Some Thoughts and Some Tchaikovsky

Certain composers seem to be able to understand the music that floats in the air between molecules, the music that describes the light, wind, war, and love. Tchaikovsky can be a bit too romantic, as the Russian composers were apt to be (a writer would call it purple prose), but in my mind there are few better songs than the 1812 Overture (right click in new tab to listen without leaving this page - this is the first part). A lot of folks dig the finale with the cannons and the fireworks, but my favorite part is the beginning choral and its recapitulation in brass just before the cannons start going off. When I listen to the 1812 Choral, I feel that Tchaikovsky translated a spirit, a meme, a truth, and that when it is over, I understand something more about being human.

In some respects, that is the lofty goal of this blog. What does it mean to be homo sapiens? How do we nurture a human, how do we heal? Since I have no patience for philosophy, I work in biology and biochemistry with a hint of practical psychology thrown in.

My style is to think out loud in blog form (such a wretched word, "blog," sounds like some sort of mucousy allergy problem). Some of the ideas are early, not fermented as it were, and I will likely change my mind about some things over the months. There are so many unknowns - it can get frustrating when you realize how much money, effort, and time have been spent looking at nutrition, metabolism, and mental health in such a way as to discover nothing at all.

But there is exhilaration too, especially in the sharing of ideas, and to have (if someone wants to listen) an enhanced ability to heal. Myself, my family, my patients.


Here is the 1812 Finale.

I don't believe in magic cures. I agree wholeheartedly with this post on PaNu, about looking for that next secret, the next hack, the next way to measure your increments of success other than feeling better, lifting better, running faster or farther, and the pantsometer. Just eat well, get some sleep, play (outdoors if possible) and worry about the tablespoons of coconut oil when everything else is locked into place. Sometimes we are broken, and modern medicine can actually help with the fix. Sometimes we are broken, and there is no perfect fix.

It always settles me a bit when I find myself in agreement with Kurt Harris. Mostly because I can tell he thinks about things. He reads and sits back and asks some questions and reads some more and he thinks about it again, and then he posts. He is not as even-tempered as Stephan Guyenet, but if he jumps at being questioned, I'm pretty sure it is because he's done the time, the reading, and the thinking.

Sometimes I post first and think about it later. A different process, and in some ways a more prolific but scattershot result. And I believe the most important aspect of a "paleolithic-style" diet is the avoidance of inflammatory load. Not too much fructose, as little gluten as possible, and keep the PUFAs minimal with enough omega 3 to more or less balance the 6, and avoid all the fake food out there. My obsession is not with what exactly goes in the mouth but how the possible toxins meet the gut, the immune system, and the brain.

The audience for this blog grows and grows. It has tripled in the last three months or so, and given the growing interest and intrinsic common sense of the traditionalist/paleo diet movement, I imagine it will only get bigger. The concept is simple, the proof of concept a lot of work, especially when only a few of the researchers are asking the sorts of questions that will yield (or not) the answers we are looking for.

The picture below is of my great-grandmother, by all accounts an extraordinary woman who graduated from Vassar with a degree in Botany. She married a publisher and died at the age of 34. Her early passing I believe cast a shadow on my family that continues in some respects to my generation.

I'm tired of illness caused by bad advice, corrupt motivations, and incompetence. I love the study of medicine and the human mind. I read and I listen to find that truth, that meme, that whisper of the mathematical dance of molecules through the gut, the bloodstream, the brain. The spark of thought and what might strangle it or snuff it out. And that is the story of my blog thus far.

Food Elimination Diet and ADHD

There is little argument that diet has a contribution in the major diseases of civilization, such as heart disease and type II diabetes.  However, the effect of diet on mental health disorders remains controversial in the conventional circles.  I'm not entirely clear why, as it has been known for a decade or more that different kinds of inflammation mediate both metabolic syndrome and the depressive disorders and schizophrenia.  It seems logical to me to look for dietary or environmental insults that would predispose one to develop these disorders, and not just in fringe journals, or Australia.

But then, I also think it is logical that our immune systems are responsible for heart disease and high cholesterol, not that our livers (in a desperate effort to do us in) release cholesterol into the bloodstream to clog our arteries like an old sock dropped into the disposal.  The reason I find the immune system to be a logical culprit is that the whole purpose of the immune system is to KILL THINGS and wreak havoc.  Sometimes your general turns tables on you.  Way of the wild.  But I'm rambling.

