Friday, November 5, 2010

Brain Efficiency

I should preface this post with another post.  If you have a minute and you don't mind, have a look at Your Brain on Ketones.  The down low is that, for various reasons, a ketogenic diet (very low carb and high fat, or moderately low carb and high medium chain triglyceride, such as coconut oil), seems to allow our mitochondria (the cells' energy factories) to make energy more efficiently.  This ability is less important in our muscles (unless you are an elite athlete), but in our brain, which uses a ton of energy and relies on energy-expensive ion gradients to function properly, efficiency is paramount.  Never so much as when you are talking about a brain disorder, such as epilepsy, migraines, Alzheimer's, or, as in the case of the paper I'm referencing today, Parkinson's disease.

Parkinson's disease (PD) is another long-term degenerative brain disease, somewhat like Alzheimer's but with more prominent muscular symptoms and a different pathophysiology.  In Parkinson's, the little cells that make dopamine, a major neurotransmitter, in the substantia nigra seem to slowly die off.  Without dopamine fueling your brain you get tremor, dementia, muscular stiffness, depression, and eventually death.  There are some genes known that predispose for Parkinson's, but most cases are idiopathic, meaning no one knows why the disease strikes a certain person and spares another.

Exposure to a certain pesticide, rotenone, and welding does increase risk of PD.  Rotenone works by inhibiting the proton pumping complex 1 in the mitochondria (okay, the biochemistry of the mitochondria is complicated but fun.  The whole point of the mitochondria is to generate the gasoline of the body, ATP, and mitochondria do this by pumping protons up gradients via several complexes, "proton pumping complex 1", etc.  Think of the proton pumping complexes as ski lifts carrying skiers up to the top of the hill, where they are set loose to glory in the thrill of gravity.  So rotenone is a hater of snowy fun and shuts down the ski lift.)  Another inhibitor of proton pumping complex 1 is MPTP, famous for being an adulterant in synthetic opiates, and causing immediate irreversable Parkinson's disease, killing your dopamine-making neurons.  Don't do drugs, kids.

Caffeine and tobacco (which juice up energy efficiency) use seem to reduce the risk of PD.  So drink up that coffee!  (Don't smoke).

Our intrepid researchers took genetic data from 410 post-mortem brains with Parkinson's Disease and "healthy" controls.  They analyzed "6.8 million raw data points from nine genome-wide expression studies" (I *heart* geneticists), focusing on genes active within the substantia nigra.   They found several gene sets that seemed to cluster in the PD folks, and many of these genes seemed to be a part of the mitochondrial complex called the electron transport chain.  Part of the proton-pumps.  Part of the energy factories of the cells.  These 95 energy factory genes seemed to be "underexpressed" in Parkinson's sufferers.   That means the substantia nigra was suffering an energy shortage, so the cells that make dopamine went kaput, out of gas.

The researchers found a second set of genes that seemed to be associated with Parkinson's.  These genes affect glycolysis.  (Que?) Remember, the brain can't run on ketones alone.  Certain long nerve tendrils are too spindly to carry mitochondria.  Those spindly bits need to run on pure glucose.  Glucose becomes ATP directly via glycolysis.

 Glycolysis turns glucose into pyruvate, yielding several ATP along the way, and then pyruvate enters the citric acid cycle to become ATP.  Glycolysis is also part of how some anaerobic bacteria turn sugar into alcohol (called fermentation), so enjoy your biochemistry, preferably on the weekends.

Now we come to a third gene, PGC-1alpha.  I know I've already exhausted you, but carry on!  PGC-1alpha is a "master regulator of mitochondrial biogenesis and oxidative metabolism."  It seems to control protein-folding and direct proteins where to go in the mitochondria.  Underexpression of the PGC-1alpha gene was highly associated with Parkinson's Disease, and mitochondrial activity and ATP concentrations were severely decreased in the brain samples of Parkinson's patients.

All of these gene sets are associated with the energy efficiency of the brain cells, and were not only associated with Parkinson's, but also with Parkinson's precursor states, suggesting these are causative, not a result of whatever insult causes Parkinson's.

And then the researchers got very cute.  They fabricated a virus to infect rat brains, a virus that causes the overexpression of PGC-1alpha.  Then they exposed the rats to rotenone, the pesticide that causes Parkinson's.  With the extra PGC-1alpha, these rats seemed to be more immune to Parkinson's than the average rat exposed to rotenone.  Other researchers found that mice without any PGC-1alpha were more susceptible to the Parkinson's caused by the MPTP. 

And, finally, magnetic resonance spectroscopy of living Parkinson's patients shows that their brains seem to have more lactate on board than normal.  Meaning their brains are struggling with the metabolism of glucose and are running on anaerobic pathways instead.  When your brain seems to be running like fermentation bacteria, you have a big problem.*

It seems probable that the dopaminergic neurons of the substantia nigra need more ATP than most, so if your brain is inefficient, they suffer first.  Therefore a variety of genetic susceptibilities in the electron transport chain, glycolysis, and basic energy creation in the brain presents as Parkinson's disease first and foremost.

I'll quote the article here:  "If this hypothesis is valid, it would suggest that modulation of cellular energetics could be used to prevent or treat PD, and that monitoring cellular energetics could serve as a diagnostic tool."

The only way I know to modulate brain energetics is to avoid carbohydrates or drink down a lot of coconut oil. (You can only drink so much coffee, but I thought of some more ways to modulate energy use in the mitochondria, which will be the next post.)

Food for thought!

