Saturday, January 01, 2000

Beyond Folklore: Stress Can Make You Sick

The Balance Within: The Science Connecting Health and Emotions

By: Esther Sternberg M.D.

When you say, “My resistance is down, I’ve been worried about my divorce,” or “I pushed myself too hard at work and got a cold,” you have accepted folk wisdom about how stress affects your health. In this excerpt from, The Balance Within: The Science Connecting Health and Emotions, scientist Esther Sternberg explores the science of short- and long-term stress, stressors we can or cannot control, and what happens in burnout and post-traumatic stress syndrome. Both our genes and our techniques for handling stress make the difference between being well and being sick.

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From The Balance Within: The Science Connecting Health and Emotions by Esther M. Sternberg. To be published by W. H. Freeman, May 2000. Used with permission of W. H. Freeman & Company.

We embrace new ideas in a series of more or less predictable steps. One step is widespread acceptance, at least by experts and interested laymen, but without the kind of conviction that would translate that idea into systematic practice. Perhaps that is where we are with the theory that stress, including emotional stress, affects our health. We say:  When I’m exhausted, I get colds. When work pressures are awful, my resistance is down. When you’re fighting a really serious disease, like cancer, it’s important to be optimistic. But do we, as yet, really understand and accept this theory down at the level that affects how we behave, how we run the workplace, and what we do in hospitals?

The Balance Within, by Esther Sternberg, M.D., a Canadian-trained rheumatologist who is now a section chief at the National Institute of Mental Health, makes the case that we must understand how our brains link emotions and health—for example, how an emotion can reach and affect an immune cell—before we grasp the importance of stress to our everyday health, and even our survival. To understand how stress may affect each of us, as individuals, we also must realize that there are differences between short-term and long-term stress, physiological and emotional stress, and stress that we can control and stress that we cannot. Underlying these factors is new evidence that we may inherit some of our degree of vulnerability to stress, while some can be modified by experience. But evolution may compensate some of us by making us less vulnerable to other illness, like arthritis.

In this excerpt from The Balance Within, scheduled for May publication by W. H. Freeman, Sternberg argues that we know more than enough to take stress seriously, and suggests an agenda for further research that could give us new mastery of our own health.

“THAT EPHEMERAL THING CALLED STRESS”

We have all at one time or another experienced it: we push ourselves for weeks on end to make a deadline at work or at school, or to care for a sick relative; we over-exert ourselves with exhaustive physical training; we go through a lengthy divorce—invariably, when we push our bodies too much in this way we get sick.

Can stress really make you sick? To answer that question, we need to answer another question first: Do the hormones of stress change the way our body defends itself?

Is there any scientific truth to this? Can stress really make you sick? To answer that question, we need to answer another question first: Do the hormones of stress change the way our body defends itself? Because unless that ephemeral thing called stress has some concrete way of reaching immune cells, it simply can’t make you sick. Yet all those hormonal and nerve pathways that kick in when we are stressed could make you prone to sickness, by interfering with the way immune cells cope with disease. Are there differences then in the ways individuals experience a stressful event, differences that could lead to variation in hormonal stress responses and ultimately susceptibility to disease? 

Professionals in all fields—executives, doctors, lawyers, anyone who must make frequent rapid decisions or perform under pressure—learn to take advantage of their stress response, to use it to bring their performance to a peak. But such individuals also learn to lower their stress response. This may be done subconsciously, or it may be explicitly trained. Doctors in emergency rooms, airplane pilots, stockbrokers, business executives, secretaries, homemakers—anyone who has successfully learned to juggle many tasks simultaneously, learns to quickly assess a situation, break it down to its most manageable parts, prioritize each component, and deal with these in order of urgency. By going through this exercise, whether we have learned by trial and error or have been trained, we are following a pattern of behavior that minimizes our hormonal stress responses. We feel, and then become, more in control. 

Imagine for a moment the following scenario. You are sitting on the porch reading, and out of the corner of your eye, you see your child run down the driveway and fall while chasing after a ball. You feel a rush of anxiety, but you also feel a rush of power—energy that you didn’t know you had. Your heart beats faster, you feel flushed, you sweat. Any fatigue or drowsiness you may have had before suddenly dissipates. You jump up and run to the child, and without realizing it, you assess the situation: no cars coming and the child did not reach the street; child moving, crying; bump on forehead but no blood; child reaches for you and climbs into your arms—child is fine, unhurt. As suddenly as your energy surged, your heart sped up, you now feel a wave of relief, as you subconsciously check each item on the list. In a matter of minutes, it is resolved: your stress response has mobilized you, and by systematically assessing the situation, you have then controlled your stress response. But had there been blood, had the child’s scalp been cut, without experience and training, and the means to treat the cut, you would have continued to feel increasingly anxious, sweaty, a rapid pulse, and even faint. Your stress response might have mounted to a point where you were helpless, and in fact, feeling helpless in a situation makes your stress response spin out of control.

HOW MUCH IS TOO MUCH?

The dose effect of stress—some is good, too much is bad—comes from the biology that underlies the feelings. As soon as the stressful event occurs, it triggers the release of the cascade of hypothalamic, pituitary and adrenal hormones—the brain’s stress response. It also triggers the adrenal glands to release epinephrine, or adrenaline and the sympathetic nerves to squirt out the adrenaline-like chemical norepinephrine all over the body: nerves that wire the heart, and gut, and skin. So, the heart is driven to beat faster, the fine hairs of your skin stand up, you sweat, you may feel nausea or the urge to defecate. But your attention is focused, your vision becomes crystal clear, a surge of power helps you run, these same hormones and chemicals released from nerves make blood flow to your muscles, preparing you to sprint.

If you prolong the stress, by being unable to control it, or by making it too potent or long-lived then the same molecules that mobilized you for the short haul now debilitate you. 