ADHD in children.  Controversial, of course, as stimulants are a primary treatment.  The controversy looms large in part because behavior is primarily felt to be a parental/discipline problem.  And there has always been the idea that "sugar" makes kids "hyper" - so we have this cultural meme of lazy parents and spoiled kids chowing down on skittles and garbage, driving the teachers nuts - the teachers, being lazy themselves, want the kids medicated into oblivion so that no one will have to do any work (especially, presumably, the psychiatrist, who happily prescribes addictive drugs in a 4 minute visit to keep the families coming back and to collect a large paycheck.)  Do we really live in a world where everyone entrusted to keep our kids safe and happy is hopelessly lazy and corrupt?  Because if the cultural meme is true, we are screwed.

Let's get to reality, where families really suffer with the disorder, and teachers want kids to do better, and doctors try to spend some time in multifaceted ways to help.  ADHD is a recipe list of symptoms - hyperactivity and inattentiveness being primary.  Part of the issue is the stupid recipe list - ADHD symptoms are a function of problems with the frontal lobe of the brain, and while several neurotransmitters are involved, an inefficiency of dopamine transmission may be the key player.  And, indeed, there are some families with lots of ADHD who have known genetic issues with their dopamine receptors.   There.  Simple.  It's dopamine.  A kid has the symptoms, hand them dopamine in a ritalin tablet, and call it a day. 

Not so fast.  Problem is, a lot of different issues can cause problems with the frontal lobe and other associated ADHD areas, not just genetic issues.  Depression, for one, seems to torch our ability to stay focused.  So will anxiety.   Lack of sleep (I'll be more specific about sleep and ADHD symptoms and defiant behavior in another post).  Other kinds of inflammation.  Issues with a thinning frontal cortex in development.  The vulnerability to the different insults will be genetic, and families in general face similar environments, so a family with lousy sleep or lousy eating habits might all turn up with ADHD symptoms, just like the family with the primary dopamine problem.  Stimulants will generally help perk up the frontal lobe and behavioral changes can help too, regardless of the cause - but one never wants to ignore an ongoing environmental insult that is damaging the brain while you correct the symptoms with a band-aid.

The stakes are high.  Kids with ADHD are much much more likely to grow up and get divorced, lose jobs, be in car accidents, and commit felonies.   We don't want to dismiss the problem as non-existent and focus entirely on behavioral treatments, but we also don't want to throw ritalin at every kid who spazzes out in school.  It's a complex issue, a complex and multifaceted disorder, and for a while now I have suspected dietary causes to be the problem for some kids.  I've even blogged about it a couple times - mostly reviewing the work of a British group who did a well-designed study of 300 some-odd kids in 2007 called the Southampton Study.

In short, the researchers gave kids in the community (so just a random sample of kids, not particularly any diagnosed with ADHD, though some of them may have been diagnosed with it), in blinded crossover fashion, placebo drinks or two types of food additive drinks, with washout periods in between drink trials.  Kids on the additive-laden drink were significantly more hyper in the reviews of parents, teachers, and independent observers.  It's the kind of study that should really make your ears perk up - sure, it ought to be repeated, but the results were pretty definitive.  (When I talk about conventional medicine's lack of support for the idea that diet could possibly be related to mental illness, the title of an article in Harvard's Mental Health Letter in June 2009, two years after the Southampton Study, was " "Diet and Attention Deficit Hyperactivity Disorder - Can some food additives or nutrients affect symptoms? The jury is still out.").


Well, the British researchers continued to dig deeper into the results of the Southampton Study, and last year they published another study in The American Journal Of Psychiatry (these guys to great work, and get their stuff published in all the premier journals).  I blogged about it here - ADHD, Food Additives, and Histamine.  Again, in short, the researchers checked out the genetics of the same kids from the Southampton Study, and found that kids who were made more hyper by the food additives were significantly more likely to have certain problems with genes regulating their histamine system.  Anyone who has ever taken a benadryl for swollen eyes and a runny nose on a pollen-laden spring day will know what histamine is, more or less.  Our bodies release it in response to some sort of allergenic stimulus.  I made the point in my blog that the Southampton study seems to show us that, indeed, in some children (not all!), ADHD symptoms are a food allergy.

This week, another excellent study was published in The Lancet that took the next logical step of scientific exploration.  There is also an editorial.  (Neither are free full text, unfortunately.)  The INCA study is Belgian, and involved a randomized controlled trial with an open label phase (looks like it was single-blinded) followed by a double-blind crossover trial of an elimination diet vs. a "healthy diet" (control).  The 100 children studied were were 4-8 years old and did have a diagnosis of ADHD.

