How Exercise Trains the Stress Response

This Week’s Research Highlight

For most of human history, the heart was more than a pump. It was the seat of emotion.

From Egyptian embalming texts to medieval romantic poetry, the heart was believed to house the soul, to ache with sorrow, to race with passion. And even today, that connection feels deeply intuitive. Love, fear, grief — they all seem to reside in the chest.

Modern neuroscience, of course, tells a different story. We know now that our thoughts and feelings originate in the brain.

But in a way, those old metaphors may not have been far off the mark. Emotional stress still leaves its deepest marks in the cardiovascular system.

When the brain perceives threat, it activates a cascade of signals: heart rate rises, blood vessels constrict, and inflammatory molecules are released into the bloodstream. These reactions are adaptive in short bursts. But when they become chronic — when the stress response stays switched on — they begin to erode the heart and vasculature from the inside out.

In a powerful illustration of this phenomenon, researchers asked people to perform a public speaking challenge. For some, that stress alone was enough to trigger myocardial ischemia, a restriction in blood flow to the heart. Over the next five years, those individuals were more than twice as likely to suffer a heart attack or die from cardiovascular causes.

Stress, in other words, is more than emotional. It’s physiological. It reshapes the nervous system, activates the immune response, and accelerates the breakdown of the cardiovascular system — silently, persistently, and sometimes fatally.

That brings us to physical activity. If there’s one thing we know for sure, it’s this: exercise protects the heart. Again and again, studies have confirmed that individuals who meet the standard exercise guidelines — 150 minutes of moderate or 75 minutes of vigorous activity per week — have markedly lower cardiovascular risk.

One of the most comprehensive analyses to date found that meeting these guidelines was associated with a 40% lower risk of dying from cardiovascular disease. And the benefits didn’t stop there. People who exercised well beyond the recommended dose — up to five times as much — saw even greater reductions in risk.

But here’s the mystery.

When researchers try to pinpoint how exercise delivers this protection — by looking at measurable changes in cholesterol, blood pressure, blood sugar — the math doesn’t quite add up. In one telling analysis, exercise reduced cardiovascular disease risk by 40% more than would be expected based on its effects on traditional risk factors alone.

In other words, something else is at work.

One possibility? Stress regulation.

What if part of exercise’s protective power lies not in how it changes the body directly — but in how it trains the brain to perceive, process, and recover from stress?

That’s the question a team of researchers at Massachusetts General Hospital set out to examine. Drawing on brain imaging data, behavioral surveys, and long-term health outcomes from tens of thousands of participants, they traced a pathway that runs from physical activity, to stress-related brain activity, to the health of the heart.

Inside the Study

To explore the hidden pathways linking physical activity to heart health, scientists turned to one of the most data-rich resources in medicine: the Mass General Brigham Biobank. This ongoing cohort includes health records, behavioral surveys, genetic data — and crucially, a subset of high-resolution brain scans.

The team zeroed in on a neural stress pathway anchored by the amygdala, a deep brain structure that detects threat and mobilizes the body’s defenses. It helps trigger vigilance, fear, and physiological arousal. But in some people, the system becomes hypersensitive — sort of like a motion sensor that goes off at every flutter of movement.

Normally, this stress response is reined in by the ventromedial prefrontal cortex (vmPFC), a region just behind the forehead involved in emotion regulation and decision-making. The vmPFC acts like a braking system, interpreting whether a situation is truly dangerous or merely inconvenient. When it falters — like in mood disorders like depression — the nervous system can get locked in a state of permanent overreaction.

To capture this dynamic, the researchers used a neuroimaging metric called the AmygAC ratio, or the ratio of metabolic activity in the amygdala to that in the vmPFC. It’s measured via 18F-fluorodeoxyglucose PET/CT, a type of functional imaging that tracks glucose uptake across the brain, kind of like a heat map of brain activity. A higher AmygAC ratio reflects a brain tilted toward threat detection rather than regulation — a profile linked to both psychological distress and cardiovascular disease.

This dual approach, combining real-world medical outcomes with high-resolution brain imaging, gave the researchers a unique window into how subjective stress might leave objective biological traces. Drawing on brain scans from 744 individuals, and cardiovascular outcome data from more than 46,000, the researchers tested three linked hypotheses:

• Do physically active people show reduced stress signaling in the brain?
• Can those neural differences help explain their lower risk of cardiovascular disease?
• And might the effect be even stronger in individuals with an overactive stress response to begin with?

