Breakthrough, Spring 2024

NEWS OF THE ME RESEARCH YOU ARE HELPING TO FUND

breakthrough 39 / SPRING 2024

BRAIN IMAGING UK RESEARCHERS NANOELECTRONICS VISUAL PROCESSING RESEARCH ROUNDUP FUNDRAISING 1

CONTENTS 4

ONLY CONNECT

18 INTERVIEW

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MAKING WAVES

22 NEW SHOOTS

Brain abnormalities detected by advanced imaging

Gemma Samms at Edinburgh University talks about her PhD

UK scientists pushing boundaries and spearheading a new era

New studies on nanoelectronics and visual sensory processing

12 RESEARCH BITES

26 COUNTING THE COST

14 SAME DIFFERENCE

30 FUNDRAISING

Brief summaries of newly published studies

Experiences of post-exertional malaise

Does ME/CFS present differently in men and women?

Marathons, hill-climbing, Walk for ME, and a pot of tea

Breakthrough magazine is published by ME RESEARCH UK, a Scottish Charitable Incorporated Organisation with the principal aim of commissioning and funding highquality scientific (biomedical) investigation into the causes, consequences and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We INFLUENCE, INFORM and INVEST in ME research globally by identifying potentially important areas for future biomedical research, and by producing high quality professional reviews and reports. Breakthrough is an open-access publication and, apart from images and illustrations, the content may be reproduced free of charge, subject to the terms and conditions found at meres.uk/bt-terms. © ME Research UK, 2024 – SCIO Charity No. SC036942, The Gateway, North Methven Street, Perth, PH1 5PP, UK, Tel: 01738 451234, Email: contact@meresearch.org.uk, Web: www.meresearch.org.uk.

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EDITORIAL Jonathan Davies Chair, Board of Trustees Welcome to our Spring 2024 edition of Breakthrough magazine. I’m going to keep my editorial short for this issue and let the content do the talking.

Due to your support, we have continued to be able to fund research that we hope and believe has the potential to make a positive difference to everyone who is affected by the terrible disease that is ME. A further two newly funded research projects are highlighted in this issue, and more are in the pipeline.

We are really encouraged by the growing interest that researchers around the world are showing in ME; indeed, our most recent funding call yielded twenty-four applications – the highest ever. Our standards remain high, and only those applications that meet our rigorous criteria (including 3

external peer review) are ultimately considered for funding.

We have been very fortunate over the past few years to have had the capacity to fund all research that has met our exacting standards, but are now entering a phase where our ability to fund new research will become constrained by the available resources.

We want to do more, and are entirely reliant on the generosity of all those who raise funds or donate money to allow us to invest in highquality biomedical research. You won’t be surprised, therefore, to find a fundraising leaflet included with this edition!

Enough from me. I hope you enjoy this issue, and thank you once again for your support and trust to allow us to do what we do on your behalf.

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ONLY CONNECT Dr Leighton Barnden and his team at Griffith University have recently published more findings from their ME Research UKfunded study using advanced imaging techniques to look at brain abnormalities in people with ME/CFS.

Many of the symptoms experienced by people with ME/CFS – including problems with concentration, memory, vision and heart-rate control – suggest abnormalities in the brain and nervous system. Indeed, research has demonstrated changes in brain structure in ME/CFS patients, as well as impairments in the connectivity between different regions of the brain, and disruption to the autonomic nervous system (which regulates many body functions).

The aim of Dr Barnden’s study (funded by ME Research UK with the financial support of the Fred and Joan Davies Bequest) was to build on previous findings by using a stronger 75

Tesla MRI scanner – which provides increased sensitivity and resolution – and to uncover more information about brain abnormalities in people with ME/CFS. Their first results identified specific areas of the brainstem that were increased in volume in people with ME/CFS (and in those with long COVID), compared with healthy control subjects. Importantly, these differences in volume correlated with measures of pain and breathing difficulty.

The brainstem is responsible for many of the vital functions of life, such as breathing, consciousness, blood pressure, heart rate and sleep.

Dr Jiasheng Su, Dr Leighton Barnden & Dr Kiran Thapaliya

The team’s new findings (recently published in the journal Frontiers in Neuroscience) look at communication between different areas of the brain (functional connectivity) in people with ME/CFS, and how this is linked to other measures including duration of illness and memory.

in processing pain, emotion and motivation.