The results were pretty astonishing (well, maybe not to me, or to a lot of parents, but to the diet skeptics out there, it should be pretty darn astonishing).  Nearly two-thirds of the kids on the elimination diet for 9 weeks experienced significant reduction in ADHD symptoms and oppositional defiant behavior.  The symptoms returned when the kids went back to the "healthy" control diet.  The most up-to-date crowd of "Paleo" diet followers will grin when they hear the elimination diet - it was restricted to rice (some might avoid white rice for the excess carbohydrate with little other nutrient value, but most will agree it is essentially toxin-free and not objectionable "safe starch"), meat, vegetables, pears, and water.  There was a less strict diet where small amounts of potatoes, wheat, and other fruits were allowed but by the end of week 2 of the diet, 41% of the kids had no response to the less strict version and were placed on the stricter diet.

There were a couple of interesting wrinkles.  The kids were all tested for IgG antibodies to food, supposedly helping one sort out food intolerances.  These tests are widely used by doctors and para-professionals alike to diagnose food allergies, but when you get down to it, there is not a lot of evidence these tests tell you much about what you might actually be allergic to.  IgG antibodies simply mean that somewhere along the way your bloodstream was exposed to food allergens.  To be honest, I think people with tons of positive IgG food allergies have leaky guts, that wheat and poor gut biome are reasonably likely culprits, and the foods that show up in the IgG test are a random sampling of what happened to make it through the leaky gut.  In the INCA study, the kids were carefully rechallenged with their IgG + foods, and their symptoms of ADHD seemed to have nothing to do with the IgG test.  So I'm right ;-)  (maybe).

A quote from the Medscape article summarizing the findings and the editorial:

Dr. Pelsser's team concludes that a strictly supervised restricted elimination diet "is a valuable instrument to assess whether ADHD is induced by food, [but] the prescription of diets on the basis of IgG blood tests should be discouraged."

In her [editorial], Dr. Ghuman notes restricted elimination diet studies are "complex and challenging." The INCA study was "well-designed and carefully done, showed a benefit with a supervised elimination diet, and provides an additional treatment option for some young children with ADHD.  "For interested parents," Dr. Ghuman told Medscape Medical News, "clinicians should encourage them to seek the advice of the child's primary care provider and a nutritionist for appropriate monitoring of the child's nutritional status and needs. The parents will need appropriate guidance and supervision for a structured protocol to determine any benefit and identify incriminated foods."

So more evidence piles up.  In fact, the same researchers ran a pilot randomized controlled trial with 27 kids published in 2009 (free full text this time) and found that 11 of 15 children on the study diet improved by at least 40%, whereas none of the 12 kids on the control diet improved. 

I may not be completely off base with my basic premise after all.

(Thanks to Dr. Trevisan for alerting me to the Medscape article!)

Sad Monkeys Hopped Up on Omega 6 PUFAs

Today, the amazing Victoria sent me a paper that is way too great to pass up: Depression and altered serum lipids in cynomolgus monkeys consuming a Western diet*

I know, it's monkeys, not humans.  But these researchers actually took the connection between diet, cardiovascular disease, and depression seriously, and found a reasonable animal model that covered everything.  More or less.  They are lipophobes, but with a spoonful of sugar, they did eventually discover that the omega 6 fatty acids go down in the most alarming way... and couldn't find a way to directly blame the sat fat.  But that's the punch line.  Let's throw out a few facts and then get to the set-up.

First off:  Your brain is 60% fat, and, even more importantly, the important neuronal plasma membranes are 30-50% of the fish-derived (and you-are-dreaming-if-you-think-you-can-get-enough-from-flax) omega 3 DHA.  Yeah.  That much.   Arachidonic acid (AA), derived from the pro-inflammatory omega 6 fatty acids, is the other major PUFA in the brain. (DHA is widely distributed throughout the brain, AA is found primarily in the white matter - the gray matter is where a lot of the actual neuronal communication takes place.  White matter is more like wiring.)

One of the main differences between traditional and ancestral diets and our Western diet is the vast excess of omega 6 PUFAs, primarily in the form of Doritos and Hidden Valley Ranch and Hellmans Real (ahem) Mayonnaise, I mean stuff fried in and composed primarily of vegetable seed oils such as corn or safflower or soybean oil.

I'll quote the article here:

Several studies suggest that patients with clinical depression have either an elevated ratio of circulating long chain ω6:ω3 PUFAs, or just low circulating long chain ω3 PUFAs. There is a 60-fold variation across countries in annual fish consumption and a strong inverse relationship between national per capita fish consumption and the prevalence of depression. Early clinical trials suggest that dietary fish oils reduce signs and symptoms of depression in some, but not all patient populations 

And just to reinforce the fact that these monkeys are rather reasonable models of human-like depression - these female monkeys respond to stress via depressive-behaviors (certain depressed postures, decreased movement) which is accompanied by changes in the hypothalamic-pituitary adrenal axis in a similar way to humans experiencing depression.  They also show decreased hippocampal volumes, ovarian function changes, serotonergic system changes, and changes in serum cholesterol similar to humans with depression.  Depressed female cynomolgus monkeys also develop four times the coronary atherosclerosis as their non-depressed counterparts.

