Brain Shrinkage and B Vitamins

As we discussed before, humans are rather unique among primates in that our brains appear to shrink as we age.  When I first posted the article, Steve Parker, M.D.* noted that there was a recent article on PLOS1 about B vitamins decreasing brain shrinkage, so I thought I would investigate the matter further.  Recently I've been going through this years' issues of The Carlat Report** to get some CMEs, and they mentioned the B vitamins and that study too.

Snow Patrol:  Called Out in the Dark (right click in new tab to open)

But before we get to that study, let's look at an older one, from 2002:  Homocysteine and Brain Atrophy

(I KNOW.  Homocysteine.  That bad boy of the folate cycle.  Always hanging out when everyone wants him to be recycled and go home.  Possibly cleaving your disulfide bridges and leaving your arteries and cartilage all crispy and brittle.  Maybe just a sign that you aren't eating all your B vitamins, amino acids, and various co-factors that you need.)

Homocysteine (Hcy) has been implicated as a risk factor for vascular disease as well as brain atrophy.  There is evidence to implicate Hcy in increased oxidative stress, DNA damage, the triggering of apoptosis and excitotoxicity, all important mechanisms in neurodegeneration.  Hcy… also causes damage to the vessel wall… the high prevalence of hyperhomocysteinemia in the population and its easy treatability [via B vitamin supplementation - ED] make Hcy an interesting amino acid for future intervention studies in the prevention of degenerative brain disorders.

  So if we want to break it down, homocysteine is part of the one-carbon metabolism cycle.  B12 and folate are also an important part of this cycle, and deficiencies in these are clearly related to nerve damage and neural tube defects in infants.  Deficiencies in either of these vitamins will lead to an increase in homocysteine, which is also apparently directly neurotoxic.

The brain might be particularly vulnerable to higher levels of homocysteine because it lacks two major metabolic pathways for eliminating it (biochem nerds, hold on to your hats), remethylation and transsulfuration.

All right.  There's theory, and lots of it.  What about the observational evidence?  Well, a number of cross-sectional studies have examined a relationship between too much homocysteine and brain atrophy.  In an Australian study of stroke patients, high homocysteine was related to increased brain atrophy, and the OPTIMA and Rotterdam studies replicated this finding in healthy elderly.    Other observational studies have shown a correlation between higher homocysteine level and Alzheimer's disease, to the point where homocysteine levels seemed to be able to predict the speed of progression of the disease.

If we look at specific cognitive impairment trials, higher homocysteine levels have been shown to correlate with poorer performance on a number of cognitive tests - story recall, spacial coping, etc.  In fact, homocysteine levels accounted for "7-8% of the variance in late-life cognitive ability."

In a prospective observational study (the Framingham heart study), higher homocysteine at baseline was related to an increased risk of developing Alzheimer's later on.  Several other smaller studies have repeated this finding.

Moving onto trials - B vitamins lower homocysteine levels.  Folic acid supplementation can lower homocysteine by 25%, B12 by a further 7%.  Betaine is somewhat less effective.  These B vitamins have been used in mild cognitive impairment and dementia.  In small, open-label trials, B vitamin supplementation (typically folate and B12) have been helpful in some tests of cognitive impairment and homocysteine levels…

Fast forward to 2010, when the freely available study at PLOSone came out:  Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in  Mild Cognitive Impairment: A Randomized Controlled Trial

Sounds cool, right?  Well, turns out the first author has a patent for a folate or B vitamin something or other in the treatment of Alzheimer's so keep that in mind.  But still cool.  168 folks with mild cognitive impairment were randomized to placebo or B vitamin supplementation (0.8 mg/d folic acid, 0.5mg/d vitamin B12, and 20 mg/d vitamin B6).  Both groups of people underwent baseline and serial follow up MRIs and cognitive testing.

In the end, the B vitamin supplementation seemed to slow the brain atrophy compared to the control group.  The treatment response was related to baseline homocysteine levels - the rate of atrophy in patients with a homocysteine level at baseline of >13 micromol/L was 53% lower in the active treatment group than in placebo.  A faster rate of atrophy was associated with lower cognitive testing scores.

So, pretty interesting.  And certainly treating our elders with B vitamin supplementation seems to have few downsides.  A lifetime of offal eating might leave us well-served in that regard.

* Steve Parker MD is the go-to person where I send my patients leery of my wild and wooly evolutionary approach who are looking for something a bit more… conservative.  He has a great set of evidenced-based blogs and books on the Mediterranean Diet, with some ketogenic options, and has recently started up a Paleo Diabetic blog as well.

** The Carlat Psychiatry Report is my go-to source for unbiased, evidence-based round-ups of everything in psychopharmacology and beyond.

