What is Evolutionary Psychiatry?

I am in the midst of a new academic year of talks. Last week I went to the Brigham and Women's Hospital behavioral neurology interest group talk, and last Thursday to Boston University Medical Center Psychiatry Grand Rounds.  I do like these academic talks, though naturally the audience is much more skeptical than the Ancestral Health Symposium and PaleoFx folks. Skepticism is good. Keeps me on my toes. At the Brigham Behavioral Neurology group, I had immediate questions involving how long our ancestors lived, how old was the individual who owned the beautiful choppers in the ancient Maori skull when he/she died, and what exactly were the questions asked by Staffan Lindeberg and company to determine that the Kitavan elders didn't seem to have symptoms of dementia.

All important questions! I didn't have answers to as many as I wanted to… but I think I held my own. I do try to make the point that my blog is not about answers, but rather about asking these questions for research in a meaningful way. If the government food plate leads us to "whole grain" sugary honey nut "O" cereal as a big healthy part of our diet, and beautiful nutrient-rich egg yolks are deadly, maybe we should step back and think about that for a moment.

Grand Rounds at Boston Medical Center went well. I thought the talk was received with interest, and I certainly thank Dr. Searl and Dr. Chapman for inviting me to speak. I hope that someone thinks about a research idea…I'm particularly hopeful that we will get more research about fructose malabsorption and depression. We'll see.

Them Swoops: Work Around It

Recently I've been hard at work reading an amazing textbook about the immune system and evolution recommended to me by Kurt Harris.

The textbook has quite a bit to say about mental illness, a whole chapter (pages 189-220), which is quite amazing, as most anthropology and hygiene hypothesis tends to avoid mental illness. So much easier to focus on diabetes and obesity and autoimmune disease. All easily marked and tallied. Not so mental illness, defined by the recipe book of symptoms we call the DSMIVTR.

Well. Stress-related psychiatric disorders (which is nearly all of them, when I think about it), particularly depressive and anxiety disorders, are associated with markers of inflammation, particularly raised levels of proinflammatory cytokines.  Some of the proinflammatory cytokines (most famously interferon alpha, used to treat hepatitis C) can induce depression in folks with no previous symptoms. Thus it is reasonable to assume that immune dysregulation, that is our immune system a bit out of whack, like an army milling about without clear leadership, could be part of mental illness.

Like autoimmune disease and allergic disorders (athma, hay fever, type I diabetes, multiple sclerosis, and inflammatory bowel diseases such as ulcerative colitis) have been increasing preciptiously in the developed world in recent decades. The "old friends hypothesis" suggests that we are, in effect, missing a major regulator of our immune system that we co-evolved with for thousands upon thousands of generations. That is, three classes of organisms who have lived within us or passed through us, all of our ancestors, until very recently. They are the pseudocommensals, the commensals, and the parasitic worms. (More about the old friends hypothesis in this article.)

The down and dirty of it is that we have several arms of our immune system, kind of like infantry and navy and military intelligence. There are various forms of T helper cells (Th1 and Th2) that secrete inflammatory cytokines to tell which arms of our immune system to come forth and attack.  What will tell the Th1 and Th2 cells to back off is a third variety of T cell, called Tregs (short for regulatory T cells). Infection with our "old friends" (such as pinworms, or tapeworms, or the pseudocommensals like soil mycobacteria) seems to cause continuous activation of the Tregs, keeping the Th1 and Th2 cells in check. In effect, these "old friends" organisms have always been there, and have become a part of our immune system. It is no wonder that we have problems when we no longer have the old friends at our disposal.*

Both Th1 and Th2-regulated inflammation have been associated with anxiety and depression. The "pro-inflammatory cytokines" IL-1, IL-2, IL-6, IL-12, TNFalpha, and interferon alpha and gamma. On the Th1 side, IL-6 and IL-1 levels are related to symptoms of depression in cancer patients and others. Downstream agents, such as C reactive protein, cerulosplasmin, and lower levels of zinc and albumin are also associated with depression symptoms. There are also increased levels of neutrophils and complement proteins** seen in acute exacerbations of bipolar disorder and major depressive disorder. Seems that people with increased levels of background inflammation are more susceptible to interferon and IL-2 administration causing depressive symptoms as well.

