1996 LECTURE SERIES

Stress and the Brain: Good News and Bad News

Dr. Robert M. Sapolsky
Department of Biological Sciences
Stanford University
June 11, 1996

Definition of Stress
Stress. What do I mean by stress? Back to ninth grade biology. I guarantee you had this term back then and hopefully haven't thought about it since then – homeostasis. Do you remember homeostasis? You've got an ideal body temperature. You've got an ideal amount of glucose in your bloodstream. You've got an ideal whatever. A stressor is anything in the outside world that knocks you out of homeostatic balance. You're a zebra, and some lion has lucked out and ripped your stomach open, your innards are dragging in the dust and you can't go into shock right now because you've got to get out of there. If this doesn't count as being out of homeostatic balance, I don't know what does. Or, you're that lion. You're that lion that's half starved to death and if he can't catch that zebra, you're not going to survive the night. Short-term physical emergency. A stressor is what knocks you out of homeostatic balance. The stress response is a bunch of hormones you secrete. We all know about adrenaline. We've just heard about corticus steroids, 20 other hormones as well that I won't torture you with. A stress response is what your body does to re-establish homeostatic balance.

Great, that's all you need to know if you're thinking about zebras and their problems. If you're thinking about us and stress, you've got to expand that definition in a very specific way which is a stressor can be when you've been knocked out of homeostatic balance. In addition, a stressor can be when you think you're just about to be knocked out of homeostatic balance, and if it turns out you're right, that's wonderful. Hooray for you! You have a cortex, it's fabulous. You know, the elephant doesn't have to have stomped you yet for you to see it coming and thinking maybe this is a good time to increase my blood pressure to get me out of here. An anticipatory stress response can do you wonders. On the other hand, if you think you're just about to be knocked out of homeostatic balance and you really aren't and you think that way all the time, we have a technical way to describe you. You're being as neurotic as hell. You're being neurotic. You're being anxious. You're being paranoid. You're being hostile. You're being profoundly human. Take a hippo and sit it down and try to describe mortgages to a hippo and it's not going to see what the big deal is, but we see what the big deal is. They don't worry about mortgages and the ozone layer and blind dates and the Internal Revenue Service and we do all the time. The central concept of a stress-related disease is turning on the stress response for three minutes or three hours in order to save your life from the predator coming after you and it does you wonders. Turn on the stress response for 30 years for psychological reasons and it gets you sick. We as humans take the system that evolved in 99 percent of the beasts on this planet for dealing with a short-term physical crisis and we turn it on for great lengths of time. If you do it chronically, you're at risk for getting stress related diseases. That's the centerpiece of the whole field.

Now if you think about it, what I'm telling you actually doesn't make any sense at all because what I'm saying is there's this stress response, this thing you do with your body. If you're a zebra running away from a lion, if you're a lion running after a zebra, if you're too hot, too cold, or if you're nervous about speaking in public, why should your body do the same thing in all of these circumstances? I mean this is crazy! If you're trained in physiology, what you're trained to think of is your body comes up with a very specific solution to a very specific problem. If you're too hot, you sweat. If you're too cold, you shiver. Totally opposite things. What's this crazy stress response that they turn exactly the same way whether you're too hot, too cold, nervous, anxious, whatever? Why should it be convergent?

Early Stress Experimentation
Now the person who first got a sense of this is pretty much the godfather of stress physiology. This was an Austrian physician named Hans Sellia who started the whole field about 60 years ago. Sellia was the first one to deal with this notion that there's this stereotype stress response, and basically Sellia started this whole business because he was very smart and very intuitive and incredibly bad at handling laboratory rats. This is how the field began.

Okay, Sellia was a young Assistant Professor at the time. In the 1930s he was up in Miguel University, Montreal looking for some research project that was going to make him famous and some biochemist down the hall had just isolated some chemical out of somebody's pancreas and nobody knew what this stuff did. Sellia decided he was going to figure out what this pancreatic crud does. So he gets a bucket of this stuff down the hall, brings it back to the lab, starts injecting the rats, and this was not a pretty site. He was in there every day, injecting the rats and dropping them and chasing them and they were chasing him and half the morning with a broom getting them from underneath the sink. They let months of this go by. After which Sellia inspects the rats and discovers something amazing which is all the rats have stomach ulcers. Ah ha, he just discovered the effects of this pancreatic stuff on the body. It gives you stomach ulcers. Wonderful.

Fortunately at this point, being a good scientist he did what you're supposed to do and he ran a control group. He injected rats just with saline instead of the pancreatic stuff. So he's in there now injecting them and dropping them and chasing them and they were chasing him, months of this go by and all of the control rats have stomach ulcers. Okay, so your average scientists at this point gives up and goes to business school, but he realizes this has nothing whatsoever to do with the pancreatic stuff. There's something else going on here and he thought through this and said, "well what's happening here." I'm really lame when it comes to handling laboratory rats. They can't be having a great time. Maybe what I'm seeing is some kind of non-specific response of the body to generalize unpleasantries, and what he set about doing was systematically exposing rats to generalized unpleasantries. He put some of them up in the roof of the building in the winter and others in the boiler rooms and others with loud musics and others with cats or whatever. All of them get stomach ulcers.

