Wednesday, August 17, 2016

Ketones, TBI, and brain function


I'm not a doctor of any sorts.  Hell, I didn't even stay at a Holiday Inn Express last night.  In fact, on my trip back home to see my family we ended up staying at the Hampton Inn on two separate occasions (which promoted fat baybay to say on the drive home "we better not stay at another freaking Hampton Inn!").

Nevertheless, I read an enormous amount of studies and research articles to do my best at understanding the various facets of hypertrophy, nutrition, and of course as of late, all the benefits that come with the intake of exogenous ketones.

I've documented much of the success I've had with them in regards to physique competitors in the depleted stages of contest prep.  I've used them to help people get over nagging injuries, and even helped people overcome hypoglycemia with them.

But as of late, the one area I've spent the most time reading about in regards to them, is how they function in regards to those that have suffered a traumatic brain injury, or TBI.

The reason for this is because it has become a serious issue with players in the NFL.  And from my outside view, the league has done very little to actually address the seriousness of the issue.

Let me be clear here about one of my biggest problems with the NFL before I delve into this.

I abhor the NFL's policies on performance enhancement drugs.  But all the while having no problem prescribing narcotic drugs to their players, some of who end up with serious addiction and dependency issues on them well after their careers are over.  I'm going to put on my tin foil hat here and just take a stab that the NFL somehow is in cahoots with big pharmacy from a financial perspective.  I mean it just makes too much sense to me.

We can't have players taking growth hormone, or peptides.  Which have been proven to speed up healing and would get them back on the field faster.  But it's fine to load them up with a various cocktail of drugs that numb them down but don't actually address the problem causing the pain.  Players know their livelihood depends on playing, and playing at a high level.  So they will do whatever it takes, and play through a litany of injuries to keep their jobs because they are all aware that their time in the league most likely, is going to be very short lived.  The average NFL career I believe, is a little less than three years.  So if a guy is always in the trainers room, he won't be on the roster for very long.

The NFL has made some rules now about players and concussions.  As they are required to leave the field and get clearance before they can return to play.  However, even if the doctor rules they can't return to play that day, it doesn't take away the fact that the player is going to deal with the aftermath of said concussion.

Even worse, by the time a guy reaches the NFL, it's very likely he's already suffered concussions all the way from high school, through college.

There's actually a list of former players who, upon post post-mortem inspection, were found to have suffered from something called chronic traumatic encephalopathy, or CTE.

From wiki..........

Chronic traumatic encephalopathy (CTE) is a progressive degenerative disease found in people who have had a severe blow or repeated blows to the head. The disease was previously called dementia pugilistica (DP), i.e. "punch-drunk", as it was initially found in those with a history of boxing. CTE has been most commonly found in professional athletes participating in American football,rugby, ice hockey, boxing, professional wrestling, stunt performing, bull riding, rodeo, and other contact sports who have experienced repeated concussions or other brain trauma.

This hits slightly home with me, because one of the players who was diagnosed with CTE was a friend of mine.  Jovan Belcher.  The middle linebacker for the Chiefs, who was involved in a murder-suicide.  He killed his girlfriend at the time, then drove to the Chiefs facility where he shot himself.

Junior Seau, the all time great for the San Diego Chargers, shot himself in the chest, so that his brain could be examined.  



On January 10, 2013, Seau's family released the NIH's findings that his brain showed definitive signs of CTE. Russell Lonser of the NIH coordinated with three independent neuropathologists, giving them unidentified tissue from three brains including Seau's. The three experts along with two government researchers arrived at the same conclusion. The NIH said the findings on Seau were similar to autopsies of people "with exposure to repetitive head injuries."

Seau had no prior reported history of concussions.  Junior was a football warrior.  Anyone that ever watched him play knew the kind of wreckless abandon he played with and he was admired and feared as a tenacious player.  But in the end, his brain just couldn't take the damage that had been caused by all the human car wrecks he had subjected himself to.  

Neither Jovan or Junior are alone in this regard.  All it takes is a google search to find all of the players whom, upon autopsy, suffered from CTE.  

Sports related concussions occur when there is a sudden acceleration or deceleration or rotational forces imparted to the brain.  The connection between TBI and CTE is clear.  CTE is caused by those who have suffered repeated concussions or traumatic brain injuries, such as those in contact sports, and even our military personnel.  

http://www.protectthebrain.org/Brain-Injury-Research/What-is-CTE-.aspx

The brain of an individual who suffers from chronic traumatic encephalopathy gradually deteriorates and will over time end up losing mass. Certain areas of the brain are particularly liable to atrophy, though other areas are prone to becoming enlarged.


