Open Protocol: Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: A cross-sectional neuroimaging study 2022 Shan et al

Full title: Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: A cross-sectional neuroimaging study toward its neuropathophysiology and diagnosis

Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), is a debilitating illness affecting up to 24 million people worldwide but concerningly there is no known mechanism for ME/CFS and no objective test for diagnosis. A series of our neuroimaging findings in ME/CFS, including functional MRI (fMRI) signal characteristics and structural changes in brain regions particularly sensitive to hypoxia, has informed the hypothesis that abnormal neurovascular coupling (NVC) may be the neurobiological origin of ME/CFS. NVC is a critical process for normal brain function, in which glutamate from an active neuron stimulates Ca2+ influx in adjacent neurons and astrocytes. In turn, increased Ca2+ concentrations in both astrocytes and neurons trigger the synthesis of vascular dilator factors to increase local blood flow assuring activated neurons are supplied with their energy needs.

This study investigates NVC using multimodal MRIs: (1) hemodynamic response function (HRF) that represents regional brain blood flow changes in response to neural activities and will be modeled from a cognitive task fMRI; (2) respiration response function (RRF) represents autoregulation of regional blood flow due to carbon dioxide and will be modeled from breath-holding fMRI; (3) neural activity associated glutamate changes will be modeled from a cognitive task functional magnetic resonance spectroscopy. We also aim to develop a neuromarker for ME/CFS diagnosis by integrating the multimodal MRIs with a deep machine learning framework.

Methods and analysis: This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by consensus diagnosis made by two clinicians using the Canadian Consensus Criteria 2003. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI.

The HRF, RRF, and glutamate changes will be compared among four groups using one-way analysis of covariance (ANCOVA). Equivalent non-parametric methods will be used for measures that do not exhibit a normal distribution. The activity measure, body mass index, sex, age, depression, and anxiety will be included as covariates for all statistical analyses with the false discovery rate used to correct for multiple comparisons.

Open access, https://www.frontiersin.org/articles/10.3389/fneur.2022.954142/full

The data will be randomly divided into a training (N = 188) and a validation (N = 100) group. Each MRI measure will be entered as input for a least absolute shrinkage and selection operator—regularized principal components regression to generate a brain pattern of distributed clusters that predict disease severity. The identified brain pattern will be integrated using multimodal deep Boltzmann machines as a neuromarker for predicting ME/CFS fatigue conditions. The receiver operating characteristic curve of the identified neuromarker will be determined using data from the validation group.

Ethics and study registry: This study was reviewed and approved by University of the Sunshine Coast University Ethics committee (A191288) and has been registered with The Australian New Zealand Clinical Trials Registry (ACTRN12622001095752).

Dissemination of results: The results will be disseminated through peer reviewed scientific manuscripts and conferences and to patients through social media and active engagement with ME/CFS associations.

See post #15 for information on how to join the study

 

I like it, it sounds pretty rigorous.

 

Isn't a 3 Tesla magnet too low resolution, though? IIRC anomalies in pwME have usually been seen only at 7T when using MRI?

 

I like that they're using more than healthy controls. Since I believe ME is neurological (or neuroimmunological), this is the kind of ME research I like to see.

 

The use of sedentary controls is a big deal. They're at least trying to eliminate the potential effect of activity level. While the average sedentary control will be less active that the average pwME, it's still a step towards rigorousness.

 

I’m not familiar with the authors, but this looks like a very impressive study. I don’t know how much evidence there is for their hypothesis beyond “well, that would explain a lot”.

It’s worth spelling out what they’ve done well t (and haven’t even done the study yet):
– published a protocol. This is important generally and particularly in MRI studies where there is a lot of scope for researcers to slice the data in different ways to get an interesting result.
– sedentary and disease controls.
– A training and a validation set. This is absolutely critical. It’s easy to get a positive results in a study (particularly if you’re flexible with analysis), it’s all together harder (and more impressive) to replicate that. Because they’re randomly dividing the sample into, they will have matched groups and identical methodologies.
– sample size . 91 is very big by the standards of MRI studies, though I gather hundreds is better (which can only happen with collaboration). So they will end up with two groups of 45 patients and because that is a fairly small sample, I think it increases the chance they won’t be able to validate any findings simply through lack of statistical power.

It’s still the best MRI study protocol I can remember seeing (Which might just mean better than the last two studies I’ve seen…).

 

This looks very thoughtful and useful on first read through. Once again, neuroimaging has the potential to unlock much that has been hidden.

In response to @rvallee's question on using 3T vs 7T, higher field strength gives greater spatial resolution (or same SR with increased speed of acquisition if preferred). So 7T is going to be really valuable when looking at small complicated structures, like the brainstem (VanElzakker). I think this study is looking more at cerebral cortical blood flow, diffusion and spectroscopy and 3T will probably be ideal, as they want to sample contiguous small regions rather than little dots. Also, there's the practical matter that it's available where these researchers and patients are, and 7T ain't.

Their hardware is top notch: Siemens Skyra is the best clinical platform in my view (and what we use at ours). Importantly, they're using a 64 channel head coil which is best-in-class. It gives high bandwidth and high signal-to-noise over a large field-of-view, and I would expect their set-up will be ideal for this task.

 

It's not clear, but will their diagnostic process also include exclusionary testing? If so, then it would seem to be quite rigorous.

 

Yes, since we don't know the field of view necessary to find ME's abnormalities, we might need studies at different scales. If a brain-wide scan shows abnormalities, they can probably get funding for a higher-resolution, smaller FOV study. Patients are likely to show abnormalities in different areas of their brain--producing an individual's set of symptoms--so you need the wide FOV to know where to focus on a particular patient.

 

@SNT Gatchaman
Thank you for your explanation of this study.

