Research Projects

Dr. Alexander Hoon, Kennedy Krieger/Johns Hopkins

Quantifying Chronic Pain in Individuals with Cerebral Palsy: The First Step to Better Treatment

Over 80% of the 17 million children and adults living with cerebral palsy suffer from daily debilitating pain, which greatly diminishes quality of life. We know with greater understanding of the cause(s), pain symptoms are both preventable and treatable. Our intensive 2018 chronic pain study will look closely at the impact of individual injuries that lead to CP and discern how pain symptoms correlate with sensation and specific abnormal biomarkers. Through this study, we will identify people with CP who are most at risk for suffering chronic pain, so pain symptoms can be prevented and treated effectively through early interventions.

RESEARCH PRIORITY: CHRONIC PAIN


Evan Snyder, MD, Sanford Burnham Prebys Medical Discovery Institute

Evaluating the Synergistic vs. Antagonistic Actions of Human Neural Stem Cells in combination with Hypothermia for Neuroprotection in Perinatal Hypoxic-Ischemic Brain Injury

Lack of blood flow & oxygen to the newborn brain (called “hypoxic-ischemic injury [HII]”) remains a devastating & common problem with serious lifelong neurological consequences, including CP, severe motor, sensory and cognitive impairment, epilepsy, learning disabilities, & autistic behaviors.

The cost to the US economy is more than one million dollars per child for life-long medical and rehabilitative care; the indirect costs based on the impact on family dynamics is 2-5 times more. Presently there is no treatment or even an accurate predictor of this type of injury. The current, most modern clinical intervention is immediate head and body “cooling”, which only helps modestly and only if started within the few hours of life, meaning that many babies miss the tight window for this sub-optimal therapy.

We have strong evidence that neural stem cells may repair and protect at risk regions of the brain subjected to HII. We have also devised a brain imaging strategy for monitoring the evolution of the injury, selection of appropriate patients and tracking improvement. Any new interventions for HII must be coordinated with cooling which is now standard-of-care. Yet, it is not known how to coordinate the administration of these two modalities in a way that enables them to work complementary with each other and not antagonistically. Once we have answered this question, we are prepared to request permission from the FDA to launch a clinical trial in babies at high risk for CP. There is a dire need for better, later and more broadly-applicable treatments against HII that better target injuries. If we can identify a treatment that reduces the morbidity associated with neonatal HII, the benefits for affected infants and children, their families and society at large would be enormous. In addition, brain imaging paradigms to be used in this proposal could be applied to many acquired or degenerative neural diseases of all ages.

RESEARCH PRIORITY: REGENERATIVE MEDICINE


Terrence Sanger, MD, MPH, University Southern California   

 A new method for identifying optimal targets for Deep Brain Stimulation in children with cerebral palsy and secondary dystonia.

Children with cerebral palsy and other acquired or genetic disorders can develop severe movement disorders including dystonia, chorea, or myoclonus.  These disorders have minimal effective medical treatments, and children can end up trapped within their bodies, unable to move, speak, or communicate because they do not have control of their muscles.  Deep-brain stimulation (DBS) can treat some children with movement disorders, using a wire inserted into the brain, connected to an implanted pacemaker, to block the abnormal signals.  DBS has the ability to cure dystonia, and to allow children to walk or communicate for the first time in their lives.  But for most children we do not know where in the brain to put the wire, and as a result many children only receive partial or minimal benefit, even after such a complex neurosurgical procedure. 

RESEARCH PRIORITY: REGENERATIVE MEDICINE


Zinaida Vexler, PhD, University of California
San Francisco

Mesenchymal Stem Cells (Derived from Extracellular Vesicles) for Repair after Neonatal Stroke

 More than half of all children with cerebral palsy are born full term, and perinatal stroke is one of the major causes of CP for this population; currently with no effective preventative treatments. Stem cell therapy, particularly Mesenchymal Stem Cells (MSC), has emerged as a potential treatment for many brain diseases, injuries and conditions, including neonatal brain injury cause by stroke. However, at this time, the mechanisms and long-term effects of MSC therapy are not fully understood

 In this innovative investigation, we will determine if extracellular vesicles released from Mesenchymal Stem Cells carry the long-term, therapeutic effects of MSC in an animal model of neonatal stroke and cerebral palsy, the first step in preparation for human clinical trials.

