Fri 26 Apr 2024
Thu 11 Apr 2024
Dr. Zachary Vesoulis, Washington University in St. Louis
NIRS Monitoring to Stop Injury
The current standard of care monitoring (pulse oximetry) for premature infants provides inadequate information to guide ventilator and oxygen management for optimal neuroprotection. Near-infrared spectroscopy (NIRS) is a light-based non-invasive device, approved for use in neonates, which provides information about oxygen levels in the brain, something not
easily available in any other way.
There are an increasing number of reports which link low oxygen levels to brain injury and it is a high-priority target for intervention.
This project will randomize preterm infants to either a “standard of care” group or a “NIRS-directed”group. In this second group, the infants will have NIRS monitoring for the first 72 hours after birth. If their brain oxygen level goes outside of the normal range, a standardized treatment protocol using evidence-based strategies will be employed. The primary outcome of this study will be a reduction in death or severe brain injury.
This project was piloted in a group of 166 infants with a remarkable 25% reduction in this outcome, suggesting significant potential benefits.
Dr. Evelyn Shih, Children’s Hospital of Philadelphia
Dissection of the Bioenergetic Network of the Neurovascular Unit in Focal Ischemic Stroke: Building a Foundation to Design Mitochondrial Therapeutics for Childhood Stroke
Stroke is the most common cause of hemiparetic cerebral palsy. Ischemic stroke occurs when a blood vessel to the brain is blocked, resulting in brain cell death. Stroke affects ~5,000 children in the USA yearly. The risk of stroke is highest around the time of birth (perinatal), occurring in ~1 in 4000 live births. Up to 70-80% of children who suffer perinatal stroke develop cerebral palsy.
Currently, the only treatment for stroke is restoring blood flow through the blocked vessel. Unfortunately, >90% of children and all babies with stroke are not eligible for these treatments. Thus, new treatments are needed.
Mitochondria are the “energy powerhouse” of the body. In stroke, mitochondria become dysfunctional and cause harm, leading to brain cell death. We aim to identify mitochondrial targets for new treatments. In order to design effective treatments, we first need to understand the changes that occur within mitochondria during stroke and how these cause cell death. This study uses a novel mouse model of childhood stroke to investigate the effect of mitochondrial dysfunction in two main brain cell types (neurons and astrocytes).
Using genetic engineering, we will induce mitochondrial mutations in neurons and astrocytes, separately, and measure stroke size and motor disability. We postulate that selective mitochondrial dysfunction in neurons will be protective by reduction of damaging oxidative stress. In contrast, we hypothesize that selective mitochondrial dysfunction in astrocytes will be harmful due to the loss of cues that keep brain cells alive. Thus, a treatment that indiscriminately affects mitochondria in all cell types would be unlikely to work. We will test a potential cell-selective therapeutic strategy to
reduce stroke severity. This study has high potential to illuminate new approaches for treatments to reduce brain injury and improve stroke-related disability, including cerebral palsy.
Assistant Professor Colleen Peyton, DPT, Northwestern University
The Ontogeny of Fidgety Movements in Infants At Risk of Cerebral Palsy
This study is an international collaboration between the United States, Australia, and Italy.
The international guidelines for the early detection of cerebral palsy (CP) established a decision-making framework to facilitate earlier and more accurate diagnosis of CP in infancy. The Prechtl General Movement Assessment (GMA) is a clinical tool that was recommended as one of the best motor assessments to identify CP in infants less than five months old. While the GMA has been proven to be a robust predictor of CP, the age at which the test is most accurate is less clear.
The presence of “fidgety movements,” an age-specific marker of typical motor development, was traditionally believed to be present and detectable at 12 weeks post-term age. However, in the years since the guidelines have been published, new evidence has emerged challenging this time frame. The emergence of fidgety movements should be studied rigorously as there may be variation among high-risk groups. This has not yet been tested in a large, diverse sample of infants.
Our objective is to understand the time at which the GMA is most effective to improve accuracy of early detection of cerebral palsy. We will compare the onset of fidgety movements in children with medically complex histories to a healthy control group. Parents will be able to obtain GMA data at six time points in development (10, 12, 14, 16, 18, 20 weeks post-term age), using the Baby Moves smartphone application.
Over the course of two years, infants from Europe, Australia, and North America will be enrolled in the study. The movements will be analyzed by expert GMA assessors to determine the time when fidgety movements are most clearly present.
It is imperative that clinicians following the early detection guidelines understand the optimal time to use the GMA in order to accurately identify infants with CP.