3. The cerebellum is involved in maintaining balance and coordinating voluntary movements.

4. The pontine nuclei allow us to perform skilled movement by linking the motor cortex and cerebellum.

Brain networks A brain network is a collection of areas of the brain that work together to perform a function. Connections within and between these networks are therefore crucial. In this study, the researchers looked at four areas of the brain:

MRI experiments MRI scans of the brain were obtained in 31 people with ME/CFS and in 15 healthy control subjects while they were undergoing a sequence of tests assessing concentration and attention difficulties (known as the Stroop Colour Word Test). Information on respiratory rate was also collected during the scans, and questionnaires were used to collect information from participants about their duration of disease, quality of life, ability to carry out tasks of daily living, and the characteristics and severity of ME/CFS symptoms.

1. The default mode network is active when you are daydreaming or letting your mind wander while you are at rest.

2. The salience network is thought to be involved in switching between different brain networks, as well as 6

Functional connectivity In general, participants with ME/CFS had impaired functional connectivity compared with that in the healthy controls. These abnormalities affected areas of the brain involved in movement, cognitive function, sensory processing, the sleep–wakefulness cycle, self-awareness and autonomic responses (such as blood pressure and temperature regulation). In addition, functional connectivity in people with ME/CFS was associated with respiration, length of illness, fatigue severity, pain intensity and memory scores.

point in time, rather than looking at changes over time. Most clinical measures were self-reported, and therefore not only subjective but also potentially dependent on how participants were feeling at the time of the study. While the sample size was relatively small, it was sufficient to detect significant differences between the groups.

Conclusion Dr Barnden and his team say that their findings highlight the involvement of the brainstem and cerebellum in the mechanisms of ME/CFS. They also suggest that their results indicate that ME/CFS may be associated with ongoing changes in the brain. For this reason, research that follows individuals over time is needed. We look forward to seeing more results from this research, and how Dr Barnden and his team will build on these findings in their ongoing studies.

Strengths and limitations This is the first study to examine differences in brain functional connectivity between people with ME/CFS and healthy controls using such a detailed type of MRI scan. However, it was a cross-sectional study, and therefore only provides information at a single 7

MAKING WAVES Cort Johnson from healthrising.org looks at some of the UK scientists pushing boundaries and spearheading a new era in ME/CFS research.

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For years, cognitive behavioural therapy (CBT) and graded exercise therapy (GET) were crushing the competition. Plentiful funding from government sources gave them extraordinary prominence in the small ME/CFS field.

A survey of ME/CFS treatment trials from 2013 to 2015 found that 69% of the citations referred to behavioural, exercise or pacing studies. The real news, though, involved study size. The average study size of the top two CBT/GET practitioners (Knoop and Crawley) was a whopping 367 participants. Compare that with six ME/CFS drug trials, only two of which had more thirty participants, and two of which had fewer than five. The nonbehavioural approach to ME/CFS didn’t have a chance.

With thirteen original CBT studies published between 2018 and 2020

(five by UK researchers), the CBT/GET grip on ME/CFS appeared strong. But then something changed. Whether it was the controversy from the PACE trial or simply the mediocre results, the CBT/GET field appears to have mostly collapsed. During 2021 only four original CBT studies were published – and only one by UK researchers. The decades-long CBT/GET boom that so dominated the ME/CFS field appears to be over.

Now UK researchers are making different kinds of waves. A review of the UK boom in ME/CFS pathophysiological work that’s taking place has to start to with genetics, and any genetics overview has to begin with the massive DecodeME genetic study, led by Chris Ponting at the University of Edinburgh [see our interview with Gemma Samms on page 18]. Its scope is unprecedented, involving some 25,000 genetic samples. This one-of-akind study – which received funding from both UK and US sources – should help us start to answer the question on so many minds: “Why did I come down with ME/CFS when so many others didn’t?”

In Oxford, Steven Gardner at PrecisionLife used his unique combinatorial analytics approach to pluck out genetic mutations affecting the stress response and/or infection, mitochondrial dysfunction, sleep disturbance and autoimmunity that appears to contribute to ME/CFS. That was an encouraging start given he’ll be applying the same approach to a much, much larger set of DecodeME samples.

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Prof. Chris Ponting, Edinburgh

Gardner’s recent long-COVID/ME study uncovered something potentially crucial when it found similar gene abnormalities in the “fatigue dominant” (ME-like) long-COVID group and ME/CFS patients. Once again, Gardner plucked out genes involved in areas that make sense in these functionally impairing illnesses, such as mitochondrial function and energy production. As Gardner uncovers genetic issues, he’s also searching for possible drug targets so that if/when his findings are validated he’ll have options at the ready.

