Happy Thanksgiving! Chow Down on Dopamine Primer 2

Hope you are having a great time on your Turkey Day (assuming you celebrate it as the majority of my blog readership does). I baked a paleo pumpkin pie last night, and today I'll make (and eat) the crab stuffed mushrooms (finally, a use for the oregano plant we mostly killed in the fall) from the same Everyday Paleo page. We're having our turkey (I'm told it is organic free range, and if it isn't, I don't want to know) with some relatives on Saturday, so by then no doubt I will have baked another pie to bring with me to the gathering, only this time I'll likely add vanilla and coconut flakes to the butter pecan hazelnut crust. Yum! Gotta love a Thanksgiving where you don't even mentally count the fat grams. Just avoid the gluten...but the rolls and stuffing were never my favorites anyway. Give me meat and pie and I'll be happy.

Back to dopamine. My favorite neurotransmitter, and also (I'm assuming) the favorite neurotransmitter of Dr. Fred H. Previc who wrote The Dopaminergic Mind in Human Evolution and History which will be, once again, the major source for much of the information here, though there will be some from the psychiatry clinical trenches too (let's assume I did learn something in residency). Dopamine is special because it divides the humans from the beasts, as it were, and yet some of our more bestial qualities stem from chasing that dopamine feeling - via ultimate fighting, cocaine, speed, and also the reward pathways in binge eating, drinking, gambling, shopping, etc. etc. etc. Anything that involves competitiveness, drive, sex, planning, working memory, concentration, aggression... dopamine plays a role.

Dopamine is distributed quite differently on the different sides of the human brain, and is is speculated that this lateralization is responsible for how very human we are. The left brain (in almost all right-handed and most left-handed people) is responsible for language, linear reasoning, mathematics, that sort of thing, whereas the right side is usually responsible for intuition, holistic reasoning, some elements of music and speech intonation, etc. It's funny, really, how different the sides of the brain are. They look much the same. My right and left lungs look a little different, but they have the same function. My right and left feet do pretty much the same thing. But remove my left brain, and I'll be a different person. Amazingly, if one is young enough, half the brain can be scooped out and removed (if necessary, usually to control intractable seizures), leaving the child with pretty normal intellectual functioning (though motor functioning on one side is usually irrevocably lost). This finding (among others) led one prominent neuroscientist to pen a famous chapter called "Is Your Brain Really Necessary?"



The human brain has 100 billion neurons. Only 20,000 or so carry dopamine, and they do so along four major tracts. Keep in mind that the brain is a gorgeous and mysterious place with many wonderful names, like Rivendell or Brigadoon. The areas are named either anatomically (the dorsolateral prefrontal cortex) or because it reminded the anatomist of yore of some other important anatomical structure (the mammilary bodies). Or for some other obscure reason (the tegmentum? Oh, that's Latin for "covering." Okay!)

Dopamine is made in two little areas in the deep animal recesses of the brain - the substantia nigra and the ventral tegmental area. From these starting gates, the dopamine tracts reach out to various segments.

1) The nigrostriatal tract is important to neurologists. It brings dopamine from the substantia nigra to the striatum or "basal ganglia." These neurons are responsible for a lot of the motor control of the body. Death of dopaminergic neurons in the substantia nigra leads to the symptoms of Parkinson's disease - tremor, stiffness, loss of voluntary movement (though someone with advanced Parkinson's may not be able to toss a ball to you, if you toss a ball to him, he might be able to use different reflex motor brain tracts and catch it). This pathway is also affected in various choreas, such as the possibly wheat-related Huntington's Chorea.

2) The mesolimbic pathway goes from the ventral tegmental area to the limbic system. The limbic system of the brain controls reward and emotion, and includes the hippocampus and the medial frontal cortex. This is the pathway that is thought to be responsible for addiction and psychosis.

3) The mesocortical pathway goes from the ventral tegmental area to the dorsolateral frontal cortex. This is the pathway responsible for planning, responsibility, prioritizing, motivation, and some elements of emotional response. This is one of the damaged areas in ADHD and depression.