All this occurs quickly. If you were to measure the stress hormones in your blood or saliva, they would already be increased within three minutes of the event. In experimental psychology tests, playing a fast-paced video game will make salivary cortisol increase, and norepinephrine spill over into venous blood almost as soon as the virtual battle begins. But if you prolong the stress, by being unable to control it, or by making it too potent or long-lived, and these hormones and chemicals still continue to pump out from nerves and glands, then the same molecules that mobilized you for the short haul now debilitate you. This dose effect in physiology is called the inverted U-shaped curve, because, if you were to graph it—dosage of hormone vs. performance—it looks like an upside-down U. On the rising arm, as hormonal levels increase, performance improves. But then it peaks and as you slide over the top to the descending limb of the graph, performance fails. Although the point at which performance peaks or fails depends upon the type of task that is involved, and the kinds of hormones that are being measured, the trend is always the same. And this behavior of the system— some is good, but too much is bad—is not surprising since it is a general principle of biology which applies to many things: food and drugs, as well as almost any natural substance in your body.

The next question is what about short-lived stress? Does it affect your immune response and your health? When does stress turn from good to bad, as far as your immune system is concerned? The answers to these questions lie in part in the differences in response time between the nervous and immune systems. The nervous system and the hormonal stress response react to a stimulus in milliseconds, seconds or minutes. The immune system takes parts of hours or days. It takes much longer than two minutes for immune cells to mobilize and respond to an invader, so it is unlikely that a single, even powerful, short-lived stress on the order of moments could have much of an effect on immune responses. However, when the stress turns chronic, immune defenses begin to be impaired. As the stressful stimulus hammers on, stress hormones and chemicals continue to pump out. Immune cells floating in this milieu in blood, or passing through the spleen, or growing up in thymic nurseries, never have a chance to recover from the unabated rush of cortisol. Since cortisol shuts down immune cells’ responses, shifting them to a muted form, less able to react to foreign triggers, in the context of continued stress we are less able to defend and fight when faced with new invaders. And so, exposed to, say, a flu or common cold virus when you are chronically stressed out, your immune system is less able to react, and you become more susceptible to that infection.

Without a safety net, a chronic load of stress accumulates, and eventually takes a toll on aspects of your health. This happens because, unless the body has a chance to recuperate, the effects of stress hormones accumulate and build up.

Now think for a moment about the stressful phases of your life—not day to day events, but on a longer scale. There are some weeks or months or even years when we may go through more turbulent times than usual. This sometimes has to do with the stage of life, and sometimes just with chance. You may be the mother of an adolescent, learning the difficult process of letting go as the child grows. At the same time your aging parents may be ill. You are continuously on call for unexpected responsibilities and difficult decisions. Or, at another phase of life, you are the parent of a young child, your first, and you are juggling career and the pressure to succeed. If at such times you are hit with yet another unexpected stress, say the loss of a loved one, you cannot cope. If these stresses are staccato rather than continuous and unstopping, if between stressful events your life settles down to a quiet baseline, then your system will have a chance to recover and be ready for the next assault. But without a safety net, a chronic load of stress accumulates, and eventually takes a toll on aspects of your health. This happens because, unless the body has a chance to recuperate, the effects of stress hormones accumulate and build up. These ideas have been borne out in the work of Bruce McEwen at Rockefeller University. McEwen, who has worked on stress and stress hormones for over thirty years, has shown experimentally that the cumulative effects of high-dose steroids have a different, more long lasting and harmful impact than if the body produces single short bursts. McEwen calls this compounding of stress effects the theory of “allostatic load.”

“THESE MEN WERE CRYING...”

What kinds of stresses can deplete the body’s will to fight? Chronic illness is one. And of course psychological stresses. But there are others as well. Strenuous, unaccustomed, and prolonged physical stress, as strong as running to your max on a treadmill, for example, but lasting for days; or chronic physiological stresses, like lack of sleep and food, will all deplete the stress hormone reserves. At first, such chronic stresses keep the response switched on, working at its max as long as the stress persists. But if such extremes persist, the response can fail, reach exhaustion and finally burn-out. 

For four nights and three days it rained and we were awake 90% of the time. No food for five meals, or water. No ponchos for protection...We walked through jungle so thick a machete didn’t hardly help. Our bodies took a worse beating than any man should endure...

Few men were bullet casualties, but we had to walk back [through] 10 miles of waist deep water (sometimes chest deep). No choppers because of foul weather. We suffered better than 45% casualties in my platoon because of ‘immersion foot’....Some were so bad their feet were a mass of blood...

Have you ever seen a grown man cry? Probably not, well these men were crying while we were returning. It’s hard to explain the pain unless you’ve felt it yourself...

Richard Sutter, a marine in Vietnam in 1966 and 1967, wrote this gripping description of a “routine” patrol by his battalion, in a letter he sent to a childhood friend back home. Sutter later died, shot down in an ambush.

War is an experience that combines all possible stresses in the extreme, and it does so for prolonged and unrelenting periods, the threat of unpredictable life-threatening attacks; physical stress and unrelenting strenuous exercise in the harshest environments of extreme heat or cold; lack of sleep—down to 3 or 4 hours a night for days on end; the lack of food, eating one meal or less a day for days on end; and the psychological stress of life-depending need for peak performance. In the face of such multiple massive challenges, it is surprising that many soldiers recover without permanent effects on their stress responses. What is not surprising is that some don’t recover, and continue to suffer hormonal, psychological and physical effects long after they have returned to peace and home. And while we don’t yet have an explanation for the syndromes of soldiers returning from war—likely many factors and exposures contribute to their cause—the biological effects of massive chronic stress could almost certainly play a role. It remains to test this possibility in experimental settings, to determine whether there are some predictors to tell us which soldiers will and which will not develop later symptoms after being exposed to the same stressful assaults.

