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Mild Traumatic Brain Injury and my journey toward understanding it (7/2/07) Walk into a doctor's office with a list of complaints and you're almost sure to get some odd looks, and I sure got my fair share of them. I was just out of college and finally had time to look into a few things I thought were a bit odd but not quite worthy of the ER. I could hear high pitched noises that no one else seemed to such as fluorescent lights and dimmer switches, I'd feel like someone was drilling into my head, my eyes would burn on exposure to dim lights, I always seemed to be the first to smell some odd smell, and when tired I seemed to be pretty good at forgetting basic words like "chair", "sink", and "home". Such a list doesn't just happen to a person without something major going wrong such as a tumor. The MRIs didn't reveal one so what there wasn't much to go on except for the vague hunch I had that went back to a few concussions I had as a child. Without something solid, like a tumor, a diagnosis is hard and a doctor is forced to go hunting for the problem, sometimes through blind guesses alone. Since the concussions didn't seem likely we tried an allergist and then a neurologist, and eventually a few psychologists. I made marginal progress and found it hard to navigate "the system". A lot of doctors just didn't seem interested in helping me beyond keeping me in their office for billing purposes. I was continually being sent to specialists for everything under the sun, and then some. That entire time was a rollercoaster for me. The specialists would run down a list of problems, all with the end result of an early death or being completely insane. As I made my way through all of the tests, most of which seemed to have a needles or strange devices strapped to my head, I did a lot of reading. The first time I was told I should see a psychologist I was so worried I read the DSM-IV cover to cover in one sitting, which is a bit like reading an encyclopedia but one that only contained mental health information. Fortunately I was fine. Slowly progress was made. A Leahy neurologist tried an off label prescription for amitriptyline (Elavil) that had worked in similar cases in the past. The thing about these drugs is you have to build up and, if you want to quit taking them, peter off of them. Everything is done very slowly, and we won't really know if they are working or not for several months. Finally, after a few years without side effects the migraines went away. Why was the big question, and no one seemed to have the slightest clue! As a last ditch effort I got tested for an anxiety condition by another psychologist. After she had finished with me and told me, yet again, that I was sane, I broke down (no crying thankfully) and asked her to listen to everything and serve as an independent ear since the doctors were out of places to poke, stab, and/or scan. She patiently listened to me describe all of my symptoms and then out of nowhere made the observation that mentally I seemed fine, but that my body gets out of whack when I'm stressed, almost as though I have an anxiety condition but without the anxiety. She called it a "biological sensitivity to stress". So I did what any stubborn person would do and set out to become an expert... in my spare time of course! I wrote every doctor who had ever seen me asking for my medical records so I could get an idea of what had happened to me, what had been done already, and their thoughts over those times. I also read everything I could get my hands on, including:
Electronic resources ran the gamut but three stand out:
Of course at the time my reading plans weren't nearly as logical as I have laid out above, but slowly a picture began to emerge. The Rosetta Stone was a journal article from some doctors in Copenhagen published in 2004 concerning that off label prescription that got rid of my headaches. In it the doctors prove amitriptyline's headache suppressing ability isn't due to its effect on serotonin (called 5-HT in the article), which is why it is used as an antidepressant, but to something as yet unidentified. Like any good journal article of this type the authors closed with further research hints:
"This suggests that the analgesic effect of amitriptyline in CTTH is not solely due to 5-HT reuptake inhibition and that other mechanisms such as norepinephrine reuptake inhibition, NMDA receptor antagonism, blockade of muscarinic receptors and ion channels should be addressed in the future research."
Aha! Direction! The information on the NMDA receptors proved to be the watershed event:
"Amitriptyline and clozapine at 10 mumol/l both decreased the maximum effect of NMDA by around 17%, but left its EC50 unchanged. This suggests a "classical" non-competitive antagonism and excludes an uncompetitive or "use-dependent" antagonism. Considering the important role of NMDA receptor-mediated effects in spinal nociception the analgesic properties of tricyclic antidepressants may partly be explained by their inhibitory action on spinal NMDA receptors, in addition to their enhancement of monoaminergic transmissions in the dorsal horn."