4) The tuberoinfundibular pathway has my favorite name (though not as fun a name as the as the anterior inferior thoracoacromial artery). It's a dopamine pathway between the hypothalamus and the pituitary gland, and the most important part is that dopamine inhibits prolactin release. So inhibiting dopamine means prolactin increases, enabling breastfeeding and whatnot.

Having fun yet? In psychiatric terms, the mesolimbic and mesocortical pathways are by far the most important. They have a lot to do with how we behave, and who we are. Now go eat some turkey and be happy.

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Depression and Diabetes, Together Again

Waaay back in June I wrote up Depression 1, which referenced a few of the studies linking depressive disorders to metabolic syndrome and diabetes.  Today a new study came out from some of our favorite epidemiologists, Frank Hu and crew.  Dr. Hu actually wrote an editorial questioning the wisdom of population-wide nutritional advice that resulted in replacing saturated fat with refined carbohydrates.  However, he also signed off on that monumentally silly paper about "low carb" meat eaters versus low carb veggie-lovers that everyone made fun of a few months back.

Today's paper is "Bidirectional Association Between Depression and Type 2 Diabetes Mellitus in Women" from the Archives of Internal Medicine.  The researchers followed 65,381 women in the Nurses' Health Study from 1996 to 2006.  Clinical depression was defined by having diagnosed depression or using antidepressants, and depressed mood was defined as having a high score on the 5 item Mental Health Index questionnaire.  The nurses self-reported having type 2 diabetes which was validated by medical record review. 

During the 10 years of follow up, there were 2844 new cases of type 2 diabetes.  Those with poor mood had a higher chance of developing diabetes.  7415 women developed clinical depression, and women who were on insulin to control type 2 diabetes had a risk ratio of 1.53 for developing clinical depression.  Overall, the data showed that diabetes increased the risk of depression, and depression increased the risk of diabetes, and that more severe depression and more severe diabetes increased the risk of the other illness even more.  Countless covariates did not explain the bidirectional connection.

On a population level, 23.5 million American adults have diabetes (about 10%, though about 23% of those >=60).  6.7% (14.8 million) of the US adult population has depression in any given year, with a  lifetime incidence in women of around 20%.  A previous meta-analysis (1) found that the odds of depression in the diabetic group was twice that of the nondiabetic comparison group.  In a couple of papers, diabetes risk was increased by 60% in patients who had diagnosed depression.  Frank Hu's group paper from this week made some effort to figure out what comes first - depression or diabetes?  Depression (atypical depression that is) can make you crave carbs and leave you unmotivated to perform exercise.  Having diabetes is usually pretty stressful too, putting you at greater risk for depression, and "depression may result from the biochemical changes directly caused by diabetes."

That last quote is perilously close to my theory, that metabolic syndrome and leptin/insulin derangements probably underlie both disorders.  That's more "big picture" evolutionary medicine style thinking than I'm used to in reading the discussions of these papers, but don't get too hopeful, it was only touched on in that one sentence.  I discussed the underlying mechanisms of depression and metabolic syndrome and how they are connected in Stress is Metabolic Syndrome and Chronic Stress is Chronic Illness.  These aren't really radical ideas.  Oh well.

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Dopamine Primer

Hi! Tonight a quick basic post for some necessary background. I will try to make it as painless as possible. But we need to examine dopamine more closely. Why? Well, dopamine may well be the secret to what makes us human. Meaning awfully bright, able to plan ahead, and resist impulses when necessary.

What is dopamine? It's a neurotransmitter. It controls communication in the brain - it's a chemical that can tell a neuron to fire off a signal or not, and modulates the signals. Dopamine is ancient - found in lizard brains and every other animal along the evolutionary tree up to homo sapiens. But humans have a great deal of dopamine, and over many generations we have evolved to have more and more.

