When renowned psychiatrist and neuroanatomist David McKenzie Rioch established a Division of Neuropsychiatry within the Army Medical Service Graduate School in 1951, it was the launch of a golden age. His research group, which had helped to establish a new terminology for situational behavior disorders during World War II, was a historically significant prototype for the modern neuroscience laboratory: It was a wide-open scientific think tank where the boundaries of departments and research disciplines were deliberately blurred.
Neuroscientist Robert Galambos, a member of this founding group, later recalled: “The Rioch organization came into being because the Army wanted to solve a pressing practical problem. The commandant of the Walter Reed Army Institute of Research [WRAIR], Col. William Stone, defined it when he interviewed me for the job. He said, in effect, psychiatric casualties had reached the top of the Army’s list of medical problems, and Rioch’s mission was to supervise the basic research effort that would drop it to the bottom.”1
“It was possible to take more long-shots without becoming panic stricken if things didn’t work out brilliantly in the first few months. … Scientifically, I could hardly have chosen a better place than Walter Reed.”2
It was to this organization that an Army draftee, the 29-year-old neurobiologist David Hubel, reported for duty in 1955. “One then had little of the feeling of frenetic competition that is found in graduate students today,” Hubel later wrote. “It was possible to take more long-shots without becoming panic stricken if things didn’t work out brilliantly in the first few months. … Scientifically, I could hardly have chosen a better place than Walter Reed.”2 In 1957, Hubel launched his main research project at the WRAIR, an electrophysiological study of axonal neurons in the brains of cats. This study laid the groundwork for later discoveries Hubel and research partner Torsten Wiesel would make about information processing in the visual system – discoveries that would earn the pair a share of the 1981 Nobel Prize in Physiology or Medicine.
The experiences of American warfighters in Vietnam shifted the division’s objectives. Rather than broad-based studies of the entire nervous system, the group took on a more mission-focused research program. In the 1960s and 1970s, it dispatched the Army’s first expeditionary psychological research teams – precursors to today’s Mental Health Advisory Teams, or MHATs – to observe, study, and document substance abuse by young soldiers. The group’s “jet lag” studies in the late 1970s helped the Army develop simple countermeasures to reduce fatigue and improve performance after long-distance air deployments.
Renamed the Center for Military Psychiatry and Neuroscience (CMPN) in 2009, this group at the WRAIR continues to pursue a vision much like that of Rioch – a vision that: focuses on issues critical to the psychological and neurological health of service members; attracts and develops world-class researchers; fosters a creative, innovative, and collaborative culture; and moves products from the bench to the field to promote service member wellness.
For more than 60 years, from World War II to the Global War on Terrorism, WRAIR’s psychiatry and neuroscience program has been remarkably productive; its research innovations have yielded more than 30 patents for scientific contributions. Today, research-based solutions delivered by CMPN scientists are aimed at the different types of challenges facing contemporary Service Members, embodied in the center’s organizational structure. The center’s four research directorates, housed within WRAIR, are:
- Brain Trauma Neuroprotection and Neurorestoration
- Blast-Induced Neurotrauma
- Behavioral Biology
- Military Psychiatry
Brain injury has always been one of the leading causes of military casualties – probably even more so over the last decade. Up to 30 percent of combat trauma suffered by service members in Iraq and Afghanistan has occurred in the head and neck region. The vast majority of this trauma has been caused by the enemy explosive devices common to these conflicts: improvised explosive devices (IEDs), mines, mortars, bombs, and rocket-propelled grenades. A 2003-2008 study revealed that more than half of the military’s evacuated neurosurgical patients had sustained a traumatic brain injury (TBI) caused by a blast event, and that 71 percent of these victims also suffered a penetrating traumatic brain injury, or PTBI.
Advances in armor and battlefield medicine have rendered these injuries less deadly – but have also increased the number of patients who, as a consequence, confront a lifetime of cognitive and physical disabilities. TBI victims, in general, have a shorter life expectancy, and are more likely to suffer from seizure disorders, neurodegenerative diseases, neuroendocrine disorders, and psychiatric diseases. One such long-term consequence of TBI, chronic traumatic encephalopathy (CTE), has recently gained attention as a potentially devastating outcome for people who suffer from multiple mild TBIs.
Under the leadership of Dr. Frank Tortella, senior scientist and TBI subject matter expert for WRAIR and its command, WRAIR’s Brain Trauma Neuroprotection and Neurorestoration (BTNN) Branch aims to protect service members from these outcomes, with investigations that have two ultimate objectives: a means of diagnosing mild to moderate TBI promptly, in the field; and identifying new treatments to protect brain tissue, decrease the short- and long-term neurological damage associated with TBI, and increase the likelihood that brain tissue will recover and heal.