Quick Talk Update

Just a quick reminder that I will be speaking to the Harvard Law School Food Law Society at Noon on Monday, October 31, 2001.  Further details about the event are here:  http://hlsfoodsociety.weebly.com/events.html

I am told it is open to the public.

I've been deluged at work, but have managed to pull a few interesting papers today, so cross fingers that I will get a moment to blog about them later tonight or tomorrow.

Conventional Wisdom and the Lunatic Fringe

This weekend I had a terrific opportunity.  Nathan Rosenberg is an exceptional fellow who is co-president of the Harvard Food Law Society and a key organizer of next year's Ancestral Health Symposium.  He found me at AHS11 and asked me if I might be interested in speaking at Harvard Law School - I said sure, though I wondered what I would say, seeing as how doctors and lawyers are natural enemies. (Kidding.  Sort of.  Actually I have a GREAT lawyer.  He probably sleeps better not knowing about this blog.)

My talk is next week, on Halloween - the link is here.  I'm really looking forward to it.  My focus will be on how diet is likely a large actionable component of our mental health problems, and how mental health is both expensive and disabling.

However, on October 21st, the Harvard Food Law Society sponsored a great event - TEDx talks on obesity, with some of the foremost obesity researchers in the country (including Willet, Ludwig, Lustig, and Guyenet) along with many lawyers and policy makers talking about their efforts to encourage local agriculture and vegetable consumption over promotion of the commodities crops and CAFO operations.

The talks will be freely available some time - maybe follow the TEDx website?  They were fascinating - I was, frankly, shocked by Willet's dietary prescription based, for the most part, on epidemiologic evidence.   He advocates cereal fiber and polyunsaturated fats as a major portion of a "prudent" diet.  He was very pro-Mediterranean diet and whole foods, but was quick to say "it's all digested to the components" - so does he think a whole grain cracker fried in seed oil and sprayed with some vitamins is equivalent to nuts and legumes?  He was anti-saturated fat and red meat, but pro-poultry and fish.  He mostly stuck to obesity and heart disease, but used epidemiology and small, short randomized controlled trials as evidence.  Willet is, apparently, the 2nd (or 6th?  I forget) most cited person in the scientific literature.  He is HUGE.  He is conventional wisdom, in a nutshell, though Stephan Guyenet told me Willet is pro-egg, and Willet himself says that the food pyramid, demonizing fats and, in effect, promoting low-fat processed carbohydrates in favor of whole foods, was a public health disaster.

If we rely on epidemiology alone we would still have 90 y/o women taking hormone replacement therapy.  But Willet seemed convinced that confounders are easy to account for.  His confidence was… breathtaking.  Willet also dismissed anecdotes of traditional diets as the weakest form of evidence (which isn't entirely wrong, but ignores the compelling congruence of these healthy human diets across many cultures).  Willet also said that ancestral diets are not useful because "those people only lived to 50-55 and we don't want that."  Sigh.  Willet eats kashi grains for breakfast, apparently.

Ludwig's talk began, very promisingly, with an evolutionary history, but ended with the basic Harvard School of Public Health prescription for a healthy diet.  (Ludwig got a lot of media flack recently for suggesting that obese kids should be taken from their parents - the actual editorial he wrote suggests that foster care could be an option in intractable cases and I feel was taken out of context).  I was puzzled how we got to cereal fiber (how do we have cereal fiber, on a viable level, without processed foods?) and seed oils, but that's epidemiology for you.  He was quick to point out that if we substitute nuts and legumes for a big mac, once a week, we would have a measurable difference in obesity over time.  Okay - Stephan Guyenet was quick to point out the sleight of hand.  The substitution does not mean that red meat is bad for you.  Well - Ludwig looked great (very slender, not-inflamed looking at all) and apparently might be interested in speaking at AHS12.  It seems he is thinking in evolutionary health ways, but has not strayed from the conventional wisdom fold as of yet.  Very interesting.

Stephan's talk was excellent; it was mostly a historical review of the changes in the American diet over the past 150 years.  He pointedly showed the increases in fat (primarily polyunsaturated), poultry consumption, and linoleic acid over the last 50 years, coinciding with the obesity and diabetes epidemics.  His major point was that we have gone from all home-cooked foods to a high level of fast food, restaurant food, and pre-prepared convenience foods at home.  Does convenience kill?  Most likely...

(An important note - heart disease has been in decline for the past 30-40 years, though it might be leveling off now.  It is unclear if that is due to aggressive control of high blood pressure, dietary changes, or even statins.  But don't make the false proclamation that heart disease is increasing lately, because it is not).

