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

[Jaybee00]

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

 

[hibiscuswahine]

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.

 

[SNT Gatchaman]

In long COVID patients a strong negative relationship was detected between midbrain volume and “breathing difficulty.”

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.")

Located in the midbrain, the periaqueductal gray (PAG) serves as an interface between the forebrain and the brainstem to produce integrated behavioral responses to internal or external stressors (e.g., pain or threats). The PAG coordinates respiratory, cardiovascular, and pain responses, as well as plays a part in vocalization, cough, sneeze, swallow, crying, laughter, micturition, arousal, thermoregulation, and sexual behaviors. As part of the “emotional motor system,” a major role of the PAG is likely to regulate breathing in response to emotional challenges and survival programs such as “fight or flight” or freezing responses.

The PAG receives inputs from the prefrontal cortex, amygdala, hypothalamus and nociceptive pathways and coordinates respiratory, cardiovascular, motor, and pain responses via efferents to the brainstem, forebrain and spinal cord. Electrical or chemical stimulation of the PAG changes breathing patterns in rodents. Importantly, the pattern produced is dependent on which part of the PAG is stimulated. The effects of PAG stimulation on breathing include increasing respiratory frequency (e.g., tachypnea) and inspiratory effort (dorsal PAG, ventral part of lateral PAG), lengthening (e.g., apneusis) or shortening the inspiratory period (lateral PAG), or apnea (ventrolateral PAG). The PAG is part of a descending system that modulates airway sensory processing, critical for control of breathing and breathing related behaviors, via projections to the nucleus of the solitary tract. The PAG can also directly control breathing through projections to the preBötzinger complex that modify the activity of pre-inspiratory neurons. In addition, the PAG projects to the nucleus retroambiguus, a medullary region important for airway control during breathing, vocalization, and other behaviors, as well as the Raphe nuclei and adrenergic nuclei. Thus, the PAG relays information from the forebrain to the brainstem to ensure that breathing patterns suit current behavioral or emotional needs such as fleeing predators, freezing, talking, crying, coughing, etc.

Spoiler: Additional animal study that may upset some members

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

 

[Wyva]

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.

 

[Hutan]

Hmm, Barnden is a good researcher, but, as the research team acknowledges, the sample sizes are small. Also, the gender ratios are a bit skewed, there are a higher proportion of women in the healthy controls than in the LC and ME/CFS cohorts. I expect they adjust brain volumes for males/females, but then the adjustment is a potential source of error.

Such volume increases may reflect edema of inflammatory responses, neurodegeneration, and/or viral invasion

The researchers suggest that the increased brainstem and pons volumes might be due to these factors.

I find pain and breathing difficulties rather odd choices of measures of severity; I would have thought that an overall quality of life or measure of incapacity might have been better. The researchers had a whole lot of measures available to them, so I wonder if perhaps these two symptoms were the only ones that happened to correlate well with some of the brain measures?

Symptom presentation was collected using the NCNED Research Registry questionnaire developed by NCNED with the Centres for Disease Control and Prevention (CDC) Symptom Inventory Questionnaire distributed online through LimeSurvey. The presence and severity of each symptom was assessed on a five-point scale: (1) very mild; (2) mild; (3) moderate; (4) severe; and (5) very severe. Validated patient-reported outcome measures were used to determine participant quality of life (QoL) and functional capacity. The 36-item short form health survey (SF-36) (Alonso et al., 1995) has been frequently employed in previous observational studies to assess QoL among people with ME/CFS (Eaton-Fitch et al., 2020), as well as, more recently, among people with the long COVID condition (O’Kelly et al., 2022). Eight QoL domains were assessed including physical functioning, role limitations due to physical health problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to personal or emotional health, and emotional wellbeing/mental health. Survey item scores were assigned a value between 0 and 100, before scores were averaged for each domain.

For subsequent correlation analysis, the severity measure of “pain” was extracted from SF36v2, while breathing scores were obtained via the NCNED Research Registry questionnaire.

If you look at Figure 3A-D which plot the individual results, the results are rather underwhelming and there is further selectivity about what is shown. For example for 3B which is pain vs brain stem volume, we are only shown the ME/CFS results, and you only need to ignore a couple of results to end up with pretty much no relationship at all between pain and brainstem. The results for breathing difficulty vs midbrain volume don't look that convincing to me. If you take one point away from each of the charts for ME/CFS and LC, there isn't much of a relationship.

I find the lack of variability in the ME/CFS volumes in Figure 2 a bit odd.

I think we need to see this study repeated in a larger cohort before we get too excited that there is something real here.

 

[Jonathan Edwards]

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.

 

[Robert 1973]

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.”

