The Doctor Weighs In

By Dov Michaeli MD, Ph.D

I vividly remember a conversation I had with a London cab driver just before the election that unseated John Major (Conservative party) and elected Tony Blair (Labor party). I asked him who he was going to vote for, fully expecting him to make a “rational” decision and vote his economic interests. But, to my astonishment, he was going to vote for the conservatives. Why? I asked in disbelief. The answer was shocking to me. I’ll paraphrase: “because we working class blokes should know our place. The Aristocrats have been running this country forever, and they have done a bloody good job at it. And every time labor got its hands on power they made a bloody mess”.

This episode was etched in my memory, so incredible and yet so profound it was. How to explain such reverence to social hierarchy? Is it a product of generations of social brainwashing? Shakespeare, himself not an aristocrat or even a minor noble, portayed with great disdain characters of low social standing who tried to reach beyond their class. But is it really just a function of culture? Did anything change in the USSR after the revolution, when all classes were abolished with the stroke of a pen (and a bullet, for added emphasis)? Definitely not. The peasant still “knew his place”, only the superior feudal, properly addressed as “gospodin”( sir, master) was replaced by a newly minted commissar, addressed as “tovarish” (comrade).

So if it’s not purely socio-cultural, what is it?

It’s all in your head

A wonderful paper was published in the latest issue of Neuron, the neurobiology magazine. It was authored by Caroline Zink, Ph.D., Andreas Meyer-Lindenberg, M.D., Ph.D., and colleagues of the NIMH Genes Cognition and Psychosis Program.

Prior studies have shown that social status strongly predicts health. Animals chronically stressed by their hierarchical position have high rates of cardiovascular and depression/anxiety-like syndromes. A classic study of British civil servants found that the lower one ranked, the higher the odds for developing cardiovascular disease and dying early. Lower social rank likely compromises health through psychological effects, such as by limiting control over one's life and interactions with others. However, in hierarchies that allow for more upward mobility, those at the top who stand to lose their positions can have higher risk for stress-related illness. Yet little is known about how the human brain translates such factors into health risk.

To find out, the NIMH researchers created an artificial social hierarchy in which 72 participants played an interactive computer game for money. They were assigned a status that they were told was based on their playing skill. In fact, the game outcomes were predetermined and the other "players" simulated by computer. While their brain activity was monitored by fMRI, participants intermittently saw pictures and scores of an inferior and a superior "player" they thought were simultaneously playing in other rooms.

Although they knew the perceived players' scores would not affect their own outcomes or reward -- and were instructed to ignore them -- participants' brain activity and behavior were highly influenced by their position in the implied hierarchy.

What did they find?

Key study findings included:

 The area that signals an event's importance, called the ventral striatum, responded to the prospect of a rise or fall in rank as much as it did to the monetary reward, confirming the high value accorded social status.

•  Just viewing a superior human "player," as opposed to a perceived inferior one or a computer, activated an area near the front of the brain that appears to size people up -- making interpersonal judgments and assessing social status. A circuit involving the mid-front part of the brain that processes the intentions and motives of others and emotion processing areas deep in the brain activated when the hierarchy became unstable, allowing for upward and downward mobility.
•  Performing better than the superior "player" activated areas higher and toward the front of the brain controlling action planning (prefrontal cortex), while performing worse than an inferior "player" activated areas lower in the brain associated with emotional pain and frustration (amygdala).
•  The more positive the mood experienced by participants while at the top of an unstable hierarchy, the stronger was activity in this emotional pain circuitry when they viewed an outcome that threatened to move them down in status. In other words, people who felt more joy when they won also felt more pain when they lost.

Surprise?

These findings are actually not very surprising. Anybody who ever observed monkeys and apes in their natural habitat could easily pick out the alpha male and female, and the submissive behavior of the rest of rest of the clan. But a more detailed observation reveals subtle gradations in social standing among the “lower class” members. Each member of the clan ”knew his or her place”, and acted accordingly. Furthermore, violations of the boundaries of social standing were promptly punished. Is it surprising then that a specific area in the brain, called the striatum, is dedicated to assessing one’s place in a group? Furthermore, it is located right behind the prefrontal cortex, the area that is making rational decisions based on the inputs that reach it from all areas of the brain. The proximity of the striatum to the prefrontal cortex reduces the time for a message to reach the decision-making circuits--a biological testament to the importance ascribed to social animals “knowing their place” in their society.