Assistant Professor Colleen Peyton, DPT, Northwestern University
Accuracy of the General Movements Assessment in Prediction of Toddler-Age Developmental Outcomes in Children With and Without Medically Complex Histories
This study is an international collaboration between the United States, Australia, and Italy.
The international guidelines for the early detection of cerebral palsy (CP) established a decision-making framework to facilitate earlier and more accurate diagnosis of CP in infancy. The Prechtl General Movement Assessment (GMA) is a clinical tool recommended as one of the best motor assessments to identify CP in infants less than 5 months old. While the GMA has been proven to be a robust predictor of CP, the age at which the test is most accurate in predicting later outcomes is less clear. In the years since the guidelines have been published, new evidence suggests that the presence of “fidgety movements,” an age-specific marker of typical motor development, may be seen more clearly at a different age window than was originally recommended.
With initial funding from the Cerebral Palsy Alliance Research Foundation, our international team of interdisciplinary healthcare researchers is now studying the timeline of emerging fidgety movements in a large, diverse sample of children between 2- and 5-months corrected age. We would next like to understand how this timeline relates to the children’s development over the first few years of life.
Our objective in this proposal is to understand the time at which the GMA is most effective at predicting long-term outcomes to improve accuracy of early detection of cerebral palsy. Currently, we are collecting the GMA at 6 timepoints in early infancy, to understand when fidgety movements are most detectably present in children with both typical and medically complex histories. Next, in this proposal, we plan to measure the development of these children at one- and two-years of age and compare their development with the initial timing of their fidgety movements.
It is imperative that clinicians following the early detection guidelines understand the
optimal time to use the GMA in order to accurately identify infants with CP.
Assistant Professor Colleen Peyton, DPT, Northwestern University
Motor Optimality in Infants With and Without Medical Complexity
This study examines the knowledge gap about which clinical tools can best determine the prognosis for a child with cerebral palsy. It compares a specific behavioral assessment at six timepoints in early infancy with two-year neurodevelopmental outcomes in a large population of children with and without medical complexity. It aims to further improve upon early detection, which will ultimately improve individual prognosis and open the door to earlier and targeted therapeutic interventions for children with CP.
Dr. Sahar Hassanein, Ain Shams University, Cairo, Egypt
Developing an International CP Registry in Arabic-Speaking Countries
Investigators throughout Egypt, Tunisia, Jordan, and Saudi Arabia are evaluating the practicality and affordability of a multicenter CP registry in different settings and developing nationally driven evidence-based guidelines to follow children with CP in Arabic-speaking countries. This study will help develop a multicenter registry in Arabic-speaking countries and has the potential to greatly improve public health policies and clinical practice by narrowing the knowledge gap around CP characteristics. A registry of this caliber will serve as a foundation for ethically entering, storing, and sharing information reliably among participating institutions and Arabic-speaking countries.
This study is funded through CPARF’s partnership with the American Academy of Cerebral Palsy and Developmental Medicine.
Dr. Cristina Sarmiento, University of Colorado
Priority Setting for Multicenter Research Among Adults with Cerebral Palsy: Using Stakeholder Engagement to Co-Create a Research Agenda
This study is funded by CPARF’s Accelerator Grant to the Cerebral Palsy Research Network and features a CPARF staff member with CP as a co-investigator.
Aging with cerebral palsy (CP) has been identified as the top CP-related research priority for clinicians, researchers, and people with lived experience. The Cerebral Palsy Research Network (CPRN) created a patient-reported outcome registry (the Community Registry) focused on functional changes and chronic pain, though its current population does not reflect the diversity of the CP population.
Additionally, prior research has shown that adults with CP are at higher risk for many chronic diseases and at younger ages compared to the general population, including kidney disease, bone health issues, and other conditions amenable to preventive screening in the primary care setting.
Its objective is to address well-identified negative health outcomes in adults with CP and move to the next phase of research by bringing in a variety of voices to advise on the design of the most meaningful studies. This study engages with lived experience stakeholders at the beginning stages of research study design, offering the opportunity to include interested consumers in future studies as co-investigators.
This project will also establish a multicenter research program focused on adults with CP, leveraging the infrastructure of the CPRN. The aggregated results will facilitate the development of two larger multicenter grants informed by the critical perspectives of individuals with CP, clinical investigators, and community organizations to optimize their significance, community and clinical value, and likelihood of success.
The following adulthood-focused projects are funded by CPARF’s support of the Cerebral Palsy Research Network.
Dr. Liz Boyer, Gillette Children’s Hospital
Quantifying the Frequency and Consequences of Falls
There is little known about the physical and psychological consequences of falls in children and adults with CP. The purpose of this study is to quantify frequency of falls, fall characteristics, fall-related injuries, and psychological consequences.