The closest controlled peacetime situation that resembles war in its totality of stressors is military endurance training. Army Rangers, for example, are selected for their top physical and mental form, their peak performance in other military tasks. These young men undergo a grueling training period lasting 8 weeks, meant to train them to withstand the stress of war. First at sea level, then in mountain settings, they cross-train by running, climbing and swimming, in extremes of temperature and terrain from dripping jungle to freezing nights in rocky mountains, to desert sun and heat. During this time they average 3-4 hours sleep a night. Because they eat little, out of anxiety and lack of time, they may lose up to 15% of their original body weight.

STRESS AND THE IMMUNE RESPONSE 

A group of Army researchers under the guidance of the U.S. Army Research Institute of Environmental Medicine (USARIEM), based at Walter Reed Hospital in Washington D.C., and other research centers measured hormone and immune system responses in these soldiers before, during and after this grueling training, to determine whether such massive stress would affect immune response and perhaps susceptibility to disease. There was reason to believe that such prolonged physiological stress might be associated with greater susceptibility to infection in animals. Rats that are not allowed to sleep for prolonged periods, for example, die from overwhelming infections. As we’ve seen, chronic stress of any sort results in increased cortisol which should attenuate immune responses and make the host more susceptible to infectious disease.

The army researchers chose to measure salivary cortisol and immune system reactivity to common environmental proteins to which we have all been exposed. For this they used a simple standard skin test much like the Tine test that children often receive from their pediatrician. They also measured the ability of immune cells to produce the interleukin “tumor necrosis factor,” TNF, a molecule that usually enhances immune function. They found that by week 4 or 6 of their training, well into the most stressful phase, the Rangers’ cortisols had increased and their immune responses decreased, in some cases so low that the soldiers showed no skin response at all. But 3 days after the training period ended, and after a period of rest, the soldiers’ skin test and interleukin responses returned, and cortisol fell back to the same levels as before the training started. In this setting, then, the increased cortisol and stress hormone responses, and associated fall in immune function, was a transient thing, lasting only as long as the chronic stress, and returning with a bit of rest. Although these tests still do not tell us if some individuals might not recover from such stress, they do hint at the direction in which future studies should be directed.

We can ask the question of people in the general population by exposing them to one component of this stress—the strenuous exercise—and measuring hormonal and immune responses. If you exercise in this way, rather than in a graded way for training and endurance, you will activate all sorts of neuroendocrine and nervous system pathways. Within ten minutes of beginning the exercise your hypothalamus starts pouring out CRH, your pituitary gland, ACTH and your adrenals, cortisol. The cross-talk between hypothalamus and brainstem also turns on your sympathetic nervous system, and the sympathetic nerves innervating your heart and muscles, pour out norepinephrine, while the adrenal glands secrete adrenaline. Thus your heart rate goes up, oxygen metabolism increases, and eventually fat and glucose stores are broken down.

If you were to measure immune cell function at these times, by counting different types of cells in venous blood or by measuring interleukin production from these cells, you would see that many shifts take place. Certain types of lymphocytes decrease and others increase: the helper cells that help to increase antibody production go down, while natural killer cells, cells that kill off tumor cells, go up. Cytokine production shifts from a pattern that increases inflammation to one that decreases it. Taking glucocorticoids—steroid hormone drugs like cortisol—mimics some but not all of these changes. (These are not the same steroid hormones we hear of in the news that make athletes break all records. Those are male sex hormones—chemicals with the same central ring-like chemical structure, but very different atoms hanging off the rings. In fact, while taking male sex steroids will make a person’s muscles grow and strengthen, and give him—or her— other masculine features, taking corticosteroids for prolonged periods will weaken strength.) Thus, it seems that all the hormonal systems that kick in during exercise play a role in changing the immune responses during this physical stress.

Is there evidence in average people that chronic psychological stress can change immune function and predispose to susceptibility to disease? 

WHEN STRESS BECOMES CHRONIC

But physical stress is only one component of the stresses associated with immune suppression in something as grueling as Ranger training. And such stress in laboratory settings is short-lived—lasting only 20 minutes or so. What about other forms of stress—psychological stress that is also chronic? Is there evidence in average people that chronic psychological stress can change immune function and predispose to susceptibility to disease?

In the early 1980s, Ronald Glaser and Janice Kiecolt-Glaser, a virologist-psychologist husband and wife team at Ohio State University, put their expertise together to ask whether the psychological stress of studying for exams had any effect on immune defenses in medical students. In order to answer this question, the Glasers first needed a way of standardizing and assessing the stressful stimulus. They also needed a way to measure precisely some function of the immune system that might be affected by stress. They decided to take advantage of Jan’s expertise in measuring stress and Ron’s in measuring antibody responses to viruses. They took advantage too of the fact that medical students must be immunized with hepatitis B vaccine, and must receive two booster shots over the course of 12 months. Then they asked whether those students receiving their vaccines during stressful periods of studying for exams showed a lower “take” rate to the vaccination than those exposed when not under stress. The Glasers collected after-vaccination blood from students in whom they had carefully measured psychological levels of stress. They measured antibody levels to hepatitis B vaccine in the blood after vaccination, and found that compared to non-stressed students, students vaccinated during stress did indeed show lower antibody levels and fewer achieved the clinically significant take-rate of a four-fold increase of antibodies in the blood.

The types of stress that affected immune function in the soldiers are forms of stress that can be considered physical or physiological— exposure to extremes of heat and cold, lack of sleep, poor nutrition. Some of these forms of stress may have also been at work in the exam-stressed medical students—lack of sleep, poor nutrition. But in both the medical students and the soldiers, there was also an important element of emotional or psychological stress. In both, the anxiety of needing to perform at peak in the face of exhaustion, the fear of failure, produce stress. For the soldiers, these fears grow from deadly risk in life and death situations; in the medical students such risks, although not life-threatening, are still perceived as potent stressors—fail the exam, do not become a doctor. 