The experiment showing that in unstable hierarchies people at the top are just as anxious and stressed as people at the bottom is truly revealing. What is the societal equivalent to “unstable hierarchies”? Democracy, of course. Today you are on top, but your position there is constantly challenged, and eventually you have to give up your exalted position. Anybody who observed our presidents at the beginning of their term, and at the end, couldn’t fail but notice how much they aged. Even a clueless president like George W has aged noticeably.

What is truly remarkable in this study is the documentation of the existence of the ‘social brain’. It has long been hypothesized that areas in the brain are specializing in directing social interactions like emulation, attunement, empathy and altruism. This study provides unequivocal neuro-anatomical proof.

By Dov Michaeli MD, Ph.D

Alcoholism is a major public health problem. This we all know. But did you know that as alcoholism evolves, stress systems in the brain play an increasing role in motivating continued alcohol use and relapse. In other words, someone who is a moderate drinker will drink more if subjected to stress. And that, in turn would increase her sensitivity to stress, which would result in yet an additional increase in alcohol consumption, which in turn… you get the picture.

The stress response

Deficiency of a stress response is life threatening. For instance, in response to stress blood pressure goes up, heart rate increases and more blood is pumped into the brain and skeletal muscles. On the other hand, less blood is pumped into the GI tract or the kidneys. What’s the physiological rationale? Just imagine you are about to be mugged by a gun totting robber—a common American stress. You would like to assess the risk and think of an appropriate response, and then run as fast as you can to save your life, or stand your ground and fight, and maybe die a hero. Or if you are philosophically inclined, you might muse about the second amendment and its role in your predicament. All these considerations go through your mind at lightning speed, which requires blood supply and the energy (oxygen and glucose) that it provides. Either way, the last thing your body needs during this emergency is to waste precious blood supply and energy on digesting your last meal, or making urine.

The usual suspect for hormonal response to stress is the stress hormone cortisol. This hormone is released into the circulation after a rise in the level of another brain hormone called Corticotrophin Releasing Hormone (CRH). And rise in cortisol level in the blood will cause all the effects we have described.

The stress of alcoholism

Since the demonstration that alcoholism can result from repeated bouts of stress and drinking, several experimental drugs were tested to see if one could break the vicious cycle by inhibiting release of CRH. Alas, not much success.

Apparently, the CRH/cortisol system is not the only one alerting our body that it is subjected to stress and causing it to physiologically adapt quickly. Another brain hormone system, substance P (SP) and its receptor neurokinin 1 receptor (NK1R) is highly expressed in brain areas involved in stress responses and drug reward, including the hypothalamus, amygdala, and nucleus accumbens. In rodents, psychological stressors induce release of SP in the amygdala, whereas genetic deletion or pharmacological blockade of NK1R inhibits the associated behavioral responses. Interestingly, SP is also involved in the transmission of pain from the peripheral nervous system to the brain. And the expression of SP/NK1R system is especially high in the vomiting center in the brain stem. Food for thought.

In a paper published in the latest Science issue ( March 14, 2008 ) a group of scientists from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health , tested the hypothesis that the NK1/NK1R system is largely responsible stress-induced alcoholism. They went about it in two ways. First, they “knocked out” (inactivated) the gene that codes for NK1R in mice, so in effect they created mice that lack this system of stress response. They then subjected wild type (normal) mice and mice deficient in NK1R to escalating concentrations of alcohol, starting at 3% and ending with 15% over 60 days. Lo and behold, they created what amounts to holier than thou mice: the wild type mice consumed an average of 10g/kg body weight, whereas the “knocked out” mice consumed only 6g/kg. They also showed an increased sensitivity to the sedative effects of alcohol. In other words, they drank little, and they couldn’t “hold their liquor” very well. Party poopers.

What about us, humans?

In a randomized controlled experimental study, recently detoxified alcoholic inpatients were treated with an NK1R antagonist (LY686017; n = 25) or placebo (n = 25). LY686017 suppressed spontaneous alcohol cravings, improved overall well-being, blunted cravings induced by a challenge procedure, and attenuated concomitant cortisol responses. Brain functional magnetic resonance imaging responses to affective stimuli likewise suggested beneficial LY686017 effects.

