Breakthrough, Autumn 2024

NEWS OF THE ME RESEARCH YOU ARE HELPING TO FUND

breakthrough 40 / AUTUMN 2024

MICROCLOTS NEUROIMAGING SEVERE ME/CFS NEUROPATHY RESEARCH ROUNDUP FUNDRAISING 1

CONTENTS 4

LOOKING FORWARD New studies on microclots and neurocognitive impairment

20 INTERVIEW

Tina Katsaros at La Trobe University talks about her PhD

10 UPHILL STRUGGLE

24 CONFERENCES

14 RESEARCH BITES

26 MAKING SENSE

16 THE SPICE OF LIFE

30 FUNDRAISING

Cort Johnson on what we know about severe ME/CFS

Our highlights of the Unite to Fight conference

Brief summaries of newly published studies

The evidence supporting small fibre neuropathy in ME/CFS

Disease variation presents challenges to ME/CFS research

100-km challenge, Alpine trek, barbecue, and a triathlon

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 Breakthrough. Our work on your behalf continues, and this issue introduces two new projects, as well as an interview with Tina Katsaros, one of the PhD students we are currently able to support as a result of your fundraising and donations.

I am sure many of you followed the extensive media coverage of the Coroner’s inquest into the tragic and unnecessary death of Maeve Boothby O’Neill. She wrote in 2021: ‘Biomedical research must be done to understand what is happening to our bodies, and to prevent very ill people getting worse and help us to get better.

My only hope lies in biomedical research, and adequate funding for this requires the medical establishment to set aside the inaccurate idea that behavioural treatments can cure ME.’ We exist solely to fund biomedical research into ME; thanks to your generosity we have invested over £4 mil-

lion to date, and will continue 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. We have been very fortunate over the past few years to have had the capacity to fund all the research that has met our exacting standards, but are now entering a phase where our ability to fund new research is constrained by 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 high quality biomedical research. The fundraising stories in this edition both humble and inspire – thank you all for your continued support; we can’t do it without you!

On that note, our Christmas cards are now on sale, and an order form is included with this issue.

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LOOKING FORWARD ME Research UK continues to build our portfolio of innovative ME/CFS research, and here we introduce two more studies announced recently.

Read about all our projects at meresearch.org.uk/research

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Muscle microclots and microvascular pathology in ME/CFS Lead researcher: Dr Rob Wüst, Vrije Universiteit Amsterdam Background Symptoms affecting the muscles are one of the key features of ME/CFS. Muscle pain, weakness and fatigue cause significant suffering, and can severely limit individuals’ day-to-day activities and quality of life.

Furthermore, these and other symptoms of the disease can worsen or return following even modest physical exercise – a crucial characteristic of ME/CFS known as post-exertional malaise (PEM), which can last for days or weeks.

Very little is known about the causes of muscle abnormalities and PEM in ME/CFS, but Dr Rob Wüst and colleagues at Vrije Universiteit Amsterdam in the Netherlands believe they may have a lead.

Much has been made of the similarity in symptoms between ME/CFS and long COVID – the chronic condition that some individuals develop following COVID-19 infection – and whether the two might be linked.

Dr Wüst’s own research in a cohort of people with long COVID uncovered a number of abnormalities in muscle function following exercise, as well as an increase in the accumulation of microscopic blood clots (microclots) in the muscle tissue. The density of these microclots was higher in muscle samples from people with long COVID than from healthy control subjects, and was increased following an exercise session to induce PEM.

Photo by Patrick Siemons

Name Dr Rob Wüst Position Assistant Professor Institution Department of Human Movement Sciences, Vrije Universiteit Amsterdam Main research interests The regulation of cardiac and skeletal muscle metabolism, and mitochondrial bio-energetics, as well as its consequence on whole cell and organ function.

More information research.vu.nl/en/persons/robwust 5

These findings therefore provide some evidence of a link between exercise, local microclot accumulation and immune cell activation in people with long COVID. But could there be a similar picture in people with ME/CFS? This is the question Dr Wüst and colleagues want to answer in this new study.

Electron microscopy will also be performed to assess the structure of the capillaries (microscopic blood vessels) and mitochondria (responsible for energy production in cells) in the skeletal muscle fibres.

The third aim is to look for markers in the blood that indicate muscle tissue stress, and to determine whether these correlate with abnormalities in muscle tissue structure.

Study aims The researchers will collect skeletal muscle biopsy samples and venous blood samples, before and after the induction of PEM, from 25 people who fulfil Canadian Consensus Criteria for ME/CFS. Samples are also being collected from patients with long COVID and healthy control subjects.

Immunofluorescence techniques will be used to identify and assess the location of microclots in the muscle and in blood samples, and to correlate these with the presence of clinical symptoms.