Dr. Ed Hurvitz, University of Michigan
Examining Adult Care Satisfaction
This study will examine adult satisfaction with their primary and specialty care providers for CP. It will use a pre- and post-measurement after an educational video has been watched to explain the importance of specialty adult care.
Dr. Garey Noritz, Nationwide Children’s Hospital
Ongoing Population of a Clinical Registry for Cerebral Palsy
This rich data set is being built by the CP Research Network through enrolling participants through participating centers. It contains demographic, medical, and functional information, and has the ability to accelerate discovery by facilitating and feeding multicentered research projects and future grant submissions.
Dr. Joyce Trost, The CP Research Network
Ongoing Population of a Community Registry for Cerebral Palsy
The Community Registry is powered by individuals with CP and their caregivers through surveys that are developed by CP Research Network researchers. This large data set has provided opportunities for young researchers to access community members for future research projects as well as to learn what is important to them.
Dr. Amy Bailes, Cincinnati Children’s Hospital
Screening and Classifying Pain in Adults with Cerebral Palsy Across Centers
This is a CPARF-funded study within the Cerebral Palsy Research Network.
Pain management is a priority for adults with CP, and the biggest barrier to this is the pervasive lack of pain screening and classification of pain by physicians. There is an urgent need to fill this gap to serve the increasing number of adults with CP.
This study standardizes procedures for screening and classifying pain in adults with CP within four Cerebral Palsy Research Network institutions across the US by identifying a set of procedures and employing these procedures at centers to gather a sample of more than 200 adults with CP.
Researchers aim to characterize pain types to advance collective knowledge and compile a straightforward protocol that can be applied across institutions. The results from this study will create the foundation for establishing, testing, and improving treatment options for pain in adults with CP.
The following chronic pain-focused projects are funded by CPARF’s support of the Cerebral Palsy Research Network.
Dr. Mary Gannotti, University of Hartford
Investigating Adult Well-Being and Pain
This study seeks to develop a data-driven perspective on the functional health, well-being, and presence of chronic pain in adults with CP.
Dr. Mary Gannotti, University of Hartford
Testing Methods for Adult Recruitment for CP-Related Studies
This grant allowed the CP Research Network to test additional recruitment methods to increase the enrollment in our longitudinal study of adult well-being and chronic pain.
Dr. Julie Stutzbach, Regis University
Low Back Pain in Adults with CP: Cross-Sectional Analysis of Cerebral Palsy Community Registry
This qualitative study of low back pain uses our community registry to recruit people with different levels of low back pain and then interviews them to learn more about their experience with this most common difficulty.
Dr. Julie Stutzbach, Regis University
Qualitative Study of Low Back Pain
Chronic low back pain is a common problem in many adults with cerebral palsy, leading to increasing disability and functional decline. Improving pain management strategies is critical to improving quality of life as people with CP age. However, participants’ perspectives on living with low back pain have not been thoroughly examined. This study proposal will use interviews combined with survey data to explore how pain interferes with daily function as well as how adults with CP experience seeking treatment for low back pain.
Dr. Sruthi Thomas, Texas Children’s Hospital
Developing Evidence to Treat Dystonia
Developing evidence for the best way to treat dystonia in CP is crucial to improving outcomes. This study is a multi-arm randomized control trial to test the range of medications used with patients with dystonia in CP.
Dr. Collin Bowersock, Northern Arizona University
CPARF Fellowship: Validation of a Robotic Exoskeleton for At-Home Use for Individuals With CP
People with CP who walk need a wearable device that can be used as a gait aid and rehabilitation tool in their home and community, rather than solely in therapeutic or medical settings. This study’s primary aim is to determine the effectiveness of a lab-proven ankle-powered exoskeleton device to activate ankle muscles for people with CP while they walk. Researchers believe that people with CP will experience improved walking in the community, and the results will shape the ways this device and others are used for future at-home rehabilitation.
Parag Gad, SpineX
Fine-Tuning the Nervous System With Neuromodulation
SpineX Inc. is an early stage bioelectric medtech company developing noninvasive neuromodulation devices. SpineX is committed to helping individuals with unmet clinical needs. Our goal is to use rigorously tested neuromodulation technologies to aid recovery and restoration of several functions for people with cerebral palsy, including bladder, bowel, and sensorimotor function.
CPARF’s current grant supports ongoing clinical and device development for Spinal Cord Innovation in Pediatrics (SCIP) to enable voluntary movement and control for children with cerebral palsy. SCIP is recognized by the FDA as a breakthrough device.
