASD, difficulty processing facial information conveying identity, emotional expression, and/or gaze direction, may underlie these diagnostic features of ASD in some individuals. However, there is considerable variability in face task performance which could in part be due to individual differences in underlying neural circuitry. Neuroimaging has identified numerous, yet variable, brain regions that demonstrate group-level differences in ASD participants during face processing tasks. To date, however, it remains unclear which of these observations are causal, compensatory, or simply serve as correlative markers of atypical face processing.
Utilizing data from another population with face recognition impairment, i.e., patients with acquired prosopagnosia, we have identified specific brain connections that appear uniquely affected by strokes that cause face recognition impairment. While most patients with ASD do not have a history of stroke or obvious neuroanatomical abnormalities, individuals with Tubersous Sclerosis Complex (TSC) do have cortical tubers that are thought to affect the function of surrounding cortex, are at significant risk of developing ASD, and have also been found to demonstrate atypical face processing.
Leveraging this unique combination in this project supported by the PERF Shields Research Grant, we aim to: 1) identify whether cortical tubers implicate a common neuroanatomical basis for abnormal face recognition in TSC patients, which we hypothesize will be consistent with acquired prosopagnosia, and 2) determine if functional connectivity data acquired from individuals with TSC, independent of tuber location, is abnormal in areas implicated by acquired prosopagnosia. If successful, this project provides a proof of concept for utilizing corical tuber ‘lesions’ to identify the putative neuroanatomy for other symptoms present in TSC and across neurodevelopmental disorders. The long-term goal of this work is to generate biomarkers that can be used for diagnosis or guide therapy for specific symptoms and targets fro trials of non-invasive neuromodulation.
2018 PERF™ Shields Research Grant Recipient
April Levin, MD
Boston Children’s Hospital
Electrophysiological Markers of Neural Network Timing in Autism
Autism spectrum disorder is a prevalent neurodevelopmental disorder that profoundly impacts affected individuals and their families. Early biological markers of brain activity in autism offer the opportunity to better understand how autism develops, and potentially to improve outcomes for individuals with autism by allowing treatment to begin even before behavioral manifestations occur.
In the search for early, predictive biomarkers of autism, infant siblings of children with autism provide crucial clues. The risk of autism in these infants is about 20 times higher than the risk of autism in infants with a typically developing older sibling. Additionally, even among those high risk siblings who do not develop autism, the risk for other neurodevelopmental concerns is increased as well. By following these infants closely over the first 3 years of life with serial EEGs and developmental testing, we can begin to identify neurological markers early in life that predict later developmental outcomes.
Typical brain function depends upon tightly regulated timing of neural activity, across numerous neurons within a network. Such timing can be measured using phase amplitude coupling (PAC) on electroencephalography (EEG), in which the phase of a lower-frequency oscillation (e.g., alpha) modulates the amplitude of high-frequency activity (e.g., gamma). PAC allows the brain to create perceptual windows that integrate and segregate temporally relevant and irrelevant information, respectively.8 Excessive PAC leads to windows that are too small; in theory, this could lead to difficulties integrating complex social and sensory information, as seen in autism. Indeed, excessive PAC has been previously found in older children with autism, as compared to children with typical development.9
In the project supported by the Shields award, we will therefore measure PAC in high-risk infants who will later develop autism, in relation to unaffected high-risk infants and low-risk infants. We will also evaluate the extent to which PAC underlies a spectrum of neurodevelopmental abnormalities extending beyond autism. The long-term goal of this work is to unveil early biomarkers that can, during the first few months of life, predict future diagnoses of autism and biologically-related disorders, allowing appropriate treatment to begin early.
2017 Shields Research Grant Recipient
Melissa Walker MD, PhD
Massachusetts General Hospital
A Novel, Single Blood Draw Test for Mitochondrial Disease
Mitochondria are the energy-producing compartments found in almost every cell. Mitochondrial dysfunction causes a group of often devastating multisystem genetic disorders. Neurologic disease, including epilepsy, developmental delay, hearing loss, vision loss, neuropathy, and myopathy is a common feature of mitochondrial disease. While individual disorders are rare, mitochondrial diseases as a group are estimated to affect 1 in 5,000 live births. Because mutations in over 1200 different genes can cause mitochondrial disorders with many different symptoms, diagnosing these diseases is very difficult; there is no single diagnostic test of mitochondrial function. Currently used techniques require invasive biopsy procedures and highly technical procedures which are performed and interpreted only at select centers. The resultant complexity in diagnosis poses a significant impediment to patient care and research.
Patients report significant stress and increased medical costs resulting from what is often a protracted diagnostic odyssey. Uncertainty in diagnosis additionally limits our ability to develop and test therapies for a group of potentially devastating diseases for which no certified treatment currently exists. A cell-based assay of mitochondrial function that can be performed using tissue obtained by relatively non-invasive techniques at any standard clinical laboratory is therefore needed.
