That Tapeworm Ate Your Depression

I'm a little embarrassed that Mark Sisson got to this one before I did.  But I'm sure he has several minions to scan the literature for him, whereas I have a few loyal friends and fellow bloggers.  Here it is, though, a new paper from the Archives of General Psychiatry, "Inflammation, Sanitation, and Consternation: Loss of Contact With Coevolved, Tolerogenic Microoganisms and the Pathophysiology and Treatment of Major Depression."

And I have to admit, after reading Mark's little blurb, I went to the paper expecting to be annoyed.  There are a lot of versions of the hygiene hypothesis (basically the idea that our environments are too clean) that make it sound as if your mom is a crazy germophobe and that's why you have asthma. Which doesn't make sense, because that remote control your kid is chewing on has about a billion microbes on it.  Also, you will often hear that "children just aren't exposed to childhood infections anymore" as we have vaccines and smaller family sizes and antibacterial soap.  But the typical childhood infections such as chicken pox, whooping cough, diphtheria, etc. are all as modern as eating grains, and were established in humans as we developed higher population densities and domesticated animals, so lack of exposure to those bugs wouldn't necessarily mess with our evolved immune system (also, there is some (association) evidence that exposure to common viruses increases inflammation and may increase our risk for depression).  That particular version of the hygiene hypothesis is dealt a death blow by the fact that inner city kids rife with childhood infections have the highest rates of asthma, much higher than isolated rural kids living out in the country with all the ragweed (1).

But I set aside my preconceptions and took a look at the paper, and thank goodness I did, because it is epic, amazing, and brilliant.  All psychiatrists, psychologists, and other doctors download it now if you have access and have a look.  It even includes the Dobzhansky quote "nothing in biology makes sense except in the light of evolution."

So here we go.  I've made a point before that depression is a result of inflammation.  Specifically, depression is associated with higher serum levels of IL-6, NFkappabeta, TNF alpha, and a host of other pro-inflammatory cytokines.  Medically healthy individuals with depression and a history of early life stress mount a larger inflammatory response to laboratory psychosocial stressors than do nondepressed controls.   The prevalence of major depressive disorders is increasing in all age cohorts, but especially in younger people, and countries transitioning to be part of the developed world experience increasing rates of depression along the way.  One would hypothesize, then, that something environmental in the modern world makes us vulnerable to depression (and other inflammatory diseases of civilization, such as MS, inflammatory bowel disease, type I diabetes, asthma, etc.).

"Overwhelming data demonstrate the prevalence of helper T cell type I...mediated autoimmune and inflammatory bowel and Th2 mediated allergic/asthmatic conditions have increased dramatically in the developed world during the 20th century, with increases in immune-mediated disease incidence in the developing world during the same period closely paralleling the adoption of first world lifestyles." 

Asthma, hay fever, type I diabetes, inflammatory bowel disease, and multiple sclerosis have all increased 2-3 fold in the developed world in the last 60 years.  Many of these conditions are highly comorbid with major depressive disorder.

I've focused on a pro-inflammatory diet as a hypothetical cause for increasing depression (along with obesity and the other diseases of civilization).  The vast majority of the depression literature, I would say, has focused on the pro-inflammatory aspects of a stressful modern life (which I contend isn't necessarily more stressful than life was 60 years ago, or 800 years ago, during the Bubonic Plague, for example).  This paper focuses on "the loss of a microbial modulated immunoregulation" of our Th1 and Th2 immune cells.

Quick review - childhood viral infections tend to mobilize type I T helper cells.   Since Th1 cells seem to balance and modulate the Th2 cells, one might expect that a lack of Th1 activation due to a sanitized environment would lead to naughty Th2 cells running rampant, causing asthma and allergy and the like.  That makes sense, except naughty Th1 cells seem to cause other autoimmune issues, like Crohn's disease, and the incidence of Crohn's disease has increased steadily along with asthma and allergy.   In fact, "most follow up studies have failed to show an association between childhood infection and increased autoimmune and/or atopic conditions in the modern world while continuing, in general, to find correlations between a first-world lifestyle and increases in these conditions."

But humans have been living with some microorganism and parasites for much longer than the childhood infectious diseases of the last 10,000 years of agriculture.  These ubiquitous organisms seemed to keep Th1 and Th2 cells busy without causing problems, in other words, the "old friends" germs "induced and maintained an adaptive level of immune suppression."  Or:

"the mammalian genome does not encode for all functions required for immunological development, but rather that mammals depend on critical interactions with their microbiome (the collective genomes of the microbiota) for health."