Effects of Stress
We know exactly what Sellia had discovered. This was the tip of the iceberg of stress-related disease. There's this physiological stress response that gets turned on whether you're too hot, too cold, injured, hungry, whatever, and under some circumstances it saves your life, but if it goes on for too long, it makes you sick. Everybody in the field at the time thought this was absolutely crazy that there's this stress response that gets turned on in all these circumstances. But if you think about it, it's actually makes a great deal of sense. Why should you have the same stress response in all these different settings? Well what we see here is a demonstration of why this actually makes a great deal of sense. Whether you are that zebra or that lion, there are certain things you are going to have to do with your body. The first thing is if you are going to save your life running away from the lion or running after lunch, you need energy. Energy right now not tucked away in your fat cells for next spring. You need energy right now, and a hallmark of the stress response is you go to your fat, you go to your liver, you go to the bank, you empty out the savings account and you turn it into cash in your pocket. Glucose, sugar in your bloodstream handed to whichever muscles are going to save your neck. Wonderfully logical. The next thing you do whether you are that zebra or that lion is, you increase cardiovascular tone. Your blood pressure goes up, your heart beats faster. You breathe faster. All is part of the strategy. Get that glucose, get that oxygen and deliver it to those muscles as quickly as you can, and that makes sense whether you were that zebra or that lion.

The next set of things you do during stress make wonderful sense as well--you turn off the long-term building projects. If a tornado is due this afternoon, this isn't the day you repaint the kitchen. You don't know if there's going to be a kitchen tomorrow. You don't worry about the long-term projects until you know there is a long-term. You shut down digestion. If you are that lion, you just haven't staggered out of an all-you-can-eat buffet anyway. Your stomach is empty. If you are that zebra, you're running for your life. You're not going to get any energy from your stomach. That takes hours. You're going to get it from your fat cells. You've got better things to do. You're trying to avoid being somebody's lunch. Don't worry about breakfast. You get a little bit stressed say speaking in public and your mouth gets dry. You've stopped secreting saliva, the first step in shutting down the whole gastrointestinal tract. So that's wonderfully logical. In addition, during stress, you shut down growth, you shut down reproduction, and this is quite logical as well. Big expensive, optimistic things to do with your body, especially if you were a female mammal and this is no time for it. You're running for your life. The lion's two steps behind you, you know, ovulate some other time. Don't do it right now. Ovulate some other time, grow antlers next week, hit puberty tomorrow, don't worry about it, don't even think about it. You've got other things in your mind. Forget sex, shut down the whole system and that's exactly what occurs.

The next step during is stress you shut down the immune system, and this is very logical as well. Immunity is a wonderful thing to have. Your immune system will spot some tumor that would otherwise kill you in six months. It makes antibodies that are going to help you in a couple of weeks. Your immune system is going to do nothing for you in the next three minutes when you sprint across the Savannah. Make your antibodies tonight. Don't do it right now. Turn off anything that is not essential.

Finally, during stress you shorten cognition. Your memory gets a little bit better. You store things away better, your sensory thresholds improve and we all know examples of this. We all know where we were when Kennedy was shot. We can't remember where we were 24 hours before that. Big events we file away. Stress tells you how important the information is. Also, you're much more sensitive to sensory information and we all know examples of that. You're sitting at home, it's midnight and you're watching some terrifying movie on TV by yourself. It's a really frightening moment, you're just on the edge of your seat, and some car back fires half a mile away and you practically have a coronary. You're much more sensitive to sensation at those times.

At the metabolic end, if you never store energy, your storage sites waste away. Your muscles atrophy, you suffer from myopathy. You're exhausted all the time for very complex reasons. You wind up being more at risk for adult on-set diabetes, as chronic stress will cause adult on-set diabetes. If you already have it, it will worsen. This is a classic Westernized disease. Diabetes like this did not exist among our ancestors. It does not exist in most parts of the developing world. This is a disease of growing older and sedentary with the Western diet. And this is a classic one made worse by stress. So you get into trouble there. Obviously, at this level if some lion is coming after you and your blood pressure is 180 or 120 or something, you're not suffering from high blood pressure, you're saving your life. On the other hand, if your blood pressure is 180 over 120 every time you're stuck in a traffic jam, you're not saving your life, you're suffering from high blood pressure and if you do that chronically, you are going to get into trouble.

One of the great myths in the field is the way that stress makes you sick in the cardiovascular realm. You get some major stressor, and you've got that sudden stress related heart attack. That's actually a very rare event. Far more common, is you increase blood pressure over time and you just begin to damage the surface of your blood vessels. You begin to tear away at them, a little bit here, a little bit there, and once you tear the surface, that's just the sort of place where fat and glucose and cholesterol love to stick to and you start getting plaque. Where's the fat and the glucose and the cholesterol coming from? That's exactly the stuff you're mobilizing. So you get into trouble in that way. That's not good.