So, the actual experiment.  32 monkeys were placed on an "atherogenic Western diet."  (I'm sure they meant the crystalline cholesterol + butter, beef tallow, and lard.  I'm a bit suspicious of the sucrose and the safflower oil, myself.  And was there any choline?)

Diet composition was the following:

Casein
Lactalbumin
Dextrin
Sucrose
Alphacel (this is "non-nutrative bulk" otherwise known as "fiber")
Lard
Beef tallow
Butter, lightly salted (guessing this was not Kerrygold ;-)
Safflower oil (linoleic)
Crystalline cholesterol (yum!)
Complete vitamin mix
Mineral mix
Calcium carbonate
Calcium phosphate

Diet composition (% of calories): 38.3% carbohydrate, 42.4% fat, and 19.4% protein
with 0.28 mg/cal cholesterol.  I'm not sure what sort of "Western" diet this is supposed to mimic - it looks a lot like milky sugar in animal fat and vegetable oil sprinkled with cholesterol to me.  Where are the grains?  But that's okay, I suppose.  Adding the grains might add an extra variable that we would have to parse out, and now we don't have to. 

When you get to the actual fat content, it was about 60% saturated, 30% monounsaturated, and 10% PUFA.  But the PUFA omega 6-3 ratio was a whopping 25:1, and to add insult to injury, there was 0.00 DHA or EPA. 

So what happened?  The monkeys were put on this diet for a total of about two years and observed for signs of depression, and several body and serum measurements were taken. 

Interesting and significant developments - a whopping 42% of the monkeys developed depressive behavior.  The depressed monkeys tended to eat less and have a lower BMI (this is actually typical for a classic depression and more short-term severe depressive episodes - people tend to gain weight over the long term or in atypical depression).

The researchers compared fasting lipids of the 6 saddest monkeys compared to the 6 happiest ones.  (Measures of depression included the amount of time spent in depressed postures and pretty objective signs of depression.  They did not have the monkeys fill out the depression scales we tend to use for humans).  The sad monkeys had higher total cholesterol, but lower HDL (I would call this a cholesterol pattern consistent with inflammation).  The happier monkeys had lower total cholesterol and a higher HDL.

The researchers also broke down the fatty acid composition of the monkeys' plasma - there was no correlation between saturated fats and the amount of depression (which does not surprise me or the readers of Evolutionary Psychiatry, I would hope).  However, the depressed monkeys had significantly (42%) higher circulating omega 6 fatty acid (which would also mean that the higher circulating omega 6 fatty acids would match up with those monkeys with higher total cholesterol and lower HDL.  Hmmmmmm) than the nondepressed monkeys.  Omega 3 fatty acids were not much different between the two groups (possibly because they got so little omega 3 anyway).

So there you have it.  There was no control, which is problematic.  It would be nice to know how much depressive behavior these monkeys have in the wild, and in a similar captive situation but with their Indonesian forest diet flown in.  But I think that if you are a female cynomolgus monkey who is apt to be in a stressful subservient social position, you ought not to eat a diet of omega 6:3 PUFA in a ratio of 25:1.  I'm guessing that a moratorium on soybean oil mayonnaise for the human animals out there might be a good idea too. 

 
*Chilton FH, et al, Depression and altered serum lipids in cynomolgus monkeys consuming a Western diet, Physiol Behav (2010), doi:10.1016/j.physbeh.2011.01.013

Appetite Regulation and the Brain

Before we get back to sleeping, there's a bit of brain signaling that it is important to get a handle on.  Most of this information is derived from rodent studies, but I have no reason to believe their brain signaling about appetite and whatnot would be much different from our own.  I want to go over this bit about satiety and hunger pathways in the brain because they overlap with the sleep pathways that we will cover next. 

The center of appetite is in the hypothalamus of the brain.  The most important part of the hypothalamus with respect to appetite is the arcuate nucleus.  (When we talk about neurons, a nucleus is generally a collection of neuron cell bodies with long branches called axons that spread out to different brain regions, spreading signals along the way).

Now it is time to introduce some players.  Bear with me, as there are a few too many.  Within the arcuate nucleus,  one set of neurons makes CART and POMC.  POMC is cut up into a neurotransmitter called alpha melanocyte-stimulating hormone.  This critter acts on various areas of the hypothalamus to reduce appetite.  Another set of neurons in the arcuate nucleus makes appetite-increasing neurotransmitters and sends axons to the same areas of the brain as the POMC (appetite reducing) neurons.  The appetite increasing chemicals are AgRP and neuropeptide Y.