When we go over to the Th2 side of things (Th2 excess seems to be associated with allergies and hay fever and ulcerative colitis, whereas Th1 excess is associated with other autoimmune diseases such as type I diabetes and crohns), the evidence for specific cytokines is not as clear. However, people with allergies are known to have a greater incidence of depression. 50% of asthma sufferers seem to have clinically significant depression, and allergies are associated with an increased risk of suicide.  Asthma is also clearly associated with anxiety (in studies, and also any experienced clinician can tell you… trouble breathing causes great anxiety and worries about future attacks). However, that association begs an important question…is it the immune dysregulation causing both anxiety and asthma, or the asthma symptoms particularly prone to causing anxiety? Until we have a better handle on the Th2 cytokines such as Il-4 (experimental tests are problematic) we may not know.

So, there is an enzyme called IDO, which can act on tryptophan leading to a depletion of serotonin. Inflammation seems to activate IDO, whereas antidepressants (such as SSRIs) seem to deactivate it, which may be the secret to how they might work. In pregnancy, there is a bias toward Th2 and regulatory T cells (thought to prevent immune attack on the growing fetus. Mothers-to-be are in a somewhat immune compromised state, particularly in the third trimester, which can actually decrease the incidence of some autoimmune symptoms during pregnancy). After pregnancy, however, there seem to be a Th1 "bounce back" that can lead to exacerbation of inflammatory disorders and depression. There is increased metabolism of tryptophan and increases in Th1-related cytokines.

The Dead Weather: I Can't Hear You (starts with an ad that can be skipped after a few seconds) 

What about the gut and depression? Are raised levels of immune cytokines seen in depression caused by "leaky gut"? Levels of antibodies directed against several gut bacterial species are elevated in people with depression, suggesting leakiness. Leakiness is associated with increased bacterial endotoxin crossing the gut barrier, leading to increases in proinflammatory cytokines, which could plausibly cause depression symptoms. Gut epithelial barrier permeability is highly dependent upon the enteric immune system, and parasites and healthy, normal commensal organisms may help regulate and protect normal gut integrity. It's not a coincidence that Chron's and ulcerative colitis are associated with higher levels of affective disorders. 

Depression is also very common in folks with vascular disease (those at high risk for heart attacks and thrombotic strokes). Metabolic syndrome, associated with athersclerosis and heart disease, is also associated with depressive symptoms. Brain-derived neurotrophic factor (a nerve fertilizer of sorts) seems to be diminished in depression and in vascular disease. Levels of BDNF are low before treatment, and seem to rise in response to succesful treatment. Autoimmune diseases such as MS are also noted for low levels of BDNF. 

There are a lot of intriguing connections between whole-body immune pathology and depression and anxiety symptoms. Gut and immune dysregulation may be keys to these disorders. It will take more time and more asking the correct questions to find out whether these issues are of fundamental importance or not. Psychiatrists might want to read up on the immune system, however, as a part of continuing medical education.

*there are clear benefits to a hygenic water supply (unless you like cholera for breakfast), not eating dirt, and not having unchecked parasitic infections. Don't go drink untreated pondwater after reading this post. But my guess is that better study of these organisms will lead to safe and ingenious ways to emulate the old friends with much less risk than drinking untreated water and living with hookworms.

** a thorough grounding in immunology is beyond the scope of my post. However, these wikepedia articles can give you a good start.

Depression: A Cosmetic Cure?

"Fake it until you make it." This phrase, though often met with derision, constitutes some practical advice when dealing with a devastating problem like chronic depression.

There are, at the base of it, two major psychotherapeutic approaches to the treatment of depression. One way to explore relationships and history to find past trauma and metabolize it in order to get through it and better under stand current pain. Another approach is to focus on appropriate lifestyle and coping habits to reduce depression. The phrase "fake it until you make it" speaks to the second "cognitive behavioral" method.* One extreme (but interesting) version of behavioral therapy is called "solutions based" therapy. I learned about it in residency and dabbled a bit with the ideas in practice, but saw it popularized most recently in the scorching (but intolerably paced, plotted, and characterized) "50 Shades" trilogy. Solutions based therapy apparently helped the billionaire hero, but not enough so he could give up his sex dungeon. It takes a co-ed implausibly promoted to senior book editor to do that.

Two Door Cinema Club: Sleep Alone

In any event, solutions-based therapy begins with the "miracle question." Let's say in the middle of the night while you were asleep, a miracle happened and you were cured of depression. How do you know you were cured? What do you feel when you wake up in the morning that is different? How is your energy? What does your face look like when you first see yourself in the mirror? How would your loved ones know you are cured and what would they see? The idea is to focus on those "solutions." If being happy means having energy in the morning and looking at yourself in the mirror and seeing  bright smile, then maybe changing some habits so your sleep improves and grinning at yourself in the mirror can be part of the cure.

