PoNS users place the electrode-covered device on the tongue for a 20- to 30-minute stimulation therapy called cranial nerve noninvasive neuromodulation. That is coupled with a custom set of physical, occupational and cognitive exercises based on the patient's deficits. (J. Ellen Crown / Army)
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Cooling the brain after a traumatic injury can prevent the development of epileptic seizures in patients later, a breakthrough that offers a potential new treatment for concussion-stricken soldiers, according to an Army official at the forefront of the effort.
The study, one of hundreds of research projects funded by the Army on traumatic brain injuries, was published in February in the Annals of Neurology. Researchers at Washington University in St. Louis made the find using special cooling headsets on patients.
After more than a decade in which blast-related concussions have been a signature wound for soldiers, the Army is pouring money into TBI research. Since 2007, the service has spent $700 million on the problem and funded 500 research projects, according to Army data. Three hundred of those research projects are ongoing.
“There’s a lot happening,” said Col. Dallas Hack, a doctor and director of Combat Casualty Care at Medical Research and Materiel Command, Fort Detrick, Md. “In 2007, the world didn’t really know a lot about TBI, and in the scheme of medical advances, what we’ve made in that time has been very rapid.”
In a telephone interview with Army Times, Hack elaborated on several areas of TBI research. Among them are the nontraditional therapies such as brain cooling, the use of “combination” therapeutics that mitigate or reduce TBI-induced brain damage and seizures, and several promising new drugs.
Dr. Stephen Xenakis, a retired Army psychiatrist and brigadier general, told Army Times he disagreed that TBI research has made fast progress with the Army’s help, and said the Army’s response has lacked coordination.
“I think they have spent that much money,” Xenakis said of the Army, “but I don’t think they have a strategy. Up until 2009 and 2010, there were as many voices in the Army saying TBI wasn’t a real problem and that its symptoms could be attributed to [post-traumatic stress].”
Xenakis conceded the Army is doing well by recognizing alternatives to pharmaceuticals, which “have very disturbing side effects and they have limited efficacy.” Cooling the brain, though it is not well understood, he said, “should be in the tool kit.”
The research at Washington University showed the brain and nervous system recover better from injury when they are cooler than normal. After a brain injury, brain cells break down and become toxic to the cells around them, a process that is slowed by cooler temperatures.
There are two kinds of toxicity in the brain after a concussion, Hack said. The contents of the cells themselves are toxic, and the brain goes into a hypermetabolic state that requires high levels of glucose and is also toxic.
When Buffalo Bills football player Kevin Everett suffered a spinal cord injury in September 2007, he was given an experimental treatment: Paramedics immediately pumped ice-cold saline into his veins. Though it’s unlikely Everett will play football again, the treatment reduced swelling in his brain and may have prevented him from being paralyzed, Hack said.
The University of Miami and the Walter Reed Army Institute of Research are conducting research related to brain cooling, which the Army hopes to use to improve treatments in Afghanistan and elsewhere. The heat outdoors, particularly in Afghanistan and Iraq, raises body temperatures in ways that can increase the toxicity and severity of brain injuries.
Even one degree counts, Hack said, “so even getting a patient to a normal body temperature, you’ve done a lot.
“Animal studies have shown that this is more effective than any known drug at reducing the consequences of a brain injury,” he said.
Researchers reportedly tested cooling headsets on rats with brain injury-related seizures. Rats whose brains had been cooled only experienced a few brief seizures as long as four months after an injury, while rats that wore inactive headsets had progressively longer and more severe seizures weeks after the injury.
'Electroceuticals' regulate brain
The brain not only has metabolic, chemical processes, but an electrical process that can be treated with “electroceuticals,” Hack said. Like a pacemaker for a patient’s nervous system, these devices send electrical impulses to the brain to regulate its functioning.
Cranial electrical stimulation has been used to treat certain types of epilepsy, and it is being studied for treating multiple sclerosis, migraines and Alzheimer’s disease. One device, a vagus nerve stimulator, is implanted under the skin and sends signals to the brain stem to stop seizures.
In a similar vein, the University of Wisconsin has invented a system that treats the tongue as a gateway to the brain, stimulating it with electrical impulses to restore lost mental and physical functions.
Montel Williams, a former talk show host and military veteran, has championed the device and reportedly uses it to treat his multiple sclerosis. NeuroHabilitation Corp., a company supported by Williams, signed a collaborative research agreement with the Army in February.
The battery-operated device is placed on the tongue and used in concert with physical, occupational and cognitive exercises. The goal is to retrain the brain’s organizational ability and allow the patient to regain neural control.
“Your tongue has the highest density of nerve endings in your body, and it holds a direct connection to your brain stem, which is your brain’s switchboard,” Hack said. “By doing this electrical stimulation with repetitive brain activity, you can dramatically shorten the rehab process.”
People who develop balance disorders such as vertigo, which often happens after a brain injury, would use the device to practice walking and balancing. It works because of neuroplasticity, meaning “the brain can adapt far more than we give it credit for,” Hack said.
The Army’s testing will include a study with researchers and clinicians at the Blanchfield Army Community Hospital in Fort Campbell, Ky.
Army tests new drugs
In the realm of pharmaceuticals, the Army is pursuing research into combination therapies, meaning that instead of treating each symptom separately, the drugs would be part of a holistic treatment.
“It’s starting out with a combination, and not just having another drug to fix the side effects from the one before, as we typically do,” Hack said. “It’s a package of treatment ... or pharmaceuticals together with the rehab techniques we’ve been talking about.”
Using pharmaceuticals to treat brain injuries is a relatively new approach, and many companies have gotten out of the business because the research costs so much, without a quick payoff, Hack said.
More than 200 stroke treatment drugs have failed in final Food and Drug Administration trials, and more than 30 meant to treat TBI have failed in final FDA trials.
The Army has nevertheless found pharmaceutical research it believes is worth funding. An Army-funded study is looking at how well the anti-inflammatory properties of the cholesterol medicine Simvastatin limit swelling in the brain. The drug is in final clinical trials, according to Hack.
With the Army’s backing, the New Zealand company Neuren pharmaceuticals is in pre-clinical testing for a neuroprotectant drug, NNZ-2566. Adapted from a naturally occurring chemical in the brain, the drug is said to reduce inflammation and cell death by protecting the neurons and their surrounding infrastructure, and inhibiting post-injury seizures.
In animals, the drug is more effective than any other the Army has examined, Hack said. Testing in humans with TBI is underway and due to wrap up in a year.
Battlefield blood test
The Army has entered the pivotal clinical trials for a battlefield blood test for TBIs, and the global study is set to have all 2,000 test patients enrolled by the end of this year, Hack said.
The idea is to produce a means of detecting and measuring the proteins that spill out of damaged brain cells and into brain fluid and the blood.
War-zone trials of the blood test have shown promise, detecting concussions in cases treated at recovery centers in Afghanistan.
The test would replace subjective methods for diagnosing a soldier with a mild TBI, which involve the soldier balancing, repeating words, answering questions or following an object with his eyes.■