• “To be or not to be”

Posted May 1, 2012

“To be or not to be”
- Hamlet

In this most famous of soliloquies, Hamlet broaches the dark subject of suicide. Just last month, yet another retired NFL player, former Atlanta Falcons’ Ray Easterling, ended his own life; a life that seemed blessed with all the success and happiness our society bequeaths to our sports heroes. There are now more than 1,000 ex-football players who have become plaintiffs in various lawsuits alleging irreparable damage from the constant battering of their brains. The worst of these cases have led to depression, cognitive losses and, ultimately, suicide. In 2011 Dave Duerson, an ex-Chicago Bear All Pro Safety, famously shot himself in the chest presumably to preserve his brain, which he asked be donated to the NFL’s brain bank for study. His condition was known as chronic traumatic encephalopathy, or CTE. Common sense, of course, tells us that repeated head collisions are bad for you. But just how bad is something we are only now discovering.

A recent study of 109 professional boxers using state-of-the-art MRI scans shows clear changes to the brains of fighters - including reduction in the size of the hippocampus region - in brains of those with more than six years in the ring; in addition, the study found clear loss of cognitive function for fighters who displayed this hippocampus damage who also had more than 12 years in the ring. In the past, almost all research in this area has focused on infrequent, hard blows to the head; what we think of as concussions. Rarely did anyone study less severe but continuous exposure from blows to the head such as those absorbed by boxers, and football players. Concussions are clearly bad, but evidence is piling up to show that injuries that may not rise to the level of “knocking one out,” but which reoccur often, can cause equal long-term damage.

And now, a third piece of this puzzle may have been added. The first case of CTE in a Marine returning from active duty in the Mideast has recently been reported. That Marines exposed to constant explosions could be subject to CTE should not be a surprise. But the more interesting, and I think important, implication reported here may relate to Post Traumatic Stress Syndrome (PTSD). As the report on the Marine case stated, the overlap between many of the symptoms of depression and CTE is great. And the overlap with the symptoms of PTSD is also very high. Patients experience high levels of anxiety, depression, anger, confusion (and other cognitive issues like inability to focus) and tragically for some the story ends with suicide. PTSD is generally treated with counseling and/or medication. Many Veterans will tell you that the Army’s “culture” makes it hard to admit to the symptoms and those in the VA treatment system feel that the disease is not taken “seriously” by the treatment community. Yet the fiscal costs for a lifetime of treatment of (most likely) hundreds of thousands of ex-soldiers are going to be staggering; of course, the cost in ruined lives is incalculable.

It is crucial not to jump to conclusions here. In science we often learn the hard way that correlation does not mean causation. But science is also not exempt from a fundamental law of nature: “where there’s smoke, there’s fire.” It is very possible that the continuous exposure to low level but frequent assaults on the brain that lead to CTE in boxers and football players is mimicked by the continuous exposure to explosions and low-level physical trauma to the head on the battlefield. If this were proven to be the case, then perhaps PTSD can be treated more as a physical issue, than purely a “psychological” issue, and hopefully with a great deal more success. Only time will tell.

We believe that the overlap of symptoms between CTE and TBI (traumatic brain injury), depressive disorders and hippocampal atrophy cannot be ignored. Scientists have known for a while now that there is hippocampal atrophy in depressed patients, and indeed in many other indications associated with cognitive loss. We now have the same link with these brain trauma-related indications. This month, Neuralstem is beginning its Phase Ib trial to treat Major Depressive Disorder (MDD) with NSI-189, a drug discovered by Neuralstem specifically to help heal and rebuild the human hippocampus. This discovery was made possible because Neuralstem alone has the technology that enables the growth and screening of human hippocampal neural stem cells in dishes. Ironically enough, this discovery effort was funded by the U.S. Department of Defense (for a very different purpose). We have approached the NFL and the DOD and the VA to suggest trials of NSI-189 at the conclusion of our Ib MDD trial, to see if we can treat these other indications with this novel first-in-class neurogenic drug. (We have finished a healthy volunteer safety trial; now we need to see that it is equally safe and side-effect-free in depressed patients).

Also, ironically, both the U.S. Army and the NFL have historically denied that there is a problem here that needs addressing on an institutional level. But that is clearly changing, and both groups appear now to be ready to go after these problems (no pun intended) head on. I hope that is the case, and I will keep you all apprised of the progress we make with them.