There is some neurobiological truth to the smile therapy. The mere act of smiling sends positive signals to the brain and can lift the spirit, while the act of scowling can make you feel immediately grumpier. It's subtle, but give it a try.

Believe it or not, there is some research to suggest that treatment with botox, paralyzing certain muscles to prevent deep scowling, can be an effective antidepressant treatment as well. And no, this treatment is not exactly "evolutionary psychiatry" but I do like to explore novel ways to look at the pathology and treatment of mental illness, and I would say the cosmetic cure qualifies. Even looking at smiling faces makes people happier. Do you think our ancient ancestors were more carefree than we are? More relaxed? More apt to smile? I wish I knew the answer to that question. It's not preserved in the fossil record.

Can butulinum toxin improve mood in depressed patients?

The largest and perhaps most famous trial of resistant depression patients was the STAR*D trial (and I did have the privilege of sitting in on some of the weekly research meetings at MGH while this trials were being conducted).  "Resistant" depression means depression that lingers despite antidepressant treatment. Only 30% of these patients find significant relief from the medication antidepressants that are available, of whatever variety. Nearly 50% of medicated patients discontinue antidepressants within 6 months, though most data suggests that treatment of 9-12 months after remission is most effective.

Other new technologies, such as inserted vagus nerve stimulation (VNS) devices and transcranial magnetic stimulation (TMS) have tried to fill the void in resistant depression treatment. They remain out of reach for most patients as insurance will generally not pay for them. The other treatment for severe resistant depression is electroshock therapy, which tends to be quite effective but has many side effects and can be very disruptive. In truth, the data for resistant depression for most modalities is poor. Not much we've discovered so far will work well, and drug companies don't want to spend millions on a trial that will likely result in failure. To find a new experimental method used in resistant patients is actually rather exciting.

(Lest we get too excited) the study I'm reviewing is merely a pilot trial.  30 people with resistant depression (average duration of 16 years) were randomly assigned to botox injection or saline placebo injection (and by the end 90% of people were able to tell whether or not they got the active agent, which pretty much negates the blinding). The single injection was made into the glabellar region (right at the top of the nose, where forehead scowling lines will center). To try to preserve a bit of experimental blinding at least for the raters for the follow ups, everyone wore a skullcap to cover the forehead. Scale ratings were done via the rather classic Hamilton D 17 item depression scale.  Inclusion into the trial involved full structured clinical interview with a diagnosis of major depressive disorder, which is gold standard. Response to treatment was tracked from week 2 to 16 weeks after the injection.

HAM-D scores improved a whopping 10.1 points in the treatment group in 6 weeks versus 1.7 in the control group. Nonresponse is characterized as a <25% reduction, partial response a 25-50% reduction, and >50% reduction in HAM-D score is considered "remission" and the holy grail of psychiatry in resistant depression treatment. In this trial, partial response in the treatment group was 86.7% vs. 26.7% of the placebo. That's a pretty big deal in resistant depression. Actual depression remission occured in 33.3% of active treatment vs. 13.3% of placebo which was not statistically significant given the small sample size. Let me put it thusly:

In this little study, a single botox injection was a bit better than the classic antidepressants and really blows the expensive and/or invasive TMS or VNS treatments out of the water. The only side effect reported was a mild short-term headache. Antidepressants tend to cause sexual dysfunction and/or weight gain or stomach upset or sweating or a number of other issues, and botox needs to be repeated only every 4 months or so, rather than daily pills.

There are a lot of limitations in this study. It was small. Mostly women. Mostly the melancholic subtype of resistant depression (which can actually be easier to treat). Most of the patients guessed correctly whether they were in the treatment group or not, so blinding was a huge issue. But the theory is that the more positive facial expressions after botox treatment deliver positive neurofeedback, improving mood, and causing the treatment effect.

But, as a psychiatrist, the most exciting procedure I tend to perform on patients is checking blood pressure. It might be nice to inject some botox now and again. I'm a terrible evolutionary psychiatrist, when it comes down to it.

*In actuality, most therapists in practice combine the two methods, and a manualized and studied version of that is called short-term dynamic psychotherapy, the textbook of which was written by one of my teachers in residency, Leigh McCullough, PhD. I was saddened to learn she died of ALS earlier this year.

Omega 3, the Elderly, and Getting It Right

New study seen on twitter (as I see most cool stuff, partly because I can't really bear facebook and am pretty bad about checking out the usual blogs these days).

The Strokes. Last Night.

