Contributor Ramtin Hakimjavadi
The conclusion of BMSA’s first Editorial Board event left students much more knowledgeable about concussions and how it is being studied. A special thank you to Dr. Gregory Dekaban and Dr. Arthur Brown for graciously dedicating their time to describe their research at the Robart’s Research Institute. Following their presentations on their complementary approaches to studying concussion, the discussion focused on important issues in today’s current landscape of research and considered its possible future directions.
There is an overwhelming prevalence of traumatic brain and spinal cord injury, especially in populations less often associated with the disease — such as the elderly. The presence of persistent brain changes beyond symptomatic recovery remains to be a focus of current research, because it relates to understanding the long-term consequences of concussion.
Above all, there are significant challenges involved with studying concussion to improve outcomes for patients. Even with tremendous efforts in both clinical and basic science research, there are many barriers to establishing clinically significant biomarkers or developing therapeutic strategies.
Dr. Dekaban’s concussion studies with bantam hockey males and female varsity rugby players revealed the complex nature of mild traumatic brain injury (mTBI). Studies on the male hockey players specifically focused on finding feasible ways to diagnose concussion earlier than current methods allow. They explored many avenues: hematology, mass spectrometry analysis of metabolites, phenotyping of leukocytes, analysis of monocytes. Often these techniques failed to detect significant differences in concussed athletes, or were not clinically useful (e.g., they could not be replicated during the normal time-frame of a patient would present with symptoms). FMRI imaging did show promising results by comparing a metric called the resting state connectivity between baseline and concussed populations.
Despite these important findings on the long-term brain changes in concussed athletes, it is currently difficult to draw clinically significant conclusions. Dr. Dekaban’s research established significant differences against the baseline in the resting state connectivity of bantam male hockey players showing post-concussive symptoms, after three months. However, researchers do not know whether the hyperconnectivity observed in these athletes represents an underlying pathology or some kind of repair state and brain plasticity. An optimist would hope that it represents increased brain plasticity and repair. Furthermore, deeper issues with CTE and other chronic neurodegenerative diseases are long-term questions being posed in a short-term window. Until larger cohorts are recruited for more long-term longitudinal studies, it is difficult to know for sure.
Fortunately, Dr. Brown’s work nicely complements the studies on concussed athletes and provides some insight on how to approach some of these more difficult questions. His research on rat models of concussion show how innovative research design can help answer difficult scientific questions. As with any study on animal models, it is important to consider how findings will translate when they are replicated in humans. One specific issue with studying concussion is that it is not possible to control variables in human subjects – such as by administering concussive impacts – the same way it is possible in rats. Human studies are therefore often limited in their design. There is a trade-off between the direct studies on humans that yield correlational data and the less restricted studies on rat models that have questions about their generalizability to human subjects.
In the context of mTBI, the only current therapy is rest – an approach that leads to full recovery in 85% of patients within a few weeks. However, the other 15% experience post-concussive symptoms and are the focus of research. The primary injury is the actual concussive impact; given that someone seeks help only after getting concussed, this part is inevitable. After the initial impact there is also a secondary response to the injury, which is largely driven by neuroinflammation. A possible approach to treatment could therefore be to reduce this inflammation.
This is exactly how Dr. Brown approached the problem. A certain antibody, anti-CD11d mAb, significantly reduces inflammation in rat models of severe concussion. As a result, half of the neurons in the brains of these rats were able to be rescued.
There are several significant hurdles between the current understanding of concussion and the point where patients with post-concussive syndrome can be effectively treated. Firstly, the best way to define an effective treatment remains unclear; current efforts focus simply on not exacerbating any of the symptoms. Another key ingredient to successful clinical outcomes is the ability to identify the 15% of the population that experiences post-concussion syndrome, and as early as possible.
Otherwise, it is difficult to run any clinical studies on effective treatments; it is crucial to know if a given treatment is actually working or if it is the 85% of the population that recovers spontaneously. Lastly, referring back to the resting state hyperconnectivity identified in concussed hockey players, it is important to explore whether these changes in the brain underlie a disease process or a healing process.
This is essentially where the current landscape of concussion research stands today. The collaborative efforts of Dr. Dekaban and Dr. Brown at Robart’s have been able to make magnificent leaps in our understanding of the disease. Their innovation, ability to approach the problem from multiple angles – combining human and rat studies – and integration of multiple scientific disciplines inspires confidence in one’s hope for the future. Their research has received significant support from the National Hockey League Players’ Association (NHLPA) and both Dr. Dekaban and Dr. Brown remain to be leaders in their fields.
Advances in the research of concussion hold fascinating implications for other issues in society. Namely, how concussion is depicted in the media and how our ever growing understanding of the disease will impact our engagement in high contact sports. Concussion and chronic traumatic encephalopathy (CTE) are used almost interchangeably in the news. However, the link between concussion and CTE remains unclear. Until larger, more long-term longitudinal studies are conducted, it is difficult to draw any firm conclusions. With regards to sports such as football and hockey, a troubling thought is the potential role that subconcussive impacts may have in causing concussion and post-concussion syndrome. If subconcussive impacts do play a role, then hits that do not immediately cause symptoms could be contributing to more long-term, accumulative damage. This effectively widens the scope of physical activities that one should approach with caution. A future where we must question the extent of our engagement in sports, both as participants and as spectators, seems imminent.
For those interested in learning more about concussion research, the annual “See the Line” event returns in the summer. It is another opportunity to join medical experts from around the world in engaging panel discussion.