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Can We Really Measure Stress?

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Have you ever felt stressed?

It’s an unpleasant sensation. That constriction of your breathing, the tight ball that forms just behind your breastbone, and the fuzziness that enters your head are all classic hallmarks of getting a bit wound up. Or are they? Perhaps that’s just my experience of stress; maybe your stress feels like a gnawing dread in the pit of your stomach, or a desire to run away, or even a lump in your throat (that’s the globus sensation, for those who are interested).

While we all know what stress means in an abstract sense, what it actually feels like and how we respond to stress can vary hugely from person to person. As such, science has yet to develop a reliable method of measuring stress. Psychologists have tried, with questionnaires such as the perceived stress scale (PSS), but the holy grail of stress diagnostics would be a reliable biomarker; a biological measuring stick that would sum up all the physiological and emotional changes caused by stress and plot them on a simple chart. But is this possible? Oxford Medistress, developers of the Leukocyte Coping Capacity (LCC) test, think so. 

The company, a spinout from Oxford University, say they have developed a simple test that, with just a drop of blood, can quantify your stress levels, be it at work, on the sports field or behind the wheel of your car. Remarkably, it can even quantify your stress if you are a badger.

The stakes couldn’t be much higher – stress costs US industry $300 billion annually. But we’ve been here before with drop-of-blood diagnostics. The specter of Theranos and its bogus "Edison" testing device has not stopped haunting the field. Can the LCC test live up to its promise? 

Chronic and acute stress in the body

The story of stress starts in your brain. The American physiologist Walter Bradfort Cannon coined the term homeostasis to describe the correct balance of the body’s internal state that must be maintained to ensure wellbeing from cell to system level. When the body is unable to maintain this delicate equilibrium, said Cannon, it entered a high energy state of stress to make sure that the disruptor can be combated or escaped. For this, he devised the infamous term fight or flight.

Subsequent researchers mapped out how the body responds to stressors, sketching the first diagrams of our body’s stress system. This is a finely tuned machine, which is kicked into gear upon the perception of a stressor (a speeding car heading straight towards you, a pan boiling over, or a particularly annoying work colleague, for example).

There are two stages to your average stress response, involving a whole host of your brain regions working together to secrete a selection of stress hormones; chemicals that communicate to your body’s other systems that it’s go time. The first stage involves catecholamine hormones like adrenaline, secreted from the adrenal medulla, which generate short term actions; “Get out of the way of that car!”, or, “Linda is at the water cooler again, hide!”. The second stage involves the hypothalamus and produces slower, but long-lasting and far-reaching hormone secretion like that of the classic “stress hormone”, cortisol.

Stress in your spit: The saliva stress test

When it comes to biomarkers of stress, cortisol is as close as we have to a current “gold standard”. But as Ana Tiganescu, a researcher at the University of Leeds who investigates how our skin responds to stress, is well aware, there are plenty of challenges involved in measuring stress through cortisol: “Our systemic cortisol levels vary during the day, which means you have to take repeated measures of cortisol in serum over a longer period in order to get a picture of stress level,” says Tiganescu. A day’s worth of blood donation doesn’t sound like a user-friendly test.

Luckily, cortisol really does get everywhere. This hormone is small enough to move where it wants to throughout your body, including into your spit. This has made salivary cortisol an attractive target as a biomarker for stress. In a well-cited review paper from 2009, Dirk Hellhammer and colleagues investigated why salivary cortisol is and isn’t useful for measuring stress. Hellhammer concluded that salivary cortisol is a reliable test only when a whole set of potential variables is accounted for. Especially, says Tiganescu, variability between people. “You have to consider different thresholds – someone who undergoes a stressful event, and has high cortisol, might not necessarily report feeling stressed. People have different tolerances for stress. And that’s hard to measure without a big study.” Could Medistress’s test solve these problems?

Putting a number on stress

Whilst stress affects almost every system our body contains, Oxford Medistress’s test focuses specifically on the immune response to stress, by examining white blood cells (leukocytes). As their co-founder and Chief Scientific Officer Rubina Mian tells me in an interview, “Stress is hugely complex, and it involves just about every system in the body. It involves the sympathetic nervous system, endocrine factors, blood biochemistry, cytokines, red blood cell hemodynamics… And the interesting thing about leukocytes is that they respond to all of those factors.”

The LCC test involves mixing a drop of blood with a chemical called Phorbol Myristate Acetate (PMA). PMA stimulates white blood cells to produce oxygen free radical molecules, a process that is usually designed to fight off microbials. This free radical burst response is measured by the addition of a luminescent marker to the mix. Stressed out and tired blood cells aren’t as good at producing these free radicals, and so the relative luminescence goes down.

Can it really be that simple to put a number on stress?