Potential benefits Understanding the clinical consequences of PEM needs better comprehension of the mechanisms involved, and the researchers anticipate that their findings will help do this.

The results will be integrated into the newly developed Netherlands ME/CFS Biobank and Cohort, and may pave the way towards a new therapy which, if it is based on established treatments, could be implemented relatively quickly.

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Neurocognitive impairment in ME/CFS

Lead researcher: Prof. François Jérôme Authier, Université Paris Est-Créteil Background Cognitive problems are one of the most frequent and disabling symptoms associated with ME/CFS, and most people with the disease report memory and concentration difficulties.

Several imaging techniques have been used to investigate the brain in ME/CFS, and one significant finding has been a correlation between cognitive deficits and areas of reduced blood flow in the brain.

A reduction in the metabolic activity in brain cells has also been identified in certain areas of the brain in ME/CFS, but it is not yet clear whether this too is associated with cognitive problems.

Prof. Authier and colleagues at Université Paris Est-Créteil and Henri Mondor University Hospital in Paris are planning to look at this topic further, and to try and answer some of the questions raised in previous research.

Their central hypothesis is that cognitive dysfunction is a basic feature of ME/CFS, contributing in its own right to disease-related disability, and correlates with changes in brain functional imaging and systemic biomarkers of ME/CFS. In the COGNIME study, the researchers plan to analyse clinical, neuropsychological and neuroimaging data from people with ME/CFS, and also from patients with persistent, profound chronic fatigue but who do not meet diagnostic criteria for ME/CFS. 7

Name Prof. François Jérôme Authier Position Professor of Histology Institution Faculty of Medicine, Paris EstCreteil University Main research interests Characterisation, classification and pathophysiology of neuromuscular diseases and ME/CFS; mechanisms of postinjury muscle fibre regeneration; and innovating therapies.

More information me-pedia.org/wiki/François_ Jérôme_Authier

Study aims The aims of the study are to: • Analyse neuropsychological performance in 100 people with ME/CFS. • Compare these findings with those from 200 people with persistent, profound chronic fatigue but who do not meet diagnostic criteria for ME/CFS. • Assess whether the cognitive findings correlate with structural and functional changes in the brain detected using neuroimaging.

• Use the neuropsychological and neuroimaging data, in combination with collected blood samples, to establish a biobank for further research.

The assessments have already been carried out, and the focus of the project will be to perform an analysis of the data obtained in order to address these issues.

The neuropsychological assessments included measures of pain, fatigue, depression, executive functions and attention, processing speed, memory, instrumental functions, and dichotic listening.

Neuroimaging was performed using magnetic resonance imaging to assess brain structure, as well as positron emission tomography with a tracer chemical (fluorodeoxyglucose) to examine brain metabolism.

Potential benefits The investigators anticipate that their results will provide a detailed picture of cognitive abnormalities in ME/CFS, emphasising the significance of these symptoms in contributing to disability, and the importance of conducting an accurate neuropsychological evaluation in individuals with the disease.

The short-term practical impact may therefore be to improve the care of ME/CFS patients, to improve their disability assessment, and to develop specific therapeutic approaches.

Evidence of cognitive deficits should also prompt the establishment of further studies aiming to understand the pathophysiological mechanisms at work. The identification of potential risk factors may help physicians to detect patients at risk of cognitive dysfunction and propose adapted care for them.

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THE BIG GIVE MAKES A DIFFERENCE This year’s Big Give Christmas Challenge runs between the 3rd and 10th of December, when any donations made to ME Research UK via the biggive.org website will be doubled.

At the end of last year’s campaign, we had – thanks to our pledgers, donors and Charity Champion, the Reed Foundation – raised over £30,000. This was a fantastic total for which were are very grateful.

As promised, the proceedings of the 2023 challenge are being invested in ME/CFS research, and are being used to provide a second project grant to Prof. Leighton Barnden and his team to build upon their earlier work at Griffith University in Australia.

We looked at their earlier studies in the last issue of Breakthrough.

Hailed as a ‘world first’ in Australian 9

media, this research (with funding from the Fred and Joan Davies Bequest) looked at brain abnormalities in people with ME/CFS and those with long COVID. The researchers uncovered a number of findings which throw more light on these abnormalities, including brainstem volume changes, as well as impaired functional connectivity between specific brain regions and during cognitive exertion.

Prof. Barnden’s new three-year study will use the same 7-Tesla MRI technology to investigate brain changes and disease progression in ME/CFS patients over time. There will be more information in the next issue.

Funds from the Big Give have allowed us to empower these scientists to build on their previous work, which is all too rare in ME/CFS research.

UPHILL STRUGGLE Cort Johnson from healthrising.org addresses how little we know about severe ME/CFS, while highlighting what research is out there.