RESEARCH PRIORITY: REGENERATIVE MEDICINE


Dr. Joanne Kurtzberg, MD, Duke University

A Phase II, Multi-Site Study of Autologous Cord Blood Stem Cells for Hypoxic Ischemic Encephalopathy

Cerebral palsy results from in utero or perinatal injury to the developing brain, often through stroke, hypoxic insult or hemorrhage. Currently available treatments for patients with cerebral palsy are supportive, but not curative. Umbilical cord blood (UCB) has been shown to lessen the clinical and radiographic impact of hypoxic brain injury and stroke in animal models. UCB also engrafts and differentiates in brain, facilitating neural cell repair, in animal models and human patients with inborn errors of metabolism undergoing allogeneic, unrelated donor UCB transplantation. We hypothesize that, in the setting of brain injury, infusion of autologous UCB will facilitate neural cell repair resulting in improved function in pediatric patients with cerebral palsy.

In this Phase II study, multi-site study we will test the safety and efficacy of the infusion of a baby’s own (autologous) umbilical cord blood as compared with placebo in babies born with history and signs of hypoxic-ischemic brain injury.   

RESEARCH PRIORITY: REGENERATIVE MEDICINE


Dr. Sandra Juul, University of Washington

Reducing CP in Premature Babies through Epigenetics

Babies born very early are at extremely high risk of developing cerebral palsy and neurodevelopmental problems. The field of Epigenetics has revolutionized our understanding of how gene expression abnormalities can cause disease. Through modern imaging and screening, we will utilize a state-of-the art approach to identify infants in the early stages of disease that can lead to cerebral palsy and employ novel therapy treatments to reduce the effects of CP and improve lifelong outcomes.

RESEARCH PRIORITY: PREVENTION


Donna Ferriero, MD, University of California at San Francisco

Metabolomic Identification of at Risk Newborns

The ability to recognize babies who are at continued risk for brain damage will enable us to design more effective therapies and prevent the lifelong consequences of cerebral palsy.

Using a newly developed, non-invasive imaging technique called “hyperpolarized carbon-13 MRI”, we’re urgently assessing newborns at risk of CP by looking at their immediate metabolic state. This technology and methodology allows us to see rapid changes in the metabolic pathways of tissue that can lead to injury and provide immediate feedback and identify [patients as risk of brain damage.

RESEARCH PRIORITY: PREVENTION


Shenandoah Robinson, MD, PhD, Johns Hopkins University

Making the Most of Mother Nature:  Neonatal Combinatorial Therapy with Endogenous Neurorepair Agents

 Preterm infants are prone to cerebral palsy and associated learning and behavioral problems caused by early brain injury, reduced placental blood flow and intrauterine inflammation.

 This study proposes the use of a novel combination of Erythropoietin (EPO) and Melatonin (MLT) to repair the developing brain and spinal cord following early, neonatal brain injury. Both EPO and Melatonin therapies have been proven safe in children and we predict that administering the two together for newborns who have suffered brain injury will support early repair of the brain and reduce the likelihood of a CP diagnosis and other developmental concerns.

RESEARCH PRIORITY: PREVENTION


Dr. Zachary Vesoulis, Washington University

Newly Developed Oxygen Monitoring Systems to Reduce CP-Related Brain Injury

 Premature babies experience frequent and often severe fluctuations in oxygen levels, making them ten times more likely to suffer Injury that causes cerebral palsy. Although this occurrence is well known, the current standard of care for affected newborns does not involve routine monitoring of oxygen levels in the brain, making it difficult to adjust oxygen treatment with the aim of reducing brain injury. In this study, we will test a novel method for monitoring brain oxygen levels that will provide personalized guidance for oxygen management and reduce CP-related brain injury.

RESEARCH PRIORITY: PREVENTION


Dr. Srinivas Manideep Chavali, University of California, San Francisco

Improving Myelin Production as a Therapeutic Strategy to Treat CP

 Babies who suffer an oxygen deprivation event at birth are at high risk of developing cerebral palsy. This study looks closely at oligodendrocytes, a special brain cell that is responsible for the generation of myelin, a vital brain component that ensures proper nerve signal transmission and brain development. In this study, we’ll look closely at signaling targets that inhibit myelin production, and test a hypothesis of blocking the signals as a therapeutic strategy to treat CP.

