Researchers from the University of Oxford have been sharing their work with the public at the Royal Society Summer Science Exhibition (1-7 July 2019).
Breathe Oxford is a diverse group of neuroscientists, psychologists and clinicians studying the neuroscience of breathlessness. Their work shows that breathing is about more than just the lungs. In fact, the brain has a powerful influence on our experiences. This explains why some people still feel out of breath, even when they have been provided with medical care.
They explore how the brain controls our feelings of being out of breath using cutting-edge brain imaging technology. Understanding this control system could lead to revolutionary, personalised treatments for breathlessness.
Their exhibit at the Royal Society Summer Science Exhibition will bring the topic of ‘Breathing with your Brain’ to life, helping visitors to understand the how the brain controls our feelings of being out of breath.
Researcher and lead organiser Dr Sarah Finnegan said: 'Our research has shown the power of the brain-body interaction in influencing how we perceive our breathing.
'This is a relationship that we are only now just beginning to understand, and we hope eventually to develop target treatments for individuals, helping millions of people who are limited by their breathlessness.
'We are thrilled to be able to share some of the cutting-edge neuroscience that takes place at Oxford with visitors to the Royal Society, and hopefully we can inspire some future scientists!'
It is estimated that one in nine people experience some form of breathlessness, which is most common in conditions such as heart failure, lung disease, panic disorder and Parkinson’s. But there are also significant numbers of people who have unexplained breathlessness, which Breathe Oxford hypothesise might be driven by the networks in the brain.
Breathe Oxford has examined breathlessness in athletes, healthy individuals and people with chronic lung disease, seeking clues as to why some individuals become disabled by their breathlessness, while others, with the same lung function, live normal lives.
Visitors to the exhibit will be able to simulate living with chronic breathlessness by exercising on the ‘Steppatron’ with a straw in their mouth and a clip on their nose. They will also be able to witness the brain’s relationship with breathing on a 3D-printed scale model of a human torso with breathing lungs and LED lights which will highlight the neural pathways between the brain and the lungs. A specially commissioned animation will also reveal more about the background to the science.
Other stalls at the Summer Exhibition this year that involve Oxford research are:
Robots in the Danger Zone - Dr Maurice Fallon and others from the Department of Engineering Science's Oxford Robotics Institute will be demonstrating their research into robotics for inspection of dirty, dull and dangerous places, specifically with walking robots, such as their quadruped ANYmal. The stand is being presented by the ORCA Robotics Hub. See a video of the group's work here.
Living on the Moon! - an interactive experience highlighting the progress of lunar science since the Apollo 11 Moon landings 50 years ago. The exhibit illustrates the journey from Moon landing, to Lunar sample science, to the current generation of Moon rovers looking for water on the Moon, and provides a look forward to the next 50 years and a vision of a permanent human presence on the Moon. (Researcher: Dr Neil Bowles from the Department of Physics.)
In Your Element - 150 years of the periodic table: Investigating the elements that are essential to life. Biogeochemists from the Department of Earth Sciences' OceanBug team are presenting the journey of elements from the earth’s crust through the ocean and ultimately to feed life throughout Earth’s history. The exhibit is led by the University of Warwick.
Professor Kyle Pattinson from the Nuffield Department of Clinical Neurosciences explains how brain scanning could help doctors to personalise treatment for people with chronic breathing disorders.
Ever realised you’ve forgotten your inhaler and immediately felt your breathing become more difficult? Ever wanted to walk upstairs to get something, but the thought of becoming breathless has stopped you? You’re not alone! Our brains store a phenomenal amount of information about the world, based on our past experiences. This helps us to assess situations quickly and anticipate how our bodies will respond, such as when we will become breathless. These ideas are learned and updated constantly throughout our life, and quickly adapt if we develop something like a chronic breathing disorder.
These learned ideas, or ‘priors’, are thought to not only influence our actions (such as avoiding the stairs), but can materially alter the way we perceive a symptom like breathlessness. This theory is termed the ‘Bayesian brain hypothesis’, and it explains how our priors are compared to incoming sensory information in the brain, and both pieces of information are used to create our conscious perception.
Breathlessness can be experienced by people with a wide range of conditions: those with respiratory, cardiovascular or neuromuscular diseases, as well as some people with cancer or conditions such as panic disorder. Symptoms vary, but can include hunger for air, increased breathing effort, rapid breathing and chest tightness. These breathing symptoms have been known for a long time to be influenced by psychological states such as anxiety, but also by low mood, hormone status, gender, obesity and level of fitness. However, the influence of our previous experiences and learned associations has only more recently entered into the equation.
When we have repeated or frightening exposures to breathlessness, such as an asthma attack or severe breathlessness, our brain can quickly learn and update our priors. This system is designed to help us to avoid threats and keep us safe, but generating very strong expectations (priors) about breathlessness can then exacerbate our symptoms on future occasions. What’s more, certain personailty traits such as higher anxiety, or greater body awareness may also influence this system, making some people more susceptible to developing strong expectations about their breathlessness. Once these expectations are embedded, they can be difficult to ‘un-learn’ – the brain can easily catastrophise about the potential worst case scenario, such as having another asthma attack.