What are these organisms?  First off are the pseudocommensals, saprophytic mycobacteria that are found in mud and untreated water and on unwashed food.  They don't colonize the body, apparently, but were known to pass through it in large quantities historically:

A bunch of commensal species are known to inhabit our gut, among them Bacteroides, Lactobacilli, and Bifidobacteria.  And finally, the helminths (internal parasites, such as tapeworms) are the third member of the triad of "old friends."

There is a whole body of literature dedicated to animal studies showing how exposure to these "old friends" reduces autoimmine, inflammatory conditions, and even cancer.  A sugar molecule from Bacteroides species protected against colitis and distorted immune system development in germ-free mice.  Prebiotics known to increase Bifidobacteria in the rodent gut reduced serum concentrations of cytokines such as TNF alpha and IL-6.  "Metabolic products from gut microbiota reduce inflammation in animal models of a variety of human autoimmune and allergic disorders, as well as in [test tube] preparations of human [immune cells].  The health of the human gut microbiome has been shown to impact varied physiologic processes such as pain sensitivity, sleep, and metabolism (all of which are abnormal, by the way, in major depressive disorder.)  A parasitic worm, Schistosoma mansoni, can make a friendly phospholipid for us, phosphotidylserine.  Exposure to a pseudocommensal organism, M vaccae, reduced serum TNF alpha concentrations over a three month period compared to placebo (in humans and human monocyte cell lines).  Recall that TNF-alpha is increased in depression, and antidepressants reduce TNF-alpha - it does make one wonder if these "old friends" have antidepressant effects.

Without constant exposure to these immune modulating "old friends,"  it is plausible that modern humans are at risk for mounting inappropriate inflammatory responses, leading to many of those undesirable diseases of modern civilization, including depression.  I wonder if using inappropriate food, such as vast quantities of fructose, could destabilize the gut microbes and be part of the inflammatory process.  One could further postulate that exposing depressed individuals to "old friends" could act as a treatment.

Gut-depression links are already well known - psychological stress in humans is associated with reduced fecal Lactobacilli, and individuals with major depressive disorders had some fragments gut bacteria inappropriately floating around in their blood, suggesting the presence of leaky guts.  One small study showed that giving people a prebiotic that favors Bifidobacteria reduced anxiety in patients with irritable bowel (2), and another 2 month placebo-controlled study showed that lactobacillus treatment reduced anxiety (but not depression) in people with chronic fatigue (3).  Probiotic treatment did not reduce depressive symptoms in chronic fatigue patients in another small study, but it did improve some cognitive symptoms that are common in major depressive disorder (4).  M vaccae was administered to patients with renal cell cancer, reducing serum IL-2 and some depression symptoms (5), and in another larger study, killed M vaccae reduced depression and anxiety symptoms in lung cancer patients receiving chemotherapy (6). 

There is a long way to go before we start feeding people dirt and worms as an evidenced-based strategy for treating depression.  But...the ideas are intriguing, based in common sense, and scientifically sound.  People with the "short" genetic form of the serotonin receptor, for example, are known to be more vulnerable to major depressive disorder, and they are also more vulnerable to known forms of depression caused by inflammation, such as depression caused by interferon alpha treatment.  These findings link genetic vulnerability to environmental inflammatory factors to depressive symptoms.  Priming the body with known anti-inflammatory modulators should help depression.  Even if it might not seem that...tasty.

The Monolith

Where evolutionary psychiatry meets history and anthropology is where we become modern humans. It is a tricky question when that happened, because as best as we can tell, we have been genetically modern for the past 200,000 years, yet we didn't have beads and art and tool advances and religious icons and all those uniquely human attributes until 60-80,000 years ago.  Here's a song (right click in new tab) to get you thinking on it.

It is hard to imagine you and me and our neighbors sitting around twiddling our thumbs for 120,000 years - surely we would have carved a bead or two and perfected the spear along the way. But there's no evidence we did anything of the sort until some folks in southern Africa started munching on shellfish. All modern humans are descended from those southern Africans who later migrated up to the Middle East. And anthropologists who followed the trail of our ancestors found the first evidence of widespread consumption and transport of shellfish.

Shellfish are rich in iodine and omega 3 fatty acids. We've discussed the omega 3s at some length, but now let's look at iodine. Iodine is needed to make thyroid hormone, which in turn stimulates the enzyme tyrosine hydroxylase, which is an essential step in the making of dopamine, that neurotransmitter responsible, perhaps, for us being all too human. In addition, the omega 3 fatty acids increase dopamine receptor binding and dopamine levels.