A situation need not entail risk of life to be a real and potent stressor. And conversely, a situation that involves a risk of life is not necessarily perceived by all as a major stress.

A situation need not entail risk of life to be a real and potent stressor. And conversely, a situation that involves a risk of life is not necessarily perceived by all as a major stress. George Solomon, a psychiatrist at UCLA, and one of the early pioneers who tackled the field of psychoneuroimmunology while most scientists were still skeptical, showed this fact in studies performed together with Margaret Kemeny, and John Fahey, a psychologist and immunologist at UCLA. Within hours of the “Northridge” Los Angeles earthquake, they measured immune and hormone responses in people who had been at the earthquake’s epicenter. They found that while some individuals seemed to respond with high stress and low immune responses, others did not. But all these examples are relatively short-lived stresses. Do different sorts or longer duration stresses more uniformly affect immune and hormone responses?

BURNOUT

Inescapable exposure to many different stressors simultaneously—a move, full-time work, care of the children and/or household, and/or mate—can lead, after many months, to a kind of extreme exhaustion. We call this burnout, and members of certain professions are more prone to burnout than others—nurses and teachers, for example, are amongst the highest risk. These professionals are faced daily with caregiving situations in their work lives, often with inadequate pay, inadequate help in their jobs, and too many patients or students in their charge. Some studies are beginning to show that burnt-out patients may have not only psychological burn-out, but physiological burn-out: a flattened cortisol response and inability to respond to any stress with even a slight burst of cortisol.

In other words, chronic unrelenting stress can change the stress response itself. And it can change other hormone systems in the body as well. One of the most important of these is the reproductive system. Chronic high stress can shut down reproductive hormones in both men and women: In soldiers undergoing extremes of boot-camp training; those with a heavy care-giving burden; athletes; and those who engage in repeated bouts of extreme dieting. All these situations can stop a woman’s menstrual cycle, for example, because stress hormones shut off the monthly surge of sex hormones, which otherwise run the cycle like a clock. In men, such stress also decreases sex hormones, like testosterone, and so can decrease sperm count and fertility.

With sufficient rest, persons suffering from burnout can recover their ability to make all these hormones, and normal cycles are reestablished. We don’t know yet whether early menopause can be triggered in a woman close to menopause who experiences such degrees of chronic stress, although irreversible physical changes certainly can be wrought from stress. Women who experience prolonged bouts of depression, in which the stress response is stuck in the on position, do experience permanent changes in their bones—weakening of bones and osteoporosis of the same degree as a menopausal woman twice her age.

In contrast to such chronic unrelenting caregiver stress—McEwen’s allostatic load— there is another form of work stress: the demand for rapid-fire decision making. There is a much more staccato quality to the rhythm of job stress experienced in such professions—frequent, short but high intensity bursts of stress. At one time it was thought that professionals in such jobs, without a break and under constant, often uncontrollable demands, frequently experience exhaustion, loss of morale, depression and increased frequency of illnesses.

Imagine a job in which you must be constantly vigilant—even one second of lack of attention might lead to the death of hundreds of people whose lives depend on your moment-to-moment judgments. Imagine that in this job you are working at a small workstation, surrounded by dozens of other co-workers, each of whom is also trying to concentrate on his mission. There is constant movement around you and distracting noise that you must blot out nonetheless or lose your concentration. You must have lightening quick eye-hand coordination and an ability to react and give commands and directions in response to any shift in the tiny blips you are watching on the screen in front of you. And you must do this job perfectly for hours at a stretch, sometimes late into the night, or at the break of the dawn. You are an air traffic controller—a member of an extremely high pressure, high stress profession. You are someone who is at risk for high blood pressure, stroke, heart disease, accidents and depression.

In the late 1960s, Bob Rose, a psychiatrist and then an army Captain at Walter Reed Army Hospital in Washington D.C., was asked by the Federal Aviation Agency and the air traffic controllers’ union to resolve a controversial question, using unbiased scientific methods. The question was whether air traffic controllers were at greater risk for developing stress-related illnesses because of their work environment. This was a contentious issue—the union claimed that the stressful work conditions predisposed these workers to illness, and the FAA claimed that this was not the case.

Rose spent one year traveling the country, observing controllers at their work stations, interviewing them and their managers, assessing their reports of their home environments, before beginning the actual collection of data. In all, he studied 400 air traffic controllers over three years to find out what elements of their jobs and their own physiological responses added up to “stress.” And he wanted to know what sorts of illnesses they would develop.

Rose’s most dramatic finding was related to blood pressure. Over 50% of the workers studied over the three-year period developed or had high blood pressure. And these men were only in their late thirties. Not all the men developed high blood pressure however. It was a group of men whose blood pressures were normal off the job, and which increased only while at their workstations, who had problems. These men eventually went on to develop high blood pressure even when off the job. In this case, it was the change in heart rate, controlled by the rapid response sympathetic nervous system that, more than cortisol, matched immediate changes in work stress.

Many of the controllers also experienced depression and anxiety disorders. The single factor that was linked most closely with such illnesses was something that could not be measured in urine or blood or with a blood pressure cuff. It was the pervasive sense amongst all these workers of alienation and abandonment by their employers that mapped most closely to these illnesses. Those who perceived their work environment to be uncaring and unsupportive were at greatest risk. And in this group, it was the men who felt the greatest sense of distance from their employers, the greatest sense of “we against them,” who developed illness.