Not so fast, suggests John Martin, Professor of Cardiovascular Medicine at Imperial College London. Speaking to me whilst on leave in France, Martin raises a basic point about the need for a new test at all, “What is stress? Stress is a multi-system response to an external environment and there are lots of ways of looking at stress," says Martin. "Pulse, sweating, cortisol.  Why should any new test, even when it was validated, be better than that?"

John Oliver explores the medical device industry
Far beyond the LCC test, which is yet to be approved as a medical device by any regulatory agency, medical devices have been under the spotlight. A recent segment on John Oliver’s Last Week Tonight brought this issue into sharp relief. Gaping loopholes in Food and Drug Administration (FDA) regulation mean that certain devices can reach consumers without requiring even a fraction of the evidence that drug compounds do. And whilst many of these devices don’t have the potential to do damage, others, like the Essure device that Oliver reported on, most certainly do.

Stress and the immune system

So, is Medistress’s LCC test better? Mian says that the test result should avoid cortisol’s diurnal fluctuation. “There are sufficient numbers of variables acting on the leukocytes that we are able to achieve steady baselines throughout the day,” says Mian. The duration of the change to the test reading is proportional to the intensity of the stressor, with deeper, more taxing stressors causing the LCC metric to take longer to recover, and the measurement can be assessed rapidly, within 10 minutes. Compared to a day’s worth of blood donation, a ten-minute stress test sounds pretty good. If the LCC test can perform as promised, then it could revolutionize the field of stress diagnostics; that much is clear.

But it’s not that simple. The high number of variables that the LCC test considers can be seen as a strength, but also as a weakness – what if a stressed-out person has a cold? Does that mess up their readings? Mian says that the LCC test wouldn’t necessarily be able to say why a person’s stress levels are out of kilter.

In certain situations, that might not be a problem – the LCC test has already been trialed with two Premier League Football teams in the UK, and it’s easy to see how any stress, no matter the cause, might be something clubs want to know about in their players – but it certainly doesn’t seem more accurate than cortisol. What about variation between immune systems – how would we know that an LCC reading is abnormal for a particular patient based off one reading? Mian concedes, “What we do is take baseline readings and work out statistically what the average is for that person. We work out the baseline for every individual. Over a number of days, number of weeks, we work out what is normal for that person.” So, not exactly a ten-minute test.

Martin, for one, is clear about what would be required to convince the field that Medistress’s test is a true game-changer: “[They need] a statistical study whereby people who are stressed are demonstrated to have this response or not, compared to a controlled group who are not stressed," Martin says. "Then you’d have to do a confirmatory study against other markers to show it was better.” Is there a killer experiment, a large, randomized study that proves the LCC test is the next big thing in stress diagnostics?

The evidence for a stress test

Medistress lists five publications on its site documenting the science behind their test. One of these studies was conducted in a small population of badgers. The others were, at least, observing human stress, but not using classical psychosocial stress tests. Instead they all revolve around the operation of various aspects of car equipment. This seems like a niche choice. Could it be because all four studies were sponsored by Jaguar Cars Limited? I’m preparing to ask Mian, when she brings it up herself. “We are collaborating with a number of different industries; perfume industry, lighting industry, car designers. It’s a case of a delicate balance of the pure science, which we love, obviously, producing papers, and maintaining a commercial advantage. They were the initial papers and obviously with the industries we were collaborating with, it’s not in their interest, necessarily, to have something published straight away, but we have lots of data in the pipeline. The studies need to be much bigger.”

There seems to be far more needing to be done before Medistress’s test could be considered robust enough to be mass marketed. Mian talks of benchmarking different stressors, looking at averages, age, sex, ethnic origins. It sounds like a big project, that is still largely unfinished. Mian says it’s a start, and that the field might take a while to come around to their test. “It’s like in the early days of glucose measurements or cholesterol measurements, where it was all, “Why do you want to measure cholesterol in the first place?” That was the thinking at the time.” Medistress’s ultimate aim is to make the test into a medical device. But, she says, “That takes numbers and money. There’s a way to go before it becomes a medical device.”

But therein lies the true problem of medical device development. Unlike pharmaceutical compounds, there’s no mandated requirement for these pieces of medical equipment to meet stringent regulatory standards or be assessed in gold-standard randomized controlled clinical trials before being marketed to consumers. The Medistress test, Mian reminds me, has already been rolled out to professional football clubs. A clinical rollout is on the horizon.

Consumers are expected to navigate a gauntlet of products that claim to have potential medical benefits. Does the LCC test outperform salivary cortisol tests? Can it put a number on stress? It might, and it could. But the evidence base to back that statement up doesn’t exist yet, and evidence is everything in science. If you don’t have the big studies, says Martin, “It’s like everyone advertising vitamins on the tube.” Whilst Medistress seem determined to produce that evidence, as the law stands there is no real requirement for other device developers to do so before putting their products on the market. Does that make you feel stressed? You might want to get that measured.