Gagneux et al notes that there appears to have been a huge increase in T3 (thyroid hormone) with the advent of modern humans (chimps, for example, have much higher levels of transthyretin, which binds thyroid hormone and keeps it inactive). It is noted that both chimpanzees and Neanderthals had superficial features in common with developmentally iodine-deficient humans (large femurs, extended brows, and shorter stature). Humans have larger thyroids than chimps, whereas chimps have larger adrenal glands (brain dopamine is essential for inhibiting the systemic arousal caused by activation of the adrenal glands).

Shellfish aren't the only explanation for the rise of modern humans. After all, plenty of animals eat crabs and the like and they don't fly airplanes or...blog. Another (even more speculative theory) suggests that increased human intelligence via marine animal consumption led to longer lifespan, which led to increased populations and increased socialization, communication, and migration. The competitive stresses and achievement drives to out-perform one's neighbor would have plausibly helped to select for brains with more dopamine - though as you may recall there don't seem to be any specific genes for dopamine lateralization. And, once again, we are genetically and physically very similar to our ancestors of 200,000 years ago (except our brains are a little smaller). I'll let Previc explain: "Cultural and dietary influences on dopamine, transmitted prenatally, would have been passed on and enhanced in successive generations and thereby rendered a permanent part of our inheritance. Even when humans moved inland and no longer relied as much on aquatic fauna, their dopaminergically mediated cultural achievements were self-sustaining."  It was just around the time of this human mind "Big Bang" that we went through a population bottleneck.  All of us are descended from a few thousand people from 65-70,000 years ago - Previc doesn't mention this bottleneck in his book, but the timing is mighty suspicious.  It might be that only the humans who were able to fully utilize our super dopamine tracts were able to survive whatever crisis rocked our species back then.

So our ancestors did not need a monolith to spark our leap forward - we needed some clam-digging and crab catching. Iodine and omega 3s enhanced our dopamine-dependent traits - enhanced working memory, cognitive flexibility, the capability of thinking in temporal and spacial distance, creativity, and increased mental speed. This dopamine upgrade in our processing skills enabled art, advanced tool-making, language (not just speech, which seems to have evolved earlier), and long-distance exchange. It made us modern and uniquely capable of wonder and destruction on a scale known only before to nature itself.

Pleasure, Pain, Wheat, and Psychopharm

There is something of an addiction theme out in the blogosphere today.  Mark Sisson is talking kicking the junkfood habit, and Dr. BG is talking politics and CRACK.  I thought I would throw in a little neuromapping of pleasure and pain, as hey, apparently folks like a bit of neuroanatomy (who'd a thunk?) with their grain-free Evolutionary Psychiatry.  Also, there's a new medicine for weight loss that will likely approved by the FDA, called "Contrave," and how it works has everything to do with subverting and modulating pleasure.   So let's dive in.

My source for today's post is mostly the clever Dr. John J. Medina, who writes a "Molecules of the Mind" column for Psychiatric Times.  Finally, someone with a geekier column than "Evolutionary Psychiatry." 

Pleasure in the brain is primarily mediated through the neurotransmitter dopamine.  Neurons in the ventral tegmental area (the starting post for those dopamine tracts I talked about a few days ago) respond to sex, drugs, rock n' roll, food, and communicate with some other neurons in the nucleus accumbens, and a third neural network in the amygdala and the ventromedial prefrontal cortex.  These are all segments of the "medial dopamine tracts" I reviewed at some length a few days ago.  It may be of interest that those of you who derive pleasure from other people's pain (schadenfreude) experience your mischievous pleasure here as well.

Pain is experienced in the aptly named "cortical pain network,"  which are regions of the brain a little separated from the pleasure centers.  The different areas of the pain network collect sensory pain (such as a splinter in one's finger) and emotional pain.  Typically, experiments used to isolate pain circuitry in the brain involve "aversive stimuli" such as electric shock.

So it turns out that social pleasure and pain have hijacked these evolutionary circuits of pleasure and pain, so that if you score a date with that hot chick and share a high five with your frat brothers, or you get arrested for that meth lab you are running in the basement of the chemistry building at school, you will experience the pleasure and pain in the same areas of the brain that you experience sex and electric shock.  It hurts to be human, sometimes.    If you feel that you are fairly treated and are feeling cooperative, your pleasure centers are stimulated.  If you grieve the loss of a loved one, your cortical pain network lights up.