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Maeve Boothby O’Neill’s tragic and unnecessary death underscored how ill-prepared the medical profession is regarding people with severe ME/CFS. Maeve’s death also raises the question of how much do we even know about people with severe illness.

Ten years ago, Dr Peterson called the severely ill the ‘elephant in the room’ that everyone had danced around for years. We’re still dancing, but perhaps more slowly now as the severely ill are getting more recognition. In 2021, the Healthcare Journal devoted an entire issue to this group, while the Open Medicine Foundation has focused a major study on them.

What’s more, the CDC’s Multisite Study was slated to include very severely ill people. However, there is still so little we know about the worst off among us.

We know that the severely ill have been around as long as ME/CFS. The bottom end of Dr David Bell’s ME/CFS Disability Scale – developed decades ago – cites individuals who ‘have severe symptoms on a continuous basis, are bedridden constantly, and are unable to care for him/her self’.

We know that having young people experience such profound disability is rare in a medical setting, and that when disability like that shows up it is usually in the elderly.

The severely ill are so debilitated and fragile that they rarely make it to doctors’ offices, and almost never take part in research. They are often selfdiagnosed and most lack insurance.

Visits to the emergency room are rare simply because the emergency room has nothing to offer them and often makes them worse.

Given the very limited number of studies on the severely ill, it’s impossible to quantify how severe is severe. One way to do that indirectly is to contrast how the functionality and quality of life of people with ‘ordinary ME/CFS’ line up with people with other diseases.

The results are eye-opening and only serve to underscore the almost uniquely difficult challenges the severely ill face. Komaroff’s landmark 1996 study found that people with ordinary ME/CFS scored significantly lower on functional and wellbeing scales than did people with heart failure, heart attack, multiple sclerosis or diabetes. Similarly, a 2011 British study found a staggering reduction in func11

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The severely ill rarely make it to doctors’ offices, and almost never take part in research. The emergency room has nothing to offer. tioning in people with ordinary ME/CFS compared to those with rheumatoid arthritis, cancer or depression. Next, a 2015 Danish study found that quality of life in ordinary ME/CFS patients was almost 50% lower than for people with serious diseases like lung cancer, stroke or diabetes.

With ordinary ME/CFS patients scoring far below other serious diseases in functionality and quality of life, it’s clear that ordinary disease criteria cannot hope to capture the state of the severely ill. Characterising them has fallen to the ME/CFS community.

The International Consensus Criteria differentiates between mild, moderate, severe and very severe patients. ‘Severe’ patients can perform only minimal self-care tasks (such as face-washing and teeth-cleaning) and are homebound but not bedridden, while ‘very severe’ patients cannot engage in even minimal self-care and are mostly bedridden.

Even the ‘very severe’ designation has not been proven to be enough, though. A recent study created an ‘ex-

tremely severe’ category for ME/CFS patients who have lost the ability to communicate and feed themselves, and often experience extreme sensory sensitivities.

How many people with ME/CFS fit the ‘severe’ or worse categories is unclear, but the number does not appear to be small. A 2021 study suggested that about 25% of ME/CFS patients in the UK (about 62,000 people) fit the severe (homebound) category.

The few studies that have assessed it have shown a remarkable difference in physiological functioning between patients with moderate disease and those with severe disease.

The percent peak oxygen consumption in those able to engage in an exercise test was 90% in mild patients, but 64% in moderate patients and down to 48% in those who were homebound but not bedridden.

Another study found that simply sitting up (20% tilt) in severe patients resulted in a 27% reduction in blood flow to the brain and a 30% reduction in heart output.

What has happened to produce such dramatic drops in physiological functioning remains a mystery. The one major effort to understand the severely ill – the Open Medicine Foundation’s Severely Ill Big Data study – ran over 1,000 tests in 20 severely ill ME/CFS patients (who were bedridden for at least 14 hours a day) and 10 healthy controls. While a conference report cited cytokine, metabolomic and genetic findings, including lower levels of a neuroprotective 12

Cort Johnson

metabolite in the tryptophan pathway, the one paper to come out of the massive study reported only a low cortisol finding.

An in-depth, 4-year longitudinal study of an extremely severe ME/CFS patient (Whitney Dafoe) fared better, however. The study suggested that this severely ill patient was different from ‘ordinary ME/CFS patients’ not in kind but in degree; i.e. he was simply worse off than other ME/CFS patients.

A substantial decrease in a ‘brainaging chemokine’ called CCL11, in combination with reductions in cytokines associated with a TH2 immune /allergic response during a time of improved health, painted something surprising – a clear picture.

