Barrow Neurological Institute at Phoenix Children's Hospital - Funded Active Research Projects
Implementation of a Research Patient Data Repository at Phoenix Children’s Hospital PI: Randa Jarrar, MD and Jeffrey Buchhalter, MD, PhD
This project will create a computer-based, automated means of searching various electronic records for data and placing those pieces of information in a Research Patient Data Repository (RPDR). Using this technology, it is possible to find, compile and categorize thousands of pieces of information on each of thousands of patients. Of note, no individual patients will be identified, thereby maintaining confidentiality. The many pieces of information that will allow an investigator to know if a project is feasible will be obtained. At that point, the investigator can apply to the Institutional Review Board for permission to review actual records with the important data elements already extracted. The two goals of this study are to install the necessary hardware and software at Phoenix Children's Hospital to create a RPDR, and then use it to determine the number of children with difficult to control seizures at Phoenix Children's Hospital and study the outcome of children with continuous uncontrolled seizures. The RPDR will eventually be a resource for every investigator at Phoenix Children's Hospital to pursue clinical research of various diseases that will enhance the lives of our patients.
Cellular Mechanisms of Epileptogenesis in Human Hypothalamic Hamartoma Tissue PI: John Kerrigan, MD
Hypothalamic Hamartomas (HH) are congenital benign tumors that occur at the base of the brain (within the hypothalamus) that results in an unusual form of epilepsy with gelastic (laughing) seizures. Seizures usually become more severe as the children get older. One characteristic feature of this type of epilepsy is that it the seizures cannot be controlled with any available anti-epilepsy drugs. Consequently, surgical resection of the tumor is usually required for effective treatment. Since 2003, the Barrow Neurological Institute (BNI) has had a multidisciplinary program to evaluate and treat patients with this disorder. We have treated more than 200 HH patients as the only program for this disorder in the United States, and the most active program in the world. Performing surgery on a large number of patients with this rare disorder has given us a unique opportunity to study the resected tumor tissue.
Gelastic seizures arise within HH tissue and spread to the rest of the brain. The primary goal of our research is to understand the exact cellular and molecular mechanisms that are responsible for seizure onset within HH. This study will test a novel hypothesis that the small sized HH neurons (the most common neuron within HH tissue) exhibit pacemaker-like firing activity, contributing to epileptogenesis, and may serve as a specific target for treating gelastic seizures. We have previously discovered that small HH neurons do indeed demonstrate intrinsic pacemaker-like firing, and this study seeks to understand the specific ionic movements across the cell membrane that are responsible for this continuous cellular firing. A complete understanding of these ionic movements may allow us to use pharmacological compounds (such as calcium channel blockers) that are already available for use but are not recognized as having a treatment role for other forms of epilepsy. This would be a major advance for patients with HH (potentially avoiding major surgery) but would also likely provide new insights into other more common forms of epilepsy.
Traumatic Brain Injury
Neural Circuit disruption by Diffuse Brain Injury: Basis for Morbidity & Therapy PI: Jonathan Lifshitz, PhD
The present proposal focuses on the persistent morbidity experienced by diffuse brain injury survivors, for whom treatment options are limited. In diffuse brain-injured rats, aberrant responses to whisker stimulation will be employed as a tool to identify pathological and reparative mechanisms associated with somatosensory whisker circuit disruption. The innovative combination of behavioral, anatomical, functional and therapeutic approaches directed at the brain-injured somatosensory whisker circuit addresses the underlying mechanisms associated with unregulated structural plasticity in the injured brain. Uncovering these processes can direct treatments to mitigate the onset, reduce the duration and/or promote the resolution of neurological dysfunction. Results from this circuit can ultimately be expanded to other circuits in rodents and then man to improve quality of life for millions of TBI survivors and potentially others suffering from progressive neurodegenerative diseases.
Inhibition of Synaptogenesis Mitigates Late-onset Post-traumatic Morbidity in Rat PI: Jonathan Lifshitz, PhD
Despite preventative efforts (e.g., helmets and seatbelts), traumatic brain injuries (TBI) occur at a staggering rate and frequently result in post-traumatic neurological impairment, including sensory sensitivity. No effective treatments are available to negate the neurological consequences of TBI. Our long-term goal is to mitigate post-traumatic morbidity (late onset, gain-of-function neurological impairment) by manipulating injury-induced circuit reorganization. This project explores the novel concept that synaptogenesis is the pivotal point that solidifies maladaptive circuit reorganization after TBI. In these experiments, we investigate synaptogenic mechanisms associated with sensory sensitivity and the role of thrombospondins (TSPs) in mediating post-traumatic synaptogenesis, which has been reported for functional recovery after stroke. The success of this study would support a paradigm shift towards prevention of late-onset morbidity, rather than treatment of the symptoms, thereby improving quality of life for countless individuals with diffuse TBI.