Small population, so it’s too early to pop the champagne. But the results are truly impressive, and as the authors state with typical scholarly restraint: “Thus, as assessed by these surrogate markers of efficacy, NK1R antagonism warrants further investigation as a treatment in alcoholism”.

Judging from results of treatments of other psychiatric conditions, a combination of drug and behavioral therapy is likely to prove more effective than drug alone. So, no—we are not likely to see AA go out of business any time soon. But the ready availability of effective drugs may make the excuse of scoundrels who “check in for rehabilitation” a lot less believable.

by Pat Salber

Well, only one more day of vacation and it is back to work.   In preparation for the long flight back from Bangkok to San Francisco, I decided to indulge in (more than) a little body work.   I am at one of the most beautiful hotels in the world, the Oriental, situated on the banks of the Chao Phraya, also known as the River of Kings. 

As with all of hotels we have stayed at on this three week journey through SE Asia, this hotel has a spa...and not only a spa, but an Ayurvedic Penthouse!  You have to take a little ferry boat across the river to reach the spa and the fitness center.  Bypassing the latter, I headed for the peacefulness of the heavenly Oriental Spa.

So what is the difference between the types of massage we get in the States and Ayurvedic?  Let me count the ways.  First of all, there are the aromatic oils...each one more delightful than the last...sweet and spicy at the same time. 

Next, unlike the typical massage in the US where you are carefully covered up and massaged one body part at a time, Ayurvedic is performed on the whole body with long strokes from your shoulders to your legs.  This means you have to be uncovered.  

I started the treatment by placing my feet in a lovely copper bowl, filled with rose petals, for a "welcome" foot cleansing.  Then I sat on a wooden stool for an oily back and scalp rub.  Finally, I lay on a traditional massage table, face down, looking into yet another beautiful bowl of rose petals.

After the massage was finished -- sixty minutes of Nirvana -- I was placed in a teak steam bath reminiscent of the steam booths in exercise studios in the 50s and 60s.  Dripping with sweat, my Thai "therapist" next led me to the shower and applied an herbal rub to remove the massage oil.  She scooped warm water from a teak barrel to pour over my body to remove the herbal rub.  This was followed by a long shower  (no water conservation here!) with scented shampoo and conditioner.  OMG, my stress level is minus 100!  I am a noodle!

Over the next few posts, I will share with you my take on diet, exercise, thinnness and fat in SE Asia.   But for now, I am going to sign off and continue to enjoy my natural Ayurvedic high.   Hmmmmmmmm....mmmmmm.

By Dov Michaeli MD, Ph.D

It is a well-known phenomenon: people under stress hit the fridge, and gorge on candy and fatty food. A gallon of ice scream in one sitting is not unheard of. But people who think deeply about such things asked themselves: why don’t they (people under stress) gorge on veggies? And what is the nature of the connection between stress and obesity? Is it simply overeating equalsobesity, or is there a deeper connection, involving the brain? After all, stress is a mind thing.

The physiology of acute stress

Almost every physiological action in our body is controlled by two systems: the autonomic nervous system, and the endocrine system.

The autonomic nervous system has this name because it is, well, autonomic: it marches to its own drum, if you will, independently of our whims, wishes or commands. This system is made up of two sub-systems: the sympathetic and the parasympathetic. Basically, they are the Yin and Yang of the autonomic nervous system: the sympathetic nerves secrete noradrenaline, a close relative of adrenaline, and it does everything you’d expect it to do: it accelerates the heart rate, increases blood pressure, in short: it readies the body to react to acute stress situations. My favorite example: you spot a lion coming at you. You want to supply ample blood to your muscles so you can run for your life, or if you are foolish enough, fight the lion; hence the increase in heart rate and blood pressure. The parasympathetic system secretes the neurotransmitter acetyl choline , and it has exactly the opposite action: it slows down the heart and reduces blood pressure.

The endocrine system reacts to stress by releasing two ‘stress hormones’: cortisol from the brain and adrenaline from the adrenal gland. Their action is similar to that of the sympathetic nervous system: increase blood pressure and heart rate.

