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Current Research Studies
Traumatic Brain Injury

The Department of Neurological Surgery is currently conducting the following studies in Traumatic Brain Injury:

In addition, Dr. Pierre Mourad conducts research on traumatic brain injury. Follow the link for more information on research in the Mourad Lab.

Traumatic Brain Injury in Latin America: Lifespan Analysis

Principal Investigator: Randy Chesnut, MD
Funded By: National Institutes of Health (NIH)

The long-term objective of this research group is to improve outcomes for TBI survivors in Latin America. The study will create a Latin American Brain Injury Consortium (LABIC) for professionals and institutions to generate research, and facilitate education, standardization, certification, the dissemination of information and resources, and the development of evidence-based guidelines. This application is to establish a network of Centers of Excellence in Latin America that will, in collaboration with U.S. partners, conduct TBI research and training programs.

The purpose is to identify factors that influence outcome in resource-poor environments. Specific aims of the study are:

  1. To create a prospective database of information about TBI in eight trauma centers with varying levels of resources in Latin America
  2. To accurately describe the TBI patient characteristics, processes of care, treatment and outcomes
  3. To identify predictors of outcome in order to build a prognostic model for this patient population, and in order to identify the treatments that, in the face of limited resources, associate with better outcomes
  4. To test the effectiveness of ICP monitor-driven treatment, compared to current practice without the use of ICP monitors, in a randomized trial
  5. To teach the full spectrum of clinical research about TBI that includes:
    • all phases of care for TBI patients
    • the creation of the capacity for cognitive evaluation of TBI patients
    • education in data collection, management, analysis, interpretation, and the management of a Data Center
    • education in how to identify, prepare, and successfully apply for funding for future research projects.

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Pediatric Traumatic Brain Injury Consortium: Hypothermia

Principal Investigator: Richard Ellenbogen, MD
Funded By: National Institutes of Health (NIH) - Barrow Neurologic Institute

Despite preventative measures, traumatic brain injury (TBI) remains the leading cause of death and disability in children. Laboratory studies of moderate hypothermia and a number of trials in children of HYPO following hypoxia-ischemic (HIE) brain injuries have supported the efficacy of this intervention. The most recently published trial of treatment with HYPO for HIE within six hours showed significant improvement in outcome, particularly in mortality, as compared to severe disability.

Based on the results from the Pilot Clinical Trial (PCT) utilizing moderate HYPO following severe TBI in children, the following application is for a multicenter Phase III RCT to determine whether induced early cooling (within six hours) (32-33°C) after severe TBI in children and maintained for 48 hours will improve mortality at three months post injury as compared to normothermia (37- 38°C).

The Secondary Hypotheses, again based on the analysis of the PCT, are that early HYPO after severe TBI in children and maintained for 48 hours:

  1. Will improve global function as measured by the GOS/ GOS- Extended Pediatrics (GOS- E Peds) and neurocognitive status across the domains of intellectual development, learning and memory, and behavior at six and 12 months after injury
  2. Will be more effective in younger children less than six years compared to older children, more than six years
  3. Will lessen intracranial hypertension and the intensity of therapy necessary for control of ICP

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Mechanisms of Neuroprotection by Histone Deacetylase Inhibition

Principal Investigator: Richard Morrison, PhD
Funded By: National Institutes of Health (NIH)

The tumor suppressor p53 is an important apoptosis regulator in acute and chronic neurological insults and neurodegenerative disorders. However, the downstream molecular consequences of p53 activation in neurons still remain obscure. Our proteomic analyses demonstrate that DNA damage-induced neuronal apoptosis involves a p53-dependent increase in the expression of proteins that comprise histone deacetylase (HDAC) complexes.