Control of dopamine and where it ends up in the brain isn't just determined by straight up mendalian genetics. As I discussed in this post, our mothers' neurochemical environment had a lot to do with how our dopamine machinery migrates and works in our brains.

Another special thing about humans is our bipedalism. Being upright while mom is pregnant exposes our fetal brains to different vestibular environments than other primates, so the theory is this elevated the dopamine levels in the left hemisphere of most people's brains. I know. Go with it for a minute. It's just a theory.

Humans also eat a lot of meat and fish compared to other primates - meat and fish give us more dopamine precursors. More dopamine is also associated with both greater competitiveness, aggression, and impulse control - one could see how that particular combination of traits would be selected for over human evolution.

Serotonin, another neurotransmitter, is our oldest neurotransmitter and the original antioxidant - dopamine is what made humans so successful.

Now the biochemistry. Dopamine is a type of neurotransmitter called a catecholamine. Catecholamines have, not surprisingly, a catechol chemical group attached to an amine.

How do we get dopamine? We eat it. The precursor amino acid from the protein we eat is called tyrosine. Tyrosine becomes dopa via the enzyme tyrosine hydroxylase, and dopa becomes dopamine via the actions of dopa decarboxylase. (One more chemical reaction can turn dopamine into its best buddy neurotransmitter, norepinephrine, but more on that later). As is the case with serotonin and its precursor tryptophan, tyrosine can cross the blood brain barrier, but dopamine itself cannot. That means that the dopamine our brain needs must be manufactured from dopamine machinery and precursors in the brain.

Still with me? What happens without dopamine, or with screwy dopamine machinery or inefficient dopamine? Well, in development this lack can cause mental retardation, which is the case in a rare genetic disease called PKU and cretinism (a type of mental retardation caused by iodine deficiency). Dopamine problems are implicated in ADHD, Alzheimer's, Parkinson's, depression, bipolar disorders, and schizophrenia. Having too much dopamine in the wrong place can make you psychotic. Illicit drugs that dump loads of dopamine (or strongly inhibit its reuptake, which is similar to dumping loads of dopamine) include cocaine and methamphetamines. Therefore high amounts of dopamine can cause euphoria, aggression and intense sexual feelings.

We need dopamine in the right place at the right time in the right amounts. When it all comes together, we are the awesomest ape around. When it doesn't, problems ensue (not surprisingly). Dopamine is linked to everything interesting about metabolism, evolution, and the brain. There's a feast of scientific info out there. Hopefully we can make some sense of it.

Information from this post is taken mostly from The Dopaminergic Mind in Human Evolution and History by Fred Previc.

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Cleaning Up

In lieu of a new and interesting post, something possessed me to organize the place this morning. So up on the right there I now have some more advanced disclaimers and a brand new site map. It's not finished yet (right now I only have the first three months up, I'm updated now - might be some fun reading for those of you newer to the site) and not pretty (a graphic designer I am not, and blogger can be fairly unwieldy with the font sizes and formatting).

My youngest child is amusing herself by trying to eat her hand. Good thing she doesn't have that many teeth. On the positive side, she learned how to say "vitamin" today! I better stop now as I need a certain aura of mystery to maintain my shamanistic role as a psychiatrist. Though it is likely the last vestiges of my dignity were lost when I joined Twitter.

A couple of music links (right click in new tab and you can enjoy them while you peruse the new map!)

The Limousines - "Internet Killed the Video Star" - The kids are disco dancing, they're tired of Rock and Roll. I try to tell them hey that drum machine ain't got no soul.

If you are of a more classical bent - Aaron Copeland* classic, "Fanfare for the Common Man." Copland has a unique sound due to what he left out - the major 3rd.

* Thanks music Doc - It's Copland. Not sure why but spelling was never my strong suit.

One more for Thanksgiving week coming up - Vampire Weekend, "Holiday."