As Ponting and Gardner dig into the genetics of ME/CFS, Geraldine Cambridge’s 2024 study at University College London took the energy production problems in ME/CFS to a new level when she found they were also present in B-cells. Not only did

the B-cells of ME/CFS have a significantly reduced mitochondrial mass, but they were preferentially using amino acids (an inefficient and dirty energy source) to power them. Since immune cells consume vast amounts of energy when activated, the study could help explain the immune problems found in ME/CFS. [Cambridge is also exploring the immune response in an ME Research UK-funded study with Eliana Lacerda from the London School of Hygiene & Tropical Medicine.]

Karl Morten at the University of Oxford made some big waves last year when his Raman spectroscopy study suggested that a long soughtafter blood test for ME/CFS may be possible. The remarkable ease with which Morten was able to accurately differentiate ME/CFS, multiple sclerosis and healthy controls from each other was promising. A blood test would legitimise ME/CFS as a biological disorder, make diagnosing it a breeze, embed the disease in the medical system as never before, give us clues as to what’s going on, and perhaps even provide a biomarker that drug companies can use to assess the effectiveness of their drugs. In other words, it would be a big deal indeed.

And that makes the next study all the more tantalising. This research bridges the Atlantic and brings together two UK funders: ME Research UK and the ME Association. The two organisations have banded together to fund a study that grew out of Ron Davis’s promising 2019 nanoneedle 10

Prof. Robert Dorey, Surrey

findings. Employing technology never used before in ME/CFS, Rahim Esfandypour and Ron Davis at Stanford University found a distinct electrical signature in ME/CFS patients. Their approach was particularly exciting because it fulfilled a sometimes daunting requirement for a usable diagnostic test: it was cheap and easy to produce.

With the creator of the nanoneedle unable to continue the work, the Stanford project stalled, but five UK researchers – Robert Dorey, Fatima Labeed and Michael Hughes at the University of Surrey, and Eliana Lacerda and Caroline Kingdon from the London School of Hygiene & Tropical Medicine – knew a good thing when they saw it and took up the challenge.

When their early data replicated the Davis paper’s findings, representing

they thought “a clear marker of pathology”, they applied for and received a grant. Not only will the larger study attempt to replicate Davis’s findings, but it will probe deeper and potentially give us clues to the cause of ME/CFS [see page 23 for more details]. Which makes one wonder – could two biomarkers come out of the UK over the next couple of years?

ME Research UK is helping to keep the momentum alive by funding a series of UK-based studies exploring “jumping genes” (King’s College London), visual functioning changes (Leicester University) [see page 24], temporal mandibular joint dysfunction, (Newcastle University) and sensory processing and cognition (Oxford Brookes University).

With the CBT/GET era apparently receding into the fog of history, UK researchers are pushing the boundaries in other areas. From the huge DecodeME genetic study, to finding similar genetic alterations in long COVID and ME/CFS, to uncovering energy disruptions in immune cells, to searching for the elusive biomarkers for which this field has been clamouring for decades, ME/CFS research in the UK is making waves indeed.

To read more about the ME Research UK-funded studies referred to in this article, please visit our website at meresearch.org.uk.

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A blood test for ME/CFS may be possible… could two biomarkers come out of the UK over the next couple of years?

RESEARCH BITES

IMMUNE SUBGROUPS

CELL METABOLISM

Rohrhofer, J Clin Med, 2024

Armstrong, Front Immunol, 2024

Researchers have identified a potential link between compromised immune responses during acute viral infections and the development of post-infectious syndromes. ME/CFS patients with immunodeficiencies had reduced levels of a protein suggestive of immune dysregulation, while those without immunodeficiencies had elevated levels of a bacterial component indicating leakage of gut contents into the bloodstream, potentially contributing to chronic low-grade inflammation.

Immune status could thus be used to distinguish ME/CFS subgroups.

Anormalities in the production of energy (metabolism) in the body have consistently been linked with ME/CFS, but less is known about metabolism specifically in cells of the immune system. This small study found that immune cells from people with ME/CFS had fewer energy-producing mitochondria than those from healthy control subjects, and those mitochondria present appeared to respond less efficiently when placed under conditions that required rapid changes in energy production – further evidence of altered energy metabolism in ME/CFS.

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LONELINESS

ME/CFS & LONG COVID

Wotherspoon, Sociol Health Illn, 2023

Jason, Neurol Int, 2023

A recent study highlights the fact that social isolation can be an unavoidable consequence of living with ME/CFS. Interviews with 42 people with ME identified three key themes: living with ME places restrictions on time and people’s ability to occupy public spaces; the disease creates a communication distance between participants and their peers; scepticism and disbelief surrounding ME leads to strain on, and loss of, relationships. Interventions to support people with ME should consider both the social needs and health challenges of individuals.

