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

John Mac

John Mac

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

Abstract
Background
Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible.

Method
To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported.

Results
63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies.

Conclusion
Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.
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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



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:
Neurovascular coupling is the term used to describe alterations in local perfusion that occur in response to changes in neuronal activity. Also known as functional hyperemia
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(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)
 
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Simone said:
I’m curious if anyone has compared and contrasted this review with Crawley’s recent similar review on structural and functional MRI studies?
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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:
"The most consistent finding was CFS/ME exhibited increased activations and recruited additional brain regions."
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Thanks for that very helpful summary @Michiel Tack
Great that Shan is proposing objective measurement of activity.

Re the collaborative neuroimaging databank for ME/CFS. That sounds good. Even just a neuroimaging databank for a range of controls would be a start - along with a whole lot of protocols for how and when to do the neuroimaging. There was the issue of even things like time of day impacting on imaging.
 
 
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)
 
SNT Gatchaman said:
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.
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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.
 
Michelle said:
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
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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 —

What are WMHs and what causes them? Are they the same as a stroke? Are they a marker for impending stroke, dementia, or death?
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Changes in the white matter of presumed vascular origin were first identified as hypo-attenuation of the white matter on computed tomography but now are more often seen as patchy areas of signal hyperintensity in deep and periventricular white matter areas on T2-weighted sequences, particularly fluid- attenuated inversion recovery.
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Aging and hypertension are the main predictors of WMHs, and genome-wide association studies have identified associations with genes involved in blood pressure regulation. Other risk factors associated with WMHs include diabetes, hypercholesterolemia, smoking, carotid artery disease, atrial fibrillation, and heart failure.
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(From your earlier comment those risk factors don't seem to apply in your case @Michelle)

The observed associations with adverse outcomes suggest that these lesions are a surrogate marker for the burden of vascular risk factors and a marker of diffuse vascular pathology involving different cerebral, cardiac, and systemic vasculatures.
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I wonder if they're more indirectly correlated.

Similar to small subcortical infarcts, lacunes, cerebral microbleeds, and enlarged perivascular spaces, WMHs are a manifestation of small vessel disease.
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Stated, but I don't think we know this for certain. Eg, continuing with —

In addition, other processes that may be involved in the genesis of WMHs include dysfunction of oligodendrocyte precursor cells, failure of the glymphatic system, venous collagenosis, and alterations in RNA transcription.
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Studies using serial imaging have shown that WMH can increase in size, shrink, or, in rare instances, disappear and, thus, raise the possibility that the process may be reversible before axonal damage and demyelination have occurred.
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Although we have learned a great deal about the etiology, associations, and implications of WMHs in the past 2 decades, there is still much uncertainty about what to do when they are identified. Because they are a manifestation of small vessel disease and have been associated with several vascular risk factors, it makes sense to screen patients who harbor WMHs in their scans for these risk factors.
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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.

SNT Gatchaman said:
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.
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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." :unsure:

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. :oops:
 
Michelle said:
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.
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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.
 
I wonder if any of the findings here are worthy of being added to the thread 'What are the top replicated ME/CFS findings?'.

I've only read (most of) the paper and haven't followed up on the cited studies. These seem to be the findings they say have been replicated in greater than two studies:

Additional brain regions recruited for cognitive tasks in patients with ME/CFS
We identified 12 task functional MRI studies of ME/CFS [14, 16, 20,21,22,23,24,25,26,27,28,29]. Different patterns of blood oxygenation level-dependent (BOLD) signal changes associated with tasks were reported in each article (detailed in SI). Of these 12 studies, 10 articles reported that patients with ME/CFS either recruited additional brain regions or had a greater BOLD response than controls for cognitive tasks but with the same performance [16, 20,21,22,23,24,25, 27,28,29], although decreased BOLD activity was also reported in specific regions. Two remaining studies tested basal ganglia function [14] and reward sensitivity [26] and observed lower BOLD changes in basal ganglia in gambling tasks [14] and lower BOLD changes in the putamen in low-reward condition gambling task [26].
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Abnormalities identified in the brain stem of patients with ME/CFS
Five studies from two groups reported structural abnormalities in the brain stem in ME/CFS using MRI [30,31,32,33,34].
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Greater BOLD response than controls for cognitive tasks but with the same performance
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Structural abnormalities in the brain stem
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