Quick recap - arcuate nucleus of the hypothalamus is the nerve center for appetite regulation.  It is responsible for sending out appetite reducing neurotransmitters (alpha melanocyte-stimulating hormone) and appetite increasing neurotransmitters (AgRP and neuropeptide Y).

Now, these things are always beautifully regulated via negative feedback loops.  The POMC neurons and the AgRP and neuropeptide Y neurons project signal to an area of the brain called the paraventricular nucleus.  (Don't let all the long names blow your mind.  They are just names.  Maybe we should rename them Robb Wolf, Mark Sisson, Melissa McEwen, or Richard Nikoley to make them more friendly.)


The paraventricular nucleus synthesizes and secretes two appetite-reducing neuropeptides (corticotropin-releasing hormone - yes, that corticotropin releasing hormone - and oxytocin) in response to the stimulus by the appetite increasing neurotransmitters.  The arcuate nucleus also sends projections to the lateral hypothalamus to stimulate the appetite increasing hormones melanin-concentrating hormone (MCH) and the orexins.  It is these last two appetite-increasing hormones that have a lot of overlap with sleep regulation, and even mood.  I'll get to them in a few days.

Phew.  Now let's get a bit more big picture.  The arcuate nucleus is the epicenter of appetite control and receives a lot of signals from outside players.  The presence of glucose, and also long chain fatty acids such as oleic acid (the primary component of olive oil, but also a major component of most animal fats) in the arcuate nucleus will inhibit feeding behavior and peripheral glucose production.

And remember those CART/POMC (appetite reducing) and AgRP/neuropeptide Y (appetite increasing) cell bodies in the arcuate nucleus?  Turns out they are the major site of action in the hypothalamus of the hormones leptin and insulin.  Both those hormones will tend to reduce appetite by suppressing the AgRP/neuropeptide Y neurons. 

Have I lost everyone yet?  There is a slew of wondrous basic science research into appetite regulation in the hypothalamus.  One of the cooler things to do is to infect the hypothalamus with various genetically modified adenoviruses* (I know, it does sound like the first act of a zombie movie).  If the adenovirus carries a gene that activates the signal of "low energy availability" (for biochem geeks, this is AMP kinase), the mice increase food intake and gain weight (maybe they will be hungry for BRAINS).  If the virus signal suppresses the low energy signal, the mice will stop eating and get a bit too slender.  Our "food is aplenty" hormones insulin and leptin will decrease the "low energy available - so EAT" signal, whereas known bingey hormones cannabis and ghrelin will increase the appetite signal and lead you to eat. 

So for many, many years, researchers have known that glucose and insulin seem to decrease appetite.  (BUT BUT BUT what about diabetes and gaining weight and too much insulin and glucose!!!!  Yes, in that case the negative feedback is broken, likely through inflammation and damage in the hypothalamus - so you need more and more glucose and more and more insulin to give the signal to cut off the appetite, and protuberant bellies and sales of "Sweatin' to the Oldies" increase accordingly).  I think this basic science, in combination with a false sense of security about high carb diets causing increased insulin sensitivity in the periphery (as opposed to low carb diets, which will physiologically increase insulin resistance in the skeletal muscle), is what led to the misguided advice for diabetics to consume carbohydrate-rich diets all these years.  It was only recently (well, 2002) that oleic acid, for example, was found to significantly reduce appetite also.  (And that basic science finding pretty much coincides with the massive enthusiasm for olive oil and the Mediterranean Diet).

Um, I hope I still have a few readers by the end of this post!  Go out there and eat healthy and get some sleep.  Your hypothalamus will thank you, as will your less protuberant belly.

As always, a big thanks to Jamie Scott, who has sent me the major reference article for today's post.

*there was a recent study showing that kids who had previous infection with adenovirus-36 were much more likely to obese than kids with no previous infection.  No, I doubt it is the mutant strain that escaped the lab.  Antibodies to adenovirus-36 are also found in 30% of obese adults.**

**get some sunshine to boost your vitamin D to ramp up antiviral immunity.  

Autism and Ketogenic Diets

I had forgotten that the good Dr. Su sent me a link to a dietary trial of ketogenic diets in kids with autism a few months ago. He reminded me of this himself when he quoted some comments I made in a recent blog post, but then "Paleo Guy" extraordinaire earned bonus margarita mixes for his machine by reminding me yet again and sending me a link to a complimentary paper that is an excellent review of ketosis in general.

I will get back to posting on sleep. It's just the continuing sleep deprivation I've been experiencing makes the reading of the sleep textbook a bit too painful. However, I'm committed to restoring good sleep hygiene habits and no more twitter at 3am. In addition, each little beastie now has an LED nightlight play toy thingie that switches off after 30 minutes. They get huggable freedom from fear of the dark, and we all get blessed nighttime blackness. Win win. We'll just ignore the shutting down of the melatonin with the 30 minutes of LED glow. It's better than leaving the hall light on all night.

