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MIND

by COL Karl E. Friedl

Traumatic brain injury (TBI) and mental health are significant medical referral issues in the U.S. military. DoD reported more than 150,000 cases of concussion among returning service members from 2000 to 2010, signaling a need for better detection and treatment of such injuries. While promising research continues in several scientific fields, injuries rarely occur in isolation, making a wider view of available treatment technologies andpractice a critical need.

The Telemedicine and Advanced Technology Research Center (TATRC) within the U.S. Army Medical Research and Materiel Command (USAMRMC) sponsors workshops of national experts to assess current tools and knowledge for development of rapid solutions to help those injured in combat.

In assessing trauma-related injuries, it is crucial to determine whether the brain is functioning properly; it may be moreimportant to identify dysfunction(s) correctly than to determine whether the condition stems from physical or psychological trauma, stress, or grief. Both physical and psychological events can cause changes in the brain that lead to debilitating conditions and increase the risk of long-term neurobehavioral dysfunction or the development of neurodegenerative conditions, such as Parkinson’s disease or Alzheimer’s.

Cellular changes and nerve injury can lead to damaging metabolic cascades after concussion. Proteins and other biomarkers in serum and cerebrospinal fluid illuminate this process, and advanced imaging techniques, such as diffusion tensor imaging and functional magnetic resonance imaging (fMRI), enable scientists to visualize the effects and see areas of decreased brain activity.

In searching for biomarkers, however, one must be cautious. Imaging techniques, as well as molecular markers, may besensitive but not specific. Some individuals will not show abnormalities but still have impaired functioning. Posttraumatic stress (PTS) and mild brain injury can cause similar brain and behavioral changes. Even more important, individuals’ pre-injury conditions vary widely. One cannot assume that abnormalities are caused solely by recent trauma or that visible change in the brain causes a specific symptom.

Thus, there is a need for research to connect the biological changes with clinical signs and symptoms, in order to confirm a biological basis for defining outcomes of concussion and other conditions. A combination of imaging techniques, physiological measures, and clinical assessments is needed to provide the early detection crucial to successful treatment.

ANGLES OF ATTACK

At a TATRC-funded workshop in May 2011 at Georgetown University on issues of combat-related brain dysfunction, key


medical leaders such as Dr. Robert J. Ursano, Chairman of the Department of Psychiatry at the Uniformed Services University of the Health Sciences; U.S. Air Force Col Michael S. Jaffee, M.D., former national director of the Defense and Veterans Brain Injury Center (DVBIC) who is currently on the faculty of the San Antonio Uniformed Services Health Education Consortium; and Dr. Donald Marion, Director of Clinical Affairs at DVBIC, discussed current solutions, ongoing research, and possible new research angles of attack. Highlights from the discussion follow.

Panelists noted that DoD took an important procedural step with a June 2010 directive to identify and treat early concussion in deployed service membersthrough mandatory medical evaluations and rest for those exposed to certain events. Because this approach does not rely on service members to report symptoms, more are being screened for injury in theater.

Neurologists, as well as information from the field, suggest that the most useful device to identify concussion within one to two hours after injury may be a smartphone application that would enable a medic to measure key physiological parameters such as balance, reaction time, and eye tracking, or a ruggedized, fieldportable device, such as the Tempus Pro, optimized for military use by TATRC in collaboration with U.S. Army Special Forces. Tempus Pro, which provides medical data capture, telemonitoring, andtelemetry, recently received recognition by the Secretary of Defense as among the best capabilities in the FY10 Joint Capability Technology Demonstration.

For cognitive assessment, the military currently uses paper-and-pencil tests as well as neuropsychological instruments, including the Army’s Automated Neuropsychological Assessment Metrics (ANAM) computerized test. Studies have shown that cognitive tests detect concussion effects in individuals even after they report themselves to be symptom-free. Dr. Robert Kane, Project Manager for the Neurocognitive Assessment Tool program at DVBIC, said that computerized tests seem to give more detail than traditional ones, thus illuminating a variety of cognitive effects stemming from different types of concussion. He and many others are also enthusiastic about the additional information that virtual reality (VR) might offer.

Dr. Thomas D. Parsons, Director of the NeuroSim Laboratory at the University of Southern California’s Institute for Creative Technologies, an Army University-Affiliated Research Center, is developing and testing VR assessment tools for return-to-duty decisions after brain or psychological injury. With Soldiers’ input, his team has recreated multisensory environments and situations from Iraq and Afghanistan.

“The beauty of VR is that it allows us to integrate standardized neuropsychological measures into interactive applications that approximate the real world of a military service member,” Parsons said. The team has worked with other partners, both military and civilian, to compare results from standardized paper-and-pencil tests as well as ANAM results. “My focus is on validating this technique, working with both clinical and nonclinical populations, so it


SIMPLE MEASURES

can become standardized and accepted as a way to add further information to the current tests we have,” Parsons said.