Lustig did his anti-sugar talk (which also pointed out the problems with epidemiology as a prescription, I am told) on Thursday night, when I could not attend.  He did attend the panel discussion, when he came out as neutral on sat fats, pro-omega3, anti-omega6, anti branched chain amino acids, and anti MCTs.  And, of course, anti frucrose, and while he would not come out against whole fruit whole hog, he did discuss the anecdote of the "fruit orgy" of orangoutangs where they seasonally develop insulin resistance and put on fat.  Lustig seems to feel that fructose, MCTs, and BCAAs are damaging to the mitochondria and lead to insulin resistance (thus he is anti-corn fed beef, as corn-fed beef is higher in BCAAs than grassfed, apparently.  I don't know enough to say whether that is wacky or not.)  Ludwig was quick to point out that there is no evidence linking fruit consumption to any chronic illness.  I'm quick to point out that I eat 1-2 bananas a day, and I rely on 1/2 banana before and after crossfit for happy lifting.

What we can all agree on - eat "real" food, and from a policy and preventative perspective, perhaps the most important, simple message is to eliminate sugar-sweetened drinks in the diet.  I think everyone would pretty much agree on that one too.

The policy/lawyer talks were terrific -- they were very interesting, and exciting, as these lawyers and seasoned politicians are going forth to help farmer's markets and soil preservation, water preservation, sustainable agriculture and align government policy incentives with the supply and availability of local, real foods.  Some of the real initiatives include penning legislation to abolish state sales tax at local farmer's markets (just as most states do not charge sales tax for staple food items at the grocery store), and streamlining state and local regulations to allow for farmer's market and production and sale of homemade low-risk specialty items (such as jams or apple pies). As the current farm bill heavily supports the commodity crops (corn, wheat, soybeans, etc.) and downgrades vegetables to "specialty crops," some changes would be nice!

I left the talks a little shaken.  I felt (as always) the standard anti-obesity message is not practical for a non-Mediterranean culture and likely to be a terrible failure here in the U.S., land of the processed health food,  and the pro-egg, fat-is-okay (albeit *cough* polyunsaturated) message has certainly not been carried to clinicians, nutritionists, and doctors in the field.   That Willet and Ludwig were not willing to support whole dairy or red meat/pigs was unfortunate.  The "whole foods" message gets really lost when we are parsing out red meat and even dairy.  Forget the "nuts and legumes" (seriously, legumes?  The only beans worth eating are refried in lard, amirite? - to clarify, this is my little joke, as beans upset my tummy) - how to we kick red meat and dairy to the curb without eating a crapload of disgusting kashi?  I can't fathom it - Stephan I think would advise in consideration of sustainability and a large scale policy level for us to add potatoes (not fried, but whole, baked or boiled potatoes) and use traditional methods to prepare grains.

However, today I was fortunate enough to be invited to a lunch with Stephan Guyenet, Mat Lalonde, and friends and significant others.  It was very refreshing to be with Mat and Stephan, who seem to be aligned with me about not supporting the some paleo fringe extremes (meaning acceptable carb levels vary, gluten and dairy levels vary in tolerance on an individual basis, etc.).  We were also concerned about ideologues who seem to support one aspect of a diet as the end all, be all to ill health (fructose, or wheat, or carbohydrate), when the scientific truth is far more complex.

One of the most interesting aspects of the discussion was reflection upon genetic adaptations to agriculture - hemochromatosis (a disorder where humans can't properly get rid of iron, which was likely protective in grain-eating, low iron situations but which would make a classic low-carb, ruminant heavy, offal heavy diet dangerous), lactose tolerance in adulthood, and variations in folate metabolism.  Evolution did not end with the paleolithic, of course, and while the generalities of "eat real food" are true for everyone, the specifics can vary a great deal depending on context - insulin resistance, obesity, large exercise volume, etc.

I don't have a specific prescription on this blog for a very important reason, but let me be explicit  - for the most part, go archevore, exercise, tighten up the sleep, learn stress reduction, and that will help a great deal, and if all those things aren't in order, meds and strict ketogenic diets and supplements may well be shoveling sand against the tide.   This all doesn't mean I'm entirely anti-meds or anti-ketogenic diets - indeed, if the issues are substantial and significantly impair functioning, I want to help in whatever rational and evidenced-based way possible… but don't look for magic.  For the most part, it fails us.

How You Like Me Now?  The Heavy

You Are What You Eat

Did you know that diet could affect mental health?  Okay, that is, perhaps, putting it too strongly.  Diet is correlated with mental health, especially in Australia.

Mental health disorders tend to be pretty chronic and can be debilitating.  And, unlike many chronic diseases of Western Civilization, they tend to strike young.  Autism in babyhood, anxiety disorders often before age 10, mood disorder in the teens, schizophrenia in the late teens and early adulthood… psychiatric disorders cost us so much in terms of productivity and health.