Your statement:

"neuroimaging has the potential to unlock much that has been hidden...", is so very right on.

Despite multiple neurological and cognitive symptoms, pwME have been extraordinarily neglected in this, and so many other areas.

 

World-first chronic fatigue study to help sufferers get answers

https://www.sunshinecoastnews.com.a...tudy-seeks-answer-to-chronic-fatigue-mystery/

enough with the 'chronic fatigue'

 

Can we find someone to hack into the internet and global replace all mention of 'chronic fatigue' with 'chronic fatigue-like-but-not-really-fatigue'?

Since I'm in favour of more studies on brain function, I'm not objecting to this study. I think it's a better use of resources than studying blood elsewhere in the body, or studying viral infection (if a virus 'pulled the trigger', you need to study the wound, or maybe the weapon, but not who pulled the trigger).

 

Then acknowledge all the subsequent effects the wound will also cause instead of saying MUS.

 

Merged thread

Sunshine Coast, Australia: Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional neuroimaging study

Multimodal MRI of myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional neuroimaging study towards its neuropathophysiology and diagnosis
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384477&isReview=true

This cross-sectional study will recruit 288 participants (91 ME/CFS, 61 individuals with chronic fatigue, 91 healthy controls with sedentary lifestyles, 45 fibromyalgia). The ME/CFS will be diagnosed by an agreed diagnosis made by two clinicians using the Canadian Consensus Criteria. Symptoms, vital signs, and activity measures will be collected alongside multimodal MRI.

Register:
https://www.usc.edu.au/thompson-institute/research/chronic-fatigue-syndrome-me-cfs-study

Register your interest in being a volunteer research participant for our ME/CFS study. We appreciate your time and commitment to participate in the study. Thus, each participant will receive A$50 as reimbursement for travel costs per visit to the Thompson Institute for data collection purposes. Participants will also receive an image of their brain.

To facilitate sharing:

 

Novel brain imaging study seeks answers to chronic fatigue mystery

https://medicalxpress.com/news/2022-11-brain-imaging-chronic-fatigue-mystery.html
(yet more misuse of 'chronic fatigue')

 

Merged thread


https://www.usc.edu.au/thompson-ins...stitute/chronic-fatigue-syndrome-me-cfs-study


UniSC's Thompson Institute is seeking volunteer research participants who will help us understand the underlying illness process of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Participants will also help us develop imaging criteria that will aid the diagnosis of ME/CFS.

The study is the first to investigate brain function in ME/CFS in terms of energy supplies and chemical messengers. It is also the first significantly sized study to attempt to develop a diagnostic tool by combined advanced MRI and machine learning.

Eligibility
The study might be a good fit for you if you are:

• aged 18-65 years old, and a healthy adult with an inactive lifestyle
  (NB: 'inactive lifestyle' means participating in vigorous physical activity for less than 160 minutes per week; such as running, gym, swimming etc. Walking is not considered vigorous activity unless it is push walking);
  
  or
• aged 18-65 years old, and have:
  • an unexplained fatigue condition, or
  • ME/CFS, or
  • Fibromyalgia, or
  • Long COVID

The nature of the study's investigations also requires participants to:

• Not be taking medication for high cholesterol, high blood pressure, or heart-related conditions
• Have a body mass index (BMI) of 35 or below (this exclusion criterion is necessary because the brain and its functions can differ depending on BMI and thus is a potential confounding factor in our data collection. Please note that BMI is not related in any way to CFS risk or prevalence).
• Meet safety requirements to participate in the study's Magnetic Resonance Imaging (MRI). This includes not having metal implants or facial tattoos.

INTERESTED?
Register your interest in being a volunteer research participant for our ME/CFS study. We appreciate your time and commitment to participate in the study. Thus, each participant will receive A$50 as reimbursement for travel costs per visit to the Thompson Institute for data collection purposes. Participants will also receive an image of their brain.

REGISTER TO TAKE PART
Seeking adults with and without fatigue symptoms
What the study involves
As a research participant, you would take part in:

• An online screening questionnaire;
• At your own pace, ten questionnaires for assessing different aspects of mental and physical health status;
• Blood pressure, pulse rate, height, weight, and oxygen saturation measurements and a joint hypermobility task;
• Wearing an activity monitor wristwatch and chest strap to capture your physical activity, sleep/wake information and heart-rate for fourteen days. The wristwatch and chest strap need to be returned after fourteen days of usage;
• One magnetic resonance imaging (MRI) scan (60 minutes’ scanning time plus preparation). If you are willing, a second scan may take place.

Participants with fatigue conditions will also take part in:

• Two interviews with two specialists. Each interview will be scheduled for 30 – 45 minutes.

Research is conducted on the Sunshine Coast in Queensland.

Why this study is important
ME/CFS is a poorly understood, debilitating, complicated illness affecting 17 million people worldwide. There is no known underlying disease process for ME/CFS and no biological basis for diagnosis. Diagnoses are typically lengthy and occur by a process of elimination. Treatments are typically inadequate due to the unknown cause. Understanding the brain disease process of ME/CFS will allow the design of biologically-based therapeutic interventions and faster, more effective diagnosis methods.

Fibromyalgia is another common, debilitating and poorly understood condition, which frequently occurs together with ME/CFS, but can occur independently. This study therefore is also investigating individuals with Primary Fibromyalgia to try to understand this condition’s relationship with ME/CFS.

Contact us
Email: cfs@usc.edu.au
Tel: +61 7 5456 5445

Ethics Approval Number: A191288
This study is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12622001095752

 

Sounds an interesting study.

I wonder how many subjects they hope to recruit and how they intend to match the controls and the different clinical groups.

 

Is this done to induce PEM before imaging?