These data suggest p53 might promote neuronal dysfunction/cell death by activating histone deacetylase activity. Our preliminary studies demonstrate that histone deacetylase inhibitors protect against p53-mediated cell death. In contrast HDAC activity is elevated in cancer cells, and HDAC inhibition actually induces p53-dependent cell death. In the present application, based on this novel finding of the neuron-specific mode of HDAC inhibitor actions, the researchers propose to test the hypothesis that p53-mediated cell death signaling in neurons is dependent on histone deacetylase activity by examining how HDAC inhibitors block neuronal cell death.

This study will specifically:

  1. Determine if HDAC inhibitors selectively protect neurons from p53-mediated cell death
  2. Determine if HDAC inhibitors directly block p53 activation and/or transcriptional activity required for p53-dependent cell death in neurons
  3. Determine if HDAC inhibitors prevent p53-dependent changes in mitochondrial integrity
  4. Characterize global changes in protein expression and protein acetylation induced by HDAC inhibition
  5. Determine if HDAC inhibitors block p53-dependent cell death in vivo

The aims of this proposal will help us better understand the molecular sites and mechanism of HDAC inhibitor action, which will enhance the utility of these inhibitors as therapeutic agents for neurological diseases and injury.

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Mechanisms of Neuronal Survival

Principal Investigator: Richard Morrison, PhD
Funded By: National Institutes of Health (NIH)

The p53 tumor suppressor gene is a sequence-specific transcription factor that activates the expression of genes engaged in promoting growth arrest or cell death in response to genotoxic stress. A role for p53-related modulation of neuronal viability has been suggested by the finding that p53 expression is elevated in damaged neurons in acute models of injury such as ischemia and epilepsy and in brain tissue samples derived from patients with chronic neurodegenerative diseases.

Moreover, the absence of p53 has been shown to protect neurons from a wide variety of acute toxic insults consistent with the hypothesis from our previous applications that p53 expression regulates neuronal viability after injury. This study's long-range objective is to assess the consequences of p53 gene expression in the CNS. However, the downstream molecular consequences of p53 activation in neurons remain obscure.

Proteomic analyses demonstrate that p53 is associated with injury-induced alterations in the expression of proteins that reside in or associate with the mitochondria. Mitochondrial dysfunction is a hallmark of stress-induced neuronal toxicity. The present research is testing the hypothesis that p53 promotes neuronal cell death by altering the expression or distribution of proteins that regulate mitochondrial integrity.

Research goals are to:

  1. Determine if the p53 protein promotes a loss of mitochondrial integrity and changes in cytoskeletal organization through the induction and mitochondrial translocation of cofilin
  2. Determine if the p53 protein promotes mitochondrial dysfunction and neuronal death by regulating the N-BAK protein
  3. Determine if dynamin-related protein-1 (Drp1) promotes mitochondrial dysfunction and neuronal death
  4. Identify p53-dependent changes in the mitochondrial proteome

These studies will help elucidate the mechanism by which p53 regulates neuronal survival and activity in response to injury and neurologic disease.

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Cooperative Multicenter TBI Clinical Trials Network

Principal Investigator: Nancy Temkin, PhD
Funded By: National Institutes of Health (NIH)

The NICHD Traumatic Brain Injury Clinical Trials (TBI-CT) Network consists of a team of academic clinical centers and a data coordinating center, as well as the National Center for Medical Rehabilitation Research at the National Institute of Child Health and Human Development.

The eight clinical centers: Temple University, University of Alabama at Birmingham, University of Pittsburgh, University of Washington and Virginia Commonwealth University, University of Maryland School of Medicine, University of Tennessee Health Science Center, University of Texas-Southwestern Medical Center (as of March 2003), have agreed to investigate problems in Traumatic Brain Injury in a collaborative manner.

The clinical centers represent premier institutions in TBI medicine with track records of excellence in clinical research. The data coordinating center was selected on the basis of their experience with the coordination of multi-center clinical trials, and with proven expertise in study design, data management and biostatistical analysis. The Data Coordinating Center (DCC) for the Network is the Columbia University Department of Biostatistics.