Stomach Ulcers Caused By Stress
What else can I tell you that's bad news. At the digestive level, if you are chronically stressed, you will set yourself up for the most famous of stress related diseases--a stomach ulcer. This is an area in which there has been a revolution in the last few years. It's been discovered there's actually a bacteria, a bacteria which gives you stomach ulcers, a bacteria which is brilliant in blowing a hole in the wall of your stomach and some of us have it. If you are chronically stressed, you suppress the immune system and you can't defend yourself against that bacteria. If it begins to proliferate, you're more likely to get an ulcer. Also, if you are chronically stressed, you are at risk for the most common of all stress related diseases--stress-related colitis. Irritable bowel syndrome, 75 percent of us will get our bowels in an uproar and some diagnostically medical way at some point or other in our life time. This is the state where you've been very stressed for the past couple of weeks and every time you eat a meal, 30 minutes later you've got gas, you've got the runs, you're constipated. Okay, let me tell you how colitis works. We've all had dinner and some great hors d'oeuvres. This is what goes wrong and what happens with your bowels. Your bowels are very interesting for those of you who have not realized this already, what's the logic of what's going on in your bowels during stress. We know the logic already, which is you stop secreting saliva, you stop stomach activity, you stop secreting hydrochloric acid during stress, you're turning down your whole gastrointestinal tract. Your small intestines are normally turning, they stop turning, everything gets turned off. We know the logic of that already. Everything gets turned off right up to the border of your large intestines. Something different happens there having to do with what an incredibly boring part of your body your large intestines are. Small intestines are fabulous. Small intestines are great. Small intestines you can put stuff in and take it out, and your body can absorb things and you can release things in there. You can spend all day doing that. Fabulous part of your body. Large intestines are very boring in that you don't get any nutritional value out of your large intestines. Once stuff gets into there, you can't absorb nutrients out of your large intestines. All you do is absorb some water so you know you don't desiccate like a prune every time you go to the bathroom, but otherwise, this is not a very exciting part of your body. So you're sitting there and what's the logic during the stress response. You shut down your stomach. You shut down your small intestines. Large intestines do something different. All that stuff is there. You're not going to get any nutritional value out of it and you suddenly have this choice. You're running for your life, the lion is coming after you and you can do it with or without five pounds of dead weight sloshing around down in the bottom there and suddenly you see the logic, get that stuff out of there. This is sufficiently well known, but in this country when people are executed, they're executed in diapers. When you are very, very stressed, you lose control over your large intestines. That's what happens here.

During stress you decrease rhythmic contraction in your small intestines, but you increase it in your large. So why doesn't this cause colitis? Here's what happens. You're going along. Life's great. You're doing a little bit of small intestinal turning, a little bit of large intentional turning. Things look terrific. Stressful period comes along. What do you do? You turn off the small intestine, you turn on the large. End of stressful period, you go back to normal. More stress, you turn off the small and you turn on the large intestines. At a period of more stress, you do it again. After many stressful periods you eventually somehow get the timing mechanisms wrong and they're both doing the same thing at the wrong time. It's a problem with choreography, and what you get there is a state where inadvertently you've got both the small and the large intestines active at the same time and you've got the runs. You've got your foot on the gas at both ends. If you've got both of them decreased, you get constipation. Things really stop working there and what's amazing is how readily this occurs. This is incredibly easy to occur and all at various points, 75 percent of us again get some kind of stress-related irritable bowel syndrome at some point or other. There's a subset of people who are stupendously vulnerable to this. You do these sorts of studies, you take these volunteers and you give them some frustrating tasks. Some puzzle that can't be solved and most of us sit there and do that and eventually say this is ridiculous, we fling down the pen and storm out. You get these folks who are colitis prone and they work on the puzzle and they say this is ridiculous and they throw down the pen and they storm out and four hours later, their large intestines are still contracting. You're very, very prone towards that. So that's not a good thing either. You get into trouble there.

Dwarfism Caused By Stress
Next category. If you grow for a living, if you're a young organism, if you grow for a living and you are chronically stressed, you can get into trouble in a way, a very rare pediatric endocrine disorder, a disease where kids stop growing for psychological reasons. Stress dwarfism, psychogenic dwarfism, dwarfism generated by psychological reasons. This is an amazing disease. These are kids who have stopped growing years behind the normal growth rate and they don't have a disease. They're not malnourished. They don't have parasites. You check their bloodstream and there's no growth hormone there. You give them synthetic growth hormone, they don't grow. Nothing works and you check around in their background and often what turns out is they have something stupendously stressful going on, and the amazing thing about this is you get those kids out of that stressful setting, and they start growing again. In every single medical textbook, always in the endocrine chapters on growth you will always see a picture of one of these kids years behind the normal growth rate. There's this ability to catch up with the growth. Absolutely wild, and this is seen in lots of different circumstances. It is a very rare disease. This is not a disease of the stress of your parents moving frequently because of job transfers, or your parents having an acrimonious divorce. This is a disease which when it occurs causes major league psychopathology. This is the police and the social worker's breaking down the door of the apartment and finding a kid who's been locked in the closet for the last six months, fed on a tray of food stuck underneath the door. Nightmare situations, but if you get the kids out of there, they start growing again.