Dr. Dawn Gano, University of California San Francisco
Trexo Robotic Exoskeleton Training in Non-Ambulatory Children <2 Years (TREx) Study
New strategies to improve motor function in young children with cerebral palsy (CP) are needed. Our goal is to bring children with CP to the forefront of the implementation of robotic exoskeleton technology. We will conduct the first study of robotic exoskeleton training in children with delayed motor skills or a diagnosis of CP at ages 1-2 years.
We will recruit 10 children to participate in an exoskeleton-training program to determine the acceptability and feasibility of robotic rehabilitation. We will evaluate whether the exoskeleton improves range of motion, strength and/or motor function. To learn how robotics may address the needs and rehabilitation goals of participating children, we will conduct interviews and focus groups with parents of participants and clinicians.
The long-term goal of this study is to apply what we learn to the design of a clinical trial that can
determine if exoskeleton rehabilitation is more effective than standard rehabilitation.
The following technology-focused projects are funded by CPARF’s support of the Cerebral Palsy Research Network.
Dr. Bhooma Aravamuthan, Washington University in St. Louis
Creating a Dystonia Video Library
This planning grant is intended to demonstrate the feasibility of building an anonymized video library extension to our registry to enable the application of shared expertise to diagnose dystonia.
Dr. Danielle Barber, Children’s Hospital of Philadelphia
Extending a Registry to Include Hypoxic-Ischemic Encephalopathy
This registry extension is intended to capture essential data points from the NICU for infants diagnosed with hypoxic-ischemic encephalopathy, which often leads to CP and other co-morbidities often experienced by people with CP, like epilepsy.
Dr. Rose Gelineau-Morel, Children’s Mercy Hospital
Supporting the Development of an Imaging Database
This infrastructure grant is intended to support the development of an imaging database linked to the clinical registry. The funds would be used to build the infrastructure to de-identify images at the site and then transmit them to the DCC. The initial study concept includes the mapping of brain lesions on to known brain network maps to diagnose dystonia.
Paul Gross, The CP Research Network
Implementing IMPROVE CP
This project implements GOAL and CPCHILD reports as an external service on the CP Research Network to enable shared decision making.
Dr. Zachary Vesoulis, Washington University in St. Louis
Deep Learning From Clinical MRIs and the CPRN Registry to Create Predictive Models of Outcomes and Co-morbidities
This study will use machine learning to read, improve, and categorize MRIs in correlation with the clinical registry to predict outcomes.
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.
Dr. Peter Sheng Chih Jin, Washington University in St. Louis
Discovery of Novel Genetic Variations in Cerebral Palsy by Whole Genome Sequencing
Cerebral palsy (CP) is a major neurodevelopment disorder and the most common lifelong physical disability. Although CP is commonly associated with prematurity or prenatal brain injury, accumulating evidence suggests that deleterious genetic variants may contribute to CP, in addition to environmental insults. However, the genetic causes of most CP cases remain unclear. Further, attempts to measure the effects of genetic variations have been limited.
We will analyze genetic information from CP families to identify genetic risk factors and perform functional studies to provide mechanistic insight into identified genetic variations. This work can identify novel genetic causes for therapeutic intervention and increase precision in genetic counseling, outcome prognostication, and treatment stratification, while informing future clinical trial design.
Dr. Michael Kruer, Board of Regents, University of Arizona
Predicting Response to Deep Brain Stimulation Through Genomic Classification of Dystonic Cerebral Palsy
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.
Dr. Sara Lewis, Phoenix Children’s Hospital
Delivering Personal Medicine and Identifying Dystonic CP Genes and Pathways
Instead of one disorder, researchers are finding that cerebral palsy (CP) includes a mix of genetic disorders. This creates both a need and opportunity for personalized medicine in CP. However, many of these genes are unknown, uncharacterized, or lack treatments. Where treatments are known, patients who would benefit are missed because of lack of access to genetic testing.
A feature of CP that needs better treatment options is dystonia. Dystonia is abnormal muscle contractions causing unwanted movements or postures that can cause pain and profound impairments in daily tasks. The genes and cell changes that cause dystonia are mostly unknown, which has made it very difficult to develop treatments.
This project focuses on creating a list of genes found in dystonic CP patients and adults with dystonia.
Some genetic causes of CP have known treatments that would improve patient outcomes. These can be missed since many clinicians and healthcare decisionmakers don’t know how genetic testing could benefit patients with CP.
Clinicians, scientists, and geneticists on this project will bridge this gap by creating a report of genes found in patients from clinical testing and research studies. This project also entails the search for treatments known to be effective for these genetic causes in peer-reviewed clinical studies.