Rose’s initial study of air traffic controllers was completed more than 10 years before the air traffic controllers’ strike, and the mass lay-off of thousands of controllers in 1983. At the time of the strike, a large percentage of controllers found themselves suddenly out of work. Here were men in their prime, heads of households, highly trained, and skilled in a very specialized profession. Suddenly, and virtually without warning, they lost their jobs, with no recourse or possibility of returning to their profession. Many experienced clinical depressions during the first year after their lay-offs. Some fell back into old habits of drinking to mask their problems. Eventually, most found new and productive occupations, and put the strike and depressions behind them. But some did not.

Ten years later, in 1993, Rose tracked down and interviewed as many of the controllers as he could find—in all, about two thirds of the original group. He found, unlike 20 years before when the men were in their 30’s, that a higher number of these men in their 50’s had illnesses such as cancer, heart disease, alcoholism and depression. This was, of course, to be expected: These illnesses occur more frequently in men in their 50s than in their 30s. But when Rose went back and looked to see which measures, if any, predicted the development of these illnesses, he found something unexpected. More important than any of the changes he had been able to measure 20 years before in blood, urine, or blood pressure, Rose found that it was the psychological factors that best predicted development of these illnesses 20 years later.

THE IGNITION SWITCH

Let’s return for a moment to the thing that began all of this: what is stress? One part of it is obviously your body’s response, the many hormones and chemicals that we’ve just discussed. This is the part of stress that directly impacts the immune cells’ ability to fight. This end of the process, the hard wiring and chemicals that make it go, is like the motor, drive shaft, wheels and axles that drive a car. But what about the ignition? What turns it on? As important as the motor is the part that happens between the event and how it is perceived.

Our perception of stress, and therefore our response to it, is an ever-changing thing that depends a great deal on the circumstances and settings in which we find ourselves. It depends on previous experience and knowledge, as well as on the actual event which has occurred. And it depends on memory too. 

For every individual exposed to an event, there is a different interpretation of its stressfulness. Recall the situation of seeing the child who runs down the driveway, falls and bleeds. A doctor or a nurse or emergency technician will feel less stressed than someone unfamiliar with such injuries. In the setting of the emergency room, the health professional’s stress threshold has been raised by knowledge and experience and ability to act. A lot of blood in this case isn’t life threatening, a few stitches usually suffice. But if the doctor or the nurse are presented with the same situation, without access to suture equipment, say on a busy highway, it takes less for their stress response to kick in than it would in emergency room or clinic, where they can staunch the bleeding right away. It takes a lesser stress to turn on the body’s stress response when we don’t feel in control. Our perception of stress, and therefore our response to it, is an ever-changing thing that depends a great deal on the circumstances and settings in which we find ourselves. It depends on previous experience and knowledge, as well as on the actual event which has occurred. And it depends on memory too.

A memory is not a threat—it cannot kill or harm, and yet a memory of a stressful event can turn on the stress response almost as much as the original event itself. This is because there are many nerve pathways leading from the brain’s memory centers to the hypothalamus that can trigger the stress response. One of these memory centers is called the hippocampus —that part of the brain named for its sea horse like shape. Another is in the frontal lobe, at the front part of the brain.

One difference between real and virtual threats, is that the more often the memory or the video game are re-experienced, without harm actually occurring, the weaker the body’s physiological responses soon become. Because we quickly learn that these events will do no harm, the stress response to such virtual experiences eventually extinguishes. Hence the desire by some to go on to try new and more stimulating videos, to see new movies with more violent special effects. But hence too the thankful relief as time distances us from a traumatic experience. Time heals all wounds because we forget.

There are some unfortunate individuals, however,  for whom the memory of a massive trauma never shrinks. These persons repeatedly re-experience the memory of the event in all its power, with all the physiological, nerve and hormone responses that it initially evoked. Even the tiniest part of an event, a glimmer of a person or object, that bears even the slightest resemblance to some part of the original, can trigger the whole cascade in its most fulminating form. Soldiers in every war, have experienced some form of this syndrome, given different names in different eras: Da Costa’s syndrome in the Civil War; shell shock in World War I; battle fatigue or “disordered action of the heart” in World War II. Today this syndrome is called post-traumatic stress disorder, or PTSD. It is seen in Holocaust survivors as well, and in civilians not exposed to war but to an equally horrific trauma—bomb, fire or rape victims, for example. If a woman was raped at dusk beside a tall boxwood hedge, seeing a hedge of approximately the same height at dusk, or smelling boxwood, can later trigger her whole stress response. Being forced to recount the events, to visualize them in memory, can trigger it as well.

Rachel Yehuda, a psychologist at Mount Sinai School of Medicine and the Veterans Administration Hospital in the Bronx, realized when caring for Holocaust survivors that the adult children of these persons also exhibited abnormal responses to stress, even though they themselves had never experienced Holocaust or war. When she began to test the hormonal responses to stress of both survivors and their first degree relatives—children or siblings—she found that they all had higher than expected cortisol rises, and lower baseline levels in their patterns of stress hormone rhythms throughout the day. This could be something learned. Thus, the survivors, when the trauma was still very fresh, may have somehow subconsciously taught their children to respond in a certain way to stressful stimulus from a very young age. But just as likely is the possibility that these patterns of stress-responsiveness are inherited. In that case, the people who go on to develop PTSD if exposed to a terrible stress would be those who have inherited stress responses that don’t extinguish. Whether learned or in the genes, or a little bit of both, for victims of this illness distance from the event does not diminish the body’s physiological response. They are those for whom memory stays alive.

Stress need not be on the order of war, rape or the Holocaust to trigger at least some elements of PTSD. Common stresses that we all experience can trigger the emotional memory of a stressful circumstance, and all its accompanying physiological responses. Prolonged stress such as divorce, a hostile workplace, the end of a relationship, or the death of a loved one, can all trigger elements of PTSD.