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Pediatric Traumatic Brain Injury in Latin America

Principal Investigator: Nancy Temkin, PhD
Funded By: Oregon Health and Science University (OHSU) Subaward

The incidence of traumatic brain injury (TBI) in Latin America is three times the international average. Worldwide, TBI is the leading cause of death and disability among children and adolescents. Mortality and morbidity due to non- neurological, secondary complications such as sepsis and pneumonia are high. There is little to no post-discharge rehabilitation for TBI, and follow-up care for these patients is rare. Treatment practices vary across centers and regions. Where resources allow, many centers use the Guidelines for the Acute Medical Management of TBI in Infants, Children, and Adolescents to guide their treatment decisions. Pilot data suggests that doing so may improve outcomes.

There is an urgent need to conduct strong research about pediatric TBI in Latin America that can lead to diagnostics, treatment, and prevention. We propose to conduct a study of TBI in pediatric patients in Latin America. It will take place in five trauma centers; three in Argentina, one in Bolivia, and one in Ecuador. These centers represent the variation in resources available for treatment of TBI in Latin America.

Specific aims of this study include:

  1. In a randomized controlled trial, test the effect of a family-provided home care intervention on functional outcomes for pediatric patients who sustain moderate to severe TBI.
  2. In a prospective, observational study, test the association between medical management and outcomes for pediatric patients with severe TBI.
  3. In a prospective, observational study, test the association between resource availability and outcomes for pediatric patients with moderate to severe TBI.
  4. Establish a registry of long-term, prospectively collected data about pediatric TBI in Latin America that can be used to generate strong scientific literature from which diagnostic, treatment, prognostic, and prevention guidelines - appropriate to resource-poor environments - can be derived.
  5. Establish sustainable capacity in the Latin American Brain Injury Consortium (LABIC) to conduct ongoing research in pediatric populations with neurotrauma and other significant brain disorders.

The estimated sample is 720 acute care patients; we anticipate 65% will survive to discharge, and will collect outcomes data on approximately 420 patients (accounting for 10% loss to follow-up). The study hypothesizes that patients randomized to the home care intervention will have significantly better functional status than those who do not receive the intervention. It further hypothesizes that outcome will be significantly associated with level of resources, and with medical management.

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Phase II, Randomized Controlled Trial of Brain Tissue Oxygen Monitoring

Principal Investigator: Randall Chesnut, MD FCCM FACS
Funded By: University of Texas Southwestern Medical Center Subaward from parent National Institutes of Health (NIH) award.

Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated cost of 45 billion dollars a year in the United States alone. Every year, approximately 1.4 million sustain a TBI, of which 50,000 people die, and another 235,000 are hospitalized and survive the injury. As a result, 80,000-90,000 people experience permanent disability associated with TBI. This results in an enormous psychosocial burden on patients, their families, and society.

This project is designed to determine whether a device designed to measure brain tissue oxygenation and thus detect brain ischemia while it is still potentially treatable shows promise in reducing secondary injury after TBI, and to obtain information required to conduct a definitive clinical trial of efficacy.

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PTSD-TBI Clinical Consortium

Investigators: Nancy Temkin, PhD (Neurological Surgery) and Kathy Bell, PhD (PI, Rehabilitation Medicine)
Funded By: DoD Congressionally Directed Medical Research Program

This is a clinical consortium of 10 university sites funded by the Department of Defense to develop protocols and cores to conduct studies leading to the prevention and treatment of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). The consortium is now identifying protocols for clinical testing. One major study originating at the University of Washington will involve studying the relationship between scheduled telephone intervention and outcome in subjects with traumatic brain injury.

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Published Research Articles

View complete lists of current research publications by faculty from the Department of Neurological Surgery.

Participate in Clinical Trials

The Department of Neurological Surgery is currently seeking volunteers for clinical trials.

Follow the link to learn more about participating in these studies.

Featured Faculty:

Franck Kalume, PhD

Dr. Kalume investigates a form of epilepsy called Dravet Syndrome, as well as the mechanism that allows the ketogenic high-fat diet to suppress seizures.

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