The Study (free full text): Older Women, Depression, Omega 3 Ratios, Inflammation, and Supplementation

Bam. I'm getting all Emeril about it because finally we are getting some thoughtful and complete studies. We're talking measuring the plasma membrane ratios of omega 3 to omega 6, supplementing, measuring again, and measuring inflammatory markers as well as response to supplementation. These studies are not phoned in by the statisticians after they whip up another algorithm on the supercomputer over at HSPH.*

Here we have a small randomized placebo-controlled trial of 22 elderly (66-95 y/o) depressed females given omega 3 supplementation (2.5 grams daily of an EPA/DHA 2:1 mix for 8 weeks) and 24 given a placebo (parrafin oil, lemon flavored, just like the other--known for being insoluble in water, poorly absorbed, and flammable). Not only were pre and post depression scales measured, but so were plasma membrane omega 6/3 ratios (measured as AA/EPA in HUMAN SUBJECTS, Chris Barrera), and lots of inflammatory markers (notably CD2, CD3, CD4, CD8, CD16, CD19 and the cytokines IL-5 and IL-15. What, no IL-6 and TNFa?  Little evolutionary psychiatry joke**).  (But it is important to remember that depression is associated with T cell dysfunction, particularly the regulatory T cells that but the kibosh on inflammation).

The paper proper begins with a rather awkward but correct statement: "An unbalance in polyunsaturated fatty acid (PUFA) status is observed in various pathological conditions, especially in chronic and/or degenerative diseases associated with antioxidant system deficiency."

Low DHA in the central nervous system has been associated with all sorts of badness, such as depression, anxiety, ADHD, and dementia. The elderly seem to be particularly at risk, because their ability to change other forms of omega 3 to the long chain forms needed in the CNS is decreased compared to younger folks. (Less delta6 desaturase activity.)

Results!

Rachmaninov (Vocalise for Violin).

After 8 weeks, only the intervention group with the omega 3 had a significant decrease in the Geriatric Depression Scale scores. AA/EPA ratio were significantly higher in depressed patients than in healthy ones (from another group of healthy, non-depressed elderly women who were not taking omega3 supplementation). Not surprisingly, the AA/EPA ratio decreased significantly in those taking the omega 3 supplement in the depression group, which correlated with the decreased depression scores. Ratios did not change in the placebo group or in the "healthy" group.

Inflammatory markers were significantly correlated with being depressed at the beginning of the study (not exactly a newsflash) but were not correlated at the end of the study, though there were some shifts in markers. Hey, it was only 8 weeks.

I like this study a lot, for several reasons. They used an omega 3 supplement with EPA greater than DHA, which are the only sorts of supplements shown to be effective in depression. They used an inert placebo (coconut oil is another acceptable substitute) in lieu of olive oil or (gasp) omega6 oil. They measured plasma ratios, depression scores, and inflammation.

I also learned something very interesting that I didn't know before, which is that mood stabilizers, particularly lithium, have been associated with greater AA turnover and increased DHA in the plasma membranes in the frontal cortex. One more mechanism whereby lithium is an essential micro nutrient? Maybe. One more reason to consider that we don't fully understand nutrition or the brain but we should probably take in a reasonable amount of these? Yes.

Stabby thinks we should add vitamin E as well.

*There is something to be said for supercomputers and 100,000 person data sets. But I'm not going to eat corn oil and kashi.

** from the study "numerous studies have indicated major depression as an inflammatory state with elevated levels of proinflammatory cytokines, e.g. Interleukin IL-6, IL-12, interferon (IFN)-γ [15], IL-1 and tumor necrosis factor (TNF)-α [16]. For this reason we decided to evaluate cytokines that have not yet been sufficiently studied to date, such as IL-5 and IL-15, in this study."

Ketogenic Diets and Bipolar Disorder: New Case Studies

Researching the viability of ketogenic diets for therapeutic usage was one of the original interests that launched this blog. And while there is growing data for brain cancers and even a Cochran review for the use of ketogenic diets in epilepsy, the bipolar story has always been theoretical.

Churchill: Change (song starts at about 30 secs)

Ketogenic (very low carbohydrate and low protein) diets should work a bit like the mood stabilizer depakote in regulating unstable moods in bipolar disorder, making them an interesting option, should the research pan out. I explore the research and details in this post:

A Dietary Treatment for Bipolar Disorder?

But, as I stated in that article, there were no randomized controlled trials, not even a pilot trial, and the only two case studies I had unearthed had one guy getting psychotic on Atkins induction and another one where a hospitalized bipolar woman showed no benefit (but despite reported enthusiasm and being in an inpatient unit where her food was supposedly entirely controlled, she never acheived ketosis).