The other type of stress

So far so good; but how does increased heart rate cause obesity? The answer is: it doesn’t. What I just described is the response to acute stress, and our bodies are well-adapted to handle it. But modern life added another type of stress: chronic stress. And here, a peptide, called neuropeptide Y, or NPY, comes into play. Its existence has been known for several years, but its function was largely unknown. It is expressed throughout the brain, but is especially abundant in circuits that regulate feeding and response to stress. Not surprisingly, like many other brain hormones, it is also secreted in tissues outside the brain that are involved in metabolism; it is secreted by sympathetic nerve endings in adipose tissue. Its function there has only recently been defined by Kuo and his coworkers. It increases adipogenesis (formation of fat tissue) by triggering both the formation of new adipocytes (fat cells) from immature preadipocytes, and by increasing the blood supply to the adipose tissue by formation of new blood vessels (a process called angiogenesis). Even more intriguing: the new fat tissue was not formed just anywhere in the body; it was formed in the abdomen, and specifically around the internal organs of the abdomen. This is exactly the fat distribution that is implicated in the genesis of metabolic syndrome. And to clinch the case: it does it only under severe chronic stress conditions. When mice were subjected to 2 threatening and severe chronic stress protocols, they secreted NPY; when they were subjected to non-threatening mild stress—no NPY. In biological experiments demonstration of a relationship between the “dose” (e.g. severity of the chronic stress) and “response” (e.g. secretion of the peptide), lends credibility to the observation, simply because in biology almost everything is dose-dependent.

Why do we prefer sweets and fats?

The mice in the experiment secreted NPY only if allowed to eat fatty or sugary food. Regular mouse chow did not support secretion of the hormone even under severe chronic stress conditions. We know that high calorie food triggers the reward circuits in the brain. In fact, chronic feeding of high calorie foods activates all the circuits and brain centers that are involved in addiction. That, in turn, induces more eating, which increases the degree of addiction, which… you get the drift. Bottom line: obesity.

The details of the connection between secretion of NPY and high calorie food still need to be worked out. Why didn’t regular, low calorie food have the same effect? What are the specific neural circuits involved in this calorie/reward/peptide axis of evil? What is the mechanism for the specific accumulation of fat around internal organs? Will withdrawal of high-calorie food result in reversal of the accumulation of fat back to normal?

Obviously, many unanswered questioned are triggered by this research. But this is the hallmark of good science: every answer raises many more questions.

In summary

NPY is the link between stress and obesity. Its action:

• Secreted from the sympathetic nervous system only under conditions of chronic severe stress
• Increases adipogenesis by triggering adipocytes formation from preadipocytes, and by increasing blood supply to the adipose tissue
• Secreted only when high calorie diet is available
• Involves the activation of reward circuits in the brain
• And last but not least, it induced a state of metabolic syndrome (obesity, insulin resistance) in the experimental mice.

What is the relevance of this research to human obesity/metabolic syndrome?

Obviously, this phenomenon needs to be demonstrated in humans. Demonstration that NPY levels are markedly higher in chronically-stressed individuals will be a big step forward. Inhibition of secretion of NPY through drugs or stress reduction techniques will add weight to the hypothesis.

The big prize: demonstration of weight reduction through reduction of NPY secretion will be a boon to us and to our strained health care budget.

Here is a thought that may have occurred to you: can our increasingly stressful lifestyle be partly responsible for the obesity/metabolic syndrome epidemic?

Another thought: rather than wait for the results of these experiments to yield the ultimate proof, why not toss out all the sweets and high calorie foods, and stock the fridge with “good for you” veggies? No activation of the reward system in your brain=no NPY secretion. Not very appetizing solution, I know. I’d rather wait for the results of the human experiments, and then decide.

Epilogue

My estimate is that to carry out the required experiments in humans would cost about $10-20M. To develop and clinically test an NPY inhibitory drug could cost anywhere from $50-100M. Can the health care mavens quickly calculate what would be the ROI (return on investment) on this sum?

By Dov Michaeli MD, Ph.D

Several months ago I received an alarming phone call from my nephew: he had terrific pain in his abdomen which caused him to double over. His stool was pitch black. It was obvious that he had an acute stomach ulcer, probably bleeding. What could cause this painful disease?

