Head conditioning in the martial arts requires repeated strikes to the head with objects of various sizes, weights and densities. Students of this discipline start with relatively soft objects and progress to using objects of higher density and strength, all with the desire to "condition" their heads to be able to absorb strikes of varying intensity. Conditioning can result in the increased deposition of calcium and bone in the forehead, however, there are no capabilities for the soft tissues of the brain to increase their capacity for trauma. Repeated blows to the head take their toll on the neural tissue underneath the skulll.
There has been much written in the medical literature about the concept of repeat concussion, now one of the major topics of discussion especially in the world of football, where repeated blows to the head are commonplace. Complications such as post concussion syndrome, traumatic encephalopathy, psychiatric issues such as depression and anxiety, among other things, are now being discovered among those who suffer from repeated injuries to the brain.
This compilation of material that follows is from a recent medical study that actually quantified the injuries that occur after concussion and repeated episodes of concussion, using the evaluation of levels of N-acetylaspartate using proton MR spectroscopy. Historically, evaluating damage done during repetitive concussive episodes was usually done at autopsy. These authors discovered a technique to quantify, and examine, the level of damage incurred during repetitive concussions, and quantified various time periods pertaining to such, with regard to time and severity. Highlights of the study are quoted below. Italic highlights are my own.
Biochemical and Neurochemical Sequelae following Mild Traumatic Brain Injury: Summary of Experimental Data and Clinical Implications
Stefano Signoretti, M.D., Ph.D., Roberto Vagnozzi, M.D., Barbara Tavazzi, Ph.D., Giuseppe Lazzarino, Ph.D.
Nov 29, 201
Mild TBI and the Hypothesis of Postconcussive Brain Vulnerability
With the exception of the reversibility of the modifications induced by mTBI (mild traumatic brain injury), it was not clear to us what was "mild" about a traumatic event that can have such consequences to the fundamental metabolic and energy states of neuronal cells.
The legitimate and natural objection to this "gloomy" view is that, in spite of everything, animals and patients with mTBI show no or minimal focal neurological problems and all show a radiologically normal brain. In other words, all these biochemical modifications are rather interesting but clinically of negligible utility just because they are all spontaneously and fully reversible.
There was, however, an initial reasonable body of evidence suggesting that the "concussed" brain cells undergo a peculiar state of "vulnerability" for an undefined period of time, during which if they sustain a second, typically nonlethal insult, they suffer irreversible damage and die.
Fascinated by this original hypothesis from Hovda and colleagues at the University of California, Los Angeles, we undertook, as a next step in our research, an analysis of the neurochemical and metabolic effects produced by 2 consecutive concussive mTBIs, the second injury occurring at different intervals from the first, to investigate how the temporal gap between traumatic events could influence the overall severity of injury. We used the same impact acceleration model and applied a new and easily reproducible protocol to simulate a "second impact" condition in rats. Neuronal injury was quantified by HLPC measure of whole-brain NAA concentration with the synchronous assay of whole-brain ATP and ADP concentrations and consequent ATP-to-ADP ratio (an indirect indication of mitochondrial phosphorylating capacity). Animals were randomly assigned to one of the following experimental groups: sham-injured; single mTBI; single sTBI; 3-day interval "double mTBI"; 5-day interval "double mTBI."
(Two fundamental findings brought N-acetylaspartate (NAA) to the attention of neuroscientists in general, dramatically accelerating the pace of research into the neurochemistry and neurobiology of this unique molecule. The first of these findings was that NAA is the most prominent compound detectable with proton MR spectroscopy in the human brain, making it one of the most reliable molecular markers for proton MR spectroscopy studies of the brain. The second was the connection to the rare but fatal hereditary genetic disorder known as Canavan disease.
Although the exact role of NAA remained to be established, brain NAA was found to be present in concentrations a hundred-fold higher than NAA in nonnervous system tissue, and it was therefore considered a brain-specific metabolite [54,82] and an in vivo marker of neuron density. Unfortunately, spectroscopic studies have dramatically outnumbered studies into the basic biochemistry of NAA, and this disparity has complicated the interpretation of proton MR spectroscopy results in various diseases due to a lack of basic knowledge of NAA function and metabolism. A decrease in NAA levels has been observed in many neurological diseases that cause neuronal and axonal degeneration such as tumors, epilepsy, dementia, stroke, hypoxia, multiple sclerosis, and many leukoencephalopathies. More generally, any major CNS disease involving either direct neuronal and axonal damage or secondary hypoxic-ischemic or toxic insult will result in abnormalities in the proton spectrum. )
We were astonished by the observation of an identical 10% mortality rate in animals subjected to sTBI (severe traumatic brain injury) and animals doubly injured by mTBI with a 3-day trauma interval, whereas no animals died when subjected to a single mTBI or double-impact mTBI with a 5-day interval.
After the second mTBI, delivered 5 days after the first, NAA decreased by 17%, a reduction not significantly different from that observed following a single mTBI. When the second trauma occurred after 3 days, however, the NAA revealed a further 43% reduction when compared with the 5-day interval, a value not statistically different from the dramatic reduction observed in severe injury, in which NAA decreased by 47% versus controls and by a further 37% versus rats subjected to a single mTBI. These findings were interesting because, at least according to the experimental model adopted, 2 consecutive mTBIs occurring within the shortest interval of time considered for the study (3 days) produced the same biochemical damage observed after sTBI. In particular, neuronal distress, indicated by reduction of NAA levels, doubled when compared with that observed after a single mTBI.