Long COVID and ME/CFS have overlapping symptoms, yet many studies overlook the proportion of individuals with long COVID who meet ME/CFS criteria. Previous research has been limited by small sample sizes and a lack of measures of post-exertional malaise. Improving on these aspects and recruiting 465 participants, Dr Jason’s study found that 58% of their long COVID patients met ME/CFS criteria. Symptom questionnaires could aid in determining the proportion of participants meeting ME/CFS criteria in future long COVID studies.

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SAME DIFFERENCE Much is made of the difference in ME/CFS prevalence between men and women, but are there are also differences in how the disease presents in each sex, and in the underlying biological abnormalities? We look at what the research says.

Even in the absence of disease, there are differences between males and females in the way our bodies work.

These differences are hugely important in explaining the variations in susceptibility to disease, and the disparities in responses to treatment.

The sex hormones, oestrogen and testosterone, have different impacts on immune responses. Consequently, males are more susceptible to infections, while females are more susceptible to the development of autoimmune conditions. There is also evidence of a sex difference in the function of the autonomic nervous system. Men have a more active sympathetic nervous system (responsible for the 15

fight and flight response), while women have a more active parasympathetic system (rest and digest response).

Since abnormalities in the immune and autonomic nervous systems have been linked with ME/CFS, these differences in susceptibility may play a role in explaining the variations in prevalence between men and women.

Age of onset Men tend to develop ME/CFS earlier in life than women, and this may partly be explained by differences in the periods of significant hormonal change in each sex. The age of ME/CFS onset for males is most commonly between 10 and 19 years, which includes pu-

berty. Evidence suggests that women have two peaks in onset: between 10 and 19 years, and between the ages of 30 and 39 years, which often includes pregnancy and the postpartum period.

Not only do these age ranges include periods of significant hormonal change, but they also may correspond to times of increased susceptibility to infection, which in turn increases the risk of developing ME/CFS. Despite this, little research has directly considered the biological mechanisms that might be involved.

Symptoms There is conflicting evidence about whether there are any differences in the symptoms experienced by men and women with ME/CFS. While one small study from 1999 did not detect any difference, studies with larger samples find that men with ME/CFS appear to report lower levels of certain symptoms compared with women. For example, in one study men reported lower levels of morning stiffness, pain, dizziness and sexual dysfunction. More recently, early findings from the DecodeME study (14,257 female and 2,817 male participants) also indicate that men report fewer symptoms (although men may be under-represented in these preliminary results).

Another consideration is whether differences might be due in part to societal pressure on men to be more masculine. Men with ME/CFS may therefore delay seeking medical advice or “battle through” their symptoms.

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Response to exercise Do men and women with ME/CFS differ in how they respond to exercise?

One study looked at immune markers in the blood and how they are affected by exercise, and reported a difference between males and females in the way genes relating to immune function were expressed (i.e. how their information was used to make proteins) during and after a maximal exercise test.

Another, more recent study looked at the longer-term effects of exercise in people with ME/CFS. Levels of fatigue were slightly lower in men than in women, but they were able to do similar amounts of activity during the exercise test, and there was little difference in how quickly they recovered in the week or so afterwards.

A more intensive exercise test might be needed to detect differences (although the ethics of this are very complex), as well as larger numbers of participants than the 30 or so who took part in these studies.

Autonomic function The autonomic nervous system is responsible for controlling processes that occur without our conscious control, such as heart rate. One way of assessing autonomic function is to measure heart rate variability, with a higher variability indicating better health.

A study from 2021, in 77 people who met the Fukuda criteria for “CFS”, found that, for both sexes, a lower heart rate variability was associated with a greater severity of disease. Men generally had a higher heart rate vari-

ability and lower heart rate than women, and higher levels of anxiety and depression. The authors suggest that these results indicate a higher activation of the parasympathetic nervous system in healthy women than in healthy men, but that activation in women with ME/CFS is reduced to a level similar to that seen in healthy men. Exactly what this means – particularly for men – remains unclear.

Fat molecule levels Fat molecules – called lipids – are important in both immune and inflammatory pathways in the body, and also in the function of the mitochondria (which produce energy). All of these activities have been implicated in ME/CFS, so differences in lipid levels between men and women with the disease may be significant.

In one study, men with ME/CFS had increased levels of a lipid thought to be involved in the immune re17

sponse, while the same lipid was decreased in women with the disease.