And what about opiates or wheat exorphins or binge eating?  Turns out those activities stimulate the dopamine reward centers of the nucleus accumbens.  That new weight loss drug is a combination of two older drugs, naltrexone and buproprion (wellbutrin).  Naltrexone is a straight-up opiate blocker.  It is FDA-approved to reduce cravings for alcohol, but to be honest I use it more often for people trying to kick an oxycodone or heroin habit.  You have to be off opiates for a couple weeks or risk an exceedingly uncomfortable precipitated withdrawal, and once you are on naltrexone, your opiate tolerance will drop like a rock, so if you go back to using like you used to, you could easily overdose.  But naltrexone isn't a controlled substance, and if you take your medicine as prescribed and try to use opiate drugs on top of it, those drugs won't work.  There's nothing like a pharmacologic lock on the opiate system to help out an opiate addict.   Naltrexone has been studied in binge eating and in gambling, and for some people, it seems to help.  I've used it on a couple of occasions for sleep eating with extreme carb (grain) cravings with some success, also in patients with celiac who can't seem to kick the wheat habit.  Naltrexone use requires monitoring of the liver, and typical side effects include upset stomach.  But both of those are less noxious than a heroin habit in my opinion, but every case is different and risks and benefits must be discussed for each situation.  

Buproprion (wellbutrin), the other drug in Contrave, was discussed in Antidepressants and Weight Gain or Loss.  It helps keep the dopamine systems humming along without interruption, so you don't necessarily need that lift from vegetable oil laden fast food french fries.  Wellbutrin can cause seizures, irritability, insomnia, and anxiety, so not a bucket of laughs by any means, but all things considered has some of the fewest side effects of any antidepressant.

I'm not clear that any insurance company in Massachusetts will pay for a combination of two medicines you can likely prescribe cheaply separately for less cost.  And I hope that my readers understand that I think a paleolithic (or, if you are a conservative sort, Mediterranean) style diet (Dr. Parker reminds me that I mean carbohydrate-restricted versions of these for most people trying to lose fat) should be attempted along with proper exercise before we hand out pills to lose weight.  In the studies, Contrave resulted in 5% weight loss.  So that's good for improvement of some health conditions, such as diabetes or hypertension, but it won't make you the star of a hydroxycut commercial by any means.

Addiction is tough.  Those who suffer need all the help they can get.  Sometimes that means the judicious use of pharmacology.  Most of us can get by with a bit of knowledge and (if we're lucky) some self-restraint.

Your Brain Loves Cholesterol (Don't Go Too Low)

Sometimes this blog writes itself.  Today I was sitting around minding my business, spreading happiness and serenity, when I got an email from the Amazing Jamie Scott, who sent me a link to this paper: Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism.  And then my receptionist handed me my mail, and the top story of this month's Psychiatric Times is "Statins, Cholesterol Depletion, and Mood Disorders:  What's the Link?"

I'm beginning to feel less small and alone in the world.

Let's start with the Psychiatric Times article.  Statins, as most biochem nerds will know, are pharmacologic inhibitors of HMG-CoA reductase, which is the key rate-limiting enzyme in the biosynthesis of cholesterol.  So our livers, doing their best to kill us off with heart disease, make cholesterol like mad fiends, while a statin will slow that pesky liver down, lowering serum cholesterol, and allowing us to live forever.*  Or something like that.

But throwing a monkey wrench into the cholesterol machinery has some... issues.  For one thing, it seems to ruin the binding and G-protein coupling (total random aside - at my medical school we had several professors of biochemistry who had Nobel Prizes to their name - among them Brown and Goldstein for their elucidation of the metabolism of cholesterol, and Gilman who discovered the G-protein.  And here they are, together at last on my heretical blog) to the serotonin IA receptors (1).  That's probably not the best thing to do - decreasing the ability of the serotonin IA receptors to work can lead to anxiety and irritability.  At the same time, there seem to be other changes in the actions of receptors in the context of "chronic cholesterol depletion" (I bet you would never find that phrase in 'Cardiology Times.').  As we know, low serum cholesterol is associated with violence, accidents, and suicide.