A Chain Reaction: From Movement to the Mind to the Heart

The first link in the chain was the brain.

Among participants who underwent brain imaging, those who met the recommended threshold for physical activity showed a marked reduction in stress-related brain activity.

Specifically, they had a lower AmygAC ratio, meaning less activity in stress-reactive circuits relative to the brain’s regulatory control center. Even after controlling for age, sex, socioeconomic status, health conditions, and genetic predisposition to stress, this association held.

The signal followed a dose-response pattern: more physical activity was associated with progressively quieter neural stress signaling. In essence, movement seemed to turn down the volume knob on the brain’s stress system. With each notch of additional physical activity, the circuitry grew quieter and less reactive.

The second link connected the brain to the body.

Higher AmygAC predicted worse outcomes. Participants with elevated stress-related brain activity were significantly more likely to experience cardiovascular events such as heart attacks, strokes, as well as needing significant interventions like cardiac bypass. For every unit increase in AmygAC, the odds of experiencing a cardiovascular event rose by 20%, even after adjusting for traditional risk factors.

Then came the third and perhaps most familiar link: people who were more physically active had fewer cardiovascular events. Over a 10-year observation window, those who met or exceeded activity guidelines had a 20% lower risk of major cardiovascular events compared to their less active peers.

But the most compelling insight came when the researchers connected all three links.

Using a statistical technique called mediation analysis, they asked whether part of exercise’s protective effect might be carried through its impact on the brain. And the answer was yes. Roughly 8% of the cardiovascular benefit of physical activity was explained by reductions in stress-related neural activity.

That may sound small, but for a behavioral factor measured at a single time point, it’s a substantial contribution. As we alluded to earlier, stress-related brain activity is only one of myriad biological pathways influenced by physical activity.

A Bigger Payoff for the Stressed Brain

Perhaps the most revealing insight emerged when the researchers split the data by mental health history.

Among participants with preexisting depression, the cardiovascular benefits of physical activity were dramatically amplified. Across multiple outcomes and event horizons, exercise was not just beneficial — it was more than twice as protective in people with depression, compared to those without.

For example, over a 10-year period, participants with depression who met standard physical activity guidelines had a 33% lower risk of coronary events versus 13% in those without depression who met the same threshold. The same dose of exercise, but a far greater payoff.

Physical activity reduces 10-year cardiovascular disease risk in all participants, but the effect is significantly stronger in those with a history of depression. In individuals without depression (left), risk drops modestly between low and moderate activity levels, then plateaus. In contrast, those with depression (right) show a steeper, more continuous decline: the more they moved, the more their cardiovascular risk dropped, with no clear point of saturation.

Why? Part of the answer, no doubt, lies in baseline brain activity.

In the neuroimaging subset, people with depression had significantly higher AmygAC ratios. Basically, their stress systems were already running hot. And in such a context, you would expect interventions that strengthen regulatory control — like exercise — to yield disproportionately large benefits.

Finally, the dose–response curve for depressed individuals was different.

In the general population, the benefits of physical activity eventually leveled off, roughly at the volume of movement recommended by current guidelines. But in those with depression, the line kept bending. The more they moved, the more their risk dropped — with no clear ceiling in sight.

A Closer Look at the Brain

But how exactly does physical activity reshape the brain’s stress network, especially in people whose systems are already hyperactive?

To find out, the researchers dissected the neural signature behind the protective effect, the AmygAC ratio. Recall that this ratio compares the metabolic activity of the amygdala, which flags potential threats, and the ventromedial prefrontal cortex (vmPFC), which helps keep those reactions in check.

You might have assumed that the amygdala, the brain’s internal threat detector, had quieted down.

But in fact, changes in amygdala activity weren’t statistically significant.

Instead, the real difference came from the other side of the equation. Participants who exercised more had higher resting activity in the vmPFC, the brain’s internal regulator.

In other words, rather than muting the stress response, physical activity seemed to strengthen the system that governs it.

And that sets up the final question: What is it about physical activity that strengthens this regulatory hub?

How Exercise Trains the Stress Response

One framework that can help us make sense of these findings is known as the Cross-Stressor Adaptation Hypothesis.