But the other day PubMed emailed me a new paper with links to the following article: The ketogenic diet for type II bipolar disorder.  Thanks to the good Dr. Eades I was able to see the full text without getting a librarian to request it for me.

And here we have not one, but two rather well documented cases of bipolar II disorder in women, beginning in youth with some hypomania, in one person predictable seasonal depressions in the summer and a bit of mania in the spring. Both women had bad responses (such as suicide attempts and suicidal thoughts) to antidepressant trials and one gained weight on quetiapine.  They were tried on lamotrigine, an anticonvulsant and mood stablizer, with okay results (one woman was finally able to maintain a job and be functional).  One tried a ketogenic diet to help with some irritable bowel symptoms, the other just wanted to try the diet. One woman ate raw cream, grassfed beef, organic pork, free range chicken, and seafood. The other ate mostly chicken, fish, and coconut oil with 2-3 cups of vegetables a day.  Both monitored their urine with ketostix or Ketone Care Test Strips most days for several months, achieving mild to moderate ketosis on most days. Both women eventually discontinued the lamotrigine and reported better symptom control with the diet than with medication.

One woman described her irritability going away and a sense of calm.  Also "having my head screwed on straight--well, it's definitely worth giving up pie." She said her symptoms seemed better with a ketone level of 15mg/dl vs 5 mg/dl in the urine. The other woman noted that if she remained gluten-free, she felt much better, even though she had never been diagnosed with celiac disease.

Neither woman had any adverse consequences and they remained stable on the diet for 2-3 years at the time the paper was published.

The paper details how a slight acidosis achieved with a ketogenic diet results in decreased intracellular sodium accumulation, which is the mechanism by which all anticonvulsants which are also mood stabilizers appear to work. In addition, the paper details some possible pitfalls of a ketogenic diet, such as difficulty maintaining it in a world of twinkies and coca-cola, and the risk of kidney stones. The author recommends >2.5 liters a day of fluids and a potassium citrate supplement to alkinilize the urine, which is done routinely in pediatric clinics where ketogenic diets are used for seizures, but may not be be necessary in adults. There is a long-term review of the ketogenic diets in kids (though I'm not a fan of the ingredients in some of the formulas used for tube-feeding some of these kids - soybean oil, soybean oil and more soybean oil) talking about complications over 6 years. Since these kids were often very ill with many other debilitating conditions, it is hard to attribute the complications (sepsis, cardiomyopathy, lipid pneumonia) to the diet itself.

Lipids were measured in one woman from a vegetarian to an omnivorous to a ketogenic diet.  As is expected her trigs dropped and her LDL and HDL went up on the ketogenic diet. Total cholesterol to HDL ratio (the best cheap test I know of relating to total LDL particle number, with a lower ratio being better) on the vegetarian diet was 4.47, 3.78 on the omnivorous diet, and 3.74 on the ketogenic diet.

All in all, the paper is a nice illustration of two motivated patients acheiving remission of their bipolar symptoms (which they had dealt with for decades) with a free-living ketogenic diet (and some other supplements, though each woman took different ones, for example, probiotics and omega 3).  Two anecdotes isn't a huge amount of data, but it is intriguing, and I would say the time for a randomized controlled trial of ketogenic diets in bipolar disorder is way overdue.

(Final note as I was in a bit of a hurry when I wrote the post at first… I did want to say there is a *lot* about these case study diets that could be therapeutic. No processed food, no sugar, lots of nutrients, lots of omega 3, low in gluten or gluten-free, likely low in histamine. The tracking of the ketones and one women's experience that the 15mg/dl ketone level felt more calming to her along with the sensible biologic mechanism makes the ketosis part plausible, but it is important to note these other possible factors).

Omega 6, Obesity, and Endocannabinoids (Again)

One great mystery in this nutritional debate is how the Harvard School of Public Health and their epidemiologists keep finding such links between the omega 6 polyunsaturates and all manner of good health. My confusion comes in part because in all likelyhood the most omega 6 fats will be eaten by people eating a load of processed crap who by all accounts should not be the healithiest. If the epidemiologists take all those people out of the equation what are we even measuring? Just the leftover folks who eat salad and chicken and fish and walk their dogs every day. Hardly seems fair.

