Understanding the stress response

Chronic activation of this survival mechanism impairs health

A stressful situation — whether something environmental, such as a looming work deadline, or psychological, such as persistent worry about losing a job — can trigger a cascade of stress hormones that produce well-orchestrated physiological changes. A stressful incident can make the heart pound and breathing quicken. Muscles tense and beads of sweat appear.

This combination of reactions to stress is also known as the “fight-or-flight” response because it evolved as a survival mechanism, enabling people and other mammals to react quickly to life-threatening situations. The carefully orchestrated yet near-instantaneous sequence of hormonal changes and physiological responses helps someone to fight the threat off or flee to safety. Unfortunately, the body can also overreact to stressors that are not life-threatening, such as traffic jams, work pressure, and family difficulties.

Over the years, researchers have learned not only how and why these reactions occur, but have also gained insight into the long-term effects chronic stress has on physical and psychological health. Over time, repeated activation of the stress response takes a toll on the body. Research suggests that chronic stress contributes to high blood pressure, promotes the formation of artery-clogging deposits, and causes brain changes that may contribute to anxiety, depression, and addiction. More preliminary research suggests that chronic stress may also contribute to obesity, both through direct mechanisms (causing people to eat more) or indirectly (decreasing sleep and exercise).

Sounding the alarm

The stress response begins in the brain (see illustration). When someone confronts an oncoming car or other danger, the eyes or ears (or both) send the information to the amygdala, an area of the brain that contributes to emotional processing. The amygdala interprets the images and sounds. When it perceives danger, it instantly sends a distress signal to the hypothalamus.

Command center

illustration of brain showing areas activated by stress

When someone experiences a stressful event, the amygdala, an area of the brain that contributes to emotional processing, sends a distress signal to the hypothalamus. This area of the brain functions like a command center, communicating with the rest of the body through the nervous system so that the person has the energy to fight or flee.

The hypothalamus is a bit like a command center. This area of the brain communicates with the rest of the body through the autonomic nervous system, which controls such involuntary body functions as breathing, blood pressure, heartbeat, and the dilation or constriction of key blood vessels and small airways in the lungs called bronchioles. The autonomic nervous system has two components, the sympathetic nervous system and the parasympathetic nervous system. The sympathetic nervous system functions like a gas pedal in a car. It triggers the fight-or-flight response, providing the body with a burst of energy so that it can respond to perceived dangers. The parasympathetic nervous system acts like a brake. It promotes the “rest and digest” response that calms the body down after the danger has passed.

After the amygdala sends a distress signal, the hypothalamus activates the sympathetic nervous system by sending signals through the autonomic nerves to the adrenal glands. These glands respond by pumping the hormone epinephrine (also known as adrenaline) into the bloodstream. As epinephrine circulates through the body, it brings on a number of physiological changes. The heart beats faster than normal, pushing blood to the muscles, heart, and other vital organs. Pulse rate and blood pressure go up. The person undergoing these changes also starts to breathe more rapidly. Small airways in the lungs open wide. This way, the lungs can take in as much oxygen as possible with each breath. Extra oxygen is sent to the brain, increasing alertness. Sight, hearing, and other senses become sharper. Meanwhile, epinephrine triggers the release of blood sugar (glucose) and fats from temporary storage sites in the body. These nutrients flood into the bloodstream, supplying energy to all parts of the body.

All of these changes happen so quickly that people aren’t aware of them. In fact, the wiring is so efficient that the amygdala and hypothalamus start this cascade even before the brain’s visual centers have had a chance to fully process what is happening. That’s why people are able to jump out of the path of an oncoming car even before they think about what they are doing.

As the initial surge of epinephrine subsides, the hypothalamus activates the second component of the stress response system — known as the HPA axis. This network consists of the hypothalamus, the pituitary gland, and the adrenal glands.

The HPA axis relies on a series of hormonal signals to keep the sympathetic nervous system — the “gas pedal” — pressed down. If the brain continues to perceive something as dangerous, the hypothalamus releases corticotropin-releasing hormone (CRH), which travels to the pituitary gland, triggering the release of adrenocorticotropic hormone (ACTH). This hormone travels to the adrenal glands, prompting them to release cortisol. The body thus stays revved up and on high alert. When the threat passes, cortisol levels fall. The parasympathetic nervous system — the “brake” — then dampens the stress response.

Techniques to counter chronic stress

Many people are unable to find a way to put the brakes on stress. Chronic low-level stress keeps the HPA axis activated, much like a motor that is idling too high for too long. After a while, this has an effect on the body that contributes to the health problems associated with chronic stress.