Amazing example of this. A few years ago, there was a paper published on a child brought into New York Hospital with stressed dwarfism from one of these horrendous backgrounds of psychological stress. What they showed was at the time this child came into this ward, there was zero growth hormone in the blood stream. Over the next two months in this ward, he got very attached to this one nurse and this was obviously the first normal emotional relationship in his life. By the end of two months, normal growth hormone levels. Nurse goes on a vacation. By the end of her two week vacation, the kid's back down to zero growth hormone. The nurse comes back from vacation, three days later, normal growth hormone levels again. Think about that. The rate at which this child was depositing calcium in his long bones was a function of how loved and secure he was feeling in the world. You can't ask for a much more dramatic example of what goes on here effects virtually every cell in our body. What is wild is there are all sorts of interesting historical examples of stressed dwarfism. Kids in war zones. Kids in periods of civil strife. I think we have enough evidence to document that kids in the Japanese American internment camps in the 1940s suffered from stressed dwarfism.

Here's the single creepiest example of stressed dwarfism I've ever heard of--and if this doesn't give you the willies, you've got something wrong with you. If you ever find yourself reading chapter after chapter about growth hormones for some inexcusable reason, you will notice there's a very interesting pattern which is a lot of these chapters make reference to Peter Pan. They start with a quote from Peter Pan or they've got some snide comment about Tinker Bell. I've seen this pattern for years and I have no idea what was going on until one day I finally found the explanation. This was a chapter talking about psychological regulation of growth hormones, stress dwarfism, all of that, and it gave the following case history. An eight-year-old boy was growing up in Victoria, England in the 1870s. One day this boy sees his beloved older brother killed in front of him in some horrible accident. He was completely traumatized by this, and he had no other siblings. The father was kind of non-existent, and this was the favorite child of the mother. The mother in this Victorian swoon goes to her bedroom, pulls down the shades and stays in bed mourning for the next 20 years.

So you've got this kid growing up in basically complete isolation, horrible scenes. He goes into the mother's bedroom with a tray of food for her and she says, "Oh David, David is that you David? (the dead son) David is that you? Have you come back to me? Oh my son, oh it's only you?" The kid growing up being "only you." Apparently the only thing the mother ever spoke to him about was this ideation she grasped onto which was well, if David had to die at least he died when he was perfect. He's one of these boys who doesn't grow up and doesn't need his mother anymore. He'll always be my perfect little boy because he didn't grow up because he's perfect. And this kid heard this. This kid heard this with a vengeance even though there was no indication of any disease in him. (Very wealthy family, no malnutrition, nothing like that.) He stopped growing at that point. He lived to be 60 years old. He was 4' 10" as an adult. Confirmed on autopsy after his death, he never reached puberty. This warranted being a wild example of stressed dwarfism. And then the chapter concludes by informing us that as an adult, this was the author of the much beloved children's classic Peter Pan. This was J.M. Berry, the author of Peter Pan, incredibly bizarre history for this man. This was a man, get this, this was a man who by 1910 this was the most widely read author in the English language. Think about that, the most widely read author in the English speaking countries and all this guy did was crank out book after book after book about boys who die and come back as ghosts and marry their mothers and all sorts of stuff like that. This guy spent the rest of his life working out this stuff. He was repeatedly in trouble with the police as an adult for sadiomacastic relationships with little boys. This guy spent the rest of his life not very successfully working through these problems.

Stress Effects in Female Reproduction
Reproduction, so what goes wrong with that. Everything goes wrong with that. Everything goes out the window if you are chronically stressed. If you are female and you plan to ovulate at some point or other, you do not want to be chronically stressed. In every species around, cycles become irregular, cycles stop all together, stressed induced amenrhia and this works in all sorts of different ways. A very strange thing that females do the world over, they secrete a certain amount of male sex hormones, a certain amount of testosterone like hormones, androgens. What are they doing that for, nobody has a clue. They come out of the adrenal glands, these things are called adrenal androgens. Not tons of the stuff, but just a little bit. Nevertheless, you've got to get rid of it. How do females get rid of adrenal androgens? There's some enzymes in your fat cells that turn the androgens into estrogens. Easy biochemistry 101, any fat cell can learn that in a semester or so. They do that everything's fine. No problem, don't grow a mustache. Things work wonderfully. So what happens if you were stressed?