There were also differences in other lipids involved in inflammation and susceptibility to autoimmune and chronic inflammatory diseases.

This study was carried out in a relatively small number of people, and so more research is needed, both to explore what these differences are with larger groups of people, and to better understand exactly what roles these lipids might play in ME/CFS. Conclusions There is currently only limited evidence on the physiological and pathological differences between men and women with ME/CFS. However, the existing research does suggest that there are indeed differences, and that more research is needed to understand better what these are, and what they mean for the diagnosis and treatment of ME/CFS.

INTERVIEW

GEMMA SAMMS Gemma works with Chris Ponting at the University of Edinburgh. Her project was the first PhD-level research to be funded by ME Research UK, and involves investigating the genetic risk factors for ME/CFS using data from DecodeME.

Could you tell us a bit about yourself?

I am from London but moved to Edinburgh to study for my PhD. I was awarded my undergraduate degree, a BSc in Psychology, by the Open University, but I gravitated towards the more biological aspects of this topic, and moved into the field of neuroscience – the scientific study of the brain, spinal cord and nervous system – for my master’s degree at Kings College London.

During my master’s degree, I specialised in diseases which cause gradual damage to the nerve cells in the brain (neurodegenerative disease), such as multiple sclerosis and Parkinson’s disease, but completed my 18

dissertation on the genetic risk factors for ME/CFS – a disease that evidence suggests does not seem to be neurodegenerative.

What is your PhD project about?

The main aim of my PhD is to uncover the genetic risk factors for ME/CFS. To do this, I am using two cohorts (groups of people with shared characteristics): the UK Biobank and DecodeME. The UK Biobank is a medical data resource of around half a million people, of whom approximately 5,000 either self-report and/or have an electronic health record for ME/CFS. DecodeME data encompasses over 20,000 individuals who self-report that

they have a diagnosis of ME/CFS. Using information from the individuals in these cohorts, the team with whom I work will perform a genome-wide association study (GWAS), an approach which looks at complete sets of DNA – known as genomes – from large numbers of people. It is hoped that through this GWAS we will be able to identify DNA variants that make some individuals more likely to develop ME/CFS. From here, we can do further work to understand the mechanisms behind ME/CFS better; for example, which cell types or biological processes are involved in ME/CFS. Such findings would have the potential to fuel further research aimed at targeting these processes.

I have also conducted work on the number of people (prevalence) with ME/CFS using data from NHS DigiTrials, which covers electronic health records of individuals in England. I have looked at the prevalence of ME/CFS across different sexes, ages, ethnicities and measures of deprivation.

What inspired your interest in ME/CFS? I was diagnosed with ME/CFS aged 18, following a viral illness, and it completely turned my life upside down. I was extremely unwell for two years and life stood still. Fortunately, my health improved slightly in the years that followed but I continue to struggle with the disease daily. Over the years I have met many others who 19

are also affected by ME/CFS, and see the devastating impact it has on their lives. The lack of understanding surrounding the disease and the absence of treatment options motivates me to study the condition.

ME/CFS is unfortunately very underresearched, so there is a lot to learn.

What does a typical working day look like for you?

My work is computational, and the data I use is securely accessed through the different cohorts I am using. A typical day is spent in front of the computer or attending meetings. I have the pleasure of working alongside others involved in ME/CFS research – including the DecodeME team – and other members of my supervisor’s lab. It is lovely to be surrounded by people who are understanding of the condition and who are also motivated to study it.

Where you are doing you PhD? I am based at the Institute of Genetics and Cancer, which is part of the University of Edinburgh, and I have the pleasure of working alongside experts in their fields (statistical geneticists, programmers, etc.). This means that there is always someone to go to for advice. The University and my supervisor are very supportive of my condition, which makes a huge difference. The University of Edinburgh is also home to the DecodeME study, and the momentum behind the study is really inspiring and great to be a part of.

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It is exciting to be able to work with DecodeME as this is the world’s largest cohort of people with ME/CFS

Why did you choose genetic risk factors as the focus of your work?

Very little is currently known about the genetic risk factors of ME/CFS. The cohorts used in current research are often small (fewer than 2,000 participants) and this does not provide adequate statistical power – the ability of a statistical test to detect a significant difference or to detect true genetic associations. It is exciting to be able to work with DecodeME as this is the world’s largest cohort of people with ME/CFS, and it is hoped we can identify DNA variants associated with the disease. A further reason I am interested in genetics is because DNA does not normally change as a result of disease (except in cancer), so anything we identify is likely causally involved in ME/CFS, rather than a consequence of the disease, which may have implications for treatment.