The symptoms of CTE can be debilitating and may have life-changing effects for both the individual and for his or her family. Some of the most common include loss of memory, difficulty controlling impulsive or erratic behavior, impaired judgment, behavioral disturbances including aggression and depression, difficult with balance, and a gradual onset of dementia. An individual with CTE may mistakenly ascribe the symptoms to the normal process of aging, or might receive a wrong diagnosis due to the fact that many of the symptoms are similar to other conditions such as Alzheimer's or Parkinson's disease. CTE has been diagnosed in several notable cases which received widespread media attention, including the suicide deaths of NFL player Junior Seau, and professional wrestler Chris Benoit who committed suicide after murdering his wife and son.

Obviously,  this is a very disheartening thing to read.  And it's one of the reasons I detest when people start talking about how "watered down" the NFL has become because they don't allow people to "spear" people anymore, or lead with their head in tackling.  I mean, I played ball.  At no one was I ever taught to lead with my head in tackling drills.  The guy sitting on the couch drinking his Coors Light on Sunday afternoon complaining about how "pussy" the league has become, will never ever sit in a trainers room after the game wondering what his name is, where he is, or deal with the incredible migraines that come in the post concussive state.  

With all that said, one of the things I happened across when I became involved in using exogenous ketones was the fact that the brain uses ketones in a very preferable way for fuel.  

So what's the tie in here, you ask? 

During a TBI, glucose metabolism is depressed.  

Mild traumatic brain injury results in depressed cerebral glucose uptake: An (18)FDG PET study.



Moderate to severe traumatic brain injury (TBI) in humans and rats induces measurable metabolic changes, including a sustained depression in cerebral glucose uptake. However, the effect of a mild TBI on brain glucose uptake is unclear, particularly in rodent models. This study aimed to determine the glucose uptake pattern in the brain after a mild lateral fluid percussion (LFP) TBI. Briefly, adult male rats were subjected to a mild LFP and positron emission tomography (PET) imaging with (18)F-fluorodeoxyglucose ((18)FDG), which was performed prior to injury and at 3 and 24 h and 5, 9, and 16 days post-injury. Locomotor function was assessed prior to injury and at 1, 3, 7, 14, and 21 days after injury using modified beam walk tasks to confirm injury severity. Histology was performed at either 10 or 21 days post-injury. Analysis of function revealed a transient impairment in locomotor ability, which corresponds to a mild TBI. Using reference region normalization, PET imaging revealed that mild LFP-induced TBI depresses glucose uptake in both the ipsilateral and contralateral hemispheres in comparison with sham-injured and naïve controls from 3 h to 5 days post-injury. Further, areas of depressed glucose uptake were associated with regions of glial activation and axonal damage, but no measurable change in neuronal loss or gross tissue damage was observed. In conclusion, we show that mild TBI, which is characterized by transient impairments in function, axonal damage, and glial activation, results in an observable depression in overall brain glucose uptake using (18)FDG-PET.



http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652873/

In contrast to dietary approaches to re-establish TBI-induced deficiencies in brain metabolites, diets have also been used to replace or redirect essential brain substrates. TBI-induced impairments of the glucose metabolic machinery may make glucose a less favorable energy substrate. In fact, hyperglycemia has been long associated with poor outcome after TBI. Early administration of glucose after severe TBI suppresses ketogenesis, increases insulin and increases lactic acid production (Robertson et al., 1991). TBI patients who were fasted or maintained on a ketogenic-like diet to minimize hyperglycemia showed significantly lower plasma glucose and lactate concentrations, elevated ß-hydroxybutyrate levels and better urinary nitrogen balance compared to standard fed patients (Ritter et al., 1996). Similar plasma substrate changes were observed with 24-hr starvation in the adult rodent after controlled cortical impact injury. The fasted animals showed significant cortical tissue preservation, improved cognitive outcome and improved mitochondria bioenergetics (Davis et al., 2008).


As I've had to read through all of these very, very scientific/medical studies, what I learned was that post TBI there is an immediate but transient elevation in cerebral glucose metabolism, followed by a prolonged period of glucose metabolic depression. The brain is metabolically flexible. So it has to ability to tab into various fuels for different needs.

For example, during fasting (not starvation, but fasting!) two thirds of the brain fuel is derived from ketones. The rest come from lactate, pyruvate, amino-acids, glycerol and other gluconeogenic precursors.

Post TBI, we have seen in studies on rats (and humans) that there is a tremendous demand for energy to restore homeostasis. To repeat myself, there is a depression in glucose metabolism during this period. Meaning, the brain cannot use glucose as needed in order to meet the demands required for said repair. This is something seen in studies over and over again.  

So where does it try to derive fuel from? 

Apparently, lactate and ketones.

TBI-induced impairments of the glucose metabolic machinery may make glucose a less favorable energy substrate.