Stress like the locusts have come and eaten your crops and for the next six months, you've got to walk 20 miles a day to get enough food. What happens if you were slowly starving. Your fat deposits go down. You have less fat in you. You have less fat around to convert the androgens to the estrogens and you get into trouble that way because in part your not making as much estrogen as usually, but mostly the androgen levels are elevating and that works in your brain and your pituitary and ovaries and things stop working and that's why if you are chronically starving, you stop ovulating if you're a female. That's also why if you're voluntarily starving, you stop ovulating. People with anorexia nervosa, one of the characteristics of that disease is you stop ovulating real early on. That's also the reason why females, human females who do tons of athletics, often stop ovulating as well because the critical muscle fat ratio has changed. You don't have enough fat around to prevent that step. All sorts of studies showing there are girls who do tons of athletics, principally dancers or swimmers or gymnasts, they reach puberty at a significantly later age. Romanian gymnasts, you know all these 60 pound kids that get the Olympic gold medals? Average age at which those girls start menstruating, 19. Seven years later than the standard Western norms. Once you've hit puberty, women who do tons of exercise also are at risk for delaying all sorts of aspects of ovulation. Again, critical muscle fat ratio there. Showing a very important lesson and one that you see with male athletes as well. Just because it's a good thing to exercise, it's not an amazingly good thing to do amazing amounts of exercise. You can overdo something. There's a physiological optima, homeostatic balance points and too much can be just as bad as too little. Most of the studies indicate that if you run more than 45 or 50 miles a week, you're probably getting to the point of muscle fat ratios where you're going to be having problems with your cycles. That's what most of the studies indicate.

Stress Effects in Male Reproduction
At the male end, all sorts of things don't work very well anymore. Very dramatically testosterone levels go down if you are chronically stressed. Take some male, some guy an anesthetize him for surgery. Slice into his belly with a scalpel and 30 minutes later, testosterone is down to nothing. Take first year male medical students who have often been studied for this, getting them during exam periods, down go testosterone. Take a male baboon, manipulate his social ranks so he drops in the hierarchy, down does his testosterone. Here's the classic population that's been looked at. Fortunately, I have no personal experience with this whatsoever, but I am told that it's not a pleasant thing to be in the Marines. It's apparently not a nice thing to do. You don't have a great time. There was one group of Marines during their first couple of months at boot camp where in addition to everything else, they pee into little Dixie cups for these Army psychiatrists doing research on them. Their hormone levels are measured and the answers came back. Guys in their first few months in the Marines have the testosterone levels of Vatican choir boys. It turns out testosterone has been a vastly over rated hormone. Males can have 90 percent of their testosterone disappear from the blood stream and you know, as long as they got a little bit of the stuff and a couple of sperm they're in business. Testosterone is mostly superfluous. That doesn't get you into trouble. The thing that gets you in trouble is erections go down as well.

Erections stop working during stress. Here's the deal with erections. Okay, you got your spinal cord, mostly it does boring stuff, your spinal cord makes you shake hands with people or write a check or that sort of thing, the things you have control over. There's also a part of your spinal cord that does all the things you normally don't have any control over and makes you blush, it gives you goose flesh, it gives you orgasms, and makes your pupils contract, all these involuntary things. A part of your spinal cord comprises this involuntary nervous system, this autonomic nervous system. The autonomic nervous system comes in two halves--one half is called sympathetic nervous system, and that's there for emergencies. It secretes adrenaline, it makes your heart speed up, arousal, all hell breaking loose, fight or flight syndrome, sympathetic for arousal. The other half is called the parasympathetic nervous system. Calm, vegetative function. Eat a big meal, you turn on the parasympathetic. Go to sleep, you turn on the parasympathetic.

Well what happens next? You know maybe you get a little bit less calm and vegetative. I don't know what happens next, but maybe you start breathing a little bit faster or something or other about having the erection. You know, you get a little bit less calm and vegetative, but you slowly turn on your sympathetic nervous system. More times goes on and you get even less calm and vegetative and you're breathing a lot faster and your curling your toes and who knows what else is going on. Slowly you're turning your sympathetic nervous system all over the place, finally you can't take it anymore. That's how erections work. So what happens then during stress, during stress you're not very calm and vegetative, you can't turn on the parasympathetic nervous system. You suffer from stress and induce impotency. You can't get an erection. Here's the other way you get into trouble. Suppose you've managed to be calm and vegetative, you've got the erection there, but then you think about oh no, what's happening with the Mexican economy, more devaluation of the Paso, that sort of thing, you're suddenly get stressed about something, you accelerate that transition from parasympathetic to sympathetic, you do it too quickly and you suffer from premature ejaculation. Incredibly easy for these things to occur. Sixty percent of the doctor's visits in this country by men complaining of reproductive dysfunction turn out not to have an organic basis. There's no disease that's identified, it is instead viewed as psychogenic. It takes remarkably little stress for this part of the body to stop working. Let me tell you something very, very useful though. Here's how you tell the difference between psychogenical and organical impotency. Here's how you differentiate the two because it's very, very easy to tell the difference. You take advantage of a very weird thing that male primates do. When they go into REM sleep, rapid eye movement sleep, that stage of sleep, they get erections. This happens. I have no idea why. I talked to the world's penis experts and nobody has an explanation for this. Primates get REM sleep erections.