RESEARCH PRIORITY: PREVENTION


Nathalie Maitre, MD, Nationwide Children’s Hospital, Columbus, OH

RCT of Feeding Intervention with Pacifier Activated Device and Mother’s Voice in Infants at High-Risk for Cerebral Palsy

Our proposal addresses the frequent feeding difficulties of infants at high-risk for CP. We aim to improve their oral feeding skills very early on in life, while still in the NICU, to decrease long-term feeding-related problems.

We will employ a training intervention using a pacifier-activated device with mother’s voice as positive reinforcement for stronger and more rhythmic sucking, compared to sucking separately from mother’s voice. Following the Guidelines for Early Detection of CP, we will include NICU infants with specific brain injury or with abnormal General Movements Assessments and follow their outcomes in the first year

RESEARCH PRIORITY: PREVENTION


Jane Huggins, PhD, University of Michigan

Innovative Assessment of Receptive Language in People with Cerebral Palsy: A Comparison of Eye-Gaze Interface and Brain-Computer Interface Test Administration  

Accurate cognitive assessment of people with cerebral palsy (CP) is necessary to target interventions for communication, social participation, and education. Current assessments require speech or motor ability, so are unsuitable for people with significant physical disability.

Some assessments can be adapted for Eye-Gaze Interface (EGI) (requiring only eye movements) and Brain-Computer Interfaces (BCI) (requiring no movement). These interfaces are promising options for cognitive assessment. This study compares EGI with BCI in administering a vocabulary test to determine which more effectively accommodates people with multiple impairments. Children and adults with CP in the United States and Australia will compare the interfaces.

Our long-term goal is to create accessible versions of established and standardized tests for people whose speech and physical impairments prevent standard assessment.

RESEARCH PRIORITY: TECHNOLOGY/TTS


Dr. Leigh Hochberg, Principal Investigator, and BrainGate researchers at Massachusetts General Hospital, Harvard, Brown, Case and Stanford Universities

Thought-to-Speech: A Life-changing Brain-Computer Interface System for Communication

Effective communication is fundamental to independence and participation in social, educational, and employment opportunities. Yet, over one third of children and adults living with cerebral palsy cannot talk and even more have co-occurring mobility challenges that inhibit their ability to use current assistive communication devices. Even the most advanced adaptive communication systems, such as eye gaze, remain extremely cumbersome, fatiguing and slow for many consumers, setting them back in our rapid response society.

Technology and modern computer science are driving change at a rapid pace, and if effectively leveraged, speech may be unlocked for millions of people who were once considered permanently nonverbal. Harnessing this transformative time, CPARF, along with world renowned research team, BrainGate, has launched a world-first initiative to develop a revolutionary communication system, called “Thought to Speech (TTS)”, a technology that leverages recent advances in computer science and brain-computer interface (BCI) to generate real-time speech, bypassing many of the impediments of currently available augmentative devices. The current goal is to launch clinical trials of a Thought-to-speech device for CP in 2021.

RESEARCH PRIORITY: TECHNOLOGY/TTS


Vedant Kulkarni, MD, Shriner’s Hospital for Children of Northern California

Smartphone App to Enable Community-Based Hip Surveillance for Children with Cerebral Palsy

One in three children with cerebral palsy may develop progressive problems with hip development that can lead to pain and challenges with mobility and seating. A regular schedule of hip examinations and XRAYS, called a hip surveillance program, has been shown to reduce and even eliminate painful hip conditions in countries with centralized medical systems. This project aims to test a free smartphone app called “HipScreen” (www.hipscreen.org) to enable practitioners to enact a hip surveillance program in a broader range of global medical contexts.

RESEARCH PRIORITY: TECHNOLOGY/TTS


Dr. Michael Kruer, Board of Regents, University of Arizona

Identifying Top Candidates for Deep Brain Stimulation through Genomics

Dystonia affects one in six people with cerebral palsy, making it very difficult and sometimes impossible to control movement. Deep brain stimulation, a cutting-edge form of neuromodulation in which electrodes are strategically placed in the brain, is proven to be a dramatically effective treatment in many people with dystonic cerebral palsy. However, there are some cases in which individuals do not respond at all to the treatment, making outcomes extremely difficult to predict and presenting challenges to both families and physicians when deciding to prescribe and proceed with the invasive procedure. This study will test a novel approach that combines genomic findings with detailed clinical data to predict which individuals are top candidates for Deep Brain Stimulation and most likely to see significant improvements.