Persistent epinephrine surges can damage blood vessels and arteries, increasing blood pressure and raising risk of heart attacks or strokes. Elevated cortisol levels create physiological changes that help to replenish the body’s energy stores that are depleted during the stress response. But they inadvertently contribute to the buildup of fat tissue and to weight gain. For example, cortisol increases appetite, so that people will want to eat more to obtain extra energy. It also increases storage of unused nutrients as fat.

Fortunately, people can learn techniques to counter the stress response.

Relaxation response. Dr. Herbert Benson, director emeritus of the Benson-Henry Institute for Mind Body Medicine at Massachusetts General Hospital, has devoted much of his career to learning how people can counter the stress response by using a combination of approaches that elicit the relaxation response. These include deep abdominal breathing, focus on a soothing word (such as peace or calm), visualization of tranquil scenes, repetitive prayer, yoga, and tai chi.

Most of the research using objective measures to evaluate how effective the relaxation response is at countering chronic stress have been conducted in people with hypertension and other forms of heart disease. Those results suggest the technique may be worth trying — although for most people it is not a cure-all. For example, researchers at Massachusetts General Hospital conducted a double-blind, randomized controlled trial of 122 patients with hypertension, ages 55 and older, in which half were assigned to relaxation response training and the other half to a control group that received information about blood pressure control. After eight weeks, 34 of the people who practiced the relaxation response — a little more than half — had achieved a systolic blood pressure reduction of more than 5 mm Hg, and were therefore eligible for the next phase of the study, in which they could reduce levels of blood pressure medication they were taking. During that second phase, 50% were able to eliminate at least one blood pressure medication — significantly more than in the control group, where only 19% eliminated their medication.

Physical activity. People can use exercise to stifle the buildup of stress in several ways. Exercise, such as taking a brisk walk shortly after feeling stressed, not only deepens breathing but also helps relieve muscle tension. Movement therapies such as yoga, tai chi, and qi gong combine fluid movements with deep breathing and mental focus, all of which can induce calm.

Social support. Confidants, friends, acquaintances, co-workers, relatives, spouses, and companions all provide a life-enhancing social net — and may increase longevity. It’s not clear why, but the buffering theory holds that people who enjoy close relationships with family and friends receive emotional support that indirectly helps to sustain them at times of chronic stress and crisis.

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Stress isn’t always a bad thing

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How changing what you eat could reduce your stress

What you eat could improve how your body responds to stress, according to experts. Introducing some new foods while cutting back on others may reduce the impact stress has on your body and day-to-day life. Here are four dietary changes designed to help you handle stress better.

As well as feeding you, the food you eat feeds the trillions of bacteria that live in your gut. Some studies find regulating gut bacteria via diet can have a positive impact on anxiety symptoms. The amount and types of bacteria in your gut are affected by your diet, and good dietary choices can “communicate calm to the brain”, according to Dr Rangan Chaterjee.

“The cheapest and simplest thing you can do to diversify and optimise the ‘good’ bacteria in your gut is to increase the variety of foods you eat…. Try to eat five different coloured vegetables every day”, says Dr Chaterjee. That’s because “minimally processed wholefoods – fibre” are best for your gut bacteria.

How does it work? The body cannot digest some fibre, including that found in many fruits and vegetables, so it’s fermented in the gut. Here it supports the growth of helpful microbes. As part of the fermentation process, the bacteria release essential chemicals and acids that interact with all the cells in your body. This interaction influences brain and immune health, according to Felice Jacka, Head of the Food and Mood Centre at Deakin University in Australia.

Jacka recommends eating foods from the Mediterranean diet, such as “fruit, vegetables, legumes and wholegrains, which all contain plant fibre”. She says fermented foods such as sauerkraut, kimchi, kombucha and kefir can nurture bacteria and yeasts in the gut, as well as being good for your wider health.

Step away from the sugar

If your idea of dealing with stress is downing a pint of ice cream, you’re probably familiar with the concept of a ‘sugar high’, and possibly the ‘crash’ that comes afterwards. When you eat lots of sugar, your body releases insulin to absorb the excess glucose and regulate your blood-sugar levels. This journey of ups and downs may have negative side-effects, such as lack of concentration and tiredness, which can “hinder your ability to cope with stressful situations”, according to dietitian Sophie Medlin.

Work out when you’ve had enough caffeine

Positive and negative effects of caffeine on anxiety have been recorded. Most studies are based on research done with people already diagnosed with anxiety, but dietician Medlin says the results can often be applied to people suffering from everyday stress.