Now it is my pleasure to introduce Dr. James Lake, a psychiatrist and chair of the APA's Caucus on Complementary and Integrative Medicine (that's mainstream medicine talk for "woo."  I emailed one of my residency mentors about my blog a few months ago as I had some questions for him - he wrote back after reading some of the entries and said I was the "alternative Harvard Mental Health Letter" - I'm still not sure if that was a positive or negative comment).  Anyway, Dr. Lake seems to have drunk some of the same kool-aid that I have, as he recommends that depressed patients with elevated cholesterol aim not to go lower than a total cholesterol of 160.  How very reasonable!

He's also been hanging out with Dr. Beatrice Golomb, who has studied data from a few websites and run some surveys of her own.  In an analysis of 324 emails of people taking statins who were bothered enough to go out of their way to email "https://www.statineffects.com/" or "http://www.askapatient.com/," 30% reported mood changes such as depression, irritability, and anxiety.  When patients who complained about statin side effects were asked survey questions, 65% of 843 endorsed increased anxiety or irritability and 32% reported an increase in depressive symptoms.  Golomb published a case series of 6 patients who self-referred with irritability or short temper on statins (including "homicidal impulses, threats to others, and road rage") - in 100% of cases, stopping the statin cured the symptoms, and 4 of the 6 had renewal of the symptoms with a statin rechallenge. 

Granted, these are all people who complained of symptoms in the first place, so it is hardly a random sampling, and the case series could represent the nocebo effect.  But when I looked at the PDR for Crestor a few months ago (I can't seem to find it again on the internet, but if I do I will link it), I didn't find anything on irritability or anxiety, and depression was only mentioned briefly as an "aftermarket" side effect - meaning the crestor folks didn't find those to be side effects in their carefully controlled studies, but there are now some reports of depressed mood in the general public after release of the medicine.  To me that just doesn't quite add up to my own experience.  I've had several situations clinically where withdrawing the statin resulted in immediate improvement of anxiety, depression, and/or irritability for some treatment resistant patients.  Of course that could be nocebo too, but nocebo and placebo effects tend to wear off after about 3 months, and I've seen patients improve after 2 years, and the biological mechanisms seem plausible.  Well, definitive answers will wait for another day.

Statins improve mortality for middle-aged men who have known heart disease, have had a stroke, or have high levels of inflammatory markers.  If you don't meet those particular criteria, statins will give you no mortality benefit.

But let's not be so negative - a literature review involving statins and mental health "found no statistically significant effect" of low cholesterol on psychological well-being.  However, there may be a difference among the different statins.  Simvastatin can readily cross the blood brain barrier, whereas pravastatin really can't.  Golomb tested 1016 healthy men and women for 6 months with simvastatin, pravastatin, or placebo.  Those on simvastatin reported significantly worse sleep, and, if sleep was impaired, worsening aggression.  It was felt that statins that cross the blood brain barrier inhibited serotonin production.  Interesting.

Now onto Jamie's paper - which is a study of diabetic mice.  The researchers found that insulin-deficient diabetic mice had a reduction of a major regulator of cholesterol metabolism, leading to a reduction in brain cholesterol synthesis and lower synaptic cholesterol content (that's bad).   The decline in brain cholesterol production happened in cases of insulin depletion OR hyperglycemia in various mouse models of diabetes type I and II, but not in obese (but normoglycemic) or insulin resistant (but normoglycemic, meaning high levels of circulating insulin were needed to keep the blood sugars normal) mice.  Diabetes type I and II can both lead to CNS complications, including delirium and faster than "normal" decline in cognitive functioning.  Diabetics, as we know, have higher rates of depression and Alzheimers.  The brain contains 25% of the cholesterol in the body, and much of it is made right in the brain.  Therefore diabetes produces a "global suppression of the enzymes of cholesterol synthesis and their master transcriptional regulator, SREB-2 in the brain... [which alters] neuronal and physiological function."  A lot of this action occurs in the hypothalamus, which is a major point of control of the endocrine system, appetite, and energy balance. 

Sometimes it all comes together.  The bottom line?  Eat whole real food, not tons of sugar and linoleic acid or wheat.  Don't get diabetes if you can help it.  Don't let anyone or anything suck the cholesterol out of your brain.  Once things get out of whack, they can continue to be out of whack in all sorts of disastrous ways for quite a while.

* not really

Genius and Madness

In the Dopamine Primer 2, I covered the four major dopamine tracts in the brain.  Today I'll break down the two most important ones to psychiatrists and anyone interested in the fabulous story of human evolution and greatness, the mesolimbic and the mesocortical pathways.