Y'all already know what I think.  (Donnie Darko, Mad World right click to open in new tab).

There is every reason to believe a modern, processed, nutrient-poor diet could have a lot of influence on mental health.  Of course, no one knows what to tell anyone to eat except for "fruits and vegetables." And that is what PLOS1 tells us today…

A Prospective Study of Diet Quality and Mental Health in Adolescents

In this study, several thousand Australian adolescents filled out surveys about diet, health, and mental health several years apart.

Here is how diet quality was assessed:

 As such, a point was allotted for each of the following: eating breakfast at home on school days; eating lunch brought from home; consuming two or more fruit serves per day; four or more vegetable serves per day; fruit and/or sandwiches as after school snacks; generally avoiding biscuits, potato chips, pies, hot chips, fried foods, chocolate, sweets, ice-creams as after school snacks; and, finally, both consuming healthy after school snacks and avoiding unhealthy after school snacks. 

(Chocolate????)

It is not terribly surprising that an unhealthy diet score in the first survey correlated with a poorer rating of mental health in the second survey several years later.  Covariates were assessed for but can never really be extinguished completely… interestingly, mental health at baseline did not predict diet several years later, strengthening the findings of the study.

But I rather love these researchers, and will quote some of the interpretation in full here:

...the prevalence of emotional and conduct problems in adolescents increased in the period between the mid 1970's and 1999, while a new meta-analysis, reporting on data collected at many time points and, thus, free of confounding by age and/or recall bias, has reported large generational increases in self-reported psychopathology in American high school and college students between the 1930s and 2007. These increases did not appear to be explained by social response biases, economic cycles or changes in student populations, and the authors concluded that changes in unidentified cultural factors have resulted in increased rates of psychopathology among American youth.

 Paralleling this possible increase in the rates of psychological illness among young people are data indicating a reduction in the quality of adolescents' diets over recent decades. A report based on trends in adolescent food consumption in the US identified a reduction in the consumption of raw fruits, high-nutrient vegetables and dairy foods, which are important sources of fibre and essential nutrients, between 1965 and 1996, with an associated increase in the consumption of fast food, snacks and sweetened beverages. Concurrently, population surveys demonstrate a substantial increase in overweight and obesity among children and adolescents over recent decades. Obesity does not necessarily indicate nutritional repletion, as high-energy foods typically have poor nutrient content.

Could it all be connected?  Increasing muffin tops and increasing psych hospitalizations in children and increasing psychopathology?  And how expensive is it to society when a lean cuisine is the epitome of healthy eating?

A very very mad world indeed.

Crisco and Cocaine, or A Fun Saturday Night

As usual there is a stack of papers awaiting my attention, but Dr. Aaron Blaisdell just tweeted this sparkling brand new one that just couldn't be ignored -- A History of Bingeing on Fat Increases Cocaine Seeking and Taking.  (Boy, rodent researchers really know how to make an intriguing combination of industrial lubricants "heart healthy vegetable oil" and cocaine sound boring.)

Song - an oldie but a goodie - The Dandy Warhols:  Bohemian Like You (right click to open in new tab)

I've discussed the rodent bingeing literature before:  see here and here and a little bit here. Rats and mice, like humans, will binge on sugary snacks.  Unlike humans, rats and mice will binge on Crisco alone, whether it is the old fashioned trans-fat kind or the modern however-it-is-they-make-vegetable-oil-solid-at-room-temperature kind we can buy in the supermarket now.  The sugar-fat combo seems to be the most damaging - though in all of these studies, a variety of vegetable oil was the fat used, so it is hard to know whether it is an omega 6 thing or a fat thing in general.

A little reminder - not all binge-eaters are obese, but 67% of them are.  And not all obese people are binge-eaters, far from it.  It seems that about 1/3 of those who seek medical treatment for obesity have binge-eating behavior, however.  If we are considering the prospect of disordered "food reward" pathways, perhaps looking at binge-eaters will help us to understand one extreme of the continuum.  Or perhaps the pathology behind binge-eating and the supposed disordered food reward leading to obesity are really different concepts.  I suspect they aren't entirely separate, but it isn't a simple comparison, either.  And certainly, exploration of binge-eating and addiction can hopefully inform our treatments of those disorders.

In this new study, researchers added the interesting twist of seeing if a history of fat-bingeing made their rodents more vulnerable to becoming addicted to cocaine in the future.  As I've noted from my clinical experience (and as is noted in the literature), binge eaters can (but don't have to) have a hard time controlling behaviors in several areas - bulimia and binge-eating often occur together with substance abuse in humans.  