This is where all of that background material proved useful. After some digging it was apparent all of these articles are looking into the mechanisms of pain surrounding a theory known as "Central Sensitization". First described in a Nature article in 1983, Dr. Clifford J Woolf outlined his theory which would shortly come to be known as "Central Sensitization" (CS):
"Because sensitization of peripheral receptors [nerves in the arms, legs, etc. -JRW] occurs following injury, a peripheral mechanism is widely held to be responsible for post-injury hypersensitivity. To investigate this I have now developed an animal model where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man. Electrophysiological analysis of the injury-induced increase in excitability of the flexion reflex shows that it in part arises from changes in the activity of the spinal cord. The long-term consequences of noxious stimuli result, therefore, from central as well as from peripheral changes."
Woolf has a good synopsis of pain hypersensitivity, of which CS plays a part, on the Wellcome Trust website:
"Pain systems need to be sensitive enough to detect potentially harmful stimuli. But often they become too sensitive, causing us pain that provides no benefit. This hypersensitivity arises because our pain pathways actually increase in sensitivity when they relay pain messages, and the mechanisms of this sensitization are beginning to be revealed." ...
The main mechanisms feature some medical terms that should sound familiar: NMDA and Cox-2, along with AMPA, Substance P, and dynorphin. Quite a lot of them, NMDA included, center on a system in the brain called the "glutamatergic system" which features the neurotransmitter glutamate. Here are some examples of places this theory is being applied:
"Both glutamate release from stimulated platelets and plasma concentrations of the amino acid were assessed by high-performance liquid chromatography, and were increased in both types of migraine, [with aura, MA, and without, MoA] although more markedly in MA. Platelet glutamate uptake, assessed as 3H-glutamate intake, was increased in MA, while it was reduced in MoA with respect to the control group."
"We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. ... CSF [cerebrospinal] glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chronic migraine patients."
"Of the former players, 61% sustained at least one concussion during their professional football career, and 24% sustained three or more concussions. Statistical analysis of the data identified an association between recurrent concussion and clinically diagnosed MCI [mild cognitive impairment] (chi = 7.82, df = 2, P = 0.02) and self-reported significant memory impairments (chi = 19.75, df = 2, P = 0.001). Retired players with three or more reported concussions had a fivefold prevalence of MCI diagnosis and a threefold prevalence of reported significant memory problems compared with retirees without a history of concussion. Although there was not an association between recurrent concussion and Alzheimer's disease, we observed an earlier onset of Alzheimer's disease in the retirees than in the general American male population."
The topic of Alzheimer's brings up and important aspect of this discussion. The mechanisms we are focusing on are just that, mechanisms. CS doesn't guarantee a person will get any or all of these things, nor does it completely explain all of the diseases, disorders, and symptoms we broached earlier. It does go a long way towards explaining them. Alzheimer's clearly has something else going on that produces the plaque in the brain, but since it is such a widespread disease there are drugs for it that should help anyone with these sort of medical problems. As an example, memantine (Namenda), a drug approved for Alzheimers and not much else, is a strong NMDA receptor antagonist, the same mechanism by which amitriptyline helps me by reducing glumate levels in my brain. It also targets serotonin and choline. Interestingly, looking at a person's glutamate and choline levels shortly after major head trauma can directly predict their outcome:
"We found that glutamate/glutamine (Glx) and choline (Cho) were significantly elevated in occipital gray and parietal white matter early after injury in patients with poor long-term (6-12-month) outcomes. Glx and Cho ratios predicted long-term outcome with 94% accuracy and when combined with the motor Glasgow Coma Scale score provided the highest predictive accuracy (97%)."
Why? Paradoxically, while glutamate serves an essential role in the brain it is also a neurotoxin! Increase the amount too much and neurons die. With Central Sensitization the levels of glutamate will fluctuate more, and have a higher average amount of it in the brain and spine. Now perhaps it's easier to see why we see the neurological deficits we see in people with brain damage and the other problems we've touched on. Sadly cat scans and MRIs aren't capable of seeing this sort of damage and so it is commonly missed. There are many sources of hope however:
Many mysteries remain and will continue to for some time, however we are making progress. If you know of anything noteworthy along these lines please feel free to contact me and I will mention it here.
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