Imagine now the following scene: you wake up refreshed and happy, then relax and read the newspaper over coffee, a sweet peach and a roll. You feel happy and secure as sunlight streams into your kitchen. Then you leave for work. Work is a hostile environment where day after day your boss disparages you inappropriately; where there is the threat of job loss because of downsizing; where there is inadequate infrastructure to support your productivity; where the physical surroundings are cramped and noisy; where you are not valued for your full worth. As you drive towards the office, your mood gradually deteriorates. As the distance shortens, you become more and more tense. The moment your car passes into the parking lot, you feel a rush of anxiety, increased heart rate, a mild flush. To add insult to injury, there are no parking spots because company policy reserves spots only for those of higher rank. You park nonetheless, with the full knowledge that when you return to your car at the end of the day, there will be a parking ticket on the windshield. You step out of your car and walk towards the elevator, anxious, angry, demoralized and dreading the start of the workday.

Or maybe your workplace is heaven— clean and airy office, supportive coworkers and boss; exciting projects; enthusiastic management that values its workers—but back home your life is imploding. You are in the midst of a nasty divorce from a controlling spouse, one who had emotionally or physically abused you during the marriage. Day after day for months on end, your soon-to-be ex-spouse’s attorney, known as a pitbull divorce attorney, a basher who takes pride in destroying lives rather than salvaging what is left of the family’s spirit, uses grinding tactics to wear you down. His repeated prying questions are designed to trap you, set you up against yourself. He waits a few days, then escalates the legal demands, threatening subpoena and depositions. His threats come in waves, so that as soon as you have regained some balance, he hits you again. You feel like one of those inflatable plastic punching toys that is slapped down the moment it pops up again. And the threat this attorney is using to break your spirit is loss of custody of your children. While the target of such attacks, you may experience palpitations, flushing, an urgency to defecate every time the phone rings, or when a letter is delivered to the door. You may have repeated nightmares—losing your children, searching for them and not finding them. You may wake up in a cold sweat. You may even continue to experience such physical symptoms and anxiety long after the divorce is over and a settlement has been reached.

You are experiencing a shadow form of the elements of PTSD. The trigger to these symptoms need not be complex, if the initial event was severe enough. Sometimes a single visual element can expose a shard of memory that evokes a physiological response. For example, something as innocent as a lawn marker for a house address—a gray stone with the address painted on it—may, after the death of a loved one, remind us of a grave stone, and for a transient few seconds bring on the rush of hormones and despondent feelings that we experienced when the loved one died.

LOSING THE OLD, FACING THE NEW

The standard list of life situations that can act as powerful stressors, quoted in textbooks of psychology and psychiatry, include loss of a loved one, divorce, loss of a job and moving. What an odd and rag-tag list of situations to juxtapose—something as mundane as moving in the next breath as something as profound as death. Yet moving is a major stressor. What could be the common elements that link all these situations? One is certainly loss—the loss of someone or something familiar. Another is novelty—finding oneself in a new and unfamiliar place because of the loss. Together these amount to change: moving away from something one knows and towards something one doesn’t.

The stress of loss comes in part from a kind of grieving. Holes are left in your memory in the places where the familiar used to be. You have moved to a new house. You reach for a book on the shelf and it’s not there—the shelf may not be there either—the room is different. You know exactly where you put the book, you see it in your mind’s eye, but the reality has changed. These losses are the same but less intense, less immediate, less emotional than in true grieving.

Certainly the loss of a loved one, especially a spouse, a child, a parent, causes the deepest levels of grief most of us will know. The presence of the deceased seems to linger: You turn to the spot on the sofa where your wife used to sit, beside you. You try to feel her warmth, but instead there is a coldness there.

You try to reconstruct her face, but can’t: it is years now since she died. The edges of the memory have faded, gradually erased, and there is nothing you can do to bring it back— the physical is no longer in the world to reinforce the image in your mind. This jarring, painful reality breaks through what was otherwise a background music of awareness that something was missing from the order of your world.

It takes time to reconstruct a new memory, a new place in your mind that matches the new shape of your physical world. And it takes time for the old memory to fade away—to fade until the intensity of the memory is less than the intensity of the reality that evoked it. And until this happens, each time you are reminded of your loss, a whole set of emotions is triggered—from anxiety at the new world order, to sadness at the loss. Grieving is all these things: unlearning of old memories, re-learning new ones. 

Our whole world is represented in our memory—peopled in familiar space, like stars hanging in a firmament for which we have drawn the bounds and filled the background. We navigate this territory of our mind more often in the day than we do our real surrounding world. 

In a way, our whole world is represented in our memory—peopled in familiar space, like stars hanging in a firmament for which we have drawn the bounds and filled the background. We navigate this territory of our mind more often in the day than we do our real surrounding world. We go there during those cracks and crevices of time when our thoughts wander from the moment. Driving down the street, stopped at a light, at our desk at work, at home in the kitchen preparing for a meal, in bed, drifting off to sleep: our thoughts shift to this other world that we carry with us all the time. And in some ways it is this world that matters most—the relation of each person to each other person. The relation of each person to their rightful place. When any of this changes—stars extinguish, patches of background tear apart; the shifting scene is unfamiliar, even frightening. Until we make sense of it, reestablish order in this internal map and re-learn connections, we cannot find familiarity and peace.

An unfamiliar environment is a universal stressor to nearly all species, no matter how developed. Even a rat, taken out of its home environment and placed in a clean, brightly lit cage will show signs of anxiety and stress: decrease its explorative behaviors, even freeze, and defecate more—all fight-or-flight behaviors. (Anyone who has had a pet small enough to hold in the hand—a hamster, gerbil or toad— will have noticed this tendency to urinate or defecate when it is first picked up.) If you were to measure stress hormones at this time, you would find them to be high. But let the rat acclimatize to its new environment, or repeatedly put it into the same, now less new, cage and the signs of anxiety, as well as the hormone levels, decrease over time. It gets used to the new environment. It learns.