This is how it works. Take it or leave it. So you're there and the question is somebody comes to you and say, "I haven't been able to have an erection during sex in the last six months," and you wonder is this stress-related or maybe the person has a pituitary tumor. Maybe they've got something wrong with their spinal cord, is it psychogenic or organic? Here's how you tell the difference. You give the person this handy dandy little penile pressure cup thing that they take home that night and they put on their base of their penis just before they go to sleep, and you know you wire it up and satellite relays and 24 hour operators and the next morning you have your answer. You've got your answer which is that guy hasn't been able to have an erection during sex for the last six months, but 30 seconds into this first REM stage he has a normal erection. He doesn't have a brain tumor, he doesn't have any sort of organic basis, it's psychogenic in origin. It's stress-related. That's how you tell the difference. You still retain the REM sleep erection. Actually, I recently heard about a great elaboration on this test because if you think about it, you've got this electronic pressure transducer and it's beeping and you're so convinced that it's going to electrocute you during the night, that it's a stressor itself. Here's what you do instead. Here's this wonderful low-tech solution. You take some postage stamps and you wet them and you put them on the guys penis. The next morning, if the stamps have been torn loose, he had an erection during the night. Can you believe how great that is. Ninety-six cents you get a lab result. It's fabulous, 96 cents for that. I don't know if insurance will reimburse you for that, so that's where you get into trouble, so if you do that chronically then you're up the creek.

Stress Effects on the Immune System
Immunity. The immune system basically is a very good thing to have. You know, you really do want to have an immune response and the centerpiece of one of the most exciting fields of biology these days is psychoneuroimmunology. In so far as stress suppresses your immune system and in so far as chronic stress chronically suppresses your immune system, you should be more at risk for all sorts of infectious diseases--and once you get them, you should have your defenses impaired against them. This is the basic question. Is this what happens? And this is an immensely controversial field. What's clear at this stage is at the boring end of stuff, there is indeed a very solid connection. If you were chronically stressed, the common cold becomes more common. If you are chronically stressed, you're more likely to get mono, things of that sort. People know this. This is very well documented. What's not at all clear is the other end of the spectrum. The one we all worry about. What is it about stress and cancer? And the safest most responsible thing that I can tell you, is there is a link between stress and cancer, although it is an infantly small one. Amid all of the examples I've given you of all of these things that go wrong with chronic stress, the link between stress and cancer is very, very penniless. In laboratory studies, there is no evidence whatsoever that stress can cause a tumor to occur. There's a little bit of evidence for three or four types of tumors that once you have them stress will accelerate their growth. However, none of these are types of tumors that humans get very frequently. It is a very weak connection. Why that is important to emphasize is because there is a remarkable number of healthcare professionals out there who are making very handsome livings selling people on the notion that cancer is a stress related disease, and that cancer is a controllable disease if you manage your stress properly, and if you have the poor luck of having terminal cancer, we know whose fault that is. It is an astonishingly damaging set of rules to be teaching people that are not based on science in the slightest. They are based on medivalism and wishful thinking. Very, very damaging stuff. It would be wonderful if it were so, but it's not so and shame on people who make a living selling sick people that view.

Stress Effects on Hormones
Hormones. Those same hormones, those corticus steroids that can get into your brain and sharpen cognition and make certain parts of your brain work more effectively for generating memory and things of that sort, it turns out if you are chronically stressed, those same hormones can kill your brain cells. Those same hormones can damage a class of neurons that are very critical to learning and memory. This is the class of neurons that are damaged in Alzheimer's disease, that are damaged after stroke, chronic epilepsy and this is what I work in my laboratory, trying to understand how do these stress hormones kill these neurons. It turns out that not only do they kill these neurons, they endanger them as well. They make it harder for these neurons to survive a stroke, a seizure, a hypoglycemic crisis. We now believe it makes it harder for those neurons to survive exposure to the AIDS virus. There's a bit of evidence suggesting it makes it harder for those neurons to survive some of the constituents that are thought to be involved. In Alzheimer's disease, what we are slowly coming to recognize in that realm is that neurological damage might be thought of as a stress-related disorder. What we are really coming to learn in this realm is the rate at which, in a rodent for example, the rate at which you are exposed to these stress hormones over the lifetime has a lot to do with the rate of degeneration in that part of the brain and we all know these stupendous variability with which we age. Some of us are aging successfully and gracefully and in wonderful shape and some of us aging disastrously. This is certainly one of those realms in which our cognitive abilities are very sensitive to how we live our lives, and we're beginning to understand how the system works.

