Visionary Ball Seed Grants
Scientific Progress Report
Pediatric Brain Injury
Acute Pathophysiological Monitoring and
Long-Term Functional Outcome after Pediatric Traumatic Brain Injury
Principal Investigator: Christopher C. Giza, M.D.
This study is unique in that it will correlate child brain injury
patients’ detailed acute neuroimaging outcomes, which will be followed
over time as the individuals mature. Although the majority of TBI
(traumatic brain injury) occurs in the pediatric and young adult age
ranges, there has been very limited study with regard to age-dependent
mechanisms of injury and recovery. Children are not little adults. Their
brain injuries are different, and treating them requires a different
approach.
Our first step to this end was to comprehensively characterize the
injury types, physiology, treatment and recovery in all children and
young adults and look for age-dependent patterns. A further
comprehensive analysis is required to map and better understand the
trajectory of recovery and how it differs in patients with good recovery
vs. bad.
Brain Injury
A Novel Treatment for Human Traumatic Brain
Injury: Infusion of Lactate
Principal Investigator: Thomas C. Glenn, Ph.D.
Recently, the UCLA Brain Injury Research Center discovered that the
injured brain changes its preference for fuel to help it recover.
Consequently, this study aims to determine how the infusion of sodium
lactate would affect the brain and systemic physiology in patients with
severe traumatic brain injury. Contrary to widely accepted medical
practice that regards sodium lactate as an inhibitor to brain recovery,
our work has shown that treating TBI patients with sodium lactate
infusions decreases their blood acidity, increases blood flow and
increases brain energy production.
The next step we take will include studying the effects of varying
sodium lactate levels on patient outcome and recovery. Our research may
show that these lactate infusions are a crucial differentiator in
successful brain repair.
Effect of Traumatic Brain Injury of Subventricular
Zone Stem Cell Proliferation
Principal Investigator: Neil G. Harris, Ph.D.
It
is now known that the adult brain can generate new cells. Consequently,
it is important to determine if these newly born cells could play a role
in recovery following traumatic brain injury. Through this grant, we
developed an experimental design for determining the fate of cells born
within an area of the brain called the subventricular zone following
injury. These studies also will determine the role these newly born
cells play in recovery of function. Given that there is an endogenous
source of new cells, this program will address possible ways to
intervene in order to enhance recovery. The first step in or
intervention is to determine if the brain grows new cells in response to
injury. It may be the case that injury retards the ability of cells to
be born, or it may hasten their growth and mobility.
Vagal Nerve Stimulation and Cerebral Glucose
Metabolism
Principal Investigator: Richard L. Sutton, Ph.D.
Our objective with this research was to explore the potential mechanisms
by which intermittent, low-level stimulation of the vagus nerve
stimulation (VNS) improves recovery after experimental traumatic brain
injury (TBI). VNS is already approved for human use in the treatment of
epilepsy and depression, but heretofore it had not been used to treat
human TBI.
Considering how the brain’s glucose metabolism reflects brain activity,
our results indicate that VNS treatment may improve behavioral recovery
after TBI. Further research demonstrating benefits of this treatment
should eventually lead us to clinical trials.
Boosting the Effects of Exercise During the Acute
Phase of TBI
Principal Investigator: Fernando Gómez-Pinilla, Ph.D.
Myelin is a protein in the human brain that can be a major obstacle for
neuron regeneration after brain injury. Our studies thus far have shown
that voluntary exercise following traumatic brain injury (TBI) enabled
the body to overcome its own production of two distinct myelin proteins
and allow for neural repair. Exercise creates a cellular environment in
the brain that is conducive to repair after TBI.
The bigger picture from our findings is exercise’s potential to elevate
the injured brain’s capacity for plasticity and repair. Our forthcoming
studies will be devoted to using other experimental manipulations to
increase the effects of exercise after TBI.
Brain Tumors
Characterization of FOXM1 in Brain Tumor Stem
Cells
Principal Investigator: Ichiro Nakano, M.D.
With this grant, our researchers sought to determine whether or not
inhibiting FOXM1, a transcription factor that plays a critical role in
the formation of cancers, will block the proliferation of stem cells in
malignant brain tumors. Our studies have shown that blocking the FOXM1
function resulted in reduced growth of brain tumor cells derived from
brain tumor stem cells (BTSC) in culture. Preliminary data suggest that
FOXM1 is likely a critical regulator of BTSC survival and/or
proliferation.
We have obtained encouraging findings with regard to the effects of
inhibition of FOXM1 on BTSC. Throughout the project, we will further
characterize the mechanism of the FOXM1 action and the effects of
siomycin treatment in malignant brain tumors.
Imaging and Tracking of Interactions Between
Tumor-Specific CD8+ T Cells and Brain Tumors In Vivo
Principal Investigator: Robert Prins, Ph.D.
Among the various strategies to treat cancer, immunotherapy may offer us
the possibility to counteract tumors with very few negative effects.
Until now, immune-based therapies for brain tumors have traditionally
lagged behind those for peripheral tumors.
Our research project will hopefully help us to better understand the
trafficking patterns of tumor-specific T cells, as well as to validate
imaging methods that may be used to determine the efficacy of
immune-based protocols for brain tumor therapy. During the next year, we
plan to continue these studies and expand the imaging component.
Cognitive Neurophysiology
Single Neuron Studies of Declarative Memory in
Humans
Principal Investigator: Itzhak Fried, M.D.
The Cognitive Neurophysiology Laboratory, under the direction of Dr.
Itzhak Fried, is studying the function of brain cells in various forms
of cognition, including visual perception and memory, auditory function,
navigation and motor function. They use a surgical opportunity to
directly record individual brain cells as they fire, using depth
electrode probes that are implanted in deep areas of the brain in
epilepsy patients who are being evaluated for the location of their
seizures, so that they can have surgery to cure their epilepsy.
The UCLA depth electrode team is celebrating the 400th patient to
undergo depth electrode implantation in more than 35 years of endeavor.
The group is recognized worldwide as a leader both in developing novel
clinical approaches to surgery for patients with intractable epilepsy
and in conducting basic research based on single brain cell recordings.
Brain Monitoring and Modeling
Rule Generation from Clinical Data: A Pilot
Study Using BIRC Database and Cardio-Respiratory Arrest Database
Principal Investigator: Valeriy Nenov, Ph.D., Ph.D.
An
automated clinical data integration and processing system was developed
to derive human-understandable rules for predicting in-hospital acute
patient deterioration toward severe cardiac arrest or unplanned ICU
transfer. In collaborating with the UCLA Medical Center Quality
Management Service, we used the system to analyze historical cases of
cardiac arrests and unplanned ICU transfers that were logged in the
calendar years 2005 and 2006. Positive results regarding the predictive
power of the derived rules were established. We are working on a further
improvement of the system for integrating continuous physiological
signals into the system.