“The way you react may depend on your genetic sensitivity to caffeine, your gender and how much you drink, as well as existing anxious feelings”, says Medlin. Drinking caffeine can affect your sleep, which may impact the way you deal with stress. If drinking or eating caffeine negatively affects you, it’s a good idea to switch to decaf (although do this slowly, as caffeine withdrawals are no joke!).

Don’t mix hunger and stress

“Never go into any stressful situation hungry… we’ve long recognised that hunger leads to irritability”, says Medlin. When you’re hungry, your blood sugar drops and your cortisol and adrenaline – those fight-or-flight hormones – rise. This is because the neuropeptides, secreted by neurons to control the chemicals in the brain, are the same for hunger as for anger. “Your body is pretty much still a caveman”, says Medlin. This explains why we often become irritable when peckish.

Adding ‘hanger’ to a stressful situation can enhance negative emotions. Have a few healthy snacks at hand to keep hunger pangs at bay, especially if you’re expecting a trying day.

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Researchers study how it seems to change the brain in depressed patients

“In 2015, 16.1 million Americans reported experiencing major depression during the previous year, often struggling to function while grappling with crippling darkness and despair.”

There’s an arsenal of treatments at hand, including talk therapy and antidepressant medications, but what’s depressing in itself is that they don’t work for every patient.

“Many people don’t respond to the frontline interventions,” said Benjamin Shapero, an instructor in psychiatry at Harvard Medical School (HMS) and a psychologist at Massachusetts General Hospital’s (MGH) Depression Clinical and Research Program. “Individual cognitive behavioral therapy is helpful for many people; antidepressant medications help many people. But it’s also the case that many people don’t benefit from them as well. There’s a great need for alternative approaches.”

Shapero is working with Gaëlle Desbordes, an instructor in radiology at HMS and a neuroscientist at MGH’s Martinos Center for Biomedical Imaging, to explore one alternative approach: mindfulness-based meditation.

In recent decades, public interest in mindfulness meditation has soared. Paralleling, and perhaps feeding, the growing popular acceptance has been rising scientific attention. The number of randomized controlled trials — the gold standard for clinical study — involving mindfulness has jumped from one in the period from 1995‒1997 to 11 from 2004‒2006, to a whopping 216 from 2013‒2015, according to a recent article summarizing scientific findings on the subject.

Studies have shown benefits against an array of conditions both physical and mental, including irritable bowel syndrome, fibromyalgia, psoriasis, anxiety, depression, and post-traumatic stress disorder. But some of those findings have been called into question because studies had small sample sizes or problematic experimental designs. Still, there are a handful of key areas — including depression, chronic pain, and anxiety — in which well-designed, well-run studies have shown benefits for patients engaging in a mindfulness meditation program, with effects similar to other existing treatments.

“There are a few applications where the evidence is believable. But the effects are by no means earth-shattering,” Desbordes said. “We’re talking about moderate effect size, on par with other treatments, not better. And then there’s a bunch of other things under study with preliminary evidence that is encouraging but by no means conclusive. I think that’s where it’s at. I’m not sure that is exactly how the public understands it at this point.”

Desbordes’ interest in the topic stems from personal experience. She began meditating as a graduate student in computational neuroscience at Boston University, seeking respite from the stress and frustration of academic life. Her experience convinced her that something real was happening to her and prompted her to study the subject more closely, in hopes of shedding enough light to underpin therapy that might help others.

“My own interest comes from having practiced those [meditation techniques] and found them beneficial, personally. Then, being a scientist, asking ‘How does this work? What is this doing to me?’ and wanting to understand the mechanisms to see if it can help others,” Desbordes said. “If we want that to become a therapy or something offered in the community, we need to demonstrate [its benefits] scientifically.”

Desbordes’ research uses functional magnetic resonance imaging (fMRI), which not only takes pictures of the brain, as a regular MRI does, but also records brain activity occurring during the scan. In 2012, she demonstrated that changes in brain activity in subjects who have learned to meditate hold steady even when they’re not meditating. Desbordes took before-and-after scans of subjects who learned to meditate over the course of two months. She scanned them not while they were meditating, but while they were performing everyday tasks. The scans still detected changes in the subjects’ brain activation patterns from the beginning to the end of the study, the first time such a change — in a part of the brain called the amygdala — had been detected.