Right. Dr. Su's paper. It is a study of 30 kids from Crete with autism who were placed on a ketogenic diet for 6 months in 1999. They went on a "John Radcliffe" version of a ketogenic diet, consisting of 30% medium chain triglyceride oil, 30% fresh cream, 11% saturated fat (oops! overshooting the USDA 2011 guidelines by a bit), 19% carbohydrates, and 10% protein along with vitamin and mineral supplements. The kids were placed on the diet in 4 week intervals, followed by 2 weeks of anything goes, so on and off. The kids' urine was tested with ketostix and their serum checked for beta hydroxybutyrate (a ketone) to measure the amount of ketosis. After 6 months, the diets were discontinued, and the kids were evaluated monthly for another 6 months.

At the beginning of the study, 2 of the 30 kids met criteria for mild autism, the rest were more severe. Interestingly enough the premise of the study was to presumably improve mitochondrial efficiency in the brain via ketosis (using ketone bodies as fuel rather than glucose). 11 years later a small study did in fact confirm that kids with autism often have problems with mitochondrial efficiency.

23 kids tolerated the diet beyond the initial 4 weeks, and of those, 5 more discontinued the diet due to lack of improvement during the first few cycles. Of the remaining 18 kids, two boys improved enough in symptoms to be taken out of the special school and placed in mainstream education. Overall the 18 ketogenic kids "presented with improvements in their social behavior and interactions, speech, cooperation, stereotypy, and... hyperactivity, which contributed significantly to their improvement in learning."

The kids who did not stay on the diet were the most severely affected by autism, and the ones who had the best response were ones most mildly affected. Another interesting fact from the study is that the kids maintained their improvements through the two week washout periods and in the 6 months after the study was over. None of the kids had any complications (such as poor weight gain or selenium deficiency) seen in other trials of ketogenic diets in kids with epilepsy.

Overall (using the original sample size of 30), 26.66% of the kids benefited significantly from the diet. The researchers also have a nice explanatory paragraph about the biochemistry of ketosis and how it favors the relaxing inhibitory neurotransmitter GABA over the excitatory, and in excess, neurotoxic glutamate:

"The increase of ketone bodies maintains the synaptosomal content of γ-aminobutyric acid (GABA) at a higher level, a phenomenon that may contribute to the beneficial effect of a ketogenic diet in children with epilepsy and perhaps children with autistic behavior. Other researchers, in an attempt to clarify the manner in which ketone bodies increase the synaptosomal content of GABA, showed that the metabolism of ketone bodies to acetyl coenyzme A results in a decrease of the pool of brain oxaloacetate, which is consumed in the citrate synthetase reaction. As less oxaloacetate is available for the aspartate aminotransferase reaction, thereby lowering the rate of glutamate transamination, more glutamate becomes accessible to the glutamate decarboxylase pathway, thus favoring the synthesis of GABA."

Couldn't have said it better myself!

Well, this wasn't a large study or a blinded study and there was no control, but for some kids, the improvement was exceptional, and ketosis didn't have to be strictly maintained. My personal preference is not to live in ketosis, but rather to dip in on occasion via 16 or 24 hour fasting and some very low carb breakfasts after overnight fasts. This study seems to suggest that dipping into ketosis can have benefit for brain energetics, though the kids went through a larger scale "dip" than I ever have.

And, once again, dietary therapies prove to be exceedingly beneficial for some, but won't do much of anything for others. It would be important for any parent of an autistic child to know that ahead of time before pinning one's hope on a ketogenic diet. On the other hand, autism is currently incurable, and a ketogenic diet seems like a nice weapon to have in the arsenal against this disease.

(Put in the links and fixed some of those bizarre sentence structures.  I shouldn't be allowed to blog when sleep-deprived.)

Edited to add links to the rest of my posts on autism.  I cover gluten-free diets, inflammation, mitochondria, vitamin D, theories about the pathology:

Diet and Autism1
Diet and Autism 2
Autism and Vitamin D
Autism 4 - Inflammation Speculation
Brain Efficiency, Pediatric Edition
Autism and Interpregnancy Interval

I Hate Homocysteine (Also It Is Elevated in Schizophrenia and Bipolar Disorder)

There are some biochemical reactions that are just gorgeous. Poetry. Glycolysis and the citric acid cycle, for example. I used to be able to draw out the whole process, and there was always something very pleasing about doing so. Enter glucose and oxygen and a few other things, and exit energy in the form of ATP, flying off the citric acid cycle like sparkling droplets of water off a spinning wheel.