Scientists at the University of Oxford are at the cutting-edge of a continually improving brain imaging technology that is being used to shed some light on what exactly is happening when we anticipate and experience breathlessness (see some examples here and here). Over the last eight years our research team has been steadily chipping away at these brain mysteries, in the hope that their findings will lead to more carefully targeted and personalised treatments for people with chronic breathlessness.
In the Nuffield Department of Clinical Neurosciences, we are using high-field functional magnetic resonance imaging to look at the brain’s workings in incredible detail. This has enabled us to start uncovering the complex neural mechanisms involved in dealing with breathlessness.
The team have been exploring brain networks of breathlessness perception in people with chronic obstructive pulmonary disease (sometimes known as emphysema or bronchitis). The most successful currently available treatment for this condition is pulmonary rehabilitation: a programme of exercise, education, and support to help people with chronic breathing problems learn to breathe more easily again. This type of rehabilitation does not influence physical lung function. That means that it must instead work by helping people to change their learned priors, which make them overestimate the threat of breathlessness (we’re back to those stairs again).
Using functional magnetic resonance imaging, we have confirmed that the people who had benefitted from this rehabilitation programme had both higher initial brain activity and greater rehabilitation-induced changes in parts of the brain linked to body symptom evaluation and emotion – the insula and anterior cingulate cortex. They are now working towards studies that can help to increase these changes in breathlessness expectations, and to identify which people in particular are most amenable to the benefits of pulmonary rehabilitation. This was the focus of our recently published study, and will help to better understand how personalised therapy may be designed for each individual.
Treating the lungs AND the brain
Clearly there can’t be a ‘one size fits all’ approach to treating debilitating perceptions of breathlessness. Current attempts to treat the complexity of chronic breathing problems have been somewhat scattered, and we must now work towards understanding the individual ‘lived experience of breathlessness’ to lead us to more carefully nuanced interventions. The different factors at play in breathlessness all need to be targeted as part of a comprehensive treatment programme: What are the brain mechanisms at work in learned expectations? How do anxiety, stress and low mood impact on breathlessness? How closely are the observable physical symptoms actually linked to lung function? Imagine the discomfort that could be reduced and quality of life that could be improved, not to mention the money that could be saved (breathlessness due to COPD costs the NHS more than £4 billion per year), if breathlessness were approached in a more holistic way.
Pulmonary rehabilitation is just one in a raft of potential behavioural and drug therapies that could be used to ease the often crippling fear of breathlessness. Only 35% of people who are prescribed pulmonary rehabilitation actually take it up (for a variety of reasons, including not being able to get out to the venues where it is run); and only 60% of those who take it up actually benefit. Therefore, more research is needed to understand the specific mechanisms of breathlessness perception, and develop different treatments that would be suitable for different people. It is the details we are gleaning about the incredibly complex brain mechanisms of symptom perception that will equip us to design more successful treatment options for those whose symptoms do not match their lung function, to bring breathlessness back under control.
'It became very hard to breathe…but I just had to remember to keep calm and still.'
You might be thinking that this sounds like a hapless victim from one of the increasingly ubiquitous Nordic noir dramas taking over our TV screens – so you may be surprised to learn that it's the experience of one of the subjects in a recent University of Oxford study! Olivia Faull and colleagues from the Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (based in the Nuffield Department of Clinical Neurosciences) devised an experiment to look at what is happening in the brain when we might be about to become breathless. And the results have striking ramifications that will help us better understand – and may eventually lead to new treatments for –asthma and other chronic respiratory disorders.
Asthma costs the NHS £1bn a year, and the economy a further £2bn, due to time off sick (Asthma UK). It has long been suspected that some cases of asthma may be made worse by stress and worry. Sometimes breathlessness is out of proportion with what is actually happening physiologically in the lungs. In some people anxiety or worry can even bring on an asthma attack. Researchers in Oxford became interested in what is happening where in the brain when this reaction occurs.
A normal functioning PAG is clearly a good thing. We need to know when we are in danger, whether from something we could run away from – such as a hungry lion – or something we can't escape but could endure, such as becoming breathless. But what happens when things go wrong?
Scientists have known for some time that a tiny part of the brain called the periaqueductal gray (or PAG for short) plays an important role in how we perceive threat. Animal studies have revealed this bundle of cells in the brainstem to be the interface between automatic processes – such as breathing and heartbeat – and consciousness. The PAG is a group of cells ('grey matter') less than 5mm in diameter. Historically it has been very difficult to study in humans because it is so small and buried so deep. But the Oxford team managed to isolate the PAG using state-of-the-art magnetic resonance imaging (MRI) with super fine resolution.