Post-Traumatic Sleep: An Individualized Indicator of Severity and Recovery PI: Jonathan Lifshitz, PhD
The purpose of sleep is suggested to be a role in restoring energy balance, permitting synaptic reorganization, or cellular repair. With a traumatic brain injury, the mechanical forces and ensuing cellular signaling disrupt energy balance, initiate synaptic interruption followed by plasticity, and damage membranes, proteins and structural elements. Thus, acute post-traumatic sleep may mitigate injury-related damage. Prevailing folklore recommends that these patients should not be allowed to sleep or be awoken regularly, which is unsupported by medical evidence. Moreover, this sleep disturbance counteracts the natural repair processes of sleep that would be promoted by the ubiquitous inflammatory response after brain injury. This project will test the hypothesis that sleep is an immediate natural response to diffuse brain injury likely promoting recovery of the injured brain. The experiments examine, for the first time, the effects of diffuse brain injury on sleep-wake patterns. Post-traumatic interventions to disrupt sleep may worsen or mitigate the behavioral and histopathological consequences of injury.
Extracellular Matrix as a Biomarker Source for Acute Neurological Injury PI: Jonathan Lifshitz, PhD and Sarah E. Stabenfeldt, PhD
In the central nervous system (CNS), the extracellular matrix (ECM) links neuronal, glial and vascular compartments together through specific ligand-receptor interactions. The ECM is composed of integrins, cell adhesion molecules, and glycoproteins, which are constantly remodeled to promote CNS functions. As a result of disease or injury, the ECM is susceptible to damage, alterations and modifications. In the case of traumatic brain injury (TBI), mechanical forces are applied to the CNS and disrupt the ECM by direct force or activation of specific enzymatic pathways. As the brain responds to injury, the ECM can be a fertile source of biological indicators (biomarkers) of TBI. Moreover, the magnitude and duration of ECM biomarker release could represent the nature of the TBI (focal vs. diffuse; low vs. high severity), if not also relate to longer term outcome. To date, ECM has been overlooked as a source of injury-related biomarkers. Thus, this proposal tests the hypothesis that the extracellular matrix serves as a biomarker source specific to brain injury mode and severity, with predictive value for neurological outcome. Mechanical forces of injury can be applied in focal or diffuse modes at varying severities using controlled cortical impact (CCI) and fluid percussion (FP), respectively, in the adult male rat. The outcome of these will determine the potential diagnostic and prognostic value of ECM biomarkers in the context of TBI with respect to injury mode and severity.
Impact of Implementing the EMS Traumatic Brain Injury Treatment Guidelines PI: Daniel W. Spaite, MD and Bentley Bobrow
Traumatic Brain Injury (TBI) is the leading cause of death and disability in children. There is growing evidence that the management of TBI in the early minutes after the injury profoundly impacts outcome. This has led to the promulgation of evidence-based TBI treatment guidelines by several authoritative bodies for both children and adults. No studies have evaluated the impact of implementing the guidelines in the prehospital setting. However, reports on the impact of implementation of the nationally-vetted guidelines in the hospital setting are very promising. Because of this, randomized trials that would assign patients to not receive guideline therapy in the prehospital setting would be unethical at this time. Thus the large, prospective, historically controlled, observational study is the best methodology currently available to evaluate the effectiveness of implementing the guidelines. However, this requires access to a vast Emergency Medical Services (EMS) system within a jurisdiction that has the authority and proven operational capability to implement and evaluate the impact of major changes in EMS care.
The societal burden of childhood TBI is immense. While the potential for dramatically reducing morbidity and mortality from TBI appears to be great, the effectiveness of the prehospital guidelines remains unproven. Identification of the impact of guideline therapy would potentially lead to widespread implementation of the effective interventions. This would dramatically reduce morbidity and mortality from this major public health problem. On the other hand, if the guidelines are not effective despite confirmed implementation across a wide variety of EMS systems, this would provide the ethical basis for conducting randomized trials in the future.
Experimental Post-Traumatic Epileptogenesis PI: P. David Adelson, MD
In the present study, we propose to examine the effects of early TBI, using a controlled cortical impact (CCI) paradigm, in two different models. The first is in a mouse model that is genetically predisposed to epilepsy (but not overtly epileptic). Specifically, we will induce CCI in juvenile mice lacking one allele of the Kcna1 gene which encodes the alpha subunit of the delayed rectifier potassium channel Kv1.1, and evaluate the development of epileptic seizures using video-EEG monitoring techniques. In the second model, we will study the neuro-physiologic changes in Sprague Dawley rats at PND 17 to assess the correlation between hippocampal histologic changes known to occur in these models and the development of spontaneous limbic seizures on EEG. As well, we will further evaluate the induction of epileptogenesis through an initial injury susceptibility with induction of febrile seizures followed a week later by the CCI injury. Lastly, we will investigate changes in biomarkers occurring during the post-TBI, pre-epilepsy time period. These models would be the first to employ an endogenous predisposition/ susceptibility to seizures and a common form of second injury as a means to recapitulate clinical pathogenesis.