Currently, mild TBI or concussion is hard to diagnose beyond the obvious symptoms: a loss or alteration of consciousness, post-traumatic amnesia, headache, dizziness, blurred vision, ringing ears, cognitive problems, and sleep disturbance. As such, the mTBI has been called the “invisible” injury of war since many, if not most, cases of mild TBI are under-diagnosed and go undetected by traditional brain imaging approaches. Consequently, it remains difficult, if not impossible, to tell how severe a mild TBI really is, or how the injury changes over time.
Researchers in the Brain Trauma Neuroprotection and Neuroplasticity Branch have contributed substantially to the growing body of work that continues to show TBI-specific biomarkers – higher- or lower-than-normal levels of proteins and enzymes associated with specific neurological mechanisms – in brain tissue and/or cerebrospinal fluid (CSF) and serum. These biomarkers have been detected and measured in animal models, and increasingly in human subjects in clinical trials, and they show great promise – but the science is still too young to link the presence of specific biomarkers to an indication for certain drugs.
“Their studies have identified some pretty good TBI-related biomarkers – biomarkers that have sensitivity and specificity,” said Col. Paul Bliese, director of the CMPN. “This has a lot of applicability to places like Iraq or Afghanistan, where someone may encounter many other kinds of injuries, but where one isn’t necessarily sure whether they’ve suffered a traumatic brain injury as well.”
There is no drug therapy currently approved as a standard of care for TBI. The directorate’s approach to discovering and developing effective TBI drugs is via cooperative research and development agreements (CRADAs) with pharmaceutical companies, as well as collaborative efforts with the Army’s Operation Brain Trauma Therapy (OBTT) program, a multicenter pre-clinical drug-screening consortium. Using animal models of severe TBI, the efforts of the BTNN research team have demonstrated what drugs are highly neuroprotective and anticonvulsant and therefore suitable for the launch of Phase I clinical trials to demonstrate safety and bioavailability in normal volunteers. With Phase I trials complete for one such drug, the next step is already under way – a Phase II trial, with cost sharing between private industry and the DoD, of the drug’s safety and efficacy in moderate and severe TBI patients.
TBI-related brain physiology is still not completely understood, and two decades’ worth of clinical trials have not produced a single drug capable of reliably protecting the brain from TBI-related harm. Single-drug “monotherapies,” which target individual or simple brain mechanisms, simply haven’t proven adequate to address the complexities of the injured brain, and BTNN researchers are among those turning increased attention to combination drug therapies that achieve efficacy through synergistic drug-pair interactions.
The center’s neuroprotection and neurorestoration researchers have also contributed to research in non-pharmacological TBI treatments, such as therapies in which human amnion-derived stem cells, transplanted into injured brain tissue, have demonstrated an ability to protect against neural tissue damage and motor deficits. BTNN Branch researchers have also conducted pre-clinical investigations, in animal models, into an innovative method for selectively cooling the brain post-trauma. The use of a cooling cuff placed around the common carotid artery can achieve rapid and sustained reductions in brain temperatures – which in turn reduces intracranial pressure, inflammation of damaged tissues, brain edema, and the permeability of the protective blood/brain barrier (BBB) – without adversely influencing core body temperature.
“They’ve been able to show that if you can just reduce the temperature of the brain one or two degrees,” said Bliese, “you can actually alter the outcome – very similar to the idea of putting ice on your knee.” The group’s isolation of the carotid artery has been an important evolutionary step from earlier interventions involving whole-body cooling, which actually increases the risk of several adverse outcomes, including blood clotting, hypotension, and infectious pneumonia, particularly prevalent in polytrauma patients. The selective technique of isolating the common carotid artery, however, also limits the therapy’s applicability, making an excellent tool but far less feasible as a clinical therapy in forward-deployed medical facilities.
Of course, the majority of the world’s TBIs are suffered not in battle, but in car accidents, and by the military’s own estimate (epidemiological data released in 2013 by the Defense and Veterans Brain Injury Center and the Armed Forces Health Surveillance Center), 80 percent of military service-related TBI occurs in non-deployed environments. The work of this research team has also led to the development of a head injury model causing true mTBI/concussive syndromes to examine changes that occur in the brain after single and repetitive concussions, and explore those changes over time to understand the link between mTBI and potential chronic illnesses such as CTE. The work of the center’s Brain Trauma Neuroprotection and Neurorestoration Branch, said Bliese, is, “despite being one of our newer programs, one that has been particularly successful, over the last few years, in rolling out some potentially very useful products. And if a group like BTNN is able to identify and develop serum diagnostics and therapies that would be useful following a traumatic brain injury, the application of that goes well beyond the military: These are products that would change the landscape of medicine and could be rolled out in emergency rooms in hospitals around the world.” Collectively, when the work of the center’s Neurotrauma and Neurorestoration Branch helps to produce a field-deployable device that can identify TBI biomarkers, and drugs that can help protect brain tissue from post-traumatic damage, these will indeed be historic breakthroughs.