Let's start with what all the folks agree upon - massive doses of sugar (really, sugar - sucrose, meaning glucose + fructose) are a bad idea, particularly in those who are vulnerable to addiction of bingeing behaviors.

Rat researchers know their bingeing and drugging.  A correlation between liking sweets and drugs of abuse (including alcohol, cocaine, and amphetamines) is known in humans, and in rats, repeated exposure to sucrose seems to enhance behavioral susceptibility to cocaine later on.  Sucrose is, in this paradigm, a "gateway drug."  Let's not forget that in sugar-bingeing rats, taking away the sugar leads to opiate-like withdrawal syndromes and worsens the withdrawal from morphine.  So let's say you are a binge-eater withdrawing from a sugar-fest -- are you more likely then to have a bottle or two of wine, some meth, or cocaine?  Could be.  Even though these different drugs of abuse affect different reward neurotransmitters, they all end at one common pathway, which makes sorting out some of the specifics rather difficult.

Here is a money excerpt from the paper:

Offering further support for the connection between the intake of sugar and fat and the intake of drugs of abuse are several studies investigating the neuroanatomical and neurochemical changes that accompany sucrose and fat consumption. Not surprisingly, these sugar and fat consumption-induced changes occur in the mesocorticolimbic dopamine system, a major component of the brain’s reward pathway, and many of the changes mimic those that occur after exposure to drugs of abuse, including turnover and release of DA, D2 receptor binding and expression, and dopamine transporter binding and expression. In addition, differential responsiveness in rats bingeing on fat has been reported when a D2 receptor antagonist is administered peripherally, or directly into the prefrontal cortex.

In short, eating fat and sugar seems to engage our reward systems in the same way that drugs of abuse do.  This is not terribly unsurprising - we have a reward system for our survival.  Protein is easy to find in the paleolithic world (ask any bug or lean rabbit) - but what about our fuels of sweet and fat?  We need it, we love it, and our big brains encourage us to find it and consume it, and drives us to find it and consume it again.  My suspicion (not first thought of by me in any respect!) is that, like cocaine, Snackwells, Oreos, Big Gulps, potato chips, peanut M&Ms and deep-fried twinkies stimulate our reward centers in ways our brains were never designed for, like a magnitude 9 earthquake taking out at magnitude 7-rated nuclear reactor.  To parse matters even further - the actual substances may be less important than the manner in which they are consumed.  A sugar binge (with all the sweaty anticipation, consumption, aching stomach and crashing blood sugar later on) is a far more worrisome issue than eating the same amount of sugar over the course of a day, at least in rats.  Here we separate those who are (for whatever reason - environment, genes, etc.) vulnerable to addiction and those who are not.  

So what happened to these rats with the cocaine and the crisco, anyway?  The methods are a bit boring, but in short, we have some rats on standard rat chow, and then some rats on standard rat show plus access to fully hydrogenated Crisco (not sure where you can get your paws on that nowadays!  J.L. Smuckers must have a special research repository in the basement.  Actually, wasn't it the partially hydrogenated Crisco that was the bad stuff?  Poisons are so confusing...)  All the rats were then transported to another lab 90 miles away (in Hershey, PA, which is a lovely community of nostalgia and chocolate), where there was no Crisco, but there was some high quality blow (actually it was IV cocaine, and the rats could control the administration by licking a certain spout, leading to an infusion of the drug.  Interestingly enough, a study was once done on humans comparing IV cocaine, IV amphetamines, and IV caffeine, and the humans could not tell the difference.)

You will not be surprised to learn that the indulgent, gluttonous crisco-bingeing rats were mostly the same ones who had a bit too much affection for the cocaine.  The other, abstaining rats were rather like Meg Ryan in "When Harry Met Sally"  "I don't like to eat between meals."  So superior, so sure that all you have to do is exercise some self control, as they do, and you could wear size 2 jeans, no problem.

I know, it is a big leap from a few crisco-loving, coke-addled rats to 60% of the population being overweight or obese.  But certainly there is something there.  And for the love of all that is precious and good, DO NOT EAT HYDROGENATED CRISCO (even though it is much better than the partially hydrogenated stuff**).  

Ever.

** In the US, anything less than 0.5mg trans fat per serving can be listed as "0g trans fat."  Does anyone know the fully hydrogenating process for New Crisco and how good it is at getting all the double bonds saturated?  Or are quite a few missed and you end up with a small dollop of trans fat each time, still?

More on Infections at Psychology Today

Updated another post (with some new research findings) at Psychology Today that is pertinent to my most recent post here:

Could Alzheimer's Dementia be Caused by a Virus?