In another application of the technology, Dr. Albert “Skip” Rizzo, Associate Director of the medical VR research group at the Institute for Creative Technologies, is using a Virtual Iraq/Afghanistan environment to deliver exposure therapy for combat-related PTS. Exposure therapy, in which a person is gradually exposed to fear triggers in a safe setting, is shown to be effective in treating PTS symptoms in many cases. Rizzo’s and others’ initial pilot clinical trials have shown that therapy using this VR tool may achieve better results than traditional therapy, with a lower dropout rate. Three randomized controlled trials are ongoing to validate initial findings.

For the many with physical or experiential brain injuries who have difficulty focusingon tasks or learning, Dr. Anthony Chen and his team are developing theory-driven cognitive rehabilitation techniques. Chen, who directs the collaborative Program in Rehabilitation Neuroscience of the University of California and Department of Veterans Affairs (VA), is using fMRI along with task performance measures to study the effectiveness of cognitive training to enhance selective attention for real-world goals.

Treatment breakthroughs may also lie in simple measures that have dramatic effects. Over the past decade, several studies have highlighted the beneficial effects of exercise on memory and learning. Some investigators, such as those at the University of California, Los Angeles Brain Injury Research Center, are studying the role of exercise in healing after TBI. While they have found that improvement is highly dependent on theseverity and timing of injury, it appears that exercise holds promise as a possible protective mechanism or a way to reduce the effects of traumatic exposure and mild brain injury.

Until recently, it was thought that no new neurons in the central nervous system could be generated after birth, but new research—much of it from Dr. Fred H. “Rusty” Gage’s laboratory at the Salk Institute for Biological Studies—has shown that neurogenesis occurs in the adult in two areas. One of these, the hippocampus, plays a vital role in learning and memory; neuronal growth there conceivably could improve cognitive abilities damaged by traumatic exposure.

Dr. Henriette van Praag of the National Institute on Aging has tagged and imaged the growth of new cells in the hippocampus and found that exercise is a strong regulator of neurogenesis, tripling neural


SHARING DATA

growth. In her studies, even aged rats learned faster with exercise.

Other benefits of exercise, such as improved mood and sleep, could greatly enhance mental health among deployed service members. In fact, many hypothesize that sleep is a natural protectant that can reduce some of the damage to the brain after trauma. In a study published in 2010, Dr. Thomas C. Neylan, Director of the Posttraumatic Stress Disorders Program at the San Francisco VA Medical Center and part of the Army-funded Neuroscience Center of Excellence, found that poor sleep quality was associated with a smaller hippocampal volume. If sleep disruptions can negatively affect this region where new neurons emerge, then perhaps improving sleep conditions or treating sleep disorders can improve neurogenesis and cognitive functions.

Because sleeplessness is the most common complaint in both mild brain injury and PTS, Neylan is exploring the possibility of promoting sleep by antagonizing the brain’s receptors for corticotrophin-releasing factor (CRF), a type of neurotransmitter involved in anxiety-related arousal control. He hopes that his tests of a CRF antagonist may lead to safer sleep medications.

Data sharing and common standards would greatly improve the progress of research toward effective solutions. Separate research efforts on both the civilian and military sides would benefit from a common data repository that all could access. Developing means to share access to the massive amount of data from current research on Soldiers and veterans, as well as completing effective transfer of medical information between the activeservices and the VA, could provide valuable insight into what treatments are working and for whom.

Currently there are different systems for defining and noting the severity of concussion, TBI, and PTS, as well as a lack of longitudinal data to illuminate the differences between those who recover from trauma and those who do not. More work among disciplines is needed so that findings can be built into training, treatment, and decompression procedures.

TATRC continues to support an organized research effort focused on three outcomes:Simple, pragmatic tools for brain “first aid” in the field.

Interventions to prevent a vicious cycle of cellular damage after injury.

Interventions to prevent and treat development of neurodegenerative conditions, such as Parkinson’s disease and Alzheimer’s, and to prevent other chronic problems.

TATRC partners with other USAMRMC programs, such as the Combat Casualty Care Research Program and the Military Operational Medicine Research Program, to provide important leadership in military-focused research efforts. For more information on TATRC’s research funding and collaborative opportunities, visitwww.tatrc.org.

COL KARL E. FRIEDL is Director of the Telemedicine and Advanced Technology Research Center at U.S. Army Medical Research and Materiel Command, Fort Detrick, MD. He holds a B.A. and M.A. in zoology from the University of California at Santa Barbara (UCSB) and a Ph.D. in biology from UCSB’s Institute of Environmental Stress. Friedl is also a graduate of the U.S. Army Command and General Staff College.

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