The folate cycle, on the other hand, is ugly. It plays a starring role in Evolutionary Psychiatry, however, and I have to come to terms with it. There are a zillion components, an army of vitamins, and end-products going every which way - amino acids, neurotransmitters, membrane lipids, and whatever the heck homocysteine is. (seriously - my anchor article for this post calls homocysteine a "non-protein amino acid". What does that even mean?)

Image from Wikipedia

Homocysteine is a by-product of the folate cycle. It is supposed to be recycled back into methionine, but if you are low in certain B vitamins (or, like 10% of people, genetically deficient in certain enzymes that work to recycle homocysteine), you end up with too much of it hanging around. And when that happens, you happen to have a higher risk of all sorts of nasty things, such as heart disease, stroke, hip fractures, and dementia. Turns out that homocysteine likes to cleave the disulfide bridges in cysteine molecules. That doesn't sound so bad, but it affects things you might need, like collagen, for example, which plays a major part in holding bones together and keeping your arteries nice and elastic. High homocysteine *sometimes* goes hand in hand with high triglycerides, high blood pressure (from those stiff, inelastic arteries, one would presume), low HDL, high fasting glucose, and abdominal obesity. All those signs together (or three of them at least, anyway) make up the so-called metabolic syndrome which plagues our Western populations.

The good news is that abnormally high blood levels of homocysteine can rather easily be lowered by B vitamin supplementation. Almost any B vitamin will do the trick - B6, B12, folate, even betaine. That's rather exciting, one would think. Plausible biologic mechanism for a big, big problem. Cheap and simple fix. The bad news is that lowering homocysteine with B vitamin supplementation doesn't seem to make one whit of difference in cardiovascular disease, or at least it didn't in the 3700 Norwegian heart attack survivors who were followed for two years in the last decade (3) or seem help 5500 folks with known vascular disease or diabetes (4).

I don't really care about your hearts or bones. That's not true. I care. But your brains interest me a lot more. A new paper came out this month in Psychiatry Research from researchers in Croatia about high blood levels of homocysteine in patients with bipolar disorder and schizophrenia. And you will not be surprised to know that metabolic syndrome and obesity (and diabetes and heart disease) are more common in these patients than in the general population. While some of the medications used to treat these conditions cause obesity and impaired glucose tolerance, when you really parse the data, there appears to be an increased risk of metabolic syndrome just from having the illnesses, apart from any medication contribution.

(A rather unrelated aside - antipsychotic medications are well known for some pretty disturbing side effects. One of the scariest ones is called "neuroleptic malignant syndrome" where you get a high fever, stiffness, blood pressure spikes, and it can lead to kidney failure and death from muscle injury. One of the fastest treatments for NMS is electroshock therapy, believe it or not. What many people don't know is that schizophrenics institutionalized in the years prior to the invention of medication would suffer high fevers, stiffness, and death (it was called "malignant catatonia"). Now there is no question that the medicines cause NMS, but there is also an additional issue with the dopamine regulation in schizophrenia that could lead to autonomic dysfunction in a serious and fatal way. Just some food for thought.)

Right. Homocysteine. Not only does it degrade important things like bones and arteries, but it also might be able to antagonize the NMDA receptor in the brain (1), which could be a mechanism by which homocysteine itself could cause psychosis directly. It has been suggested that high homocysteine and low folate and B12 are independent risk factors for the development of schizophrenia and bipolar disorder (2).

The Croatians did a pretty simple study. They measured the fasting homocysteine and other signs of metabolic syndrome in patients admitted to their hospital ward with schizophrenia and bipolar disorder. They did not measure serum folate and B12, which is unfortunate, because that would be interesting to know. Oh well. The results? 34.2% of the sample of 60-odd patients had metabolic syndrome. And 67% of those with metabolic syndrome had high homocysteine. Only 23% of participants without high homocysteine had metabolic syndrome. In addition, high blood pressure also independently correlated with high homocysteine, which at least makes biologic sense.

One more little interesting tidbit from the paper - high homocysteine has also been found to be correlated with high omega 6 fatty acid levels in patients with major depression.

The take home? As I said in the Zombieland 2 post, I tend to connect high homocysteine levels with poor nutrition in general. Also, high homocysteine can be caused by a number of drugs and supplements, including niacin, metformin, insulin, corticosteroids, NSAIDs, and some anticonvulsants cause high homocysteine levels too. Chronic high intensity exercise and smoking are also related to high homocysteine. What do we do about it? Having all the B vitamin players on the team can help, so it can be properly recycled. The Norwegians were heart attack survivors - the damage had already been done. Maybe (comparable to omega 3s for mild cognitive impairment = possibly useful vs omega 3s and Alzheimers = a disappointment) homocysteine is something to keep low in the long term as a preventative strategy. Lowering homocysteine did seem to reduce stroke incidence by 25% in the HOPE2 trial. But who knows? We'll have to wait for more studies.