Also new(ish) at Psych Today:

Parkinson's, CoQ10, and Creatine

Brain Energy

More new posts soon!

Infections and Schizophrenia Risk

Whew.  Quite a response over my disappointment in Wheat Belly.  And Melissa gives us an informed and reasoned review (mine was more of a visceral reaction).  It's hard for me to see the merit in a book just because the idea of wheat not being ideal for human consumption agrees with my own views.

On the interesting papers front, a couple of new articles shine more light on the relationship between infections and mental disorders.  I consider this type of thing "evolutionary psychiatry" as it brings us closer to finding the true pathology of illness, inflammation, and disease.  In addition, the typical evolutionary prescription of nutrient-rich and anti-inflammatory diets and appropriate amounts of vitamin D ought to increase resistance to infection and resilience to the inflammation and autoimmune issues that may be spurred on by such infections.

The first paper is from Denmark, Toxoplasma Infection and Later Development of Schizophrenia in Mothers, from August's American Journal of Psychiatry.  There is also an enlightening editorial in the same issue.

Toxoplasma gondii is a parasite that one can pick up from contaminated cat feces, from eating undercooked meat containing the infectious cysts or contaminated vegetables, and from being a fetus whose mother is infected.  Infection in pregnant women can cause major birth defects in offspring, and this fact is the origin of the common advice for pregnant women not to clean litter boxes.  Studies have linked infection with toxoplasma with schizophrenia since the 1950s.  More recently the association was confirmed in a 2008 study of the US military.  All these early studies were retrospective and observational, which is the weakest sort of experimental data this side of the anecdote.  Meaning folks with schizophrenia were compared with normal controls, and it turned out that people with schizophrenia have a higher rate of previous exposure to toxoplasma.

A step up from the retrospective, after the fact sort of study is the observational cohort study.  In this type of study, a group of people are followed for many years to see what develops.  This type of experiment presumably takes away what sorts of bias can be introduced by finding cases after the fact. (For example, do people with prodromal symptoms of schizophrenia engage in behavior that makes it more likely for them to be infected with toxoplasma - washing hands less, or not cooking meat as thoroughly?)  Scandinavian countries are hotbeds of these studies, as they've collected all sorts of medical data on pretty much all of their citizens for a generation now.

In Denmark, 45,609 women were followed from childbirth, when antibodies indicating prior prenatal exposure (or not) to toxoplasma in their babies were measured by heel-stick 5-10 days after being born.   All these antibodies circulating in the baby's bloodstream were made by the mother, not the baby, as a baby won't make too much in the way of these sorts of antibodies (IgG) until the immune system is a bit more mature, by 3-6 months.  Therefore mothers with babies who were positive for T gondii exposure were presumed infected themselves.  Some, but not all, of the mothers had been tested for IgG levels in the first trimester of pregnancy - these levels correlated with the newborn levels that were available for all the mothers.

Over the following years (the women were followed from 1992-2008), 80 of the mothers developed schizophrenia.  The ones whose babies had the highest IgG levels had a higher risk of developing schizophrenia than those who had babies with the lowest levels (the risk was increased by 1.73-fold, which was statistically significant - though with a population risk of approximately 1%, toxoplasma seems to increase the risk to about 1.7%).   Other meta-analysis have shown odds ratios of around 2.54-2.73 (odds ratios above two are considered a significant finding).  In the Danish study, adjustments were made for confounders (such as age, urban or rural, and other known risk factors), and women already diagnosed with schizophrenia at the beginning of the study were obviously excluded.

Why would infection with T gondii increase the risk of schizophrenia?  Active infection in the central nervous system can certainly cause huge problems (such as seizures) and inflammation.  In addition, our immune reactions to these infections can cause problems, especially if something on the infectious particle looks a bit like something in our own cells.  The classic example of this type of problem is rheumatic heart disease, most likely caused by our own antibodies attacking heart tissue after a strep infection.  It is also thought that neurological symptoms of lupus are caused by these neuro-specific auto-antibodies.  In the case of toxoplasma, it is a possibility that the anti-toxo IgG antibodies react with neural tissue and might help the immune system attack the NMDA receptors in particular.

The paper Progressive Gray Matter Loss and Changes in Cognitive Functioning Associated With Exposure to Herpes Simplex Virus 1 in Schizophrenia: A Longitudinal Study appeared in the same August, 2011 issue of the American Journal of Psychiatry.  In this study, there were four groups of folks - schizophrenic patients (none of whom were on antipsychotic medication) who were seropositive for HSV1 infection or not positive, and normal healthy controls who were also positive for HSV1 infection or not.  All these folks were followed with some cognitive testing and neuroimaging at the beginning of the study and at one year.  It was found that the schizophrenic folks with HSV1 infection had significant worsening of certain measures of cognitive functioning and shrinking of gray matter in certain regions (meaning the brain cells are dying off).  The other three groups of people didn't have these changes.