The findings – which fit in well with past results – suggested that mast cell and eosinophil activation, neuroinflam-

mation, blood–brain barrier permeability, nervous system sensitisation and blood vessel dysfunction were playing critical roles in his disease. They pointed to pathways that could be activated or attenuated to return immune system functioning to normal, and the authors proposed that similar mechanisms may be operating in people with hypermobility syndrome, POTS, MCAS and multiple chemical sensitivity.

While the severely ill in ME/CFS are getting more attention, the severity of their illness means they will probably never participate in many research studies – but they might not need to. Like Whitney Dafoe, the severely ill may simply be sicker in the same ways that other ME/CFS patients are sick. While their symptoms are more severe, they are similar. Even such extreme symptoms such as hypersensitivity to stimuli and an inability to eat are mirrored to a lesser degree in healthier ME/CFS patients.

While the nature of their illness makes the severely ill more difficult to treat, it should be remembered that they are not immune to help. While recovery is rare, it has happened. Different treatment regimens (alternative health, vagus nerve stimulation, craniocervical surgery, antivirals, chelation) have, at times, returned very severely ill patients to health.

In the end, the severely ill may simply need what all ME/CFS patients need – more funding and better treatment options. As Maeve’s death showed, they just need them more quickly.

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The severely ill simply need what all ME/CFS patients need – more funding and better treatment options

RESEARCH BITES

BRAIN ACTIVITY

VASCULAR ABNORMALITIES

Schönberg, JCBFM, 2024

Nunes, Cardiovasc Diabetol, 2024

We are currently funding Dr Zack Shan’s ongoing study assessing brain inflammation in ME/CFS. In previous research, Dr Shan and colleagues used MRI to perform BOLD imaging, which detects changes in blood oxygenation and therefore indicates brain activity.

Control subjects showed a decrease in activity in various regions while performing cognitive tasks, indicating normal adaptation. This was absent in patients with ME/CFS who had an increase in activity, possibly indicating less efficient use of energy which may lead to symptoms of fatigue.

The search for blood biomarkers of ME/CFS continues in this recent study from researchers in South Africa. They used mass spectrometry to look at differences in protein expression in plasma samples from 15 people with ME/CFS and 10 control subjects. Proteins associated with blood coagulation, the vascular endothelium (lining) and immune system were either increased or reduced in the ME/CFS group, versus controls, providing further evidence that these systems are altered in the disease, and highlighting potential biomarkers.

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CYCLOME REVISITED

LIGHT CHAINS

Rekeland, PLoS One, 2024

Azcue, Biomedicines, 2024

The CycloME trial reported responses to cyclophosphamide (a chemotherapy with immune effects) in around half of people with ME/CFS. Norwegian scientists have now followed up most of the participants six years after treatment, and found that 44% of those on cyclophosphamide had a score of 70 or more on a measure of physical function, indicating that it may be beneficial in a subgroup of individuals. However, cyclophosphamide has a number of side effects which limit its usefulness in ME/CFS, and the search should continue for less toxic immune therapies.

Neurofilament light chains (NfLs) are proteins forming part of the structure of nerve cells, which are released when nerves are damaged. Increased NfL blood levels are found in several neurodegenerative diseases, but have also been reported in patients with long COVID. This prompted a recent study by Spanish researchers who have detected increased plasma NfL levels in people with ME/CFS, which were associated with several measures of cognitive impairment. They suggest that NfLs may therefore be a biomarker of neurological dysfunction in ME/CFS.

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THE SPICE OF LIFE One considerable challenge in ME/CFS research is disease heterogeneity – that is, how the disease varies from person to person. A contributing factor may be differences in practice between different clinicians, as investigated in a recent study.

In ME/CFS, diversity in disease presentation could be related to a number of factors, such as differences in severity, types of symptoms, duration of illness, comorbidities and disease triggers.

However, another potential reason for differences in ME/CFS from person to person relates to the diagnostic process. As there is no validated diagnostic biomarker, ME/CFS is diagnosed based on patients’ self-reported symptoms, clinical opinion, and by excluding other conditions.

Diagnostic criteria There are several criteria which can be used to diagnose ME/CFS, including 17

the Fukuda criteria for CFS, the International Consensus Criteria for ME, the Canadian Consensus Criteria for ME/CFS, and the updated NICE Guideline for ME/CFS. Notably, these criteria have different requirements with regard to which symptoms should be present for a diagnosis to be made. For example, the Fukuda criteria do not require post-exertional malaise (PEM) for a diagnosis, while ICC, CCC and NICE all do.

These differences limit the comparability of individuals diagnosed using the different criteria, and may mean that it is not appropriate to group participants diagnosed using different methods – regrettably, this is

a common limitation of many ME/CFS studies.

In addition, it is possible that different clinicians may take alternative approaches to the same criteria. This means that even those diagnosed with ME/CFS using the same tool – or through clinical opinion alone – may not be comparable when they have been diagnosed by different doctors.