Pediatric Traumatic Brain Injury Consortium: Hypothermia
(CoolKids Trial; PI: P. David Adelson, MD)
Traumatic brain injury (TBI) is the leading cause of mortality and morbidity in children. The health burden of TBI for children, their parents and society is substantial. Despite the frequency of TBI, its impact on the health of children and years of conducted research, no new effective treatment has shown to improve functional outcome for children with severe TBIs. The Cool Kids Trial (CKT) is part of a multinational initiative developed with the goal of expanding our understanding of TBI, and improving the outcomes of children suffering traumatic brain injuries. The CKT is a study that promotes the use of moderate hypothermia (90-91ºF) as a treatment for severe traumatic brain injury. It is designed to study the effect of hypothermia on functional outcomes after traumatic brain injury in children. Phoenix Children’s Hospital is the Coordinating Center for this international effort and oversees 38 participating clinical sites around the world. The information gained from this study will improve the care for children suffering from TBI.
Imaging Microstructural Changes in Response to Brain Tumor Immunotherapy PI: Ratan D. Bhardwaj, MD, PhD and Vikram D. Kodibagkar, PhD
Brain tumors are a tremendous burden on the patient, patient family, and society in general. We propose an elegant strategy that will allow for a true cure for all malignant brain tumors; that is based on the fundamentals of our body’s own immune system. The human immune system has remarkably evolved to successfully fight and defeat a plethora of invading pathogens over a person’s lifetime. This strategy entails the creation of a personalized vaccine that is able to seek and destroy the malignant cells specifically, leaving normal brain cells unharmed. The vaccine is based on a very exciting set of basic science experiments, in which the tumor lysate as well as critical mRNA are both used to prime the dendritic cells to elicit a profound Th-1 response. Our proposed pre-clinical experiments would be to grow brain tumors in mice, via the established GL 261 model, and then to create the vaccine based on the tumor lysate and mRNA. We would then inject the tumor back into the mouse, and expect tumor shrinkage, destruction, and finally cure. We will monitor tumor growth and response to therapy using Magnetic Resonance Imaging (MRI). We will also employ a highly specialized MRI technique Diffusion Tensor Tractography to visualize white-matter tracts in the tumor vicinity and changes therein with therapy. If successful, we have the strong ambition to translate these important pre-clinical results in a safe and efficient manner into the clinical path in future studies. We hope to ultimately harness the human body’s immune system in order to safely and effectively kill brain tumor cells, and offer a real and true cure. We are optimistic that these studies will generate enough preliminary data for a joint R01 proposal by the PIs.
Rapid Cycle Outcomes Research to Improve Clinical and Operational Outcomes – database development PI: P. David Adelson, MD and Igor Dvorchik, PhD
The focus of this proposal is outcome research (OR). OR focuses primarily on the end results of medical care episodes to help determine if they are efficacious, are clinically effective, are of high quality, improve quality of life, improve patient satisfaction, and are cost-effective. Therefore, OR presents itself as a natural way to approach the existing problem of medical errors and health care efficiency. Specifically, care that has poorer outcomes than anticipated could be due to errors, ineffective care prescriptions, and/or ineffective delivery systems. Care that is better than expected may be due to fewer errors, effective care prescriptions, and/or effective delivery systems.
This initiative focuses on the principle limitation, the lack of a coordinated method to extract existing data and outcomes in a timely and cost effective manner that allows “just in time” outcomes assessment and then uses these improvements to assess the proposition that “continuous” OR will result in continuous improvements in care. Our first step supported by this proposal will be to develop a more comprehensive, automated Phoenix Children’s Hospital’s Center for Neurosciences OR database that will be populated prospectively in real time with patient data and retrospectively with information from the existing Phoenix Children’s Hospital databases (Specific Aim 1). The second objective will be the evaluation of the outcome research implementation through the initial assessment of the outcomes of common conditions (i.e. cerebro-spinal fluid (CSF) shunts, brain surgeries for tumors, cranial facial reconstructions and surgeries for spina bifida). Other conditions or procedures will be evaluated as the process evolves.
This project will be of direct benefit to the children seeking care at Phoenix Children's Hospital CNI and serve as a demonstration of the power of “rapid cycle” outcomes research for the community. The experience gained, the templates, algorithms, and organizational structure developed through the successful completion of this project will easily transfer throughout Phoenix Children's Hospital as well as to a large number of health institutions, especially the University Of Arizona College Of Medicine, Phoenix (UA COM-PHX). UA COM-PHX with its Department of Child Health is committing $300,000 to leveraging this program with the goal of Developing a Health Services and Outcomes Research Center within the Department of Child Health, UA COM-PHX.