A Civil Twilight: River (right click to open in new window)

And yet, those crafty vegetable oils elude my ability to smack them down entirely. I've done some reading on the metabolism of the omega 6s and it doesn't make for very fun blog posts. Suffice it to say that *maybe* if you pour tons of O6 down the gullet there may be some compensatory reduction in the inflammatory pathways they ought to light up like a runway. It seems that the real key to staying healthy while eating commercial salad dressings, factory-farmed eggs, and chicken skin is to make sure you do NOT skimp on the omega 3s. Also, avoid trans fats like the plague (duh) because they can interfere with uptake of the omega 3s.

Earlier this week a paper from Nature tweeted by Stephan Guyenet and Mike Eades that adds more fuel to the anti-O6 argument.  Omega 6 in large amounts: fragile polyunsaturates, biologically active, evolutionarily novel, and not nearly as tasty as steak or olive oil. Is it a coincidence that the obesity epidemic began and peaked when enthusiasm for omega 6 was at it's highest? Come the late 90s and 00s, Mediterranean diets became more the rage. Veggie oil, king of low cholesterol, began to be edged out by the monounsaturates. Nevertheless, "during the 20th century, elevations in AA-PL have been estimated from the dramatic increase in dietary LA resulting from > 1000-fold increase in per capita consumption of soybean oil from 0.006 to 7.38% of energy." (Gah) (AA-PL = arachidonic acid phospholipids, or the amount of omega 6 derived compounds in cell membranes.  LA = linoleic acid, the primary dietary omega 6 found in soybean and corn oils, etc.)

We've heard the omega 6 obesity story before, and it has everything to do with the endocannabinoid system.  Here is one of several blog posts from 2011 where I broke it down into exrutiating detail.  In short, omega 6 fats are made into natural endocannabinoids, our own happy cannabis compounds. Smoking a ton of weed is associated with: hanging out listlessly on a couch in one's parents' basement watching Yo Gabba Gabba AND the munchies.

Central cannabis receptor activation is associated with increased eating and increased fat accumulation and fatty liver. So researchers thought they would take some happy mice and increase linoleic acid as a controlled dietary variable and see if it made the little guys fat via increased levels of endocannabinoids.

So the mice were fed pellets with and pastes with 20% protein, some carbs, and then mixtures of 7 different oils.  Lipids were extracted from the mice livers and brains and levels of endocannabinoids were measured.

Mice with 8% linoleic acid diets (comparable to modern human diets) had elevated levels of linoleic acid and arachdonic acid in the cell membranes (not surprising) compared to the historic 1% mice (ahem, human) diets.  Levels of the endocannabinoids were tripled in the 8% LA diets. Dietary LA increased body weight, food intake, and fat tissue in the mice.

Here's the key, however: Adding 1% EPA and DHA omega 3s to the mouse diets seemed to undo much of the problems caused by the gallons of omega 6. Omega 6 in the cell membranes dropped, as did the levels of endocannabinoids, as did the fatty tissue, weight, and overeating in the mice. These mice didn't look quite as nice metabolically or had as beautiful cell membranes as the 1% LA mice, but it was loads better than the 8% LA omega 3 deficient mice.

Dietary LA also increased leptin and decreased adiponectin.

In the human population, dietary consumption of soybean oil, poultry, shortening, and sugars (but not grains, beef, fish, eggs, dairy, or vegetables) were positively correlated with obesity in several epidemiology cohorts from 1909 to 1999.

Honestly, this paper is the strongest one yet I've seen maligning omega 6 fatty acid in vast quantities in the diet. One can't necessarily make the leap from the observational data in humans and the controlled data in the rats to an absolute causal relationship in humans, but hey, playing it safe with olive oil and avocados and rolling on the wild side with some saturated animal and tropical plant fats doesn't seem like it would be that unwise compared to toking it up on processed fried foods, no?

The Neurobiology of Liking and Reward

I'm doing a little studying up on binge eating and the brain, so this post is more of a notation aid for me.  So if you aren't a neuroscientist, you might want to just listen to this music.

From "Dissecting components of reward:  'liking', 'wanting', and 'learning''."

Rewards ranging from sweet taste, IV cocaine, winning money and smiley face activate many brain regions (orbitofrontal cortex, anterior cingulate and insula, and also nucleus accumbens, ventral pallidum, ventral tegmentum, mesolimbic dopamine projections, amygdala.) Not clear which are the reward centers and which are activated as part of spreading network activation in response to reward.

In babies, primates, rats and mice, sweets elicit happy facial expressions while bitter tastes elicit negative expressions. Many brain systems are involved. To enhance these "liking" reactions, we can count on the opioid, endocannabinoid, and GABA-benzodiazepine neurotransmitter systems in the limbic system. These are known as the "hedonic hotspots. (One example is a tiny spot within the nucleus accumbens, about a milimeter in volume, comprising less than 10% of the nucleus accumbens.)