To look at this in more detail, in a study published in the Journal of Clinical Medicine, Dr Elizabeth Unger and colleagues investigated whether people with significantly different symptoms (including those who may not meet ME/CFS diagnostic criteria) were being diagnosed with ME/CFS by clinicians at seven clinics in the USA. Differences in diagnosis Information was collected on 465 adults who had received a diagnosis of ‘ME’, ‘CFS’ or ‘post-infectious fatigue’ from a clinician at one of seven clinics in the USA, or were a patient at one of these clinics and receiving the same care as others with ME/CFS. The eligibility of participants was determined by clinicians with ‘specialized expertise in and experience with diagnosis and management of ME/CFS’ – importantly, they were not required to fit a specific case definition for the disease.

Standardised questionnaires were used to assess the general characteristics of participants, as well as symptoms relating to ME/CFS, such as functional impairment, PEM, fatigue, sleep, 18

neurocognitive/autonomic symptoms, pain, inflammation, gastrointestinal symptoms, and emotional or behavioural symptoms.

What did they find?

While certain patient characteristics did vary considerably between the different clinics (including the age at diagnosis, duration of fatigue, and body mass index), there were actually few differences between any of the symptoms related to ME/CFS. This suggests that the physicians at each clinic were consistent in how they assessed these symptoms.

However, although there was a lack of variation between clinics, the participants within each clinic – and in the overall sample – showed a wide distribution in scores and measures, indicating overall disease heterogeneity in this patient population.

Overall, 83.4% of participants met the Fukuda criteria for CFS, while 50.1% met the CCC criteria for ME/CFS, and 57.6% met the IoM criteria for ME. A total of 352 participants (70.2%) met at least two criteria, and 41 participants (9.1%) did not meet any criteria.

Notably, 74 participants (16.5%) met the Fukuda criteria only, which do not require PEM for a diagnosis of CFS to be made. This suggests that some participants were being given a diagnosis of ‘ME/CFS’ even though they only met criteria for ‘CFS’ and were not experiencing what is said to be the cardinal symptom of ME/CFS, namely PEM.

Interestingly, the proportions of participants meeting the different diagnostic criteria did not vary significantly between the clinics.

Limitations It is important to highlight the limitations of this study, particularly that the participants were unlikely to be representative of all people with ME/CFS in the USA. Most were white, well educated and insured, and patients with more severe illness would not have been able to travel to the clinic and so would have been excluded.

Furthermore, a computer algorithm was used to assess participants against ME/CFS diagnostic criteria, which may not have given the same result as a clinician or ME/CFS specialist. There are also limitations with data that have been collected by self-report, such as interpreting questions differently, and giving more socially acceptable answers.

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Conclusions The findings of this study suggest that the clinicians involved were generally recognising the same disease – albeit one that differs from person to person.

However, 16.5% of participants were given a diagnosis of ‘ME/CFS’ by clinicians when they were not in fact experiencing PEM, and 9.1% of participants were identified by clinicians as having ME/CFS whereas they did not actually meet diagnostic criteria for the disease.

Future ME/CFS research needs to account for participant heterogeneity both in the design of studies and during analysis, and the potential impact of heterogeneity should also be considered when interpreting research findings.

However, diversity in a study population does allow researchers to assess diagnostic accuracy in different subgroups of patients, such as males and females, and different age groups.

INTERVIEW

TINA KATSAROS Tina is doing her PhD under the supervision of Dr Sarah Annesley at La Trobe University in Melbourne, Australia. Her research, which we are funding, involves investigating abnormalities in the mitochondria in ME/CFS, and how they interact.

Could you tell us a bit about yourself?

I’m a second-year PhD student at La Trobe University. Before starting my PhD, I completed my undergraduate studies in Biomedicine – also at La Trobe – and spent some time volunteering at the Royal Melbourne Hospital.

What is your PhD project about?

My colleagues previously identified several abnormalities in how cells from people with ME/CFS produce energy.

I am looking at these abnormalities in more detail, and trying to establish a cause-and-effect relationship between them.

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What inspired your interest in ME/CFS? When I first started with Dr Annesley, I was working on a project investigating calcium signalling (which drives processes within cells) in Parkinson’s disease. I’d never heard of ME/CFS, but when I heard colleagues talking about their research into the disease, I learned a lot, and it was this that inspired me to pursue a PhD looking at ME/CFS. Have you been surprised by anything you’ve learned since starting your PhD? You can read research papers, and talk to people with the disease online, but

you only truly see what ME/CFS is like when you are with someone who has the disease and see how it impacts their life. The sacrifices they have to make to avoid post-exertional malaise, and how impossible it can be to do things that healthy people take for granted every single day. For example, around the same time I started my PhD, I travelled around Europe with a friend who has ME/CFS. During that time, she had to miss out on activities that she wanted to do because they were just too much for her physically. She would have to go to sleep earlier and wake up later, and also have to take medication throughout the day just to get by.