Since the late 19^th century doctors described the existence of bacteria in the stomach, but for a variety of reasons these reports did not gain traction, or were simply not believed. The bacterium, later named Helicobacter pylori was rediscovered in 1979 by Australian pathologist Robin Warren, who did further research on it with Barry Marshall beginning in 1981; they isolated the organisms from mucosal specimens from human stomachs and were the first to successfully culture them. In their original paper, Warren and Marshall contended that most stomach ulcers and gastritis were caused by infection by this bacterium and not by stress or spicy foods as had been assumed before. Their report was met with universal disbelief. I remember my own dismissive reaction when I read the first papers. An organism living in such an acidic environment (pH 2-3)? And not as a transient tenant, but a permanent resident? “everybody” knew that stomach ulcer is caused by stress…there must be some mistake here.

The experiment that changed everybody’s mind was when Barry Marshall, in a dramatic effort to convince the medical world, swallowed a petri dish of H. pylori, showed with gastric biopsy that the bacteria indeed colonized his stomach, developed gastritis within weeks after swallowing it, eradicated it with a combination of bismuth subsalicylate (Pepto Bismol) and metronidazole (Flagyl), and a second endoscopy 10 days later confirmed that the gastritis resolved. It was only then, in 1994, that NIH ( the National Institutues of Health) published an opinion stating that most recurrent gastric ulcers were caused by H. pylori, and recommended that antibiotics be included in the treatment regimen. In 2005 Warren and Marshall were awarded the Nobel Prize for their work.

What is H.pylori?

This bacterium is wonderful example of biological adaptation. It burrows into the mucous layer (a gel-like mucus layer) of the stomach, and that’s where it stays. But to survive in this hostile environment it had to somehow protect itself from the acid. Urea is normally secreted by the epithelial cells (these are the cells lining the stomach). The bacteria secrete an enzyme, urease, which breaks down urea to ammonia and CO 2 . Ammonia does a wonderful thing for these bacteria: it neutralizes the acid in the vicinity, thus allowing them to thrive in this forbidding environment. But it does something else: it kills the epithelial cells that come in contact with it. Thus it, and some other proteins secreted by the bacterium, cause gastritis (inflammation of the stomach lining) and eventually, an ulcer.

What about the acid?

We are not completely blameless--H. pylori gets some help from us in causing gastritis and ulcers. Once the mucous layer is damaged by  bacterial colonization, the epithelial cells lie bare and defenseless against the destructive effects of the acid. This can explain the relationship between emotional upset and ulcer disease: stress hormones cause an increased secretion of acid. Coffee has also been shown to increase acid secretion.  Unfortunately, decaffeinated coffee is not going to help;  chemicals that cause increase in acid secretion are present also in decaf. The same is true for excessive alcohol consumption; it damages the mucous layer, and exposes the cells to acid. add to that H. pylori--and you are in trouble.

Eradicate! eradicate?

H. pylori is an ancient organism that has lived in human stomachs probably since the beginning of our species, about 4 million years ago. It is disseminated with the drinking water, and probably infected 100% of the human population before sanitary conditions became widespread in the 19^th and 20^th century. As we saw, the ulcer formation is really incidental, collateral damage, to the ingenious secretion of urease and neutralization of stomach acid. Even more alarming, it is now generally accepted that H. pylori is responsible for most cases of stomach cancer. So obviously, if we just treated this pesky bacterium to a dose of antibiotics-we’d solve the problem once and for all. Indeed, while the incidence of H. pylori infection in humans is decreasing in developing countries, presumably because of improving sanitation and increasing use of antibiotics, in the United States the incidence of gastric cancer has decreased by 80 percent from 1900 to 2000.

However, there are always coseqences; some of them unintended. Parallel to the decrease in H. pylori infection there is an increase in the incidence of acid reflux from the stomach into the esophagus. And even more alarming: esophageal cancer is now the most rapidly rising cancer in the U.S. and Europe.

Fortunately, in most cases we can deal with this problem quite easily: we have now powerful drugs that are called proton-pump inhibitors, such as prilosec, that inhibit acid formation in the stomach and its reflux to the esophagus.