Dr. Walker hypothesizes that blood cells obtained from a routine peripheral venous blood draw can be subjected to metabolic stresses to identify patients with mitochondrial dysfunction. The support provided by the Child Neurology Foundation Shields Grant enables studies of response to metabolic stress in blood cells from patients and healthy controls. Based on observed differences, Dr. Walker aims to development an assay that can be of a simple, broadly implementable readout of this response that can be used to diagnose mitochondrial disease in any standard clinical laboratory.
2016 Shields Research Grant Recipient
Peter Tsai MD, PhD
University of Texas Southwestern Medical Center
Cerebellar-Cortical Circuits in Autism Spectrum Disorders.
Autism is a prevalent disorder that affects nearly 1 in 68 children in the United States. Despite the high prevalence, the underlying causes continue to be poorly understood. Recent studies are emerging, however, that point to an important role for the cerebellum, a part of the brain that until recently had been believed to only have roles in regulating movement and controls of motor function. My lab and others have recently demonstrated that cerebellar dysfunction is sufficient to generate autistic behaviors in autism mouse models. However, how this brain region impacts autism behaviors remains unknown. We hypothesize that the cerebellum regulates autism-related behaviors by coordinating brain circuits mediating these behaviors. The support provided by the Child Neurology Foundation Shields Grant will allow me to investigate the brain circuits regulated by the cerebellum that mediate autistic behaviors in mouse models and to then further investigate whether these circuits are similarly disrupted in children with autism spectrum disorders. We will utilize a number of cutting edge techniques from small animal structural connectivity MRI to targeted modulation of brain circuits in our autism models to not only define these brain circuits but also investigate whether modulation of these circuits can benefit autism behaviors in these models. Concomitantly, we will also investigate the integrity of these circuits in individuals with autism, using publically available imaging from the Autism Brain Imaging and Data Exchange (ABIDE) database. Results obtained from these studies will help me prepare further studies on the underlying etiologies of autism while also providing the foundation for developing clinical studies targeting brain circuits as a potential therapeutic strategy for individuals with autism.
2015 Shields Research Grant Recipient
Patricia Musolino, MD
Massachusetts General Hospital/Harvard Medical School
Brain Endothelial Dysfunction in Adrenoleukodystrophy
Cerebral Adrenoleukodystrophy (CALD) is an inherited devastating disease where inflammatory cells infiltrate the brain and cause progressive degeneration that leads to vegetative state or death in months to years. Unfortunately, current therapies either fail to prevent cerebral disease or carry high toxicity and mortality. The support provided by the Child Neurology Foundation Shields Grant will allow me to study how the gene defect changes brain vessel permeability allowing access of inflammatory cells to the brain using imaging in patients and laboratory tools at the bench. More specifically, the study will probe the effect of the gene (ABCD1) deficiency upon blood brain barrier integrity at both the tissue and molecular level by (1) Applying new MRI tequnique to determine if changes in permeability occur prior to lesion progression in patients with CALD (Aim 1) and; (2) Evaluating in-vitro the effects of lack of ABCD1 upon the barrier function of human brain endothelial cells (Aim 2). If validated by this study, this approach sets forth a successful strategy to: (1) identify which patients are at risk of developing cerebral disease; (2) monitor and improve current treatments and; (4) develop an assay to screen for novel therapeutic targets. Results obtained will also help me to prepare future clinical research studies as well as an application to an NINDS Exploratory Trials R01. My passion for patient care and commitment to rigorous science ensures that my research will embrace new ideas and technologies in a highly interdisciplinary environment.
2014 Shields Research Grant Recipient
Joana Osorio, MD
University of Rochester
Cell-based therapy for Pelizaeus-Merzbacher disease
This research project aims to develop a cell-based treatment strategy for Pelizaeus-Merzbacher disease (PMD), a severe pediatric disorder of myelin caused by mutations in the proteolipid protein gene (PLP1). By transplanting genetically corrected cells from affected patients in a murine model of PMD, I will test their ability to rescue the phenotype and produce normal myelin. I will use induced pluripotent stem cells from patients with duplications and missense mutations in the PLP1 gene, correct the mutations by using gene-editing techniques and subsequently differentiate those to oligodendroglial fate. After intracerebral transplantation in a murine model of PMD, I will evaluate their motor performance and posteriorly the histology of engrafted cells. If this study is successful, it will provide a proof of principle that autologous cell transplantation can be a feasible strategy for treatment of congenital disorders of myelin.
My career goal as a clinician-scientist is to bridge basic research and clinical work in order to establish new treatment strategies for pediatric white matter disorders for which no cure is presently available. The Shields Award represents an important step towards this goal, by supporting my research project that will focus on Pelizaeus-Merzbacher disease (PMD). Success of this pre-clinical study will advance clinical translation of cell-based therapies that can be applied not only to PMD but potentially to other leukodystrophies.