Here is what the researchers had to say about the possibilities:

There are several plausible explanations for the observed changes. In the rodent and rabbit models of CNS HSV1 exposure, latent infection and reactivation directly affected functioning through neuronal death or dysfunction. Neuronal death resulted from apoptosis. Neuronal dysfunction during reactivation and latency resulted from modulation of apoptosis and autophagy, host cell translational shutoff, oxidative damage, and/ or neurotransmitter alterations. Even with peripheral infections, HSV1 could alter neurotransmission through release of cytokines, especially chemokines, which may be elevated in HSV1-exposed individuals. Human studies support some of these observations. These processes occur throughout the life of an infected person.

In short, infection (even a smoldering latent infection without obvious active signs) in the brain or periphery can lead to all sorts of changes in the way the cell handles energy and self-destruction and general inflammatory badness.

Monitoring, modulating, and avoiding these infections seem like different ways to decrease the risk of central nervous system symptoms.

Slam-dunked and Wheat Belly

All right.  Work has been really, well, working me lately, so I've barely had time to sleep, much less to review papers, keep up with the blogosphere, and write.

I do like this song, though (right click to open in new tab):  Days are Forgotten (and it is getting very difficult to find songs on youtube that will play without ads upfront - sorry if there is an ad on this one!  It had a glitch and skipped the ad but might not work for everyone :()

Despite the time crunch, I did manage to squeeze in Wheat Belly over the weekend (most of it), and read the rest last night.

No, I don't like it.

No, I don't eat wheat as a rule, and I am not a grain industry shill.

But I don't feel I have to put my name out in support of a shoddy, sloppy book just because the overall message "wheat sux" agrees with my thoughts that wheat gluten and other wheat proteins likely are inflammatory in many people and cause problems for more than just those with celiac disease.  I think most physicians and researchers with critical thinking skills will find this book useless and full of hyperbole.  For those not taken in by the confident tone, it may do more harm than good.

Why don't I like Wheat Belly?  In short, it is the carelessness and simplicity of the message.  Hyperbole and poorly supported, confident claims.  Obesity and chronic illness is a complicated subject.  It doesn't come down to wheat.  Wheat isn't responsible (entirely) for "moobs" or the other too-cute phrases Dr. Davis churns out ad nauseum throughout the book.

An example?  In chapter 4, Dr. Davis spends a bit of time discussing the evidence linking wheat to schizophrenia and addiction.  I've discussed this issue at some length and noted the obvious circumstantiality of the evidence and the need for more research.  (see Wheat and Schizophrenia and Wheat and Serious Mental Illness).  And while Dr. Dohan (who was the major researcher who championed the wheat causes schizophrenia meme) felt he had evidence that schizophrenia has increased incidence in wheat-eating populations, most modern schizophrenia researchers make note that schizophrenia is pretty consistent in incidence across many populations - around 1%-1.3% incidence, in the developing world and in the Western world, in rice eating Chinese areas and the wheat-eating American Midwest.

Dr. Davis says:  "while it seems unlikely that wheat exposure caused schizophrenia in the first place, the observations of Dr. Dohan and others suggest that wheat is associated with measurable worsening of symptoms."  I don't get that quote at all.  Is the incidence of schizophrenia higher in non-wheat eating countries or not?  Do exorphins cause psychotic symptoms or not?  Schizophrenia, after all, is defined by the symptoms.  Something that "worsens" schizophrenia will cause schizophrenia, a symptomatically defined illness, as I've discussed earlier in my posts on cannabis.

But where I find the book to be critically annoying is in the discussion of addiction and opiates.  Wheat, as we know, has break-down components that are exorphins, which activate the opiate receptors in the brain and nervous system (the same receptors that are activated by our natural endorphins, opium, morphine, heroin, percocet, and other opiate painkillers).  The opiate pathway is part of the reward pathway in the brain, and is actually activated by anything "rewarding" - such as sex, exercise, drugs, gambling, and rock and roll.

Where I agree with Dr. Davis is that I have seen clinical evidence that some people seem to be "addicted" to wheat.  Particularly night bread binge-eaters.  They talk about bread much like one of my opiate addict patients would talk about oxycontin.  They can't stop eating it even after they are full, and even when they desperately want to lose weight.  They will leave their cozy house and pick up crackers, pretzels, fast food with fluffy bread, or a fresh loaf to eat at night. Critically, in certain cases (where more evidence-based methods have been tried), I've managed to stop these cravings and binge behaviors with naltrexone, which blocks the opiate receptors and short-circuits reward.  The problem is, ALL reward is mediated through opiate and dopamine, so using naltrexone doesn't tell you that you've blocked specific wheat exorphins - maybe the person has a real jones for fresh steaming lovely bread for simple reward sake - like some people love chocolate, Pringles, or cocaine.