Microinject a mu opiate agonist into the hotspot, liking in response to sucrose increases. It also doubles the "wanting" for food demonstrated by increased eating behavior and food intake. Microinject opiate outside these hotspots and sometimes the opposite or mixed results happen. You might stimulate "wanting" but actually suppress "liking."

Endocannabinoids have a hotspot that overlaps the opiate one in the nucleus accumbens. It doubles liking reactions and more than doubles the food intake. (Munchies.)

The nucleus accumbens has a bunch of nerve cell bodies that project outwards to other areas of the brain, including the ventral pallidum (VP). The posterior half of the VP is another opiate "hotspot" that doubles liking and wanting. They fire more vigorously in rats given sweet than unpleasantly (very) salty. They will fire more vigorously in salt-deprived rats when given reasonably salty taste. Inhibit GABAa in the VP (anywhere) and you stimulate "wanting" without changing "liking" at all.  In humans, cocaine, sex, food, and money reward all activate the VP.

Hedonic hotspots are likely linked together "into an integrated hierarchical circuit…akin to multiple islands of an archipelago that trade together." If you block one hotspot with an opiate blocker, the other one may be affected as well. Sometimes blocking one decreases liking, but increases wanting in the other. The "liking" induced by benzos seems to need opiate help, as it is also blocked by opiate blockers. (May be why naltrexone, an opiate blocker, is useful for alcohol dependence and has been studied in overeating, cocaine, gambling, etc.)

"Wanting" and "liking" typically go hand in hand, but not always. "Wanting*" means that we are motivated to do behaviors that will reward us with that which we seek, but in a neurosciencey kind of way rather than the poetic global word "wanting." If I "want" a Ferrari, I might write down a plan and save some money and ultimately buy one, but in the addiction/reward sense that is way too cognitive, cortical, and planned. "Wanting" in the addiction sense means a more immediate desire and can actually conflict with the larger picture of cognitive "wanting." For example, you might want your liver to be perfectly healthy and want to stop drinking, but you can't stop the immediate "want" for Jim Bean so you drink a quart every day. In general, addicts "like" the stimulus they cannot stop "wanting" less and less as the addiction continues.

"Wanting" is more globally distributed in the nervous system than "liking." While "liking" is mostly mediated by opiates, benzos, and endocannabinoids, "wanting" is also mediated by dopamine globally (and dopamine interactions with glutamate on a micro level.)

There are innate "natural" rewards (such as sweet) and learned rewards, and "wanting" for either can light up the limbic system. "Crack cocaine addicts, for example, sometimes frantically "chase ghosts" or scrabble after white granules they know are not cocaine." Encounters with incentivizing stimuli (for example a bar, or the sound of glasses clinking) will increase the motivation to seek reward and "increase the vigor with which they are sought."  There are also "mirror neurons" in the frontal cortex so that if you are watching someone drink a beer, some of these neurons will activate as if you are drinking the beer, so you experience it with the beer-drinker.

Desire stimulates action in some motor neurons as well, which is the generation of actual… action. In addition, fear and desire are intermingled. Dopamine and glutamate in the nucleus accumbens can stimulate desire and dread and certain regions seem to flip like switches to motivate opposite behaviors.(Example, sitting in your comfortable home where you want to stay, then make the lights super bright and play very loud music so you want to leave.)

Stress hormones and repeatedly high doses of addictive drugs can stimulate "near-permanent sensitization of mesocorticolimbic-dopamine-related systens. This will increase "wanting" and addictive behaviors continue despite a lack of associated "liking."

The end!

*fancy neurosience term for this reward-immediate wanting is incentive salience.

Glucose and the Hippocampus

At the beginning of September, there was a bit of a twitter about this new paper in Neurology.  In fact, some folks emailed me links and tweeted it to my attention.  And the paper turns out to be very interesting.  You can tell by the way it was written that the researchers were pretty stoked at the results, and that doesn't always sneak through in the dry modern medical literature.

(Funny little bit… almost every scientific paper has a sobering end paragraph about the limitations of the study at hand followed by several paragraphs about how lame the data is for one reason or another.  This paper says:  "This study has some limitations but also significant strengths."  For some reason I find that very amusing.  But then, I'm fairly easy to amuse.)

AWOLNATION: Kill Your Heroes

What I really like about the paper is the all-out, glorious way in which they attempt to link inflammation, hyperglycemia, coagulation, glucose, and body and brain pathology.  It's beautiful and bold and a bit more outside the box than I'm used to seeing in a neurology paper.  Let's dive in.