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The Wild and Compelling Theory that Alzheimer's Dementia is Caused by Infectious Disease

As you recall, Alzheimer's Disease is a slowly progressive illness of neuronal degeneration.  The cardinal symptoms are cognitive impairment and memory loss, but the condition eventually leads to death.  I've dedicated many posts to Alzheimer's, which is a reflection of the amount of research out there.  And for today's post, I'm going to begin with a nice review article from 2008, and over another post (or several) try to finish out with some more specific looks at the various papers. 

Even if you don't find Alzheimer's that compelling, if infectious agents contribute to its pathology, then you have to open your mind to the idea that many neurodegenerative processes could be due to (or accelerated by) infection.  Neurodegenerative diseases include many neurological illnesses, but also depression, bipolar disorder, schizophrenia, autism...

What is the argument against infection as an ongoing contributing factor?  Well, where's the bug? Do a spinal tap - does the fluid grow any bacteria in culture?  Are there white blood cells (sign of active infection).  Is there an elevated level of protein (a sign of viral infection)?  Over the last hundred years we've become pretty good at finding bugs.  It's hard to imagine them hiding from us, even in the protected environment of the human skull.  So if you bring up the idea of infections causing Alzheimer's disease to a physician friend and he or she scoffs at you - that's why.  Where's the bug?

With that in mind, let's plunge forward into the review by Urosevic and Martins from the Journal of Alzheimer's Disease, "Infection and Alzheimer's Disease: The Apoe epsilon4 Connection and Lipid Metabolism."

The whole theory breaks down like so - there's a continuous, chronic infection supplying persistent live microorganisms, and their toxic products stimulate the host's (that's you) inflammation.  The pathogen itself damages the neurons, and the brain's inflammatory response also damages the neurons.  Remember that ApoE4 is the  Alzheimer's vulnerable variant of apolipoprotein, the molecular key on the lipoprotein that invites cholesterol and triglycerides into the brain. As an added bonus, any infectious disease theory of Alzheimer's also has to explain why having ApoE4 makes you more likely to get Alzheimer's.

What infectious agents are we talking?  Some viruses immediately come to mind, specifically herpes viruses.  These little guys are exceedingly common and come in lots of different flavors, and are well known to hide out in nerve cells for the duration of the host's life (an easy example of "There's the bug.")  HSVI, associated with cold sores, infects people early in life and hangs out in the trigeminal ganglia (the nerve root of the trigeminal nerve that innervates a good part of the face).  Some people get cold sores, some people don't, but those who do are more likely to be ApoE4 carriers.  People infected with HSVI are also more likely to develop Alzheimer's.  ApoE4 mice were more likely to carry invasive HSVI and have brain colonization of the virus.

Other viruses implicated include human herpes virus 6 (cause of roseola, a common childhood illness of high fever followed by a characteristic rash), HIV, hepatitis C, and cytomegalovirus (a cause of mononucleosis-like illness and fatigue symptoms).  It is well known that HIV causes a form of AIDS dementia (which happens to be more common in carriers of ApoE4), so it would make sense that other common viruses that infiltrate the neurons might lead to other types of dementia.

All the common inflammation players (TNFalpha, IL-6, nitric oxide synthase) are involved in fighting off viral infections.  We know these players have a role in Alzheimer's pathology and in depression and bipolar disorder.  Interestingly, as we get older, our immune response becomes less aggressive, and it is perhaps then that the infectious agents hold sway, leading to Alzheimer's pathology.  Other inflammation-mediated brain disease occurs at different developmental stages - late adolescence and early adulthood for schizophrenia, and infancy for autism.

There are also suspected bacterial causes.  The "spirochetes" are a type of sneaky bacteria that are known to infect nerves (as in syphillis and Lyme disease).  Some spirochetes that cause gum disease are found in the mouths of Alzheimer's patients and healthy folks, but in the Alzheimer's patients, they are found in the brain more often than in healthy folks.  Certain spirochetes have been found in the amyloid plaques in the brains of patients with Alzheimer's (once again - there's the bug).