How do you collect the data you need for your project?

In Dr. Annesley’s lab, we have a wellestablished biobank of cell lines from people with ME/CFS and from healthy controls, which I use in my PhD. These cell lines are created by extracting a specific type of cell, called a B cell, from blood samples. Researchers then immortalise these cells so that they can grow continuously. Importantly, this means that the cells are ‘metabolically active’ which allows us to easily measure energy processes.

What does a typical working day look like for you?

My day starts around 9 a.m. when I come into the lab and look at my cell line. How the cells are growing then determines how I plan my week. Once I have done this, I’ll spend the rest of 21

the day setting up and running my experiment. Later, I'll go in and do some admininstrative work, like checking emails. But of course the day is usually a lot more chaotic than that – you have to organise your time around seminars, lab meetings, committee meetings, workshops, and other things like that.

Can you tell us a bit about where you are doing your PhD? I love La Trobe. I did my undergraduate studies here and then my Honours degree, and now I’m doing my postgraduate studies here too. It’s a great school – the department that I’m in especially. It has an amazing environment with a very supportive, close-knit community.

Importantly, you can see that the academics genuinely care about the students as well.

What support do you have to help you complete your work?

I’m very lucky in the support structures available. Firstly, I have amazing supervisors – my primary supervisor, Dr Sarah Annesley, and then my cosupervisors, Dr Daniel Missailidis and Professor Paul Fisher. They are always there to talk about anything in the lab, or even if you just need to chat. The other members of my lab are great as well – we’ve got a really good team here. La Trobe also offers a lot of support for its students, such as organising workshops and events where we can practise presentation skills and share our research.

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You only truly see what ME/CFS is like when you are with someone who has the disease and see how it impacts their life

Why did you chose mitochondria as the focus of your work? What do we already know about them, and what are you trying to find out?

In the last decade or so, research has focused on energy metabolism in cells from people with ME/CFS – and that makes sense because the two main symptoms associated with the disease are debilitating chronic fatigue and the worsening of symptoms following some kind of mental or physical exertion. In Dr Annesley’s lab, several abnormalities in how cells from people with ME/CFS produce energy have been identified. We want to investigate these findings further by looking at the abnormalities in detail, and then try to establish a cause-andeffect relationship between them. One particular challenge of mitochondrial research is that it is common for different researchers to use different cell types, which leads to different 22

results that can be hard to compare. In addition, different diagnostic criteria for ME/CFS are used across studies, so it is essential to take this into consideration when looking at the literature.

What have you have enjoyed most so far, and what has been the most challenging part of your PhD? The thing I’ve enjoyed most has been the research. The most challenging part has also been the research! Of course, I love what I do – being in the lab, doing experiments, and looking at data. I am so lucky to have the opportunity to contribute to ME/CFS research – but that doesn’t mean that research doesn’t come without its challenges. For example, some experiments just don’t work – they fail continuously and you have to troubleshoot cell lines that will not grow. There is also imposter syndrome

as well, which can be quite overwhelming. I’m lucky that I love what I do – it makes dealing with those challenges so much easier and it makes it all worth it.

Where do you see yourself five years after completing your PhD? I would love to stay in ME/CFS research, but funding can be challenging to come across – which is why it’s so amazing that there are organisations like ME Research UK that help to fund the research. Ideally, five years after my PhD, I will be doing a post-doc somewhere that allows me to continue ME/CFS research, and, who knows, maybe even a fellowship.

What advice you would offer bioscience students who are considering a PhD in ME/CFS? Find your passion. Research is not easy. Several things can make it overwhelming and sometimes hard to deal with, but if you love what you do, you’re passionate about your topic, it makes all of the challenges worth it in the end. I would also say, interact with people who have lived experience of ME/CFS, and learn about their stories.

‘Thank you so much to ME Research UK for funding this PhD project and supporting new researchers entering ME/CFS research. A special thank you also to everyone who supports the charity through donations, allowing for this funding to be possible and to drive ME/CFS research forward.’ Tina 23

Don’t forget that when you do your online Christmas shopping this year, you could also be raising funds for ME Research UK (including projects like Tina’s), at no extra cost to you.

Give as You Live gives a free donation with almost every purchase you make at over 6,000 stores, including John Lewis and Argos: bit.ly/3E7LBLG And if you need to get rid of any unwanted presents in the new year, eBay allows sellers to give some or all of their sale proceeds to their favourite charities: bit.ly/45E4pOk

topics CONFERENCE Key Speakers at the conference included Research UK-funded researchers SEASON ME past and present: Prof. Carmen In May this year, ME Research UK attended the Unite to Fight conference, organised by people with ME/CFS and long COVID. Here are some of our highlights.