It proposes that repeated exposure to physical stress, like the kind experienced during exercise, leads to lasting adaptations in the systems that regulate psychological stress. Over time, that training reshapes how the mind interprets challenges, how the body reacts to it, and how quickly it recovers.

And that process starts in the brain.

Most athletes know this implicitly: exercise is as much a mental test as a physical one. It calls on focus, patience, and restraint — recruiting the same brain circuits that we rely on to manage stress in everyday life.

Over time, these demands reinforce the prefrontal-limbic circuit that governs emotional regulation, not just through repeated use, but also with some biochemical support. Aerobic exercise reliably boosts levels of brain-derived neurotrophic factor (BDNF), a molecule that promotes the growth and connectivity of neurons. The prefrontal cortex is especially receptive to these effects, thanks to its dense web of connections and high metabolic demands.

As regulatory strength builds, its influence ripples outward.

A more robust vmPFC exerts tighter control over the amygdala, reducing unnecessary threat signaling — just like we saw in this study. It also dampens output from the hypothalamic-pituitary-adrenal (HPA) axis, which governs cortisol release, and from the sympathetic nervous system, which controls heart rate and blood pressure.

With repeated training, these systems become more efficient: less reactive to minor stressors, and quicker to return to baseline after acute ones. For example, in a study of Swiss military recruits, individuals with higher aerobic fitness showed smaller spikes in heart rate during psychological stress — and they bounced back faster thereafter. A clear marker of a nervous system trained to respond, then rapidly reset.

Heart rate responses to psychological stress were lower and recovered faster in individuals with higher aerobic fitness. White dots represent the highest quartile of aerobic fitness (V̇O2max of 55.8 ml/kg/min) and black dots represent the lowest quartile (V̇O2max of 43.3 ml/kg/min). Adapted from Wyss et al., 2016.

That’s the very definition of resilience. Not the absence of stress, but the ability to move through it without carrying its physiological imprint.

And over the long haul, that capacity could quite literally save your life.

In a major population study from Germany, individuals with lower psychological resilience had a 38% higher risk of cardiovascular disease and a 36% higher risk of all-cause mortality.

The takeaway is clear: resilience matters. And the good news is that physical activity can help build it: by strengthening the brain’s stress-regulating circuits, quieting the body’s overactive alarm systems, and ultimately attenuating cardiovascular disease before it can even take root.

Summary: Researchers analyzed data combining brain imaging with cardiovascular outcomes from over 46,000 adults in the Mass General Brigham Biobank. Participants who met exercise guidelines had significantly lower stress-related brain activity, measured by the ratio of amygdala to ventromedial prefrontal cortex (vmPFC) metabolism (AmygAC). Those meeting activity guidelines had a 20% lower 10-year risk of major cardiovascular events, and mediation analysis showed that reductions in this neural stress signature explained part of exercise’s protective effect. The link was especially pronounced in people with depression, where physical activity was more than twice as protective against coronary events. Imaging showed that this benefit stemmed not from lower amygdala activity, but from increased vmPFC activity — suggesting that exercise strengthens the brain’s stress-regulating circuits, with meaningful downstream effects on cardiovascular health.

Random Trivia & Weird News

⚽ When Germany played in the 2006 World Cup, heart attacks surged in Bavaria.

During the month-long tournament, cardiovascular emergencies in Munich jumped 2.7-fold on days the German team played.

During tense elimination matches, they rose an astounding 6-fold.

Most heart events struck within the first two hours of kickoff. On non-game days? No spike at all.

Cardiovascular emergencies spiked during Germany’s 2006 World Cup matches (red line), far exceeding rates from previous years (yellow and blue lines). Peaks correspond to high-stakes games, especially knockouts (see matches 5 and 6 👀). No spike was observed on non–match days. From Wilbert-Lampen et al, 2008.

Podcasts We Loved This Week

• Eric Topol & Emily Rogalski: How “super agers” stay sharp and active longer than their peers. Via Science Friday.

• L. Mahadevan: Does form really shape function? Via The Joy of Why (Quanta Magazine).

Products We Like

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Newer studies also point to physical benefits: in trained athletes, short-term Rhodiola use enhanced strength performance, boosting bench press reps and increasing bar speed in the bench pull.

Nature’s Way Rhodiola Rosea delivers the same standardized extract (3% rosavins, 1% salidroside) used in human studies, and even got the ConsumerLab seal of approval for purity and potency. A reliable daily ally for stress and stamina.

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