Chlamydia pneumoniae is an intracellular bacterial pathogen also implicated in Alzheimer's dementia.  Not surprisingly, it is better known as a common cause of pneumonia and other acute respiratory infections, but infected immune cells could presumably carry chlamydia pneumoniae from the upper respiratory tract to the brain if the blood brain carrier is compromised in some fashion.  Chlamydia pneumoniae has been injected into mouse brains and causes amyloid deposits, which anyone will agree is suspicious behavior.  Once again, ApoE4 comes up, as ApoE4 seems to allow for greater bacterial load and numbers of infected cells.

ApoE4 is not only a bad guy when it comes to Alzheimer's.  Carriers are at greater risk of athersclerosis, stroke, and poor recovery from head injury.  And ApoE's role as a molecular marker and director of where lipoproteins go is key.  Lipoproteins are how fat and antioxidants are carried throughout the body.  It is probably not a coincidence that major conditions leading to weight loss without any particular effort are infectious disease and Alzheimer's (along with cancer and melancholic depression).   ApoE4 in particular is associated with poor clearance and recycling of lipoprotein particles.  It's just not an efficient key.  If everything is going along just fine, maybe we don't need an efficient key.  Add stress or infection, though, and you have a greater need for meabolic efficiency.  If you fall behind, garbage builds up.

The ability of a host (you, or me) to handle an infection depends on genetic, dietary, and other environmental factors such as age, stress, and immune status.  Viruses and bacteria are sneaky - I daresay sneakier even than Homo sapiens,  and the closeted nerve cells are a perfect place for an unnoticed infection to simmer for decades.  Microogranisms can continuously release toxins, leading to chronic inflammation and damage.  Treating a chronic infection, if it is found, could possibly be a useful way to fight a number of neurogenerative diseases, even Alzheimer's.

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Thursday Already?

It has been a nutty week. And right now I'm cooking steak, and the 18 month old won't let me put her down. But a few things have caught my attention:

Epilepsy's Big, Fat Miracle

A New York Times article about a parent with a kid on a ketogenic diet for epilepsy. Makes ketogenic diets sound completely bonkers, yet effective. I suppose that is the story of my blog.

The 32-year relationship between cholesterol and dementia from midlife to late life

Okay, get this. In animal and cell culture studies, high cholesterol is associated with amyloid beta deposition. YET when one reviews the human studies, the ratio between cholesterol levels and amyloid deposition becomes far more murky (declining cholesterol levels as we age is a risk factor). Also, high dietary cholesterol in RABBITS and genetically modified mice leads to greater amyloid pathology relative to controls!!! Should I eat the top round steak being simmered in grassfed ghee right now? Should I?

Well, high cholesterol in women who had high cholesterol in 1968-69 was not associated with risk of dementia up to 32 years later. Also, a decrease in cholesterol levels over the follow up period (of 32 years) was associated with an increased risk of dementia.

Here's a money quote from the study: "Thus, the unintended decreases in cholesterol levels (e.g. not via medications or cholesterol-lowering diet) greater than expected due to aging may be more indicative of dementia risk than midlife cholesterol levels and may reflect underlying dementia processes. This pattern is observed for other dementia risk factors, such as BMI and blood pressure...consequences of the dementia prodrome such as apathy or reduced olfactory function may lead to decreased energy intake, which may also affect blood cholesterol levels."

Or, just maybe, cholesterol levels are a biomarker of some other process, so following just cholesterol levels leads to confusing and contradictory information regarding dementia risk, and absolutely low cholesterol is usually bad news when it comes to the (human) brain.

It's exhausting, really, slaying the remnants of the lipid hypothesis in 2010.

Dear Conventional Wisdom Nutritional Information Purveyors: I know that allowing fat into the diet makes a big juicy steak that much less naughty. But you don't have to be naughty to have fun!! You can just enjoy a big juicy steak.

Seriously.

