Numerous Pitt investigators have received federal funding for critical medical research that will directly improve the lives of our military service members, veterans, and their families.
TEAM-TBI: Targeted Evaluation, Action, and Monitoring of Traumatic Brain Injury
David Okonkwo, MD, PhD
Traumatic brain injury (TBI) has impacted countless warriors in Afghanistan and Iraq, and will likely exceed half a million injuries before US withdrawals are complete. An estimated 3.2 to 5.3 million people in the United States live with the long-term physical, cognitive, and psychological health disabilities of TBI. Recent efforts have increased our understanding of the pathophysiology of TBI; however, these advances have failed to translate into a single successful clinical trial or treatment to date, and the heterogeneity of TBI is a large factor among many for TBI research to unravel. There is an urgent, critical need for specific diagnosis and effective rehabilitation to improve the lives of those living with a TBI based on individual patient symptomatology, and doctors at Pitt are working on exciting research to meet this need.
TBI is recognized as a heterogeneous disorder. Analogous to cancer, TBI has multiple phenotypes. To target and treat TBI effectively, one must diagnose and characterize the specific problem(s) of individual patients. Yet there are no high-sensitivity diagnostic tools, no established subgroups, and no protocols to enable any relief for TBI patients. Patients often receive ambiguous diagnoses, failed treatment attempts, and the lost opportunity for a more certain prognosis. Effective treatment of TBI is likely to require a “cocktail” of methods, creating a synergy of behavioral and technological methods to personalize and maximize brain tissue repair and reverse deficits.
Initiated on March 24, 2014 under the US Army Medical Research and Material Command (USAMRMC), “TEAM-TBI” is an innovative approach to TBI clinical trials that strives to evolve transformative diagnostic technology and treatment; improve metrics and provide rigorous tests of combinatorial self-help strategies; and lower cost and increase speed for delivery of these effective strategies. There are two goals: (1) Comprehensive intake assessment via the most advanced tools available with diagnostic clustering of patients into specific TBI phenotypes; and (2) Precision medicine with targeted strategies based on the identified subtypes to maximize improvements in symptoms. Individual progress is quantified by the Post-Concussive Symptom Scale (PCSS), which rates 22 symptoms on a 0-6 scale. Preliminary data of the 20 participants who have completed the study to date has shown significant reduced symptomatology. The mean PCSS score across these 20 subjects decreased from 71.5 at enrollment to 39.6 at a 6-month follow-up—an average improvement of a 31.9-point difference in reported symptoms (p<0.01).
Under the direction of Dr. David Okonkwo and a team of world-class experts, the study has enrolled 51 subjects to date, which is approximately half of the total anticipated cohort. Participants complete four days of thorough evaluations including sleep, vestibular, ocular motor, exertion, and neuropsychological assessments, which are then married to advanced neuroimaging modalities such as High Definition Fiber Tracking MRI, MEG, and PET imaging. The results of these myriad assessments are reviewed by our TEAM, who reach a consensus that identifies a specific treatment pathway. “Each individualized treatment recommendation is achieved thanks to an extraordinary collaboration of an interdisciplinary team of experts across multiple departments at the University of Pittsburgh. This TEAM-work allows us to pinpoint precisely what is wrong with the individuals in front of us, and focus on trying to make them better,” says Dr. Okonkwo. These recommendations may include at-home programs such as cognitive rehabilitation, mindfulness, exertion program, vestibular therapy, ocular-motor therapy, and behavioral modification. In addition, participants may also be referred for outside treatment such as psychotherapy or sleep treatment. Participants are followed over the course of six months while they implement the team’s recommendations, and then return to Pittsburgh for a repeat evaluation. “This individualized approach to the patient sounds so simple, except that it has never been done before in any traumatic brain injury study thus far,” says Dr. Okonkwo.
This study remains open to enrollment and is expected to be completed in late 2017. If you are interested in participating in this study, please call 412-383-TEAM (8326) or e-mail TEAMTBI@upmc.edu. For more information, please visit www.team-tbi.com.
Improving Viability and Functional Outcome After
Whole Eye Transplantation
Kia Washington, MD
For men and women in military service, blindness resulting from trauma and degenerative disease causes a significant decline in quality of life and the ability to return to the workforce. For many of these individuals, there are no treatments available to restore vision. Whole eye transplantation (WET) offers the opportunity to restore vision by providing viable retinal ganglion cells and an entire optical system to those with irreversible blindness. Dr. Kia Washington’s project to restore form and function after vision loss through whole eye transplantation has the potential to help service members with irreversible vision loss, and can also have broad-reaching impact on civilian medicine.
Initiated on September 15, 2014, “Improving Viability and Functional Outcome after Whole Eye Transplantation,” under the Congressional Special Interest (CSI) Vision Research Program, has seen marked progress. Dr. Washington and her team have successfully created the world’s first orthotopic vascularized whole eye transplant small animal model. Studies thus far have suggested maintenance of gross morphology, retinal blood flow, aqueous humor dynamics, intraocular pressures, and blood-ocular barriers after transplantation. Dr. Washington’s model gives the unprecedented ability to collect high quality data in carefully controlled experiments to bring WET towards clinical reality. She was recently awarded the 2015 Military Health System Research Symposium's Research Individual Accomplishment in Academia Award, sponsored by the Assistant Secretary of Defense for Health Affairs.
The next phase of the research will involve a comprehensive approach to addressing the challenges of whole eye transplantation, including controlling immune rejection and inflammation, improving retinal ganglion cell survival, and integrating the donor eye with the host brain by stimulating optic nerve regeneration.
“One of the key parts of our grant, and something we will work extensively on, is establishing a grading system for how the immune system responds to the transplanted eye. Since we’re the first ones working on this, we’ll have to set the standard. Right now we don’t really know how the body will react to a transplanted eye and what will be required in the way of immunosuppression therapies to stave off rejection,” says Dr. Washington. The current animal models do not experience an immune response or rejection, as the subjects are all genetically identical. The next step in the process is to move from a syngeneic to an allotransplantation model, allowing Dr. Washington and her team to study the rejection process and immunosuppression requirements. When asked what it would mean if the projects are successful, Dr. Washington says, “We will be achieving a miracle. The ability to give sight to someone has not been accomplished yet, and millions of people could benefit. This is very exciting work that has the potential to change lives. It is exciting to be on the cusp of what is currently happening in the research, and I want to be there when we are ultimately successful.”