The following genomics-focused projects are funded by CPARF’s support of the Cerebral Palsy Research Network.
Dr. Jason Carmel, Columbia University
Exploring a Rare Disease Network
A group of neurologists within the CP Research Network are exploring the possibility of using natural history, genetic biomarkers of CP to prepare for clinical trials for rare forms of CP.
Dr. Michael Kruer, Phoenix Children’s Hospital
Finding Genetic Causes of Cerebral Palsy
This study seeks to find the genetic causes of cerebral palsy which have already been found to be much higher than originally predicted. Finding genetic causes opens the door to better clinical interventions to improve outcomes.
Dr. Michael Kruer, Phoenix Children’s Hospital
Genetic Causes Competitive Renewal
This competitive renewal of Dr. Kruer’s original genetic causes of CP is being developed to take the learning from the first five years and use new methods to enhance discovery.
The following additional projects are funded by CPARF’s support of the Cerebral Palsy Research Network.
Paul Gross, The CP Research Network
Qualitative Study of Spasticity Practice Variation
This qualitative study sought to better understand the practice for two common interventions to reduce spasticity — chemical denervation (typically with Botulinum Toxin A) and selective dorsal rhizotomy.
Dr. Jeffrey Leonard, Nationwide Children’s Hospital
A Study to Guide Selective Dorsal Rhizotomy Decision Making
This study will provide guidance about which children with CP are the best candidates for selective dorsal rhizotomy (SDR). The project will also support understanding of how much and focus of physical therapy after SDR.
Dr. Jeffrey Leonard, Nationwide Children’s Hospital
Surgical Decision Making in Ambulatory CP
This project will describe the variation in surgeries (orthopedic, neurosurgery) that are done in children with cerebral palsy. Understanding the variability of when surgery happens will guide understanding of the best timing of surgery.
Dr. Judy-April Murayi, Nationwide Children’s Hospital
Pilot Study for Body Compensation Changes in Children With CP After Major Orthopedic Surgery
Children with more involved cerebral palsy have higher risks for complications after surgery, including longer hospital stays and time to recovery. We do not fully understand why children with CP are more likely to have surgical complications, but one of the causes may be due to malnutrition, which is common in this population. In a 2019 survey, medical providers and surgeons said that improving nutrition was the most important target to improve surgical care, but we still do not know the best way to do this. In this study, we combine the expertise of developmental-behavioral pediatricians, pediatric gastroenterologists, and pediatric orthopedic surgeons to find a solution to this problem. We aim to identify markers of malnutrition that may lead to poorer surgical outcomes (Aim 1) and understand changes in body composition in children with CP after surgery (Aim 2). This will help identify nutritional interventions that will improve surgical care for this growing population of children.
Dr. Judy-April Murayi, Nationwide Children’s Hospital
Weight Trends in Children with CP and Association With Clinical Outcomes
This secondary analysis of our registry seeks to examine the trends between patient weight and weight percentile on a CP curve and their clinical outcomes.
Dr. Unni Narayanan, SickKids
Creating the CPCHECKlist
This survey tool will help parents and physicians capture the complexity of CP and co-morbid conditions in their patients to improve the assessment of patients.
Dr. Unni Narayanan, SickKids
Determining the Effectiveness of Shared Decision Making Tools
This multisite study funded by the Canadian Institutes of Health Research seeks to determine if two popular patient reported outcome measures, the Gait Outcomes Assessment List (GOAL) and CPCHILD, can be effective shared decision-making tools for clinicians, patients, and families prior to medical or surgical intervention. The participating sites include Children’s of Alabama, Gillette Children’s, Nationwide Children’s and the coordinating site at SickKids.
Dr. Adam Ostendorf, Nationwide Children’s Hospital
Including Epilepsy Within the CPRN Registry
This infrastructure grant added standard questions about epilepsy to the registry so that clinicians could better understand and treat individuals with both CP and epilepsy.
Dr. Brandon Rocque, Children’s of Alabama
Selective Dorsal Rhizotomy Practice Variation
This secondary analysis of the CP Research Network registry seeks to describe the variation in both surgical technique and patient selection for a neurosurgical procedure called selective dorsal rhizotomy.
Dr. Richard Stevenson, University of Virginia
Supporting Nutrition in Children With CP
This study aims to further understand the growth of children with CP to help families and providers support nutritional support across the lifespan.
Dr. Jordan Wyrwa, Children’s Hospital Colorado
Determining Correlation Between Etiology and Functional Classification
This secondary analysis of CP Research Network registry seeks to determine if there is a correlation between the etiology of CP and the person’s gross motor functional ability.