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Selenium and Depression

The good news about selenium and the brain is that one can become familiar with the literature with full institutional access to pubmed and an hour or so of reading time. The bad news is that the mechanisms of selenium and the brain are rather Mysterious, so all we have are a few papers, some micronutrient supplementation, and some speculation.

All right. Let's talk pregnancy and depression for a minute. Little known fact that slightly more women are depressed during pregnancy than after it (1). And if you combine ante and post-natal depression statistics, this is what you get for the moms and kiddos: poor maternal self-care, increase in alcohol and drug use during pregnancy, decrease in seeking medical care during pregnancy, more pre-eclampsia, birth difficulties, preterm delivery, reduced breastfeeding, lower APGAR scores, poor sleep, failure to thrive, developmental delays, greater risk of illness in the baby, more behavioral problems, and at 16 years, offspring of depressed mothers are almost five times more likely to suffer depression themselves.

There are any number of social and medical factors that are linked to perinatal depression, but let's focus a bit on the nutritional ones - links have been found with folate status, vitamin B12, calcium, iron, selenium, zinc, and omega 3s. Kaplan and colleagues, in a must-see literature review, found potential beneficial effects from B vitamins, vitamin C, D, and E, calcium, chromium, iron, magnesium, zinc, selenium, and choline on mood symptoms. (Real Food = Best Fetal Dinner). A very recent study (to which I, sadly, do not have full access) showed a significantly decreased Edinburgh Postnatal Depression Scale score (that's good) in pregnant women randomized to receive 100 mcg selenium daily from the first trimester until delivery.

Back to selenium - as you recall, it is a vital component of the selenoprotein glutathione peroxidase and is required for the synthesis and metabolism of thyroid hormones. And way back in 1991, Benton and Cook did a randomized controlled crossover trial of 100 mcg of selenium vs placebo in 50 people for 5 weeks, followed by a 6 month washout, then the crossover arm of the trial. Selenium supplementation was associated with increases in self-reported mood. This same paper tells us that when push comes to shove and selenium is deficient, the brain is the last place that selenium levels drop, suggesting that in the brain, selenium is Important. More recently, Gosney et al reviewed the effects of micronutrient supplementation on mood in nursing home residents, finding that no residents started out with insufficient serum levels of selenium, yet 8 weeks of 60 mcg selenium supplementation (included in a multivitamin/multimineral with 150 mcg iodine) was directly correlated with decreases in depression scores and increases in serum levels. The supplementation of these elderly people with selenium resulted in reduced serum T4 and increased serum T3, suggesting that the additional selenium helped the rather boring T4 become the metabolically active T3 and kick some serious sluggish metabolic and depression expletive deleted here. (Any of you with hypothyroidism on synthroid (T4) get a recommendation from your doctor to supplement iodine or selenium? Hmmm.)

In other studies, selenium serum level was associated with cognition in the elderly. In a 9 year follow-up of Alzheimer's patients, cognitive decline associated with dropping selenium levels.

There's hardly enough data even to speculate, but I'll give it a whirl. Selenium is more like magnesium than zinc. I think most non-alcoholic non-anorexic meat-eaters not on thiazide diuretics probably have enough zinc on board, though stress and yellow number five might make you waste it a bit faster than normal. But magnesium is low in pretty much everyone, as is selenium (if you aren't a coal miner or a fish in selenium rich fertilizer run-off lakes). Selenium deficiency will mask itself as a somewhat subclinical (or clinical) hypothyroidism, with depression, fatigue, and grumpiness along for the ride. Replete the selenium and jazz up the T3. Happiness to follow. Not sure what that has to do with the brain holding onto selenium, but maybe that's where the glutathione comes in.

But I have a lot more reading to do before I jump into the thyroid. In the mean time - that multimineral ain't such a bad idea. Or seaweed and brazil nuts (though Barkeater was right! According to the Internet, brazil nuts have 1000 times more radium than other foods - not that much is supposedly retained in the body??) Or organ meats. Good fuel for everyone (6 months and older).

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