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What is the most challenging aspect of ME/CFS research?

It is challenging because we know so little as it is under-researched. It is difficult to know where to start, but this is also why genetics is a good starting point. Genetics research does not require a hypothesis of a particular gene which may be involved in a disease; rather, it enables researchers to consider all aspects, identifying information which can drive research forwards.

What have you have enjoyed most so far, and what has been the most challenging part of your PhD? I have really enjoyed working alongside the DecodeME team. It is a huge project and everyone involved is highly motivated to make a difference.

Learning how to perform the analyses – which often involves programming and learning how to use new software

– can be challenging. But I would say the most challenging part is dealing with the stigma associated with ME/CFS because it is so personal to me.

Where do you see yourself five years after completing your PhD? Thanks to the opportunity afforded by ME Research UK, I would like to stay in academia and pursue post-doctoral research on ME/CFS – hopefully following on from the findings of my PhD. What advice you would offer bioscience students who are considering a PhD in ME/CFS? Virtually everyone I know working in the field of ME/CFS has a personal connection to the condition – they either have ME/CFS themselves or know someone who does. It would be great for others to be motivated to study ME/CFS too. I would advise anyone to undertake Patient Public Involvement to gain insight into important considerations, to improve their research, and to make it more translatable.

One of the best ways to quickly and easily raise funds for ME Research UK, and support more projects like Gemma’s, is via a birthday fundraiser on Facebook.

Visit bit.ly/36d6o3h for details.

You can ask friends and family to help celebrate your birthday by donating to a cause that’s close to you, while at the same time raising awareness of ME/CFS.

“Thank you so much to the supporters of ME Research UK, whose donations make this PhD-level research project and the post I enjoy so much possible.

Thank you also to ME Research UK for funding the research.” Gemma

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There are no fees for donations made to charities on Facebook, so all the money goes directly to the cause you are supporting.

NEW SHOOTS Over the last few months, ME Research UK has announced funding for two exciting new projects looking at contrasting aspects of ME/CFS

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Characterising the electrical properties of white blood cells Lead researcher: Prof. Robert Dorey, University of Surrey Background In 2019, Prof. Ron Davis from Stanford University in the USA reported that his team had developed a nanoelectronics test which had been used to detect a difference in the impedance of white blood cells between people with ME/CFS and healthy control subjects.

White blood cells are part of the body’s immune system and play an essential role in fighting off infections and disease. Impedance is a measure of a cell’s electrical characteristics – in this case, how much the cell opposes (or impedes) the passage of an electric current.

The Stanford group felt their findings could represent a diagnostic marker for ME/CFS, but since then there hasn’t been any further research in this area. However, Prof. Robert Dorey, Dr Fatima Labeed and colleagues at the University of Surrey plan to continue this avenue of research in a new study jointly funded by ME Research UK and the ME Association.

The Surrey team has already used a more robust approach to identify statistically significant differences between the electrical properties of blood from people with ME/CFS compared with healthy and multiple sclerosis (MS) controls (using samples from the UK ME/CFS Biobank).

Their preliminary work suggests that the 2019 results from Stanford are repeatable and can be explored in more detail. Furthermore, they believe 23

Prof. Robert Dorey

the findings have the potential to be used as a routine diagnostic test.

Study aims In this newly funded study, the researchers will apply their improved approach to measure white blood cell impedance in a larger cohort of patients, including those with mild, moderate and severe ME/CFS, as well as healthy and MS controls. Their hope is that the results will lead towards the development of a reliable, repeatable and low-cost diagnostic tool using the electrical signature from a simple blood test.

They also aim to identify the cellular changes that have occurred in order to create the electrical biomarker,

and in so doing identify new avenues for potential treatments.

Potential benefits The findings of this study may lead to the development of a novel diagnostic tool for ME/CFS using a simple blood test. Such a biomarker is one of the holy grails of ME/CFS research, and would represent a great leap forward in the diagnosis of the disease. The results may also lead to a better understanding of some of the cellular changes occurring in people with ME/CFS. ME Research UK is delighted to be collaborating with the ME Association in part-funding this new research.

Dr Fatima Labeed

The impact of ME/CFS on visual sensory processing Lead researcher: Dr Doug Barrett, University of Leicester Background People with ME/CFS often report problems with their vision, including visual overload, difficulties filtering visual information (also called selective attention), and fatigue during visual search. These problems come under the heading of cognitive deficits because they involve the brain and nervous system, and they are relatively common and have a debilitating effect on individuals’ quality of life.