For simplicity sake (as mesolimbic and mesocortical don't have a whole lot of meaning unless you are versed in neuroanatomy, also because the mesolimbic system ends in the cortex so it is also mesocortical, and that's hella confusing), I'm going to call them the "medial" and "lateral" dopamine tracts respectively.  The medial tracts go from the center, primitive, animal parts of the brain up to the emotional centers of the brain, and then to the front part of your brain (literally the center of your forehead, more or less).  The lateral tracts go from the center, primitive, animal parts of the brain up around the outside and end up more by your eyeballs (more or less).

Both tracts carry dopamine, but the tracts are responsible for somewhat different human behaviors.

The lateral tracts are responsible for:
Future-orientation in predicting events
Strategic thinking
Rational, abstract thought
Focus and control
Unemotional

Someone who has an optimal amount of dopamine in the lateral system is going to be self-contained, practical, self-confident, and able to forgo immediate gratification in order to ensure greater reward later on.  He or she might be the perfect person to bring with you on an expedition somewhere.  However, an extreme "lateral dopamine" type person wouldn't be the one you might confide in with emotional problems.  Also, on that expedition, if you break your leg and no longer become practical, it might be just a little too easy for he or she to leave your burdensome self there in the wilderness.  So the dark side of dominant lateral tracts would be grandiosity, ruthlessness and sociopathy.   

The medial tracts (more emotional in nature rather than rational thought) are responsible for:
Action
Aggression
Future-orientation in exploration (motivation and drive)
Creativity (along with paranormal experiences and psychosis)
Hyperactivity and impulsive behaviors
Euphoria and pleasure-seeking

A more medial dopamine personality might be a bit wacky, impulsive, and free-thinking.  A hippie or an artist.  Not particularly good at planning, but often compelling, creative and interesting.  Maybe not the first person you would want to take into the wilderness, but perhaps capable of intuitive leaps of logic that could get you out of a real jam.  And as it is the serotonin/norepinephrine right brain tracts that are more responsible for emotional sensitivity and understanding social cues, the medial dopamine dominant personality may not be particularly empathetic, and might wander off and leave you alone in the the wilderness as he or she might think of something better to do.  The dark side of the medial dopamine dominance would be psychosis, paranoia and irresponsibility.  (Keep in mind that these are all generalizations - all the tracts interact in complex ways so there is rarely any such thing as a pure "medial dopamine personality.")

Too much excess in the medial dopamine tracts leads to madness.  Irrational thought, paranoia, loose thought associations, psychosis.   In just enough excess it is creative genius.  Families with schizophrenics are also more likely to have more creative individuals.  And many people considered geniuses also suffered madness, such as Nobel Prize winner John Nash, a schizophrenic who had this to say when asked how a mathematician devoted to logic and proof could believe that extraterrestrials were sending him messages:  "Because... the ideas I had about supernatural beings came to me the same way that my mathematical ideas did."   Unfortunately, since schizophrenia is ultimately an inflammatory  neurodegenerative disease, it is unlikely that a genius suffering from schizophrenia could maintain brilliance for more than a few adult decades. 

It is an interesting observation of Previc's The Dopaminergic Mind in Human Evolution and History in that these two tracts seem to line up with Freud's separation of the human mind into the ego and the id (the id here being primitive drives of sex and pleasure-seeking, loose thought processes, and impulses of the medial dopamine tracts, whereas the ego weighs risks and benefits before jumping into any particular course of action - a lateral dopamine action.  Freud's superego, or the conscience, is more likely more associated with those socially directed serotonin/norepinephrine right-brained tracts).  

Estrogen has a tendency to inhibit dopamine (allowing for a greater dominance of social empathy, balance and those norepinephrine/serotonin pathways), whereas testosterone will tend to enhance dopamine.  In the agricultural past, dopamine dominance has allowed for greatness and male dominance - Previc lists the following famous men in history and their "dopaminergic traits":

Alexander the Great - high intelligence, visionary, motivated, risk-taking, self-confident, but also grandiose, ruthless, restless, and paranoid.

Columbus - intelligent, visionary, motivated, self-confident, risk-taking, but also grandiose, ruthless, and restless.

Newton - extremely high intelligence, visionary, self-confident, motivated, but obsessive, lacking empathy and social skills, ruthless, paranoia, and neglected personal hygiene from time to time.

Napoleon - intelligent, visionary, motivated, risk-taking, self-confident, but with delusions of grandeur, ruthlessness, and restlessness.

Einstein - extremely high intelligence, visionary ideas, high motivation, self confidence, but had obsessiveness, lack of empathy and social skills, grandiosity, and personal hygiene neglect.

