Review Neuroimaging characteristics of ME/CFS: a systematic review. Shan et al. 2020

Full Title:
Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review.

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02506-6

 

Made a thread, trying the summarize the main conclusions of the review. Feel free to point out any mistakes

https://twitter.com/user/status/1301209122214416386


2) First, the review notes that ME/CFS is an under-recognised disease because the selected studies were small and unimpressive. The sample size of the smaller group (patients or controls) in 40 out of the 63 articles were equal to or smaller than 16.

3) Another problem: more than 80% of reviewed studies did not control for lifestyle differences. That’s a problem because physical activity levels can impact brain structures and functions.

4)The authors write “that there is a pressing need to establish a collaborative neuroimaging databank for ME/CFS”. That would allow for bigger and better controlled studies. They also propose objective measurement of physical activity in both patients and controls.

5) The most consistent finding was the following: 10/12 articles reported that ME/CFS patients either recruited additional brain regions or had a greater blood oxygenation level-dependent (BOLD) signal changes than controls for cognitive tasks where they had the same performance.

6) the authors also highlight abnormalities in the brainstem (caveat: most of these studies come from their own research group). Three studies reported hypoperfusion in the brain stem, however, two other studies didn’t.

7) Several studies reported abnormalities in cerebral blood flow (CBF) in ME/CFS patients compared to controls. This review indicates however that overall, the findings have been inconsistent. 8 reported decreased global or regional CBF in ME/CFS, 6 couldn’t find differences.

8) Other findings haven’t been replicated by multiple research groups or have shown inconsistent findings. I think there is a good rationale for more and better neuroimaging studies in ME/CFS.

 

Just because I have no biological training and wondered:

(If you don't get this meme I strongly suggest you check out Chubbyemu on Youtube, it's really good and you'll get the joke)

 

Zack Shan got a AUD1.2m grant from NHMRC in late 2019 (the first researcher to get a grant for biomedical research into ME/CFS from the Australian government for more than 10 years).
https://www.usc.edu.au/about/usc-ne...research-to-diagnose-invisible-illness-faster

He has already launched a study: https://www.usc.edu.au/sunshine-coast-mind-neuroscience-thompson-institute/research/chronic-fatigue-syndrome-me-cfs-study

 

I’m curious if anyone has compared and contrasted this review with Crawley’s recent similar review on structural and functional MRI studies?
https://bmjopen.bmj.com/content/bmjopen/10/8/e031672.full.pdf

Thread here: https://www.s4me.info/threads/using...fs-me-almutairi-et-al-2020.16560/#post-285354

 

They put more emphasis on studies that reported changes in white and grey matter volume compared to the review by Shan.

This review also problematically claims that "sMRI has shown evidence of treatment effects on brain volume" referring to the study by De Lange et al. that doesn't provide any robust evidence for this.

The main finding however, seems consistent with the review of Shan et al. because the authors write:

 

I found this article, re: neurovascular coupling, good to get an idea:

Age-Dependent Impairment of Neurovascular and Neurometabolic Coupling in the Hippocampus
Cátia F. Lourenço et al 2018 PMC6056650

 

Some more recent articles on neurovascular coupling —

Neurovascular Coupling in Development and Disease: Focus on Astrocytes (2021, Frontiers in Cell and Developmental Biology)
Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences (2021, Nature Communications)
Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer’s disease (2022, Brain)
Mechanistic model for human brain metabolism and its connection to the neurovascular coupling (2022, PLOS Computational Biology)
Two decades of astrocytes in neurovascular coupling (2023, Frontiers in Network Physiology)

 

I'm not sure if this is the correct thread in which to ask this, but @SNT Gatchaman's post yesterday reminded me of this thread and that I wondered if, with these studies of reduced perfusion in pwME, other patients are seeing things like White Matter Hyperintensities in MRIs.

I just had an MRI recently to check for demyelinating disease given a host of seeming neurologic symptoms (sensory, spasms, etc.) that started a couple of years ago. No lesions but they did find multiple WMHs. I have no hypertension, hyperlipidemia (well, my LDL is slightly elevated), nor diabetes. I'm not physically active (obviously) and I do have obesity (though I do eat a healthy diet). I've long had headaches (intermittent stabbing pain on the right side that last for 30 seconds or so, as well as dull throbbing at the base of my skull) that were diagnosed as migraines when I first started having them twenty years ago but I'm not sure they are.

If cerebral hypoperfusion was common among pwME, wouldn't WMH be common?

 

I wouldn't expect white matter hyperintensities to be directly related to reduced cerebral perfusion. In clinical reports and scientific papers, they are often described as too small to adequately characterise (at 3T) and that they might be either CSF/fluid spaces or small foci of demyelination. I think they are most likely to be perivascular spaces and I hope this can be more reliably proven at 7T on research magnets. If so, then I've seen proposed explanations relating to abnormal trafficking of immune cells at this BBB interface, or representing an accumulation of uncleared waste.

See thread: Semi-automated Segmentation and Quantification of Perivascular Spaces at 7 Tesla in COVID-19 (2022)

 

Please forgive my my layperson's ignorance, but did you mean WMH are CSF/fluid spaces? In the radiologist's report on my MRI, he stated that my WMH were what he thought would be consistent with sequalae of chronic migraines or the beginning of chronic small vessel ischemic disease. And when I googled WMH, most of the usual health sites have been saying the same thing. But as I don't have any clinical experience, it's difficult to know what to make of all this. However, it was what made me wonder about reports of hypoperfusion in ME/CFS and WMH.