Despite this, very little is known about the way ME/CFS impacts the ability to perceive and prioritise objects and events. It has also proved challenging to identify reliable markers of these visual deficits, perhaps be24

cause individuals’ symptoms vary so widely, or the lack of standardised neuropsychological tests.

Over the last ten years or so, a team led by Dr Claire Hutchinson at the School of Psychology and Vision Sciences at the University of Leicester have explored some of the vision-related problems associated with ME/CFS, supported in part by grants from ME Research UK. Study aims This new PhD-level project is led by Dr Doug Barrett, and the research will be conducted by PhD student, Anosha Atlaf. The study aims to address three research questions: (1) How does

Dr Doug Barrett

Anosha Atlaf

ME/CFS affect visual sensory processing? (2) How does ME/CFS affect individuals’ ability to prioritise relevant over irrelevant visual information (selective attention)? (3) Can carefully controlled tests of selective attention during visual search provide a diagnostic marker of ME/CFS? In the first stage of the project, 50 patients with ME/CFS and 50 healthy control subjects will undergo visual stimulus tests to measure their responses to sensory inputs. Further tests will assess their ability to recognise targets from within a group of objects, and will also measure behavioural and eye movement markers, and electrical activity in the brain. The researchers’ hypothesis is that reduced nerve responses will make patients slower and less accurate in responding to visual stimuli.

The findings will be used to develop online tests that can be applied to a large sample of ME/CFS patients, to identify ME/CFS-related changes in the speed and accuracy of target detection, and the associations between these objective results and subjective reports of symptom severity and fatigue.

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Potential benefits The results of this study will provide detailed information about the way ME/CFS affects the sensory and cognitive components of an everyday visual task. The researchers intend to make their findings freely available to patients via a dedicated website.

Furthermore, tests of selective attention may help provide potential, noninvasive diagnostic markers of ME/CFS and its severity.

COUNTING THE COST A study from 2020 attempted to capture individuals’ experiences of post-exertional malaise, both in daily life and following exercise testing.

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Post-exertional malaise (PEM), the cardinal feature of ME/CFS, is profoundly debilitating and often unpredictable, significantly impacting the lives of those affected. Existing definitions of PEM, such as in the NICE 2021 guideline, primarily focus on the worsening of symptoms within a specified timeframe following minimal physical or mental exertion, lasting for days, weeks or longer. However, these clinical definitions lack the depth to truly grasp the nuanced experiences of individuals living with PEM. Quantitative research, which involves the analysis of numerical data, can provide useful information about the underlying mechanisms of PEM, and is crucial in advancing our understanding of ME/CFS. But it does not fully capture a person’s experience of PEM, and qualitative research, in-

volving exploration of subjective experiences, should therefore not be overlooked.

Experiences of PEM In a paper published in Frontiers in Neurology in 2020, Barbara Stussman and colleagues explored the experiences of PEM in 43 people who reported having ME/CFS. Not only did this study provide rich descriptions of what it is like to experience PEM from an individual perspective, it also allowed a valuable comparison between day-today PEM and PEM following cardiopulmonary exercise testing (CPET).

Nine focus groups – each comprising four to seven people – were set up to allow participants to discuss their experiences of PEM. Five of these groups were restricted to individuals who had undergone CPET. The researchers allowed themes to emerge organically from the data collected, rather than imposing pre-existing theories onto the study, and a number of overarching themes were identified.

dysfunction and a myriad of other symptoms. Emotional stress emerged as another significant trigger of PEM, including that related to social interactions or unexpected visitors. In all cases, the symptoms were worse than what a healthy individual might expect to experience following similar physical or cognitive activities.

Triggers PEM was triggered by three broad categories of events: physical, cognitive and emotional. Even seemingly minimal physical activities could trigger the condition. More obvious examples included riding a bike and attending a concert, but people also reported vacation, gentle yoga, walking and driving as potential triggers. Everyday cognitive activities such as reading or engaging in conversations could also induce worsening fatigue, cognitive

Impact of baseline symptoms Participants emphasised the significance of understanding their baseline symptoms, as exertion during heightened symptom periods could compound the effects of PEM and amplify their symptoms. This compounding effect is of particular concern in relation to CPET, where travel to the testing site may itself trigger PEM. This highlights the importance of an accurate baseline assessment before CPET.

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I can go grocery shopping 1 day and I am completely spent for 2 or 3 days

Symptom range A wide range of symptoms were reported by participants, although three core symptoms were consistently noted: exhaustion, cognitive difficulties and neuromuscular complaints.

