Walking a Tightrope

We need stress – not all the time, but from time to time. For instance, our levels of the stress hormone cortisol naturally rise in the morning before we get up. They also spike if we leave the house late again and are running to catch a tram. Cortisol is the hormone that releases the energy we need to carry out our daily tasks. Once we’ve made it onto the tram and are happily making our way to work, our bodies scale back production and we relax.

It’s a different story when stress becomes chronic – then it’s as if we’re constantly sprinting for the tram. Fueled by additional stress hormones like adrenaline and noradrenaline, the body is forever revved up. At the same time, worrying thoughts spin in our heads like a never-ending carousel – and we just don’t get the breaks we need. In the worst case, this continues until we’re completely burned out and collapse, leading to the all-too-familiar burnout. Not everyone reaches that point, even under constant stress, but it’s a fact that many people in Switzerland are feeling under pressure. A representative health forecast study published this year by health insurer Sanitas found that around a quarter of Swiss people often feel stressed – and among those under 30, it’s even 40 percent.

That stress levels have risen since the pandemic is a view shared by Birgit Kleim, Isabelle Mansuy and Christian Ruff. The reasons are many. “The pandemic made us more aware of our vulnerability,” says Birgit Kleim, the psychologist who leads the flagship research project STRESS along with neurobiologist Isabelle Mansuy. “And it helped lift the taboo on talking about stress and other psychological issues.” On top of this, global uncertainties – from wars and natural disasters to climate change – weigh heavily on many people’s minds, especially among younger generations. “Grave stress is also caused by domestic violence and psychological or physical abuse, which occur across all social groups,” Mansuy adds.

Launched as part of a University Medicine Zurich initiative, the STRESS project is taking an interdisciplinary approach to gain a better understanding of the biological, neurological and psychological mechanisms of stress. The next step is to investigate what makes people more resilient – i.e. more resistant to stress.

The project is based on a combination of basic research and the development of practical applications, such as improved diagnostic tools, training apps and new therapeutic concepts designed to help us cope better with stress – or ideally prevent chronic stress in the first place. “We want to deliver interventions before problems arise and underline the positive things life can bring – joy, vitality and energy,” says Christian Ruff, the neuroeconomist in the team. Chronic stress can have severe consequences for our health, leading to conditions such as depression, anxiety and cardiovascular problems.

Scientists already know quite a bit about what makes people resilient to stress: an optimistic outlook, the ability to regulate emotions, a sense of agency, problem-solving skills, and the capacity to see something positive even in negative situations. Psychologists call this “positive reappraisal”– a reframing of events.

Take this example: If you miss the tram after running for it in the morning and know you’re going to be late for your meeting, you run the risk of succumbing to stress. You look nervously at your watch every minute, tug at your hair, and get enraged about how slow public transport in Zurich is. A better approach would be to accept the delay and use the time constructively: check your e-mails, review your presentation, jot down ideas for an ongoing project, or simply take a deep breath and enjoy the fresh morning air, knowing that the world won’t end because of one late arrival. This is a concrete example of positive reappraisal – and an effective way to manage stress.

Self-regulation is a key factor in resilience and healthy stress management, as research at UZH has shown. “Resilient people are those who display cognitive and emotional flexibility,” Ruff says. “That means being able to adapt effectively in stressful moments and then get back on track again as quickly as possible.” Like tightrope walkers, they keep their balance. They overcome wobbles and remain on the rope without falling. Kleim adds: “Many people think resilience is a fixed personality trait, or that there’s even a resilience gene. But that’s unlikely – we believe it’s precisely this ability to adapt in stressful moments.” To find out how this ability shows up in the brain and what consequences it has, she and Ruff ran a series of experiments.

In one study, conducted in collaboration with neuroeconomist Marcus Grüschow, Kleim and Ruff examined medical students at UZH during their six-month internship in the emergency room. “Imagine this: after two years of studying theory, the students suddenly find themselves in the emergency room operating theatre with a severely injured patient,” Ruff says. “That’s a huge stressor.” The researchers wanted to find out how well students handle this stress and whether differences in brain information processing could explain – or even predict – their resilience. For this reason, before embarking on their internship, the students were required to take part in a stress test in the lab. While lying in a functional MRI scanner that recorded brain activity, they were confronted with conflicting emotional information to process. Of particular interest to the three researchers was the activity in one specific region of the brain, the locus coeruleus–norepinephrine system (LC-NE) in the brainstem.

