Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients (Thapaliya et al, 2023)

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID patients have overlapping neurological, autonomic, pain, and post-exertional symptoms. We compared volumes of brainstem regions for 10 ME/CFS (CCC or ICC criteria), 8 long COVID (WHO Delphi consensus), and 10 healthy control (HC) subjects on 3D, T1-weighted MRI images acquired using sub-millimeter isotropic resolution using an ultra-high field strength of 7 Tesla. Group comparisons with HC detected significantly larger volumes in ME/CFS for pons (p = 0.004) and whole brainstem (p = 0.01), and in long COVID for pons (p = 0.003), superior cerebellar peduncle (p = 0.009), and whole brainstem (p = 0.005). No significant differences were found between ME/CFS and long COVID volumes. In ME/CFS, we detected positive correlations between the pons and whole brainstem volumes with “pain” and negative correlations between the midbrain and whole brainstem volumes with “breathing difficulty.” In long COVID patients a strong negative relationship was detected between midbrain volume and “breathing difficulty.” Our study demonstrated an abnormal brainstem volume in both ME/CFS and long COVID consistent with the overlapping symptoms.

https://www.frontiersin.org/articles/10.3389/fnins.2023.1125208/full

 

Important study with the most advanced MRI scanning (that I know of).

Small but likely to lead to more understanding of brain function in ME and what is going on in the brainstem.

It appears there is larger volumes of tissue there, ?enlarged because of feedback loops from endothelial and mitochondrial dysfunction in the periphery disrupting ANS. (Just speculating, but science seems to be pulling a lot together recently. I am not sure, but also wondering if this may explain the problems of hypocapnia seen on 2 day CPET’s (if I recall correctly). Would need to read the paper more closely.

Appears to be a lot of emerging and positive research into structural brain function in ME and LC, (and sharing same pathways in pathophysiology). Though we didn’t have this level of radiographical testing until more recent times.

 

From Forebrain control of breathing: Anatomy and potential functions (2022, Frontiers Neurology) —

("We propose that the forebrain is important for ensuring that breathing matches current and anticipated behavioral, emotional, and physiological needs.")

Spoiler: Additional animal study that may upset some members

The Midbrain Periaqueductal Gray Control of Respiration (2008, J Neuroscience).

 

I don't know if this is the reason in my case but I've had breathing difficulties since the start of my disease, even though my triggering illness had zero respiratoy symptoms. The breathing difficulty (the feeling of not enough air coming in despite normal breathing) for me is unrelated to current ongoing exertion (of course it can make it worse but that's not what starts it) and is related to how I feel in general, it fluctuates together with my other symptoms. When I was at my worst, I felt I would almost suffocate at times when I had to speak and give short answers quickly. And a few times I kind of felt like that even without speaking. One of the first signs for me that I'm starting to feel better is that I can suddenly feel more air coming in.

 

They show about a 10-20% higher value in pons and brainstem for ME than controls. That is about as much as one could credibly expect I think, so not trivial. It would make a lot of sense if brainstem was abnormal in ME and one would probably expect it to be bigger rather than smaller.

I doubt this is inflammation. If it was then I think someone would have seen a change in signal before. It might be an increase in glial cells of one sort or another. I think it is much more likely to be primary than secondary to peripheral nervous signals from vessels or muscles.

It ought to be very simple to repeat this. If it replicates I think we may be a quantum leap ahead. But it has to replicate in good studies, read blind, with good numbers.

 

ME Research UK summary: https://www.meresearch.org.uk/research/brainstem-volume-changes-in-me-cfs-and-long-covid-patients/

ME Research UK on Twitter: “Dr Leighton Barnden @Griffith_Uni has published the first results from ME Research UK's funded study using MRI to explore the brains of pwME. It reports that ME/CFS & long COVID patients have larger than normal volumes of several areas of the brainstem.”

 

Highlighted by another person:

https://twitter.com/user/status/1631691274402004994



Re brainstem finding in #MECFS, just saying: "Poliomyelitis survivors exhibit no frank grey or white matter degeneration. To the contrary, increased partial volumes can be detected in the brainstem, cerebellum [...] compared to healthy individuals." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397913/#__ffn_sectitle

- Christoph Ströck (@cstroeckw)

 

That's good, but if we don't make replication happen, it will be ignored and forgotten like every other small ME study to date. No neurologist will look at this and think "hmm, this seems significant we should try to replicate it". They only care about visible MRI lesions and focal symptoms. ME doesn't have neither so it has been declared to be a fake illness a long time ago.