It's a good message, though, and something that should be researched.  But then Dr. Davis comes up with this sentence (and also states he has seen the withdrawal and "brain fog" from wheat in "thousands of people"then later "I've personally witnessed hundreds of people…"), which is incredibly jarring and ruins the credibility of the message: "Let's pretend you're an inner-city heroin addict.  You get knifed during a drug deal gone sour and get carted to the nearest trauma emergency room.  Because you're high on heroin, you kick and scream at the ER staff trying to help you.  So these nice people strap you down and inject you with a drug called naloxone, and you are instantly not high."

Naloxone (and it's orally administered cousin, naltrexone), is an opiate blocker, or "opiate antagonist."  It will immediately knock opiates off the opiate receptor and put someone high on opiates into instant withdrawal.  This is not only extremely unpleasant, it tends to make people very agitated, unhappy, and even violent.  If you have to do it to save someone's life, you do it.  If someone is overdosing on opiates and loses the chemical signal to breathe, it will be lifesaving. If someone is alert and active and still high on heroin, injecting someone with naloxone would be a galactically stupid thing to do, particularly if you were just injured in a knife fight and needed some painkilling.  Injecting someone with naloxone will mean that the strong painkillers will not work in someone who will have a high tolerance to hospital painkillers.

Any emergency room physician, nurse, or doctor with a shred of ER experiecne will read that sentence in "Wheat Belly" and go, "huh?  What is this guy talking about, and is he galactically stupid?"

Honestly, I think it is a throwaway line that was carelessly written and carelessly published.  And other "paleo" books like  "The Vegetarian Myth" are full of lines like that.  But you know what, I have a much higher standard for a cardiologist than I do for a non-scientist like Lierre Keith.  I want real science, real risks, real data.  Not hyperbole and nonsense.

So no, I don't recommend Wheat Belly. And I don't recommend eating wheat either.

(Nor am I saying that Dr. Davis is stupid - far from it - just careless in his phrasing.  If you are going to take on Conventional Wisdom of Healthy Whole Wheat, you really have to "bring it."  It was not brought.)

Of Like Minds

As you may recall from my AHS - The People Post, one of the best experiences from my visit to Los Angeles was meeting a few other like-minded psychiatrists there.  Evolutionary medicine, as sensible and evidenced-based as I try to make it, can feel very lonely and off the beaten path.  So it is lovely to meet people who see the innate reason of it all.   The northeastern US is both protective and stifling in its conservative medical atmosphere - so to have others thinking in ways apart from psychopharmacology and psychodynamic or behavior therapy as the end-all, be-all is, well, glorious.

Beethoven - Symphony No. 9, 4th Mvt (one of the finest pieces of music ever written, though choral music is not always my favorite, I make an exception for this one - right click to open in new tab)

Not long after I returned from AHS, I received an email from a psychiatrist I had seen on Jimmy Moore's low carb doctors list, Judy Tsafrir, M.D..  She works maybe 30 miles away and has a holistic psychiatry practice in Newton (a city just to the west of Boston, which, I'm told has the highest number of psychiatrists per capita in the world - and yet we could still all be working 24/7 and turning people away.  Remarkable).  Dr. Tsafrir has extensive experience and training in both child psychiatry and psychoanalysis (unlike myself - I am a pretty run-of-the-mill adult psychiatrist).  In more recent years she has turned to dietary therapies and has become an expert in the GAPS diet.

I met Dr. Tsafrir for lunch a few weeks ago, and like most analysts she is a patient and serene sort of person - rather the opposite of myself in some ways (as I can be somewhat impatient and directive).  We talked a bit about our training and experiences and our frustration with the restrictive (and sometimes disastrous) mold that encompasses "evidenced-based medicine." And of course we are interested in the best data and best evidence for our patients, yet the money and the studies seem to be spent and performed with a different agenda.

Dr. Tsafrir has started a blog, and I am adding her to my "Of Like Minds" group to the right.  Her latest entry is about her thoughts on "Wheat Belly," entitled One Size Does Not Fit All. I encourage any readers with GAPS questions especially to take a peek, as I have only started reading the book and have no clinical expertise in that area.

People often ask me if I know of like-minded psychiatrists where they live.  There is Ann Childers, MD in Oregon, the two psychiatrists I met at AHS (I did not ask them about sharing their names or details so will not do so), and now Dr. Tsafrir!  And maybe more and more, every year.  We shall see.