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Scheibenbogen, Dr Rob Wüst, Dr Amy Proal and Prof. Bhupesh Prusty. Of the many areas of ME/CFS and long COVID research discussed at the conference, there were five key topics: 1. ME/CFS as a part of long COVID. 2. The importance of involvement in research of those with lived experience.

3. Research and experience show that post-exertional malaise (PEM) is not a result of deconditioning.

4. Stop saying ‘long COVID and ME/CFS are a mystery’.

5. Long COVID research does not appear to be learning from ME/CFS research deficiencies.

ME/CFS as a part of long COVID Prof. Carmen Scheibenbogen highlighted results from a study looking at the severity of symptoms over time for 106 people with long COVID, and compared those who met the CCC diagnostic criteria for ME/CFS with those who did not.

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Providing participants with a better experience of research.

Better communication of results at the end of the study.

PEM is not a result of deconditioning Dr Rob Wüst presented findings showing that muscle changes seen in healthy participants who undergo bed rest to induce deconditioning are not the same as those observed in studies looking at muscle samples from people with ME/CFS who experience PEM – indicating that deconditioning alone does not explain PEM.

For participants with long COVID who did not meet the criteria for ME/CFS, symptoms continuously improved.

Those with long COVID who did meet the criteria for ME/CFS reported persistently high severity of symptoms.

This group also had a correlation between a specific type of autoantibody and symptom severity – something not seen for those who did not meet the criteria for ME/CFS.

Involvement of those with lived experience Oonagh Cousins – a former GB rower forced to retire with long COVID, who now works at the University of Oxford as a patient representative in research – highlighted ways in which including people with lived experience in research can lead to benefits such as: • Increased relevance of the research to participants.

• Improved acceptability of research methods used.

• Ensuring that information for participants is presented in a way that makes sense and considers accessibility needs.

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Clear leads on disease mechanisms Dr Amy Proal stated that ‘we need to stop saying that long COVID or ME/CFS are a mystery’. In her presentation on pathogen persistence, she highlighted that there are now ‘really clear leads on disease mechanisms’ which include pathogen persistence.

But studying samples of blood and urine is not enough. It is essential to examine tissue samples from areas of the body such as the gut, muscles, bone marrow and lymph nodes.

Not learning from mistakes David Tuller’s presentation considered how ‘long COVID researchers are repeating the ME/CFS biopsychosocial playbook’. There have been many long COVID studies of exercise and cognitive behavioral therapy (CBT) with ‘lots of positive headlines and news coverage about exercise/CBT for long COVID’.

MAKING SENSE Small fibre neuropathy appears to be associated with ME/CFS in many individuals. We look at some of the evidence supporting this.

Small fibre neuropathy (SFN) is a condition that affects small nerve fibres throughout the body, leading to various sensory symptoms such as pain, ‘pins and needles’ and burning sensation, as well as autonomic symptoms such as palpitations, gastrointestinal problems and excessive sweating.

Several studies have looked at the association between ME/CFS and SFN, and many individuals with ME/CFS report symptoms that align with SFN, so it is certainly a topic of interest.

Impaired sensory function Researchers in Spain assessed 50 individuals with ME/CFS, 87 with long COVID, and 50 healthy controls. The presence of autonomic and sensory SFN was evaluated using a Sudoscan (tool that measures nerve damage by

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assessing sweat gland function), contact heat-evoked potentials (brain responses to thermal stimuli applied to skin), and quantitative sensory testing (measures changes in sensitivity to different sensations such as temperature, pressure and vibration).

Individuals with ME/CFS as well as patients with long COVID exhibited significant differences in the detection of, and response to, heat compared with healthy controls. The results indicate potential damage to types of sensory fibres known as C-type unmyelinated fibres.

SFN and dysautonomia One study noted a high prevalence of SFN in about one-third of ME/CFS patients, slightly less than the approximately 50% prevalence seen in postural orthostatic tachycardia syndrome (POTS), a type of dysautonomia (impairment of the autonomic nervous system) and a common comorbidity in ME/CFS. In POTS, individuals experience abnormal blood pooling in the legs upon standing, which is potentially due to poor constriction of veins (venoconstriction) caused by damaged small nerve fibres.

Blood pooling in the legs can also mean that there is less blood returning to the heart – a condition known as preload failure, which is associated with exercise intolerance. The researchers therefore propose that SFN is ‘the major cause of preload failure in a substantial, not yet fully measured, proportion of ME/CFS patients’.