Other manifestations included sensory sensitivity, feelings of despair, difficulty sleeping, headaches, nausea and sore throat, but PEM symptoms were specific to each individual.

The exhaustion experienced during PEM surpassed typical post-activity fatigue, and resembled more the prolonged fatigue seen in flu. Cognitive difficulties were characterised by issues with thinking, decision-making and word recall, while neuromuscular complaints included muscle pain and weakness, affecting normal, daily tasks.

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Complete rest is really the only thing that can facilitate a recovery for me

Onset of PEM While there appeared to be few differences between the range of symptoms experienced due to daily PEM and those occurring following CPET, the PEM that followed exercise testing was reported to be of more immediate onset and of longer duration. For daily PEM, most participants experienced a delayed onset of symptoms, with nearly half reporting symptoms beginning 12 to 48 hours after exertion. In contrast, more than three-quarters of participants reported that the onset of symptoms following CPET was immediate or within several hours. Furthermore, the peak intensity of PEM symptoms occurred earlier (at around 24 hours) after CPET. Symptom relief Virtually every participant said that complete rest was necessary to reduce PEM symptoms. Most agreed that this involved lying down with minimal sensory input. Importantly, many participants stressed that complete rest was not merely a strategic choice, but rather a “demand from the body”.

Avoiding PEM Participants considered planning and moderation of energy expenditure (pacing) as essential. Helpful strategies included resting more than needed and calendar management (shifting activities around depending on the amount of energy required). However, pacing was not without its consequences, as one participant described missing major life events such as weddings.

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Uncertainty and despair The varying duration of PEM contributed to an overall feeling of uncertainty, while other contributing factors included concerns about whether they would return to their baseline, and uncertainty about the triggers of PEM.

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Conclusions Limitations of this study included unclear patient selection, the lack of a criteria-based diagnosis, and a reliance on retrospective recall. Despite these shortcomings, this qualitative study stands as a crucial contribution to ME/CFS research, offering deeper insights into the nuanced experience of PEM in daily life and following CPET, and underscoring the unique experience of PEM for each individual.

It seems unpredictable…

I could do the same thing two different days, and one day it affects me a lot more than the other

PLEASE VOTE If you have a moment, please nominate ME Research UK to receive one of the Benefact Group’s £1,000 draws. You only have to vote once, and we will be entered into all the remaining draws for 2024. And it costs you nothing. Place your vote at movementforgood.com/#nominateACharity.

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FUNDRAISING

THREE PEAKS CHALLENGE

BRIGHTON MARATHON

On 20 June 2024, the longest day of the year, Simon Twomey will be attempting to complete the three peaks challenge, raising funds for ME Research UK. This challenge involves climbing each of the highest peaks of Scotland, England and Wales (Ben Nevis, Scaffel Pike and Yr Wyddfa), with a total walking distance of 23 miles and a total ascent of 10,052 feet.

This will be an impressive feat, all the more remarkable for being completed in one day. So, many thanks to Simon, and good luck for the challenge.

After months of umming and ahhing, Matt Nisbet finally took the plunge and entered this year’s Brighton Marathon, which is being held on 7 April 2024. Matt will be running in support of our work. “ME/CFS is a cause close to my heart. Research in this area of health sadly doesn't receive the same recognition or funding as other areas.”

This is the UK’s third largest marathon, and the course starts in the heart of the city and finishes, in style, on Brighton’s world-famous seafront.

Good luck, Matt, and many thanks for your support.

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WALK FOR ME

BLUE SUNDAY

ME Research UK is grateful to be chosen once more as one of the featured charities for Walk for ME. This initiative has over the years raised well over £200,000 for research. The aim of Walk for ME is to get as many people as possible – especially the family and friends of those affected by ME – to do a sponsored walk, run, swim or ride of whatever length they feel comfortable.

You choose when you wish to walk, the distance, the location and which charity you wish to support. You can find out how to take part at meresearch.org.uk/wfme2024.

Anna Redshaw’s Blue Sunday Tea Party for ME has been running every year since 2013, during which time the initiative has raised more than £100,000 for various ME charities, including ME Research UK. This year’s event is on 19 May, and Anna encourages us to “dig out your best cups and saucers, wear something blue, have a slice of cake or two, and donate the price you’d pay in a café to an ME charity”.

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For more inspiration about ways you can help raise funds, please visit meresearch.org.uk/support-us.

Scan to donate to ME Research UK via Wonderful.org

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