This anxiety about novel environments that keeps us vigilant, is controlled by two parts of the brain—a part of the brain that controls memory, and a part that controls anxiety. The part of the brain that integrates memory of our spatial world is the hippocampus. The part that controls anxiety is the fear center deep within the brain, the amygdala. Both of these parts of the brain have connections to the brain’s stress center.

When first placed into a new environment, say a maze shaped like a plus sign, the rat runs furiously in all directions, sniffing, zigging, zagging, looking up and looking down. With this activity, the rat is memorizing visual cues to construct an inner map of its environment, just like that inner map of our sensory and motor selves that Wilder Penfield mapped out when he placed electrodes into the human brain. If you were to place electrodes in the rat’s hippocampus and record activity in those nerve cells when the rat is placed into the new environment, you would see an amazing sight recorded on the computer image: The active brain cells are laid out in the exact shape of the space that the rat has explored—they are laid out in the shape of the maze’s plus sign. And the cells that are most active are the ones which record the place the rat is exploring at that moment in time.

If the hippocampal memory part of the brain is damaged, learning will not take place. And anxiety will not decrease after repeated exposures to the new environment. We don’t yet know all the wiring that makes this work, but somehow a cue in the environment—a certain tree in the woods, a building, a stoplight, a painting in a room—gets temporarily connected to the amygdala. It could be that we actually reconstruct a spatial image within our hippocampus, or it could be that the hippocampus works more like pixels in a computer—acts as a transient connecting station that links two otherwise unconnected spots. For a time, the unfamiliar images get linked to the amygdala, until, with learning and familiarity, the links are lost.

From an evolutionary point of view, this behavioral response is clearly adaptive. An animal in a new environment must map out the new territory, quickly determine where its predators may be lurking, define escape routes in case of attack, and commit them to memory. All this requires vigilance, focused attention, a readiness to flee—behaviors that are programmed and induced by the brain’s stress hormones. So in this setting, stress is not only “good”, but necessary. Of course these feelings of stress in a new environment are uncomfortable. If they weren’t uncomfortable we might not be motivated to do something about the situation to change it or protect ourselves. This is adaptive too. For different reasons then, both loss and novelty—and certainly both together— can activate the stress response.

This same sequence of events occurs with people. Walk into an unfamiliar room; hike in unfamiliar woods; arrive in a new city. Your eyes are scanning all around—taking in first the general impression and then the details. Unfamiliar surroundings bring on anxiety. Repeated visits to the place, repeatedly seeing the same tree on the hiking trail, the same picture on the same wall in the room, the same stoplight on a street, help decrease the anxiety of the unknown, help build a memory, and a sense of peace. The memory that is built like this is not one of a word, or of the object alone. It is a memory of the object in its surroundings. This kind of learning is called spatial learning. And if there is a missing piece in this otherwise familiar space in memory (including the loss of a loved one, moving, or divorce) the hole is all the more apparent. And because the brain pathways activated by the loss connect to and activate the stress response, the anxiety and loss that accompanies change can trigger all the hormone and nerve responses that can alter immune responses.

BRED FOR STRESS?

Is it possible that there are some among us who, because of a particular load of genes, may experience stress in different ways, or may be less able to extinguish painful memories or responses?  If we go back to the rats—those strains bred first for their resistance or susceptibility to inflammatory disease—we know they do have different stress responses. One strain, the Fischer rats, pours out stress hormones at the slightest perturbation, while their immunological twins, the Lewis rats, seem to wander through life apparently imperturbable, stress hormones flat no matter what occurs. In fact, rather than becoming anxious, in stressful circumstances these Lewis rats will often go to sleep. This is not a terribly adaptive behavior for a rat in the wild, since if attacked by a predator, a rat needs to be able to quickly mobilize all its defenses and run, not curl up and go to sleep. This strain of rats probably survived only because they were bred in the protected surroundings of the research lab.

Surprise—our response to a sudden unexpected event—is a very primitive reflex that is crucial for survival. It is an important element of the stress response, even if the event itself is not severe. A startling low-grade noise can act as a mild form of stress for rats, or mice, or humans. The startle response, as it is called, is a reflex all mammals have, as simple in numbers of nerve connections as the knee jerk reflex. It is a protective reflex, that readies you for fight or flight. If someone comes up behind you and claps their hands or you hear a sudden loud pop or backfire of a truck, almost instantly you will stiffen and blink. Fear can make your startle more intense. If you thought the truck’s backfire was a bullet, you will do more than blink—you will jump. A rat will do the same: learning that something should be feared by previous or repeated association—by conditioning—can intensify the startle response.

In humans, the strength of the startle response can be measured by gluing a small electrode to the eyelid. How hard you blink correlates with the degree of fear you feel. In a rat, the strength of a startled jump can be measured on an instrument much like a digital weighing scale. The reflex nerve pathway that governs this response starts in the ear, and is triggered by a sound. Electrical signals lead from the ear to the centers in the brain that interpret sound—the auditory cortex. But some signals bypass the cortex and travel through three short nerve connections deep within primitive parts of the brain’s stem. From there they move on to nerve paths in the spinal cord that lead to muscles of the eyelids, trunk and limbs. Like any reflex pathway, the startle reflex is automatic—something we are born with. But learning can modify this pathway—intensifying it, for example. If by previous experience we are startled by a fearful event, fibers from the fear center in the brain, the amygdala, can connect to these nerve routes. From there, the stress hormone CRH (which comes from the brain’s hypothalamic stress center and triggers the pituitary gland to squirt out ACTH and the adrenals to make cortisol), can increase the amygdala’s responses. So in a learned, fearful situation this stress hormone changes—amplifies —a reflex response. The startling noise can activate the stress response and the hormonal stress response can make the startle increase.

