Individuals with traumatic brain injuries, or TBIs, frequently experience the shrinking or atrophying of brain tissue near where the injury occurred, causing additional damage beyond the original harm. If this can be prevented, many could function in the future who cannot now.
Few therapies currently exist to treat TBIs, but studies suggest that cell-based, or stem cell, therapies can help. Since 2012, Charles S. Cox, Jr., director of the Pediatric Program in Regenerative Medicine at McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), has been running clinical trials for children and adults with traumatic brain injuries who received treatment with stem cells.
The adult project is supported by a $6.8 million award from the US Department of Defense (DoD) as part of the Joint Warfighter Program and the pediatric project is sponsored by a $3.4 million award from the National Institutes of Health (NIH)'s National Institute of Neurological Disorders and Stroke.
Cox and others hypothesize that inflammation causes cells to attack parts of the brain. Like all things related to inflammation, a little bit is good; too much is bad. The inflammatory response to the injury ends up damaging surrounding tissue that may be compromised, but not dead. Cox and his team are trying to dampen the immune response with stem cells from bone marrow.
“We know that the more brain tissue you lose, the worst you do in terms of neurocognitive outcomes,” he continued. “The idea is to interrupt that process to some degree, so that we have preservation of brain structures.”
Cox completed the Phase 1 safety trials with adults and child patients in 2014. The studies demonstrated that stem cell therapy following TBI is safe and that the treatment alleviates the body's inflammatory response to the trauma.
Phase 2, begun in 2013 for pediatric cases and 2016 for adult cases, seeks to determine whether the treatment preserves brain tissue and function, and, importantly, what the mechanism of action is. Their double-blind studies monitored 50 children (completed) and 27 adults thus far with severe traumatic brain injuries who received either an intravenous treatment of cells derived from the patients' bone marrow or a placebo.
The study required the researchers to track brain function in a range of ways. Collaborator Jenifer Juranek, an associate professor of Pediatric Surgery at the University of Texas Health Science Center at Houston (UT Health), is using brain imaging technologies to measure the changes in brain tissue in the days, weeks, and months after an injury.
“The neuroimaging component is multimodal, meaning that we acquire different modalities of MRI,” Juranek explained, “and different sequences,” referring to radiofrequency pulses and gradients that are adjusted to get a particular look into the brain.
These different imaging methods allow the researchers to measure the volume of the white matter and ventricles, and to track the movement of water in the brain. This water flow is revealed by diffusion MRIs, a type of imaging analysis that measures molecular diffusion in biological tissues and can reveal microscopic details about tissue architecture in a normal or diseased state.
“With diffusion MRI, you actually get numbers and the numbers are quantitative,” Juranek said. “They tell you whether diffusion is restricted, or whether diffusion happens more readily. In TBI in particular, the post-injury diffusion tends to be higher than it should be. That's most likely because things are breaking down and you don't have anything hindering that diffusion anymore.”
Juranek's imaging studies produce huge quantities of data that can't be efficiently analyzed by small computer clusters or in the cloud. She uses supercomputers at the Texas Advanced Computing Center (TACC) to help her compare brain physiology among patients, quantitatively assess the trials, and uncover patterns in brain responses.
ranek said. “Once we put the data in pipelines to look at macrostructure, volume, surface area, and diffusion, it gets huge.”
Juranek has worked with TACC since 2013 through a unique partnership known as the University of Texas Research Cyberinfrastructure — or UTRC — initiative that lets any faculty member, researcher or student at a UT System institution access TACC resources. Juranek uses Lonestar5, a dedicated system for Texas researchers, for volumetric analyses, and GPUs on TACC's Maverick2 system for diffusion studies.
Beyond raw computing, TACC has a team dedicated to aiding UT System researchers in their computational efforts. Joe Allen, a research associate in the Life Sciences group at TACC, helped Juranek adapt her workflow to TACC supercomputers by containerizing some of the more complex image analysis code and optimizing the pipeline for GPUs.
“I honestly could not have performed this work without Joe's expertise and all of TACC's resources,” she said. “I think it's important for other researchers intimidated by HPC to know that we don't have to be experts in HPC or MPI or multithreaded tasks. We just need to be willing to listen to the advice we're given by TACC folks to develop and maintain exceptional workflows on TACC resources.”
Teaming up with TACC has enabled new types of analyses for Juranek, like merging microstructural and macrostructural properties of the brain to study brain swelling.
“Having access to TACC supercomputers has opened the door for us to look at these other types of information that nobody's had an opportunity to do before,” she said.
Each year, about 2.5 million individuals experience TBIs of which approximately 50,000 result in death, and over 80,000 suffer permanent disability. Discovering why TBIs are so destructive, and how their worst effects can be avoided, would have a huge impact on countless lives.
“If medical research wants to continue to make advances, they need to pair themselves with high performance clusters,” Juranek said. “The information that we're gathering is so massive that in order to analyze it properly, you've got to have access to these kinds of resources.”