If we don't get together and make it happen (like we did with decodeME) it simply won't. This approach of "wait and hope it gets replicated" from a class of people that keep openly showing hostility towards us is not a good strategy. We cannot expect their help. I have tried in the past to involve local neurologists for a 7T MRI study (as i do think this area has untapped potential) and i was basically told to fuck off.

 

Referencing Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in CFS (2018) with its follow-on Anti-Correlated Myelin-Sensitive MRI Levels in Humans Consistent with a Subcortical to Sensorimotor Regulatory Process—Multi-Cohort Multi-Modal Evidence (2022), as well as Brainstem perfusion is impaired in chronic fatigue syndrome (1995) [Sci-Med].

(T1wSE = T1-weighted spin-echo MRI sequence. In this context high signal indicates fat / lipid / myelin.)

From the 2018 paper —

From the 2022 paper —

The 1995 nuclear medicine paper used older technology, SPET with 99mTc-HMPAO and said —

Typically you'd expect loss of myelin (demyelination) to reduce brain volume. Eg from Lesion activity and chronic demyelination are the major determinants of brain atrophy in MS (2019)

Traditionally the term demyelination indicates previously normal myelin that is damaged (eg in MS). Dysmyelination is when the myelin does not form correctly. Usually dysmyelinating disorders are seen in inborn errors of metabolism eg leukodystrophies, although practically speaking in those conditions I think it's now considered that there is often a combination of de- and dys-myelination.

These combined findings (if replicated) of reduced myelin signal but increased volume in the brainstem make me wonder whether there is an acquired process that is somewhere between dysmyelination and demyelination. I.e. that the myelin was previously normal but becomes impaired, though not destroyed, similar to if it had been malformed initially. However, rather than relating to cerebral blood flow and oxygen delivery (which might be completely orthogonal or at least indirectly related) I'd be more thinking about abnormal lipid metabolism, which is very important for myelin.

See Myelin lipid metabolism and its role in myelination and myelin maintenance (2022), which has subsections on —

• Myelin maintenance is an active process
• Continual and frequent myelin lipid self-renewal is necessary for myelin maintenance
• Leukodystrophies highlight an intersection between lipid dysmetabolism and myelin pathology
• Myelin instability and lipid dysregulation are featured in Alzheimer’s disease

Concluding —

Perhaps there is locally increased quantity as a compensation for decreased quality, so more volume but lower lipid signal?

 

@SNT Gatchaman would the brainstem problems you’ve highlighted be detectable using brainstem auditory evoked response testing (BAER or ABR)?

I noticed that within the 2007 CFS/ME guideline, the test was explicitly mentioned not to be routinely provided which I thought was odd given the symptoms such as tinnitus that pwME experience.

I’m revisiting the potentials of the test. So far, it turns out that within neurology, it is used to detect anatomic disturbances of the brainstem auditory pathways, especially those caused by myelin disruption.
https://www.sciencedirect.com/science/article/abs/pii/S0733861918308429

ABRs are also commonly abnormal in brainstem disorders such as multiple sclerosis, brainstem stroke, or brainstem degenerative disorders. To detect brainstem dysfunction, the test requires an otoneurologist to interpret the results.

 

I had a brainstem evoked response audiometry(BERA) test in 1993 because I had vertigo. It was normal.

 

I don't know anywhere near enough about ABR to comment on that, but it might be a good area for investigation. It may be that these findings are giving us a clue about problems that can be more widespread in the brain. Or maybe there are more common regions of vulnerability.

Having read through the myelination review paper, I think it's worthwhile posting it separately for discussion, as it seems to me that acquired deficits of myelination relating to impairments of lipid metabolism could quite elegantly explain aspects of brain fog, hypersensitivities and other neurological symptoms we can experience — and in particular their variable nature. In other words, with the principle that function depends on structure, this could be the structural abnormality that explains "functional" neurological disorders. I'll make a separate thread on this later today.

ETA: Thread on Myelin lipid metabolism and its role in myelination and myelin maintenance (2022)
ETA2: See also this post in the thread: Brainstem Abnormalities in [ME/CFS]: A Scoping Review and Evaluation of Magnetic Resonance Imaging Findings (2021).

 

Moved post

An article about the recent Griffith MRI study.

 

Long Covid Brain Changes Mirror Those of Chronic Fatigue, Brain Scans Reveal

"Long COVID and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) both seem to impact the oldest parts of the brain in a curiously similar fashion.

Using a high-resolution version of magnetic resonance imaging ( MRI), researchers in Australia have shown the brainstem regions of 10 ME/CFS patients and 8 long COVID patients are significantly larger than those of 10 healthy control subjects."

https://www.sciencealert.com/long-c...r-those-of-chronic-fatigue-brain-scans-reveal

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