“When we’re in a stress-inducing situation or facing conflict, this system releases the neurotransmitter norepinephrine,” Ruff explains. “It’s like our body’s own caffeine.” From an evolutionary perspective, norepinephrine primes the body for a fight; it dilates the pupils, raises blood pressure and heart rate, sharpens perception and heightens attention. But how strongly the LC-NE system reacts varies from one person to the next. The study revealed that students whose LC-NE systems showed stronger and longer-lasting responses to conflict in the tests were more likely to report symptoms of anxiety and depression after their ER internship. In contrast, those whose LC-NE systems responded more flexibly to simulated conflicts in the brain scanner had less difficulty coping with stress in the long run. “In people where the brain is able to adapt more flexibly to the demands placed on it, resilience is more pronounced,” Ruff says. With this insight, the researchers may have found a biological measure that will identify the level of a person’s stress resilience – even before a crisis arises. But that’s not all. More importantly, it opens up opportunities for developing practical training to build stress resilience.

Kleim gives an example: “Changes in pupil size, as they dilate and contract, allow us to see from the outside how strongly the stress-arousal system in a person’s brain is activated.” This enables the team to design neurofeedback training, in which people learn – playfully – to regulate their brain’s arousal system and boost resilience. As a result, two spin-off companies have already emerged from the flagship project, with the aim of developing such training tools into market-ready applications.

But this is just the beginning. In future, the researchers want to test their flexibility hypothesis with further lab experiments that simulate situations like stressful social interactions, financial decisions, or ambiguous perception tasks. “We’re interested in whether people process uncertainty differently under stress than in normal conditions,” Ruff says. “We suspect that people who are flexible in general remain flexible in exceptional circumstances – and are therefore more resilient.”

To explore this question, the UZH researchers are working not only in the lab but also – in collaboration with resilience researcher George Bonanno from Columbia University in New York – in everyday settings. “Through the use of smartphones, we can track participants’ real-life experiences,” Kleim says. “We ask them regularly about stressful situations and how they responded.”

The researchers also check how participants feel later in the day or the next day after a stressful event. This way, the teams in Zurich and New York learn from practical life situations what exactly makes people resilient to stress. The data and analyses derived from these successful real-life coping strategies will later be channeled into behavioral training programs, in which people can practice new ways of managing stress tailored to their individual challenges and circumstances.

After all, there’s no such thing as “objective” stress: how we perceive pressure varies enormously – depending not only on our individual biology, but also on our personal history and environment. That’s why training apps and therapeutic interventions to build resilience need to be individualized too. To stay with the metaphor: walking the tightrope is something each of us must learn for ourselves.

“In matters of stress and resilience, our individual perception plays a central role,” Mansuy says. “People react very differently to the same events.” Equally varied are the long-term health impacts caused by chronic stress – the focus of the neuroepigeneticist’s work. “Chronic stress can negatively affect the entire body – the brain, immune system, cardiovascular system, blood, bone quality and microbiome,” she explains.

Her research shows that chronic stress alters our epigenetic signature – the biological “control software” of our genome, which regulates how genes are activated or silenced. For her studies, Mansuy conducts lab experiments mainly with mice, and then compares her findings with human studies. “Humans and mice are, of course, very different creatures,” she notes, “but in many ways they’re similar – including many comparable biological markers for stress and resilience.”

Mansuy’s scientific work with mice includes evidence of how devastating long-term stress in early childhood can be. Such stress can result from unstable social relationships, abuse, neglect, or physical and verbal violence. “The health consequences of adverse childhood experiences – such as depression, cardiovascular disease, or risky behaviors – often don’t show up until much later in life,” Mansuy explains. “That’s why many children go undiagnosed.”

Mansuy has also discovered that the negative health effects of chronic stress in mice are not only borne by the mice directly affected, but also their offspring. Stress-induced epigenetic changes can be passed down, increasing the risk of the development of stress-related sickness from one generation to the next. But resilience against certain conditions may also be inherited epigenetically. After all, not everyone exposed to chronic stress develops stress-related diseases.

“The epigenetic inheritance of stress effects is an entirely new scientific concept that has yet to be comprehensively studied,” Mansuy says, one of the pioneers in this field. Looking ahead, she hopes to uncover more about the epigenetic mechanisms involved in human experiences – and to continue analyzing the role these mechanisms play, both in the long-term damage caused severe stress-related experiences and in building resilience to deal with them. One key goal is prevention. Researchers are currently developing diagnostic blood tests to detect any early risk of stress-related conditions and reduce them before they take hold.

In this way, Mansuy’s research adds another key piece to the broader picture emerging from interdisciplinary research on stress and resilience. It also gives new impetus for designing targeted and personalized tools to boost our resilience – and help us walk the tightrope with confidence.