I've covered several ways in which you get into trouble going about being the typical human with all sorts of psychological stressors and chronic activation of the system. You look at this stuff if you're a stress physiologist, and after awhile it seems like a miracle that any of us are alive. Okay, let me make it even worse. Let me give you the absolutely epitome of stress related disease. Here's how bad it gets, a stress-related disease, a profoundly rare state in which you get so incredibly traumatized by something or other that over the next few days your hair turns white. It's for real. It's for real. This is a real disease. Dermatologists see one case of this in a lifetime, but it really does work this way. They understand how it works. Your immune system goes crazy and it attacks your hair roots and for complicated reasons, the color appears to be different. It actually works this way. I mean looks what this comes to. You're chronically stressed. You get high blood pressure. You get diabetes. You stop growing. Your sex life is ruined, your brain is damaged, and your hair turns white. I mean how is it that any of us keep functioning?

Stress Management
Most of us keep functioning just fine. Most of us have not collapsed into puddles of stress- related disease. Most of us cope and a subset of us copes spectacularly. Why is it that some bodies and some psyches deal better with stress than others? What are the mechanisms explaining individual differences in vulnerability to stress related disease? Now when I talk about this, what should be obvious is that I'm not talking about how you manage major physical stressors. If you step out of here after the end of this lecture and you're gored by an elephant in the parking lot, you are going to have a stress response. There is no degree of psychological reframing you can do. Get gored by an elephant, you're going to have a stress response. Get stuck in a slow bank line, get stuck in a troubling occupation, things of that sort, it's not at all clear if you're going to have a stress response. The critical thing when we consider humans and our psychological stressors is, almost certainly whatever it is that would give you or me an ulcer, somebody else out there is going to pay to do as their favorite hobby. There's tremendous individual differences and that's what makes psychological events stressful for some of us and not stressful for others.

What is stress management about? What it comes down to first is figuring out why is psychological stress stressful? What is stressful about a psychological event? There have been thousands of different studies showing what precisely are the building blocks of psychological stress. Here's the sort of paradigm that's done. You have a laboratory rat in a cage and every now and then the rat gets an electric shock, mild shock, the sort you would get scuffing your foot on the carpet. Nevertheless, after a period of time, this is no fun for the animal. It's having a stress response. Blood pressure goes up, corticus steroid levels, adrenaline levels go up. As graphed here, after awhile the animal is likely to get an ulcer. You're giving it a stress related disease. Okay. In the next cage is a rat that's getting the same exact electric shocks, same patterns, same intensity, same everything as far as Hans Sallia was concerned 60 years ago. These two rats are being knocked out of homeostatic balance to the exact same extent except this time there's a difference. Every time this rat gets a shock, it could run over to the over side of the cage where there's a bar of wood that it could gnaw on with its teeth and that rat doesn't get an ulcer. It has a hobby. In the next cage, you have a rat that's getting the same shocks again, the same pattern of electric shocks except this time every time it gets a shock, it could run over to the other side of the cage where there's another rat that it can sit down next to and bite. That guy's not going to get an ulcer. The other guy is going to get plenty of ulcers, but this guy's going to do just fine. He's got an outlet for his frustrations. You don't get the ulcer then. Next variable. This time you have a rat in the next cage and 10 seconds before each shock a little warning light goes on and that rat doesn't get an ulcer. You've given it predictive information. For the same exact physical stressor, you are likely to avoid a stress related disease if you get feedback. When is it coming? How bad is going to be? How long is going to last for? We all know examples of this. You're sitting there in the dentist chair and the dentist is drilling away and it hurts and finally you whimper are we almost done, how much longer? Predictability makes stressful events less stressful.

Another example. We have here a rat, a rat that's been trained to press a lever to decrease the likelihood of getting an electrical shock. It's learned how to do this just fine. Today, the lever is disconnected. It's not doing anything at all. It's a placebo, but the rat is sitting there pounding away on the lever like crazy saying this is great. Imagine if I weren't doing this how many shocks I were going to get. The rat thinks it's in control and it doesn't get the ulcers then. But the same physical stressor, if you think you are in control, you don't get the physical symptoms. You don't get the stress related disease, and 90 percent of stress management is built around figuring out what things you can change and what things you can't. I was talking to somebody a few months ago who works for a temporary agency as a secretary. She was working one place for a week, somewhere else for a week, and I said, "God that must be incredibly stressful. You're constantly thrown into this new setting and new people and all of that and you know whatever you do is probably not up to the standards of the person who knows the job and it must be very abusive." And she said, "Actually it's not stressful at all because the minute they get to be too much of a drag, I'm out of there." In a circumstance like that, my guess is she doesn't quit very many of those jobs. You can sustain dealing with a stressful situation much longer if you feel like it's under your control. It's your choice. Have control, and stressors are less stressful.