Energetic metabolites showed a very similar trend. In single mTBI, the levels of ATP and ADP and the ATPto-ADP ratio varied by a value not significantly different from animals in which the second trauma was delivered 5 days after the initial one. In contrast, animals with a second mild injury 3 days after the first exhibited severe energetic imbalance, showing a 50% drop in ATP levels and very low (-70%) ATP-to-ADP ratio, reductions almost identical to those seen after sTBI.
These data provided the experimental demonstration of the exquisitely metabolic nature of the "brain vulnerability" after mTBI, and offered a contribution to the understanding of the complex biochemical damage underlying the clinical scenario of a repeated concussive trauma, sometimes leading to catastrophic brain injury. Most importantly, it was evident that when the second injury took place after a longer interval, recovery of the energetic imbalance was completed and the 2 traumatic insults acted as independent events, the additional injury simply representing a new "mild" event.
Similar data were reported just a few months before these findings by Laurer et al. in a study describing important cumulative effects of 2 episodes of mTBI (24 hours apart) in mice, which led to pronounced histopathological damage compared with animals sustaining only a single trauma. The authors' conclusion was that although the brain was not morphologically damaged after a single concussive insult, its vulnerability to a second concussive impact was dangerously increased.
According to Hovda and colleagues, metabolic alterations can persist for days after concussion, creating no morphological damage, but representing the pathological basis of the brain's vulnerability. In our study, after a single mTBI, we found a 22% reduction in ATP levels; although neither histological nor behavioral abnormalities have been described with this model, these data confirm that energy recovery was incomplete. The ADP levels did not increase because, despite significant ATP depletion, mitochondria were not yet irreversibly damaged, possessing a sufficient phosphorylating capacity to allow spontaneous full restoration of ATP levels, which was complete after approximately 5 days. A profoundly different situation was observed in sTBI, with a 50% decrease in ATP levels and 35% increase in ADP levels, indicating altered capacity of mitochondria to support the cell energy requirements in terms of ATP synthesis.
When the second mTBI was delivered during the aforementioned restoration period, it caused further mitochondrial malfunctioning leading to the same energetic failure observed in severe injury. It could be concluded that 2 mTBIs that occur too close in temporal proximity simulate the effects of a severe injury, and that one of the biochemical bases of the vulnerable brain is the incomplete overcoming of the initial reversible energetic crisis, triggered by the first insult.
The first striking clinical implication of these experimental data was that the metabolic effects of 2 consecutive concussions occurring within a period of days can be dangerously additive. This information might not be surprising, but similar human data regarding brain metabolites were not available.
The further clinical implications of these findings are also remarkable: because it is very difficult to establish how long the above-described period of brain vulnerability will last, one cannot predict the time point at which a second trauma would be uneventful.
The results clearly showed that after a concussion, despite normal radiological appearance and complete resolution of clinical symptoms, substantial neurochemical abnormalities were present in the injured brain and readily detectable by measurement of NAA using proton MR spectroscopy. As repeatedly observed in the laboratory, NAA decrease in concussed athletes was seen to be a dynamic process, still detectable 15 days after a concussion; its restoration over time appeared to be nonlinear (slow recovery in the first 2-week period, followed by fast recovery until normalization in the next week), and it was profoundly influenced when a second concussive insult occurred during the recovery process, lengthening the NAA normalization curve and causing a significant delay in symptom resolution. Although none of the players who experienced a second concussion in this study suffered from SIS or showed signs of sTBI, all demonstrated a more severe clinical picture, somehow not proportional to the concussive insult.
Most likely, the second concussion occurred when the brain cells were completing the recovery process and, thus, it only produced a limited cumulative effect with a moderate worsening of the expected clinical and biochemical consequences. The severe brain swelling observed in SIS is attributable to the fact that the second insult must take place when the cells are experiencing their maximum distress (oxidative, neurotoxic, mitochondrial, genetic), are still intensely engaged in restoration of their energetic integrity, and therefore are unable to withstand further energetic expenses, thus experiencing uncontrolled swelling.
Mild TBI is a relatively "neglected world" from a research point of view, especially because it is very difficult to accurately reproduce it in laboratories. Trauma is directly responsible for sudden biochemical changes occurring at the time of impact, and the severity of brain insult can be graded by measuring these biochemical modifications—specifically, ROS-mediated damage, energy metabolism depression, alteration of gene expression and ultimately variation of NAA concentration, a surrogate marker of neuron dysfunction.
Within days after injury, this complex biochemical derangement can result in a dangerous state for the brain, generating a situation of metabolic vulnerability, to the point that if another, equally "mild" injury were to occur, the 2 mTBIs would show the biochemical equivalence of an sTBI. The immediate clinical implication derived from the growing body of experimental evidence is that trials are warranted to investigate the application of proton MR spectroscopy for measurement of NAA and for monitoring the full recovery of brain metabolic functions.