Visionary Ball Seed Grants Scientific Progress Report
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.
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. 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. 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.
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.
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.
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.
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. 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.
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