Functional MRI (left) showing activation in the amygdala when participants were watching images with emotional content before learning meditation. After eight weeks of training in mindful attention meditation (right) note the amygdala is less activated after the meditation training. Courtesy of Gaelle Desbordes

In her current work, she is exploring meditation’s effects on the brains of clinically depressed patients, a group for whom studies have shown meditation to be effective. Working with patients selected and screened by Shapero, Desbordes is performing functional magnetic resonance imaging scans before and after an eight-week course in mindfulness-based cognitive therapy, or MBCT.

During the scans, participants complete two tests, one that encourages them to become more aware of their bodies by focusing on their heartbeats (an exercise related to mindfulness meditation), and the other asking them to reflect on phrases common in the self-chatter of depressed patients, such as “I am such a loser,” or “I can’t go on.” After a series of such comments, the participants are asked to stop ruminating on the phrases and the thoughts they trigger. Researchers will measure how quickly subjects can disengage from negative thoughts, typically a difficult task for the depressed.

The process will be repeated for a control group that undergoes muscle relaxation training and depression education instead of MBCT. While it’s possible that patients in the control part of the study also will have reduced depressive symptoms, Desbordes said it should occur via different mechanisms in the brain, a difference that may be revealed by the scans. The work, which received funding from the National Center for Complementary and Integrative Health, has been underway since 2014 and is expected to last into 2019.

Desbordes said she wants to test one prevalent hypothesis about how MBCT works in depressed patients: that the training boosts body awareness in the moment, called interoception, which, by focusing their attention on the here and now, arms participants to break the cycle of self-rumination.

“We know those brain systems involved with interoception, and we know those involved with rumination and depression. I want to test, after taking MBCT, whether we see changes in these networks, particularly in tasks specifically engaging them,” Desbordes said.

Desbordes is part of a community of researchers at Harvard and its affiliated institutions that in recent decades has been teasing out whether and how meditation works.

In the 1970s, when transcendental meditation surged in popularity, Herbert Benson, a professor at Harvard Medical School and what was then Beth Israel Hospital, explored what he called “The Relaxation Response,” identifying it as the common, functional attribute of transcendental meditation, yoga, and other forms of meditation, including deep religious prayer. Benson described this response — which recent investigators say is not as common as he originally thought — as the opposite of the body’s adrenalin-charged “fight or flight” response, which was also identified at Harvard, by physiologist Walter Cannon Bradford in 1915.

Other MGH researchers also are studying the effects of meditation on the body, including Sara Lazar, who in 2012 used fMRI to show that the brains of subjects thickened after an eight-week meditation course. Work is ongoing at MGH’s Benson-Henry Institute; at HMS and Brigham and Women’s Hospital’s Osher Center for Integrative Medicine; at the Harvard-affiliated Cambridge Health Alliance, where Zev Schuman-Olivier directs the Center for Mindfulness and Compassion; and among a group of nearly a dozen investigators at Harvard and other Northeastern institutions, including Desbordes and Lazar, who are collaborating through the Mindfulness Research Collaborative.

Among the challenges researchers face is defining mindfulness itself. The word has come to describe a meditation-based practice whose aim is to increase one’s sense of being in the present, but it has also been used to describe a nonmeditative state in which subjects set aside their mental distractions to pay greater attention to the here and now, as in the work of Harvard psychologist Ellen Langer.

Another challenge involves sorting through the many variations of meditative practice.

Recent scientific exploration has largely focused on the secular practice of mindful meditation, but meditation is also a component of several ancient religious traditions, with variations. Even within the community practicing secular mindful meditation, there are variations that may be scientifically meaningful, such as how often one meditates and how long the sessions are. Desbordes herself has an interest in a variation called compassion meditation, whose aim is to increase caring for those around us.

Amid this variation, an eight-week mindfulness-based stress reduction course developed in the 1970s by Jon Kabat-Zinn at the University of Massachusetts Medical Center has become something of a clinical and scientific standard. The course involves weekly two- or 2½-hour group training sessions, 45 minutes of daily work on one’s own, and a daylong retreat. The mindfulness-based cognitive therapy used in Desbordes’ current work is a variation on that program and incorporates elements of cognitive behavioral therapy, which involves talk therapy effective in treating depression.

Ultimately, Desbordes said she’s interested in teasing out just what in mindful meditation can work against depression. If researchers can identify what elements are effective, the therapy may be refined to be more successful. Shapero is also interested in using the study to refine treatment. Since some patients benefit from mindfulness meditation and some do not, he’d like to better understand how to differentiate between the two.

“Once we know which ingredients are successful, we can do more of that and less, maybe, of the parts that are less effective,” Desbordes said.

Research funding includes the National Center for Complementary and Integrative Health.

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