But what I found interesting, is that the brain had no problem using ketones and lactate as the fuel sources to help return it to homeostasis, and that the ketones also had neuroprotective effects after a TBI had occured.


Whether ketosis is achieved by starvation or administration of a ketogenic diet, the common underlying conditions of low plasma glucose in the presence of an alternative substrate (ketones) have consistently shown neuroprotective effects after various types of brain injury.

Allow me to lead you down a rabbit hole for just a second, but I promise I'll round you back to the main point in all of this eventually.  


A dietary therapy for pediatric epilepsy known as the ketogenic diet has seen a revival in its clinical use during the past decade. Although the underlying mechanism of the diet remains unknown, modern scientific approaches, such as the genetic disruption of glucose metabolism, are allowing for more detailed questions to be addressed. Recent work indicates that several mechanisms may exist for the ketogenic diet, including disruption of glutamatergic synaptic transmission, inhibition of glycolysis, and activation of ATP-sensitive potassium channels. Here, we describe on-going work in these areas that is providing a better understanding of metabolic influences on brain excitability and epilepsy.

I bolded that part for a reason.  Because it is related to the cascading issues that come with brain injuries.  

Glycolysis and TBI - 

The postinjury period of glucose metabolic depression is accompanied by adenosine triphosphate decreases, increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase (a key glycolytic enzyme) via depletion of the cytosolic NAD pool. Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism.

ATP and TBI - 


http://dmm.biologists.org/content/6/6/1307

Glucose is the primary fuel source of the adult brain and its processing through the glycolytic pathway provides carbons for the tricarboxylic acid (TCA) cycle for energy production in the form of ATP. 

Comparison of glucose metabolic changes in TBI between different age groups within the pediatric population, or a comparison between adults and children, has not yet been made in humans. Regardless of age, the prolonged glucose metabolic depression reflects a period of time during which glucose uptake into the brain is compromised. This could cause downstream negative effects if the energy demands of the brain are not sufficiently met.


Pyruvate dehydrogenase (PDH) is the enzyme that connects the glycolytic pathway to the mitochondrial TCA cycle. Phosphorylation of the E1 subunit of PDH, which inhibits PDH function and therefore carbon entry into the mitochondria, has been shown to occur at a higher frequency than normal at 24 hours after CCI injury (Xing et al., 2009). These TBI-induced alterations in glycolytic enzyme functioning ultimately decrease the ability of glucose to be efficiently processed for oxidative metabolism, and thereby contribute to the post-TBI energy crisis, reflected by reductions in ATP production (see poster, panel D).




Free radicals and inflammation - 

The other issue involving TBI is the increase in both inflammation, and free radicals.  


In addition to increasing ATP production while reducing oxygen consumption, ketone body metabolism can also reduce production of damaging free radicals [14,16,48]. The semiquinone of Q, the half reduced form, spontaneously reacts with oxygen and is the major source of mitochondrial free radical generation [14,51]. Oxidation of the Q couple reduces the amount of the semiquinone form thus decreasing superoxide production [14]. Since the cytosolic free NADP+/NADPH concentration couple is in near equilibrium with the glutathione couple, ketone body metabolism will increase the reduced form of glutathione thus facilitating destruction of hydrogen peroxide [14]. The reduction of free radicals through ketone body metabolism will also reduce tissue inflammation provoked by reactive oxygen species. Thus, ketone bodies are not only a more efficient metabolic fuel than glucose, but also possess anti-inflammatory potential.

Ok so where am I going with all of this?

First off, despite the fact that death via TBI is a major issue in this country, and a major issue in contact sports, believe it or not it's not at the forefront of research in regards to finding the most effective therapeutic solutions for it.  

What we have, for the most part, is a lot of research done on rats, and some research done on humans.  This is quite puzzling to me because TBI is, once again, a major cause of death in the world.  

But even if someone doesn't die, the amount of damage done after repeated bouts of TBI like in Rugby, boxing, football, hockey, etc means that those athletes tend to live an exceptionally poor quality of life after sports. With many, such as Jovan and Seau actually resorting to suicide.  

I'm not saying that exogenous ketones will fix all the problems associated with TBIs.  But if you look at the fact that they reduce free radicals, reduce inflammation, and provide the brain with a more preferred fuel source while glucose metabolism is depressed, then I can't understand for the life of me why more people who are responsible for the health and well being of our pro athletes aren't at least including exogenous ketones as part of dietary therapy for their players who have or do suffer from brain injuries.  

What we're currently doing is not working.  And when you add up what evidence we do have, I do see promise in regards to the inclusion of exogenous ketones as part of therapy to help players suffer minimal damage in the post TBI stages.  

Or they can just keep feeding them prescription pills from big pharma.  That's clearly working.  /sarcasm.

If you want to learn more about exogenous ketones..........


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