So here is another example of the delicate balance between us and our environment, in this case our internal environment. Recent studies showed that gut bacteria may contribute to obesity or even to our mood. So before we indiscriminately eradicate the flora that inhabited us for millions of years and upset the delicate biological balance we live in, we should carefully consider the consequences.

Dov michaeli MD, Ph.D is in the biotech industry

By Dov Michaeli MD, Ph.D

“Methought I heard a voice cry ‘Sleep no more!

Macbeth does murder sleep’—the innocent sleep,

… The death of each day’s life, sore labor’s bath,

Balm of hurt minds, great nature’s second course,

Chief nourisher in life’s feast”

Macbeth, William Shakespeare, 1600 AD.

Four hundred years later UC Berkeley scientists used brain imaging techniques to explain Lady Macbeth’s sleep-deprived brain descent into the darkness of insanity. They studied 26 young adults, half of whom were kept awake for 35 hours straight and the other half were allowed a normal night’s sleep in that same time period. Their brain was then studied using fMRI imaging. This technique shows the blood flow to different areas of the brain, and by extension, their state of activation.

What did they find?

The amygdala is the area in the brain that deals with unpleasant (or aversive) emotions, and puts the body on alert to protect itself. For instance, feelings of fear or rage are processed there. In the sleep-deprived subjects this area “lit up”, showing a high activation state.

On the other hand, the prefrontal area is responsible for tamping down those feeling, of adding some rationality into the mix; in a word, the outcome of its intervention is what we call ‘judgment’. In the sleep-deprived subjects the level of activation of the prefrontal cortex was significantly reduced.

Subjects who had gotten a full night of sleep showed normal brain activity.

This is not surprising to anybody who has experienced sleep deprivation, and that’s essentially all of us. Who hasn’t experienced the easy irritability, or alternatively the giddiness, that come after a sleepless night? Or the compulsive and nervous eating? Or the feeling that your “resistance is down” and that you are prone to a viral cold? These feelings are not “all in you head”. Sleep deprivation has been shown to affect emotional well-being, to alter metabolic control, and to adversely affect the part of the immune response (called innate immunity) that protects us from bacterial and viral infections.

There may be more to it

If the capacity to tamp down negative thinking is impaired, it opens up the possibility of a connection to psychiatric disorders like depression and anxiety. If you think of it, both of these disorders are a reflection of inappropriate or exaggerated negative response to a stressful event. Such events need not be dramatic, they could be quite trivial. A not-so-good grade at school, perceived slight from a friend, a critical remark by a coworker—all these can precipitate depression or anxiety. And the brain mechanism is identical to that of sleep deprivation: an imbalance between the negative messages flowing from the amygdala, and the moderating and rationalizing effect of the prefrontal cortex.

America the sleepless

How much sleep do we need? It varies with age and overall health. Most adults require 7- 8 hours a night. Older people may need 5-6 hours. Teenagers may require an hour or so more. Now consider the following:

· The National Sleep Foundation poll found that in 1998 35% of adult Americans got at least 8 hours of sleep a night. In 2005 this figure dropped to 26%.

· About 40% of Americans get less than 7 hours of sleep.

· 75% reported having some sleep disorder one or two nights a week.

These are sobering statistics. I can’t help but wonder if our chronic sleep deprivation is not a contributing factor to our elevated level of societal rancor, increased violence, our deteriorating civility, and our increased rate of diagnosed psychiatric disorders such as chronic depression, anxiety and sociopathic behavior.

Sleep has become synonymous with sloth in our “on the go” society. It would take more than academic studies to change this culture. We need nothing less than a paradigm shift in our outlook on life.

Dov Michaeli MD, Ph.D is in the biotech industry.

By Dov Michaeli MD, Ph.D

I remember a wonderful lecture at UCSF, about 30 years ago, by Dr. Dennis Burkitt, on “Diseases of Civilization”. Dr. Burkitt was a missionary doctor in the bush in what at the time was Rhodesia (today’s Zimbabwe ). He was also an extraordinarily astute clinical observer (he was the first to describe a hitherto unknown cancer, aptly called Burkitt’s lymphoma). At the end of the lecture somebody asked whether Africans in the bush, being free of modern world stress, are healthier. Dr. Burkitt retorted that wondering every night whether that was the night the lion was going to have you for lunch is hardly an anxiety-free thought. The message was that stress recognizes no boundaries of geography, education, income, sex or national origin.