The brain is on the front lines, and metabolic syndrome (or the inflammation behind it) has psychiatric components as well. It is all linked in ways that we only barely understand.

Dietary Fat Intake and Depression Risk

More sleep coming soon, but a paper came out yesterday that ought to be blogged about (open access, too from PLoS One):

Dietary Fat Intake and the Risk of Depression: The SUN Project

The paper begins mild-mannered:  "Emerging evidence relates some nutritional factors to depression risk.  However, there is a scarcity of longitudinal assessments on this relationship."

The researchers followed a group of Spanish university graduates, initially depression-free, for an open enrollment period of 1999-2010.  12,059 ultimately signed up.  At baseline they filled out a food frequency questionnaire to estimate the amount of saturated fat, polyunsaturated fats, trans fats, monounsaturated fats eaten, and the use of "culinary fats" (olive oil, seed oils, butter, and margarine).  During the follow up period (of median 6 years), 657 new cases of depression were identified (via a new diagnosis of depression by a physician or initiating the use of antidepressant drugs).  As is typical, confounders were accounted for, including adherence to a Mediterranean Diet (legumes, fruits, vegetables, fish, cereals, and low in meat and dairy products), which has already been shown to correlate with decreased depression (1).  Turns out there was a reasonably strong (and dose-dependent) correlation between trans fat usage and depression - the less trans fat the Spaniards ate, the less likely they were to become depressed, and those in the highest quintile of trans fat intake had a 48% increased risk of developing depression compared to those who ate no trans fats.  There was also a weaker inverse correlation with the amount of MUFA and PUFA eaten (meaning these types of fats may be protective against depression.) 

In Europe, suicide rates and mental disorders are higher in Northern Europe, and the lowest in the Southern Mediterranean countries.  I can think of a number of possible reasons for this trend (sunlight, relaxed lifestyle, vitamin D *cough*), but the overall food choices differ mainly with respect to olive oil and pulses.  Very little is known about the specific types of fat and risk for depression, except with respect to the omega 3s.  And even those studies are tricky - often, the omega3 capsule is compared to a placebo capsule of olive oil, and in some trials, both the fish oil group and the olive oil (control) group improve.  It could be that both fish oil and olive oil improve mood, or that the increased fat content in general improved mood, as there is some evidence that low fat diets adversely affect mood (2)(3). 

Now the discussion and speculation - always the most interesting part.  The commonly accepted mechanism now for depression is one of inflammation leading to a decrease in BDNF, which is a nerve fertilizer necessary for axonal growth, nerve survival, and synaptic plasticity and function.  Some of this awesome nerve fertilizer is made in the endothelium (possibly through a nitric oxide mechanism).  Now cardiovascular disease, which correlates with depression, is also likely mediated through inflammation and endothelial dysfunction.  Trans fats are thought to cause inflammation and endothelial dysfunction, so it would make a lot of sense if they trash your brain along with your coronary arteries. 

Here's a rather scary analysis (though also makes me question the conclusions of the whole study) - the people studied overall actually ate a lot of whole foods and a very low amount of trans fats, and most of it came from whole fat dairy (I'm assuming, then, they are talking about CLA, which as far as I know is a very good fat associated with reductions in diabetes and obesity (both of which individually correlate with depression also, of course) though it is in truth a natural trans fat).  In this study sample, in the highest quintile, trans fat made up only 0.4% of calories.  In America, trans fat intake is up to 2.5% of calories, and the main sources are artificial foods (such as processed snack foods and margarine.)

Olive oil, on the other hand, is thought to have antioxidant and anti-inflammatory effects, and various metabolites of olive oil can improve sleep and improve the binding of serotonin to its receptors.  The folks in the study overall (being a Mediterranean population) ate a ton of olive oil and very little butter, margarine, or seed oil.  (These researchers are big olive oil fans.)

So what can we glean from this study?  Not that much - the strength of the design was a large population, but a huge weakness is that the diet was measured only once, at the beginning of the study, through a food questionnaire.  It was felt that the use of college graduates would help the validation, as they might be more likely to give accurate information about diet.  However, it seems that most of this highly educated cohort ate very similar diets, which means the whole effort may have been something of a wash.  I'm always skeptical of the ability of epidemiologists to adjust for confounding variables.

But it does make sense biologically that olive oil and PUFA intake (since they weren't using seed oils, I'm guessing a lot of the PUFA was in fish) would correlate with a happier brain, while the inflammatory trans fats would trash the endothelium and BDNF.  So maybe we hang our hats on that a little.