 

Definitely listen to your doctors' advice on this one. I'm trying to discuss generally and point out where there are things we would like to understand better. I'm also far from expert in adult neuro-imaging, so I may have misunderstandings of what we do know.

(When reading the following, T2-weighted sequences show fluid such as water, CSF as hyperintense/bright as well as non-fluid effects such as cytotoxic oedema eg ischaemia/infarction, vasogenic oedema eg around tumours/abscesses, gliosis from 'repaired' damage, loss of myelin, blood products; FLAIR generally makes fluids hypointense/dark, but tends to leave the non-fluid causes as hyperintense/bright. Things can show as FLAIR-bright for unusual reasons other than the above, including slow flow in vessels, as a transient post-seizure effect and we sometimes see it under general anaesthesia with supplemental oxygen.)

If the WMH are defined as purely FLAIR-hyperintense (bright) — excluding FLAIR-dark — then yes I think most interpretations would weight toward them being a marker of small-vessel ischaemic change. If they allow to include T2-hyperintense (bright) but FLAIR-hypointense (dark), then they could also include perivascular spaces where the T2 signal is following closest to CSF. Probably the definitions for WMH over recent years are tightening up to refer only to FLAIR-bright / T2 dark lesions and I probably need to brush up on the more recent literature. But FLAIR suppression doesn't always follow the rules if the fluid content is not simple CSF eg high protein content might stay high; so there are caveats, which is why I'm keen for us to learn more about these small abnormalities on the 7T research magnets.

With all that said, for clinical imaging, it's difficult to know what they might mean for any individual patient. There was an editorial in Mayo Proceedings in 2019 that is reasonably readable, that tries to answer what a neurologist might do in terms of advice for referred patients. The summary is probably: assume they represent a marker of vascular pathology and look for reversible factors to try and prevent progression. However, caveat being it's hard to know with certainty what they represent for that individual patient, so this advice is generally sensible and safe, even while playing the odds —

(From your earlier comment those risk factors don't seem to apply in your case @Michelle)

I wonder if they're more indirectly correlated.

Stated, but I don't think we know this for certain. Eg, continuing with —

I have baseline MRIs of my brain from a few years ago, but I'm a bit reluctant to see what it looks like now! Especially as there's not much I can do about it at the moment.

 

Thanks, @SNT Gatchaman . That's helpful.

Are WMHs the same as the so-called "Unidentified Bright Objects" that pwME have been seeing in MRIs for the last 40 years? The UBOs have always sounded like they were simply incidental findings whereas the WMHs sound, perhaps, more significant.

I can certainly understand that. After the radiologist's report posted to my account on our healthcare system's patient portal, I popped WMHs into Google and it made for grim reading. I believe the link you posted was the first or second link I clicked on and zeroed in on the correlation with stroke and dementia, as well as the reference on another site stating that only 5% of people have WMHs at age 50 (I only just turned 50 in December). Seeing that I don't have the most prominent risk factors (though I have wondered if I might be having postural hypERtension), there's not really much I can do about them.

I am grateful that you bolded the parts about the uncertainty that still remains regarding their meaning as well as the possibility they might even disappear. So far the only "discussion" I've had with my doctor has been a message he sent me via the portal to report on the radiologist's report saying nothing in my MRI explained my symptoms, the WMHs were due to chronic migraine (something we never discussed me having), and he'd see me in 6 months. Since there didn't seem to be anything else to do, I simply replied with a "thanks, I'll see you then."

But with all the talk about hypoperfusion, endothelial dysfunction, and microvasculature issues in ME/CFS, I couldn't help but wonder where--or if--WMHs might fit into the picture. I've even started dipping my toe into the role of estradiol and endothelial/microvascular function (I'm peri-menopausal atm), though PEM and my extremely rudimentary biochemistry will limit my trip down that rabbit hole.

 

I used to quite like the term 'UBO' but it's fallen out of favour. Technically they are identified (not unidentified), it's just that they're an unknown, so the name isn't quite correct I guess. I think there's a preference for more scientific-y terms, so 'hyperintensity' instead of 'bright'. Although it's a lot easier to type and say 'bright'. It also has the benefit in a clinical conference that 'bright' sounds very different to 'dark' so the potential confusion of hyper vs hypo doesn't happen. In practice people are generally looking at the bit in the image you're talking about on screen, so that's often moot.

The other thing is that UBOs aren't necessarily confined to white matter. The term has been used in children with neurofibromatosis, where they can be seen in the central grey matter (basal ganglia). There the term has been replaced by FASI (Focal Areas of Signal Intensity).

I think these findings in ME patients will be useful to understand. It was a common enough observation and as you say, regarded as incidental because we didn't know their significance. If they're present sometimes in people without overt neurological disease and noticed incidentally in scans for other reasons, it's hard to know what they might mean. I wonder whether they will come to be seen as more important than we realised (perhaps as a marker for BBB dysfunction or chronic inflammation). Similarly: choroid plexus calcification.

If it can be tied to BBB dysfunction, then generalised endothelial dysfunction could be part of that explanation, along with pericytes and specific aspects of the BBB not seen in the more general vasculature.