What is stress?

To paraphrase Potter Stewart, a supreme court justice who grappled with the definition of pornography: “I know it when I see it”. But there is a more ‘scientific’ definition: Psychological stress occurs when an individual perceives that environmental demands tax or exceed his or her adaptive capacity”. Interestingly, an elaboration of this definition includes two elements: high psychological demands coupled with low decision latitude. In other words, stress as we commonly understand it, high and unrelenting demand, is not enough. It is the lack of control, the feeling of helplessness, which tips the scale to the feeling of stress.

Can psychological stress cause disease?

I have to admit: being a firm believer in the physical causes of disease, I was highly skeptical. I readily admitted that stress could exacerbate disease; I have seen countless cases of acute asthma attacks or acute MI precipitated by acute psychological stress. But chronic, low intensity stress? I wanted to see hard evidence.

The title of a recent article, and an accompanying commentary in the JAMA, “Job Strain and Risk of acute Recurrent Coronary Heart Disease Events”, tweaked my curiosity. The authors followed 206 patients who have had an MI, for a period of 2.5 years following their initial episode. After statistically adjusting for 26 potentially confounding factors (smoking history, hypertension, high LDL etc.) they concluded that job strain increased the risk of recurrent coronary heart disease or CHD by 100%!

How can it happen?

There are many theories, but the most plausible and the best documented is the stress hormone theory. We have two systems that get activated during stress: the HPA (hypothalamic-pituitary- adrenocortical axis) and the SAM (sympathetic- adrenal- medullary) systems. HPA secretes cortisol, SAM secretes epinephrine aka adrenaline. Both are known as stress hormones.

 If stress is so common in life, how is it that evolution allowed the hormonal response to stress to be so deleterious? And the answer is: it didn’t. Besides facilitating the fight or flight response, they increase innate immunity, our first line of defense against pathological invaders, and decrease the inflammatory response. But all this is true for acute stress (e.g. the lion is coming at you). Chronic stress is something quite different. For reasons yet unknown, chronic stress causes a decrease of the immune response and an increase of the inflammatory response—exactly the opposite effects of acute stress. Whatever the reasons may be—the effect is destructive. As an example: coronary heart disease is basically an inflammatory process, and chronic stress aids and abets it. Furthermore, macrophages, which are white blood cells that are central to the formation of a coronary plaque, were recently discovered to secrete their own adrenaline, adding insult to injury.

Does a low dose of NSAID (non-steroidal anti inflammatory drugs) to prevent CHD make sense now?

What other diseases are associated with stress?

Depression is the most obvious one. To cite some compelling statistics: approximately 20-25% of persons who experience major stressful events develop depression. And when a cohort of depressed persons was examined, it was found that 50-80% have had a major “life event” in the preceding 3-6 months. To close the loop: most depressed individuals suffer from a depressed immune response and from chronic, low grade inflammation. Based on this we still cannot conclude that there is a cause and effect relationship here; but it is an intriguing correlation nontheless.

HIV/AIDS has also been suggested to progress faster, even when taking anti HIV medications, if the patient is under chronic stress. Again, one shouldn’t be surprised if the explanation will turn out to be a depressed immune response.

In Conclusion

On the biological level, this is yet another demonstration of the mind-body relationship. In fact, a whole field of research called psychoneuroimmunology (I know, it’s a mouthful, but if you break it up to its component words, psycho-neuro-immunology, it makes sense) is thriving and is uncovering new connections between brain, mind and immune response on an almost daily basis.

On the clinical level, the strengthening evidence of the effect of stress on health and disease suggests new modalities and approaches to treatment.

What is most intriguing and potentially far-reaching, are the societal consequences. Now that we accrue more and more evidence on the effects of stress on health, it would make economic sense to pay attention to the work environment. An enlightened manager would insist on stress reduction in the workplace in order to increase productivity. Conversely, could a company be found liable if an employee is subjected to an abusive supervisor and suffers a heart attack? The medical evidence is already here.

Dov Michaeli MD, Ph.D is in the biotech industry.