Next example: take the two rats, with one of them getting 50 shocks an hour. The other gets 10 shocks an hour. The next day you switch both of them to 25 shocks an hour. Who gets the ulcer? Not the guy that's gone from 50 to 25. He sitting there saying 25, piece of cake. This is terrific. He thinks life is improving. For the same physical stressor, you were less likely to get a stress response if you interpret things as being a sign that life's improving and that's very, very powerful. Let me tell you the most striking, most poignant example I can think of with that. This is a classic study done in the early 1960s, looking at a group of humans who by all logic should have been undergoing major stress. These were the parents of children who had a 25 percent chance of dying of cancer, and amazingly in this study, the parents didn't have stress responses. The parents didn't have elevated blood pressure, elevated cortic steroid levels, they weren't being more at risk for ulcers. How could you have your child have a 25 percent chance of dying of cancer, yet you don't have a stress response. Because these were the parents of very special kids. These were the parents of kids who two months before had a 90 percent chance of dying of cancer. These were the kids during the period of remission. Now think about this. You have a perfect healthy child and overnight there's a diagnosis, cancer 25 percent chance of dying. This is a parent's worst nightmare. On the other hand, you have child who has a 90 percent chance of dying of cancer and goes into remission where it's down to 25 and this is the greatest gift you could ever have asked for. Twenty-five percent means absolutely opposite things depending on which direction you're coming from. It's not just the stressor, it's what it means. It's the context in which it occurs and that's a really powerful demonstration of that.

Finally, the last variable is one that you show not with laboratory rats, but with social primates. Take a monkey and stick it in a in a brand new cage, because monkeys don't like novelty. Their blood pressure goes up. Take a monkey, stick it in a brand new cage with a bunch of monkeys it has never seen before, its blood pressure goes up even higher. Take the monkey, stick it in a brand new cage with a bunch of monkeys it knows and doesn't like, blood pressure goes even higher. Take the monkey, stick it in a brand new cage with a bunch of its friends and his blood pressure doesn't go up. It helps to have social support, an amazing fact from behavioral medicine. You look across the board at every infectious disease there is and you look at mortality risk as a function of lifestyle, and the single biggest predictor is socio-economic status. You don't want to make the mistake of being in a poor country if you plan to be healthy. The second biggest variable is degree of social isolation. When you look at the extremes--people who are most isolated verses people who are most affiliated--there is a two-and-a-half fold difference in mortality outcome. That's a bigger effect than whether or not you smoke, whether or not you are overweight, whether or not you have elevated cholesterol. For a species that is as social as we are, social isolation is an aching stressor and what's clear is that relationship holds after you rule out the logical sort of compounds. People who live alone don't have somebody to remind them to take their medicine. People who live alone just eat cans of cold spaghetti instead of healthy meals.

What you wind up seeing when you put these pieces together is the demonstration. What is stressful about psychological stress if you don't have outlets? If you have no sense of predictability as to when it's coming, if you have no sense of control, if you feel that things are getting worse and if you have nobody's shoulder to lean on afterwards. Ninety-nine percent of what's stress management is about is trying to manipulate these variables. What is remarkable is when you manipulate those variables appropriately, it works.

One of the most dramatic examples you can see in terms of stress management, manipulating a sense of control, of predictability and so on is with some people who were massively stressed. People with chronic pain syndromes, back injuries, whole body burns, things of that sort. We all know the scenario, somebody lying in a hospital bed and every three and a half hours they're hitting the call button, "When can I get my pain medication?" About a decade ago, somebody came up with this completely lunatic idea which was, why don't you take the pain medication and give it to the patients, and when it hurts, they can take their medicine. The AMA had a fit over that. You can't do that. People are going to overdose themselves. They're going to become junkies. Somebody went and tried it--self-medicated regimes for chronic pain patients-- and you know what happened? Not only don't people become junkies, not only don't they overdose themselves, they take less pain killers. They take less pain killers than when they have to ask somebody for it, and that makes perfect, astonishing sense. You're lying there in bed, hitting the button, you don't know if the nurse hears, if the nurse cares. Now switch from that scenario to where the medication is right there next to your bed, and the minute it becomes too much, you can start the process of feeling better. In that setting, if you take less pain killers, it tells you people are medicating themselves to make the pain go away. But they're also medicating themselves to make the lack of control go away. The punch line for the rest of us, if manipulating a psychological sense of control in that setting can have that traumatic of an outcome, we should be able to do the same thing when we're stuck in a traffic jam. That's essentially where I am to leave you.

What is very clear to me as a physiologist is the physiology of the system is no where near as powerful as the psychological aspects. One is left with what sounds like remarkable platitudes. I could be your grandmother now telling you, you should take it easy. You should have friends, you should get out more often. These are not platitudes. When you change the likelihood of the disease outcome 10-fold, these are not platitudes, these are some of the most powerful interventions around. What's clear is there's a remarkable ability to manipulate in this realm. We are smart enough as a species to make up all of these psychological stressors and we are stupid enough as a species to fall for that. We should have the potential to be wise enough to put them in perspective. So let me wish you good luck with your stressors.