Inside Neuroscience: New Insights Into Traumatic Brain Injury

Every year, 2 million Americans suffer a traumatic brain injury (TBI). Severe TBI can result in permanent disability or death. Even mild injury may cause memory loss, personality changes, and emotional disturbances. During a press conference at Neuroscience 2015, researchers highlighted how a better understanding of TBI symptoms and how they manifest is leading to important new treatment strategies. 

“Despite the prevalence of traumatic brain injury, no therapy currently exists to treat the underlying causes of the pathologies suffered by TBI patients,” said Akiva Cohen, a brain injury expert at the University of Pennsylvania and session moderator. 

Most of the research on TBI has focused on the cognitive symptoms such as memory loss. In working with TBI survivors, Ramesh Raghupathi, a professor at Drexel University, realized they had a hard time coping with symptoms like depression, headache, and pain. Importantly, these symptoms differ between genders: Men more often present with depression while women report increased pain and headaches. 

To further examine gender differences in these symptoms, Raghupathi tested young male and female mice exposed to a mild traumatic brain injury similar to a concussion. The researchers used a model of depression called the forced-swim test, which measures how long mice will try to escape a swim tank before giving up and floating. In the test, injured male mice gave up more quickly than both injured females and uninjured mice. The researchers also found that injured females showed increased sensitivity to touch — a model for headache — compared with injured males and uninjured mice. Raghupathi and his team discovered injury also led to decreased dopamine signaling in males, a finding not observed in females. 

Raghupathi suspects dopamine signaling may underpin the gender specificity of these non-cognitive symptoms. “Our future work is developing these models and looking at the effect of dopaminergic signaling as the underlying basis for these problems,” Raghupathi said.

For military personnel, blasts from improvised explosive devices often result in TBI. In addition, veterans may develop post-traumatic stress disorder (PTSD) after a TBI, but the question remains as to whether TBI causes PTSD.

Carmen Lin, a graduate student in John Disterhoft’s laboratory at Northwestern University, studied male mice with head injuries similar to those caused by explosions. She then exposed the mice to fear conditioning where they learned to associate an environment or a sound with a foot shock. During the learning process, injured mice froze more than uninjured mice, suggesting increased fear. However, when tested later, uninjured mice better remembered the association between the environment and the foot shock than injured mice — uninjured mice froze in the appropriate places whereas the injured mice did not. This may indicate the blasted mice not only had problems controlling their fear during the initial training, but they also failed to remember the experience appropriately. This supports previous research showing memory problems after TBI.  

The increased fear the mice displayed mimics PTSD symptoms. Lin hopes the study will “increase awareness of the link between TBI and PTSD” and open an avenue for potential therapeutics.

Memory loss and other cognitive problems are common symptoms of TBI. Researchers have found that minocycline and N-acetylcysteine, two FDA-approved drugs, work synergistically to improve cognition and reduce cellular loss in rodent models of TBI. 

“What we’ve [previously] shown is that when we dose with these drugs one hour after injury we’re able to see a therapeutic effect,” said Michael Sangobowale, a graduate student in the laboratory of Peter Bergold at SUNY Downstate Medical Center. “But what’s of great importance is that we can have drugs that we can use beyond one hour after injury.” 

Sangobowale tested how delivering the drug combination to rats either 12 or 24 hours after a moderate brain injury affected performance on a memory test. Rats given the drugs 12 hours after injury performed better than untreated rats on a challenging memory test that required them to remember the location of a shock in a rotating arena. Rats receiving the drugs 24 hours after injury performed better than untreated rats on the easier Barnes Maze memory task. Additionally, Sangobowale found the treatment promoted remyelination in the corpus callosum, a region damaged in the injury model that may be required for success on the challenging memory test. 

“We were able to show that two FDA-approved drugs were able to be used in a clinically useful therapeutic window,” Sangobowale said.

Traumatic brain injury is the leading cause of death and disability in children and young adults. Popular belief is that children are more resilient to injury and that their brains are plastic enough to repair any damage. But “recent reports are really saying that this isn’t the case, that children are actually at greater risk, have worse outcomes, and take longer to recover from traumatic brain injury,” said Trent Anderson from the University of Arizona.

To understand why that is, Anderson investigated changes to the balance of excitatory and inhibitory signaling in young mice after severe TBI. Staining near the injury site revealed decreased expression of the protein parvalbumin, a marker for one type of inhibitory interneuron. Electrophysiology studies confirmed a loss of inhibition in the region. However, other types of inhibitory neurons and excitatory neurons remained unchanged. This is in contrast to reports from adults, where TBI affected many types of inhibitory neurons. 

“They’re losing the ability in that zone of the brain to have the brake that controls excitation and that represents a significant shift in the excitatory-inhibitory balance,” Anderson said. “The findings from our study, along with others, support the idea of a real need to understand pediatric traumatic brain injury independent of what might be going on in adults.”

The researchers demonstrated that developing new treatment strategies requires investigating TBI from all angles, including gender and age differences and the variety of symptoms. “No two brain injuries are identical,” Cohen said. “In order to hopefully develop a therapy, it is important to understand the alterations that contribute to the associated pathologies caused by brain injuries.”