*There's lactate again.  More on that in a future post too.


  1. First, rats are not mice, mice are not rats! Grrr! (off my soapbox now.)

    Second, three cheers for reduced carbohydrates AND lots of coconut oil!

    Third, do NOT live near an agricultural zone. You'll be exposed to LOTs of pesticides. There are four emeritus faculty in the Behavioral Neuroscience area of the Psychology department at UCLA who are now in their 70s or 80s. One is from Brooklyn, NY, the other three are from the midwest and grew up in rural/agricultural areas. All three of the rural faculty developed PD. The guy from Brooklyn is still sharp as a tack (and still has a thick Brooklyn accent). Things that make you go hmmm...

  2. Hi Aaron - I know that rat/mice paragraph is confusing, but the rotenone study was done in rats and the MPTP study was done in mice. I'm pretty sure. Now you've got me paranoid and I'll recheck the per tomorrow morning... But not tonight. Chris Kessler's post on toxins brushed on the fact that "toxins" reduce mitochondrial efficiency in general, leading to diabetes and other nastiness.

  3. According to this study, BCAAs can make the ketogentic diet more effective.

    Branched chain amino acids as adjunctive therapy to ketogenic diet in epilepsy: pilot study and hypothesis.

    A pilot prospective follow-up study of the role of the branched chain amino acids as additional therapy to the ketogenic diet was carried out in 17 children, aged between 2 and 7 years, with refractory epilepsy. All of these patients were on the ketogenic diet; none of them was seizure free, while only 13 had more or less benefited from the diet. The addition of branched chain amino acids induced a 100% seizure reduction in 3 patients, while a 50% to 90% reduction was noticed in 5. Moreover, in all of the patients, no reduction in ketosis was recorded despite the change in the fat-to-protein ratio from 4:1 to 2.5:1. Although our data are preliminary, we suggest that branched chain amino acids may increase the effectiveness of the ketogenic diet and the diet could be more easily tolerated by the patients because of the change in the ratio of fat to protein.

    PMID: 19687389

  4. Oh, I see. So often people switch willy nilly between the terms "rat" and "mouse" that I get a bit of a trigger finger on the subject. Back when I was an anthropology student I used to go off on folks who referred to chimps and gorillas as monkeys instead of apes. I've let that battle go a long time ago and should do the same with the rat/mouse distinction as well. I mean in the grand scheme of things it doesn't amount to more than a hill of beans (and we know how bad beans are towards human health!). (Beans and grains are bad for your heart, the more you eat the more you fart, the more you fart the worse you feel, so skip beans and grains and let your gut heal.) Oye, it's late.

  5. Tee hee - the battle chant of the Ancestral Health Society.

    Richard - interesting paper. I knew my weekly whey protein smoothie was good for me... Actually, the more I learn about nutrition, the more Martin from Leangains seems scarily on point about every last thing related to metabolism. He's a BCAA fan.

  6. Don't know if youve seen this study before but ketosis increases capillary density in the brain ( rat brain atleast )

    Whats interesting is, what happens if we extrapolate backwards? Could the low concentration of blood ketones produced by a high carb diet actively reduce brain capillary density?

  7. i think a good diet provides PLENTY of BCAA's, getting them supplemented will prolly cause 'supplemented results' in the long run, kind of like body puilders are nown to get diabetes(which i think is excessive protein powder)...

    anyway, looks like i should get back on to coconut oil, bleh i dont like it much i use it pobnoxiously on my skin and hair though, and smokw and drink coffee lol

  8. "Don't do drugs, kids."

    Funny you are saying this as a psychiatrist.

    For a real life story of what is happening with kids brains these days :

    My advice (and experience) for kids : go easy on the bread/pasta/cereal/soda, throw epsom/dead sea salt in their baths, serve fresh fish twice a week, sneak some liver/bone broth in their soups
    and you'll have happy and behaving children...

  9. Kindke - cool link - thanks.

    Malpaz - yeah, I agree real food is king. I skip breakfast probably 3x a week, eat eggs the other days, and once a week usually a smoothie but more for variety than anything.

    Anya - I'm not a child psychiatrist. It's a tough call - what would I do for my kids if I suspected ADHD? Would definitely go for a pure paleo diet, make sure they were sleeping well (recent study in an ENT journal showed that a bunch of kids who shored stopped their "oppositional" and "ADHD" symptoms after having their tonsils and adenoids removed). Behavioral treatment of course. But we are also looking at an inefficiency of dopamine transport in a number of cases - genetic or due to mom's serotonin deficiency while in the womb. And untreated kids with ADHD are much more likely to have substance abuse, car accidents, and to have committed a felony by the age of 21. It is a serious condition with clear pathophysiology and not an invention of the drug companies. No judgments can be made except on a case by case basis.

    1. I completely appreciate your reasonableness about the risks inherent in ADHD, even as you rightly report on the other ways we can help our kids and ourselves through nutrition. People have questioned my child's use of psychostimulants, citing potential risks. My only response is to say that the risks of not taking medication are too great.

  10. What do you think about the acetyl carnitine/lipoic acid formula defeloped by Dr. Amen See Thanks.

  11. I've seen reports that lipoid acid is a very effective antioxidant, so combining ti with carnitine seems like a cute idea. I haven't seen any evidence of the particular combo, however, and I have no idea of possible risks.


    Point of clarification - is it coffee or caffeine that have reduced the risk of PD? Our nutritionist recommended avoiding caffeine (many ill effects) but drinking decaf coffee.