Of course we know that hyperglycemia and type II diabetes have been linked over and over again to cognitive decline, brain aging, and dementia.  Also, insulin resistance, obesity, and a higher caloric intake over time have also been linked to faster brain aging.  But what about high-ish levels of fasting blood glucose that are still in the normal range?  Well, even those have been linked to systemic inflammation, so these researchers thought they would run an observational study to see if you could see structural changes in the brain over time related to fasting glucose levels.

A random sample of 60-64 year old Australians were selected from compulsory voting rolls.  431 individuals underwent MRI scanning and fasting glucose testing at "wave 1" and also scanned four years later in "wave 2."  After all the exclusionary criteria were weeded through (including anxiety and depression, type II diabetes, incidentally found fasting glucose of higher than 6.1 mmol/L (110 mg/dl as I'm used to seeing it), stroke, neurologic disorders, etc.), 249 scans were used to make the current dataset.  A bunch of other measures were taken and included as well, such as blood pressure, medications, education, sex, smoking, BMI, and APOE phenotype.

Hippocampi from Wikimedia Commons

The scans were perused and the volume of the hippocapmus measured in 2001 and then in 2005.  Fasting plasma glucose in these individuals ranged from 3.2 mmol/L (58) to 6.0 (108).  And after calculations and whatnot were done, the fasting glucose level at wave 1 varied linearly with the amount of hippocampal atrophy 4 years later.

The researchers flipped all over themselves to find a way to screw up their findings.  They adjusted for the smaller intracranial volumes measured the second time.  They took out anyone with a fasting glucose > 5.6 (100) because that is the more stringent criteria recommended by the American Diabetes Association, wondering if the sample were skewed so that the highest normal fasting glucose folks had more atrophy. They excluded anyone with a greater than normal BMI. But no, the line remained pretty linear on analysis.  Then they added back in the type II diabetics and high fasting glucose folks and the line was still linear.  It seems pretty clear that the higher your fasting glucose, the smaller your hippocampus will be four years later, at least if you are a 60-64 year-old Australian from a certain geographic region.

(Turns out an "average" rate of hippocampal atrophy in a 60 year old is 2% per year, and this is the rate they found for the average fasting plasma glucose level in the sample (4.92 or 88.56). Nice synchronicity there.)

So they had fun with the experiment and even more fun with the data, but it is the discussion where the exitement nearly gets out of hand. It's Evolutionary Psychiatry-level pathological lumping.  I love it.

In animal models, rats with higher plasma glucose have greater brain damage when exposed to certain toxins.  (Specifically, reduction in hippocampal dendritic spine density.)  In humans, higher "normal"fasting glucose is associated with greater risk of developing type 2 diabetes and with poorer memory performance.  Higher glucose levels are associated with increased inflammatory cytokines such as TNF alpha, IL-6 and IL-10.  Inflammatory markers peaked higher and lasted longer in those with impaired glucose tolerance.  Chronic systemic inflammation is known to cause cerebral atrophy, and is the likely mechanism behind the correlation between increased glucose and neurodegeneration.

Another feature of type 2 diabetes is increased levels of certain clotting factors in the blood.  These increases lead to increased risk of vascular and heart disease in diabetics.  Prediabetics and folks with metabolic syndrome also have similar clotting factor abnormalities.  Inducing hyperglycemia in normal volunteers also induces platelet activation and other pro-clotting factors.  More clotting means more risk of microemboli, small strokes, and vascular and brain damage over time.  Since systemic inflammation and coagulopathies also seem to induce eachother, it could be these two together synergistically amplify  the risk of something like a chronically high glucose level.

Taking another step back, it is known that depression and anxiety are associated with an increased risk of diabetes.  High stress activation is mediated by increased HPA axis activation, which is not only associated with increased risk of diabetes but also increased risk of brain atrophy (particularly in the hippocampus and amygdala) and memory problems.   It could be the psychological stress leads to the HPA activation and increases glucose levels, leading to the brain atrophy.

Yes, stress can and will eventually kill you, once it stops making you stronger.

Life is funny that way.  And high fasting glucose levels are not a great idea.  Please don't get the idea that I'm endorsing a VLC diet at this point.  Remember, fasting glucose levels in the insulin-senstive individuals will tend to be as low or lower in those who regularly consume carbs than those who don't.  I think VLC diets have their place, but I'm unconvinced they are the perfect anti-aging tool for everyone.