Which brings me to the present day, where is some respects things have flip-flopped between men and women, at least in America.  According to a recent article in Time Magazine about the "Sheconomy,"  young single urban women outearn young single urban men, and while 35% of women aged 25-29 have a college degree, only 27% of men do.  There is something going on (socially, in culture, environmentally?  I could barely hazard a guess)  that is making it easier for women to remain focused on long-term productive educational goals (a dopamine trait) in their youth.  Women now own 1/3 of the businesses in America.  As women still pay a major career penalty for having kids, and previous generations still control the Fortune 500, women have not cracked the higher echelons quite yet.  But the Generation Y numbers could indicate that it is only a matter of time.  And women still have the estrogen/serotonin/norepinephrine advantage of better being able to read social cues, which is an a helpful trait in sales, business, and even politics if coupled with enough grandiosity.

In an agricultural world, vision, ruthlessness and sociopathy allowed for one man to grab all power at the expense of his neighbors, creating kings.  In a post-industrial world, the hyperdopamine advantage may not be quite so simple.

Rant

Pubmed is awesome. It makes us all into research giants from home. I've even made my own username and password in "My NCBI" and programmed in some automatic searches, so the first Saturday of every month (today, as a matter of fact), Pubmed sends me some emails about the latest research pertaining to my keywords of interest. Today I received several emails, one of which contained a link to this piece of crap review paper from some unfortunate primate researchers in Oregon, "Perinatal Exposure to High-Fat Diet Programs Energy Balance, Metabolism and Behavior in Adulthood."

In my endless optimism, I think, hey, maybe here is a paper that discusses some neurobiological programming related to the quality of the diet. That would be awesome! But no! Do me a favor and take a gander at the abstract. Here, I'll copy a sentence for you: " Evidence from a variety of animal models including rodents and nonhuman primates indicates that exposure to maternal high-fat diet (HFD) consumption programs offspring for increased risk of adult obesity. Hyperphagia and increased preference for fatty and sugary foods are implicated as mechanisms for the increased obesity risk." The takeaway point of the article is that if you eat a "high fat" diet in pregnancy, you will have fat, depressed offspring.

Now this is a review paper. I read the whole thing. There is next to no information on the actual macronutrient content of any of the diets studied (in rodents and primates). However, there is a seeming equilibration between "junk food diets" and "high fat diets" that sets my teeth on edge. And I've read enough Hyperlipid to know that a typical research "high fat" diet for rodents is comprised of sugar and crisco or some other trans fat industrial nightmare.

So if one were, say, a journalist, without knowing the context, who had the same "My NCBI" keywords programmed in that I do, one would find this review paper and pen some misinformed news item telling everyone to avoid fat while pregnant because it will make your kids fat and depressed. So pregnant women will eat their whole wheat toast with an apologetic smear of margarine and consider themselves healthy, and wonder why they fail the oral glucose tolerance test at 21 (or 28? I forget) weeks.

JUNK FOOD does not equal HIGH FAT DIET.

Junk food is loaded with vegetable fat, grains, and sugar, all cheap commodities to make cheap, industrial, disgusting "food."

If you load up on junk food during your pregnancy, studies of rodents and nonhuman primates indicate that your kids will be more likely to be obese and crave junk food, and will be depressed.

It is not about the macronutrients. Not for children with fresh pancreases and livers. It's about the quality. Give them nutrient-rich, fresh, non-processed amazing food. Forget about whether it is high fat or high carb. It doesn't matter. Just don't poison them with omega 6, trans fats, grains, and industrial fructose.

Well, I have to finish cleaning up before the babysitter comes over so my husband and I can enjoy a proper holiday party. How is it that a 29 pound 18 month old can undo my organization much faster than I can organize? #entropy.

Brain Efficiency, Pediatric Edition

Back in November, I wrote a post titled Brain Efficiency that detailed some of the links between mitochondrial dysfunction and Parkinson's Disease.  The mitochondria are the energy powerhouses of the cells, cranking out ATP (cell gasoline) to keep pace with all our cells need to do. 

Classically, mitochondrial dysfunction was felt to be relatively rare, and it was usually investigated in cases of chronic fatigue, unexplained muscle weakness, that sort of thing - we medical types are a literal lot.  "Goodness, you have no energy?  Maybe we should see if your cells can make energy."   