Olivia and colleagues scanned a group of healthy volunteers in the ultra high-field 7 Tesla MRI scanner. The volunteers wore a breathing system similar to a snorkel, that could be altered to produce a resistance when subjects breathed in (like breathing through a very narrow straw). During the scan, subjects looked at a screen that showed three different symbols at various times. Eventually the subjects learnt the meaning of the symbols – for instance the triangle meant that nothing would happen and they could breathe normally, and the star meant that their air would definitely be restricted and they would become breathless.
Volunteers therefore learned when they may be about to find it difficult to breathe. Olivia was then able to look at what was happening in the PAG both when people thought they might become breathless, as well as during the difficult breathing itself. Olivia wanted to know what was happening when people anticipate breathlessness, to better understand the stress and anxiety that exacerbate it. The study found that averaged over all participants, a particular subdivision of the PAG (called the ventrolateral column) became active when people anticipated that they might become breathless, and another subdivision (called the lateral column) became active while they were actually breathless. This means that different subdivisions of cells within the PAG are doing different things throughout the course of breathlessness.
A normal functioning PAG is clearly a good thing. We need to know when we are in danger, whether from something we could run away from – such as a hungry lion – or something we can't escape but could endure, such as becoming breathless. But what happens when things go wrong? It could be that in people who are hyper-sensitive to threats, the function of the PAG or its communications to the rest of the brain are altered. For example, some people with asthma may get very stressed if they can't find their inhaler, and this may even bring on an attack: perhaps the PAG is telling them that they are in danger of becoming breathless (even if, physiologically, at that moment they are breathing normally).
Now that this ground-breaking MRI experiment has enabled researchers to know where and how to look at the PAG, they can carry out further studies to find out more about asthma and other conditions where the physiology doesn’t match the perception – such as chronic pain or panic disorders. Such work could lead to the development of new treatments, to see whether they have any effect on this tiny, hitherto inaccessible part of the brain. These could be new medicines or new behavioural interventions such as as mindfulness or cognitive behavioural therapy, or combinations of both.
The full article is published in the journal eLife.
A trek to Everest base camp is helping Oxford University researchers investigate the links between heart failure and the low oxygen levels suffered by patients with a range of serious diseases.
Dr Cameron Holloway, Dr Nick Knight and Dr Andrew Murray from Oxford University's Department of Physiology, Anatomy and Genetics and the Oxford Centre for Clinical Magnetic Resonance Research were among several hundred volunteer hikers walking to the foot of Mount Everest to study the body’s response to the thin air.
The team wanted to simulate the condition of hypoxia – when the body or part of the body is deprived of sufficient oxygen. Patients with pneumonia, smoking-related diseases and some forms of heart failure suffer hypoxia.
It was Dr Holloway’s first experience of such a severe climate and he was startled by some of the findings. Among the most significant were changes to blood oxygen levels and energy synthesis.
‘I was amazed at how low the arterial oxygen levels fell in our blood,’ Dr Holloway said. ‘Saturation was in the 70 and 80 per cents during simple exercise at altitude when normally you would get worried if it dropped from normal at 98 per cent to 93 per cent.'
‘Usually that level isn’t compatible with life. If someone came in with levels that low we would rush them into intensive care.’
Another ‘huge shock’ was the 25 per cent drop in the cardiac phosocreatine/adenosine-triphosphate (PCr/ATP) ratio – a measure of the amount of energy available to the heart.
‘People with heart disease often have this ratio impaired. We experienced similar impairment, even reaching the levels of heart failure. We don’t know if it was due to adaptation to low oxygen or showed that our hearts were not coping.’
Dr Holloway’s study of 14 of the volunteers ran alongside a larger research project by Caudwell Xtreme Everest, part of the UCL Centre for Altitude, Space and Extreme environment medicine (CASE). The findings were published recently in The FASEB Journal.
Before leaving for Nepal, participants underwent wide-ranging tests, including assessments of heart, vascular, brain and exercise performance. Blood and other tests were carried out at several points during the 11-day ascent from Lukla’s Tenzing-Hilary Airport at 2,850m to 5,360m base camp.
The initial tests, which took place in Oxford, were repeated within 48 hours of the group’s return from Everest and carried out again six months after the trek ended. By then all changes to the heart and energy levels had returned to the pre-trek baseline.
Dr Holloway suspects that the findings witnessed during the Everest trip may have parallels with the cause of some forms of heart failure:
‘At base camp the symptoms we had, including breathlessness and exercise intolerance, were similar to those experienced by heart failure patients.'
‘Even a small amount of exercise was really difficult. That’s what people have to deal with when they have pneumonia or other diseases.’
Dr Holloway hopes the lessons from the study will improve care for critically ill adults and children, and even babies in incubators.
‘Now we are looking at heart failure patients to see if low oxygen is the problem and if changing oxygen pathways could improve the lives of heart failure patients. We also need to work out what is behind individual differences in the changes people experience as a result of low oxygen.’