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Small fibre neuropathy potentially affects one third of individuals with ME/CFS

Underlying mechanisms Autoimmunity potentially plays a role in SFN, whereby the body’s immune system attacks its own nerves. It is also hypothesised that in ME/CFS an excessive production of substances such as bradykinin could lead to increased blood–brain barrier permeability and cerebrospinal fluid production, which in turn increases pressure on nerves, so leading to SFN. In ME/CFS and mast cell activation syndrome (another comorbidity of ME/CFS), associated SFN may reduce the production of important neuropeptides (chemical messengers) involved in dilating blood vessels.

Their deficiency in ME/CFS could lead to poor blood flow to muscles, contributing to symptoms such as fatigue and pain.

Management of SFN The treatment approach to SFN appears to be complex and dependent on multiple factors. One source states, ‘The management of SFN should involve treatment of the underlying etiology in patients with an identified cause of neuropathy… Pain management is important in the treatment of SFN, as neuropathic pain may be debilitating and cause a decrease in function and depression… Medications used in the treatment of SFN include anticonvulsants, antidepressants, topical anesthetics, narcotics, non-narcotic analgesics, and antiarrhythmics, while nonpharmacologic treatments such as heat, ice, massage of painful areas, and transcutaneous electrical nerve stimulation (TENS) may also be used.’

As stated by NICE in their guideline addressing neuropathic pain, ‘Neuropathic pain is very challenging to manage because of the heterogeneity of its aetiologies, symptoms and underlying mechanisms…’

Conclusion Diagnosing SFN in individuals with ME/CFS may 28

help shift treatment approaches to more targeted therapies, addressing the underlying mechanisms involved.

In managing comorbidities such as SFN, healthcare providers have the opportunity to alleviate the symptom burden in ME/CFS. Furthermore, as one paper aptly states, ‘More comprehensive evaluation is recommended to fully address SFN contribution to ME/CFS. Although neither ME/CFS nor any symptombased syndrome is caused by only one single disease or pathophysiology, diagnosing established diseases when present shifts at least these patients to more effective clinical frameworks and facilitates detection of remaining contributors.’

UK ME/CFS RESEARCHER TOOLKIT As part of the work surrounding the Department for Health and Social Care’s Delivery Plan process, a ‘researcher toolkit’ has been produced which illustrates funding streams available for ME/CFS research, guides Public and Patient Involvement, and provides advice on drafting a successful research application.

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The toolkit carries the endorsement of the UK Clinical Research Collaboration, the Department for Health and Social Care, UKRI Medical Research Council, NIHR, and the Chief Scientist Office. The toolkit sets out:

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Guides to embedding patient and public involvement.

Resources on developing high quality proposals.

In addition, the resource contains: •

Information on charity funding opportunities (including a link to ME Research UK).

Information on how to get involved with research for people with lived experience of ME/CFS.

The Researcher Toolkit is an output of the UKCRC ME/CFS Research Working Group and can be downloaded from: bit.ly/4cOS3pF

UK Government research funding opportunities.

Support available for researchers to help with their applications.

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FUNDRAISING

100 KM CHALLENGE

TREKKING THE ALPS

Throughout the month of August, Nathan Baxter challenged himself to run a total of 100 km in aid of ME Research UK‘s research work. As he writes on his fundraising page, ‘My sister has severe ME. Before she became ill she loved dancing, netball, drama and was always active. She now has to spend all day in bed. I want to raise money to show my support for my amazing sister and to help towards more research that is so badly needed.’ We can whole-heartedly agree with that sentiment, and many thanks to Nathan, who completed his 100 km challenge on 31 August!

Congratulations and thank you so much to Anna Doll who has completed the 12th Pitz Alpine Glacier Trail, a 62km route in the Alps. On 3rd August she navigated logging roads, singletrack and Alpine tundra over mountain passes at more than 3,000 metres, all in aid of ME research. ‘We had a challenging race with many ups and downs (literally and metaphorically) trying to beat various cut-off times throughout, which would have disqualified us. After 20:51 hours, we made it over the finish line (both proud and achy).’

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CHARITY BARBECUE

A BUSY WEEKEND

While barbecue season is long past here in Scotland, back in July Alan Alvis organised a fundraising event with a charity barbecue as part of Walk for ME, raising funds for ME research and Surrey Stands With Ukraine. Despite the showers, it was a huge success, with thanks to The Epsom Club for use of their facilities and to AvitaCatering who helped with the food.

Many thanks to Alan for his efforts, and of course to everyone else who took part in Walk for ME events this year.

A diary miscalculation led Richard Heywood to compete with his son Samuel in the Fylde Coast Runners Blackpool ‘Run the Lights 10k’ on 17th August, only to next day be taking part in the UK Triathlon York event, raising money for ME Research UK in both. Richard was happy to report that he completed the races, and topped his personal best times for both. Congratulations and thank you, Richard!

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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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