However, my readers know that that pile of gelatin quivering between your ears is one of the most energy hungry parts of the human body.  It is 5% of our body weight, but comprises 20% of our metabolism.  Therefore, any genetic predisposition to dysfunctional mitochondria may show up was a brain problem.

Earlier this week, this article was published in JAMA, "Mitochondrial dysfunction in autism." This is the first study to examine the function of mitochondria in a well-defined population of children with autism, which is a disorder that strikes in infancy to early childhood and can result in poor social skills, developmental delay, and stereotypical repetitive movements among other symptoms.  It was a small study, 10 children diagnosed with full spectrum autistic disorder and 10 controls, but they examined everything soup to nuts, as it were.

The children and their cells were examined for problems with mitochondrial DNA, the actual energy-generating capacity of their actual mitochondria (lymphocytes* were put on ice and immediately taken to a lab to measure the respiration!), and for signs of leftover metabolic garbage hanging around.  The results were pretty remarkable. 


Cell respiration (mitochondrial capacity to take glucose (or ketones!) and oxygen and turn it into energy) can be measured by the amount of input of fuel and output of the byproducts of respiration.  I'm not the most mechanical of people, but I imagine measuring cell respiration has the automotive equivalent of measuring horsepower.  Some of us have Ferraris, others Ford Festivas, and most will be somewhere in between.  The autistic kids had lower average NADH oxidase activity - their average was 4.4 (95% CI, 2.8-6) as opposed to 12 (95% CI, 8-16) in the control kids, and the majority of the autistic kids had levels that were below the range of the control kids.  The mitochondria of the autistic kids seemed to putter along, compared to the more zippy mitochondria of the control kids. 

Now let's look at some metabolic byproducts of slow or inefficient cell respiration.  Higher pyruvate levels were found in the autistic kids (pyruvate levels should be relatively low if your mitochondria are efficiently processing oxygen and glucose) than in controls (0.23 vs 0.08), and 8 out of the 10 autistic kids had pyruvate levels higher than any of the controls.  This finding matched the decreased amount of pyruvate dehydrogenase activity found in the autistic kids.   Levels of hydrogen peroxide were also higher in autistic kids.  

At a genetic level, the kids with autism had a lot more copies of mitochondrial DNA in their cells.  (Our mitochondria are probably evolved from energy-producing bacteria that another ingenious and cheeky cell gobbled up long, long ago to create its own internal power plant.  Therefore our mitochondria, within our big old animal cells, have their own DNA called "mitochondrial DNA."  This mDNA (also sometimes called mtDNA) is inherited from our mother, and her mother, and her mother etc. etc. back to that first precocious gobbling cell, as we get all our cell organelles from our mother's egg, and only a bit of good old human DNA from Dad.).  An average human cell mitochondria has 2-10 copies of its DNA hanging around.  5 of the autistic kids had more mDNA than expected.  2 of the autistic kids also had deletions of certain areas of their mitochondrial DNA.

So what does all this data mean?  It was felt, all told, that the autistic children had cells that were in a state of chronic oxidative stress.  This would explain not only the respiration issues, but also the higher copies of mitochondrial DNA, made either due to errors from free radical damage, or to compensate for the inefficient mitochondria.  But don't jump to conclusions.  We don't know if mitochondrial dysfunction is the cause of autism, or one of the myriad effects.  Maybe the kids were born with Ferraris, but adulterants in the fuel causes it to run like a Ford Festiva.  It also make sense, as we know the brain needs  efficient mitochondria motoring along to keep all those ion gradients that power thinking online, that inherited defects in mitochondria could leave one more vulnerable to developmental insults and problems as the brain forms.

This finding could relate to modern diets and habits in all sorts of ways.  It occurs to me that one stand-out epidemiologic link to increased rates of autism is in kids whose moms had gestational diabetes, so presumably higher glucose, insulin, and other neuronal hardships for the developing baby.  We also know that ketosis helps mitochondrial efficiency and promotes neurogenesis and neuronal repair - vitamin D also has a role in promoting neuronal repair.    And inflammation in general would require mitochondria to be in tip top shape to keep up with the metabolic requirements and clean-up. 

I love it when a little more information comes along in real time to add a piece to the puzzle.

*lymphocytes are cells of the immune systems and easily sampled from a simple blood test, compared to painful muscle biopsies or scary brain biopsies.  Since lymphocytes use equal amounts glycolysis and oxidative phosphorylation to make energy, it was felt they would be a fair tissue to use to measure oxidative capacity of the cells of the autistic children versus the control children.