When we first discovered the difference in stress responses in Lewis and Fischer rats, we also tested whether they would startle differently when exposed to a sudden noise. They did. But surprisingly it was the low stress Lewis rats that startled more than the Fischer strain. Stafford Lightman, a British neuroendocrinologist, later used sophisticated computerized laboratory equipment to study what happens to stress hormones in these different strains of rats when they startle. Lightman was able to continuously collect tiny volumes of blood, in which he monitored the concentrations of stress hormones throughout the day. When the rats were resting, feeding or just wandering about their cages, they showed the expected regular “pulses” of the hormone corticosterone.

At different times of day, there is a regular pattern of ebb and flow of all our stress hormones. This is the background music of our stress response that goes on regardless of those external stresses to which we are exposed. What appears as smooth waves of hormones surging and falling when we measure these in blood, are actually made up of many mini-pulses of each stress hormone. (This pulsating pattern of stress hormones occurs in all species, and comes from the rhythm of the hypothalamus, although why the hypothalamus ‘beats’ like this, we don’t completely understand. It has something to do with the brain’s other biological rhythms, which begin in the clock center of the brain.) At times when these pulses increase in frequency or in size the hormones measurable in blood also increase. In humans this happens in the early morning when we wake up, and plasma cortisol and ACTH reach their peak. As the day wanes, the pulses spread gradually apart, and decrease in size again, until, in late afternoon and early evening, they bottom out, to stay low until they surge again in early morning, sometime around dawn. The nadir of these hormones coincides with the late afternoon dip in energy we often feel that drives many of us to seek a cup of coffee in order to re-fuel. In fact, one effect of the caffeine in your coffee is to stimulate the release of hypothalamic CRH—in other words, it gives your stress hormones a jolt. If on the other hand the early morning peak occurs too soon, when we are experiencing chronic stress, we will wake up—bolt upright, heart racing, ready for the day—but far too early, before the dawn, at exactly the time the stress hormone surge occurs, in the middle of the night.

Rats have the same rhythm to their stress hormones, except that their circadian rhythms are exactly reversed: they bottom out in the morning and peak in the middle of the night (not a surprising pattern for a nocturnal animal). As expected, Lightman found this same pattern in his rats, each one rising from baseline to a peak over the course of about one minute. Then, by monitoring the hormone levels and exposing the rats to a quick burst of noise either at a low point between peaks, or on the way down from a peak, Lightman discovered something unusual. Most rat strains exposed to noise during a low, responded with a burst of stress hormone, but, if they received the noise during a peak or on it’s downward stroke, they did not respond at all, and were refractory to the stress.

But Lightman discovered something else as well: In the hyper-stress responsive Fischer rats (these are also the rats that are resistant to arthritis), there was no refractory period. They responded to a noise experienced during a naturally occurring peak with the same amount of stress hormone that they would if exposed during a naturally occurring trough. And with repeated noise, their stress response did not extinguish, as it did in the non-stress responsive strains. They responded to each noise as if none had come before. From Lightman’s experiments then, it would seem that hyper-responsiveness to stress and the inability to become accustomed to a stress in these purebred rats might be genetically determined and perhaps present from birth.

These two rat strains are genetically selected, and show on the one hand hypersensitivity to stress, and on the other, sluggish hormonal responses. The hypersensitive responders are protected from arthritis, but are easily triggered to respond to stress, while their cousins show the opposite—protected from the effects of stress, they are not protected from diseases like arthritis. Are there genetic situations in humans that are comparable? Situations in which different groups of people show a greater or a lesser hormonal response to stress? And if there are, do these people show different tendencies to autoimmune or inflammatory diseases? We are beginning to discover groups of people predisposed to inflammatory disease whose response to psychological stress is also blunted. (These are the children with allergic skin disease or asthma, whom Angelika Buske-Kirschbaum found to have low levels of saliva cortisol in response to public speaking and mental arithmetic.) We don’t yet know if these individuals also experience stressful situations differently from the high cortisol responders.

HORMONAL YIN, HORMONAL YANG

So there is a yin and yang to stress hormone responses. On the one hand, the degree of stress responsiveness you begin with can predispose or protect you from disease. On the other, just being stressed, and being stressed for a long period of time, can change your susceptibility to disease. But instead of a susceptibility to inflammatory or allergic diseases, such prolonged stresses pre-dispose to the opposite—infectious diseases. In the first, the immune response is unchecked, and in the second, it is held in check too much.

So, stress can make you sick because the hormones and nerve pathways activated by stress change the way the immune system responds, making it less able to fight invaders. There are many parts to stress between the thing that happens to us and those hormones’ effects on the function of immune cells. There is our perception of the event, and there is our own genetic set-point of our stress responses.

Some of us are high and some of us are low stress responders. Certainly we can do something to change our perception of an event as stressful, tone down our physiological responses to that stress, and minimize stress’ effects on disease. Here memory and learning play a role. Memory of what was or memory of what should have been. But even learning and familiarity, can’t entirely override the degree of stress-responsiveness we are born with.

In all these stressful situations there is another element that contributes to the perceived stress. In each of these settings, besides physical, physiological and emotional stresses, there are interpersonal relationships, which in some cases contribute to, and in other cases can buffer us from, the stress of the job. In many ways, relationships can be the most powerful stressors that most people will encounter in their waking, working lives. And they can be the greatest soothers too.  

References

Washington Post, July 19, 1998, p. A-17; from story by Phil McCombs, Washington Post Staff Writer.



About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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