 

[Hutan]

Improving Accuracy of Brainstem MRI Volumetry: Effects of Age and Sex, and Normalization Strategies
That paper found that estimated brainstem volumes didn't change much with the scanner or protocol used. From a sample of 110 people:

Men had significantly larger unadjusted volumes of the total brainstem, mesencephalon, pons, and medulla oblongata (all p <0.0001, respectively), compared to women with total brainstem volumes of 28274.0/2670.1 for men (mean [mm3]/SD) vs. 24826.2/2824.1 (mean [mm3]/SD) for women.

Using these figures, the LC and ME/CFS results from this new study are looking more normal (23,000 and 23,000 respectively) than those of the healthy controls (19,000).

Here's the results of another study of people with MS and healthy controls:

Volumes of whole brainstem, medulla, and pons showed a significant decrease in RRMS cases compared to controls (p < 0.05). Brainstem volume had a mean volume of 22.17 and 25.09 cm3 in cases and controls, respectively.

So, still, the LC and ME/CFS volumes are looking more normal.

A malfunctioning brainstem would make sense in terms of some symptoms, and maybe it is the most vulnerable part of the brain to impacts of infection. It's not an unreasonable idea. But, with such small samples and the reported brain volumes in this new study not appearing to be larger than we might expect in normal brains, I'm just not sure we are seeing a real effect.

 

[Hutan]

Here's another sample of normal brainstem volume in 182 healthy subjects. x axis is age. Sorry for the poor quality image. Most people had brainstem volumes between 22.5 and 27.5 cm3 (1 ml = 1 cm3).

Maybe there was something unusual about the measurement approach in the Thapaliya study?

 

[Midnattsol]

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.

We have a thread on breathlessness and air hunger in ME, where more of us report not getting enough air/at least feeling like we don't get enough air: Breathlessness and air hunger in ME/CFS

 

[FMMM1]

Highlighted by another person:




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)

 

[Hutan]

The above paper about polio survivors concluded:

Our imaging data indicate cortical and white matter reorganisation in polio survivors, which may be interpreted as compensatory adaptation to severe lower motor neuron injury acquired in infancy.

There's this 2020 review which did not report evidence for increased brainstem volume.
Neuroimaging characteristics of ME/CFS: a systematic review. Shan et al. 2020
Specifically, there is the supplementary table with summaries for each study. There are studies with conflicting results on the brainstem volume question.
Also this review covering similar ground:
Using structural and functional MRI as a neuroimaging technique to investigate CFS/ME. Almutairi et al. 2020

 

[Hubris]

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.

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.

 

[Hutan]

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.

Indeed. Both those reviews I linked to reported that past studies have been too small and otherwise flawed. There needs to be funding for sufficiently well powered studies.

 

[SNT Gatchaman]

In ME/CFS patients, decreased myelin-sensitive T1-weighted spin echo signals were detected in the brainstem and the brainstem perfusion ratios were reduced. The brainstem contains the nuclei of the reticular activation system which control arousal, the sleep/wake cycle, gait, and memory via cortical connections and cardio-respiratory function.

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 —

In CFS T1wSE was elevated in sensorimotor WM and decreased in the brainstem. In both healthy controls and CFS, T1wSE (myelination) in sensorimotor WM showed the same inverse correlation with T1wSE in the brainstem. This relationship, previously unreported in either healthy controls or CFS, suggested a possibility that in CFS a normal regulatory mechanism had responded to impaired brainstem signal conduction to stimulate elevated sensorimotor myelination. This complements evidence in CFS for severity dependent myelin upregulation in the internal capsule. Deficits in brainstem function in CFS can have broad consequences for regulation of cerebral function in general and myelination in particular and should be a focus of future research in CFS.

From the 2022 paper —

In cross-sectional studies using multimodal human brain MRI images with voxel values sensitive to myelin levels, in 9 independent image-sets, we confirmed the novel anti-correlation between subcortical (brainstem) and sensorimotor myelination reported in 2018. The inverse relationship was confirmed in two T1wSE, one T2wSE, MTC, T2SPACE and a relative WM volume image-set, all of which respond to myelin levels.

Lower myelination in the subcortical region was associated with increased myelination in sensorimotor white matter, and vice versa. This study is unique in that it reports unprecedented observations of a myelination relationship across human populations with good reproducibility.

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

Brainstem hypoperfusion appears to be the differentiating factor between our ME-CFS patients and those with major depression. Other recent findings seem to corroborate our results.

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)

Because myelin sheaths occupy approximately 25%–30% of the white matter volume, loss of myelin will lead to a direct reduction in brain volume.

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 —

Myelin requires enrichment of diverse lipids, including cholesterol, GalC, and plasmalogens. Disruption of lipid metabolism is detrimental to myelin formation and stability, an observation reinforced by mouse and human genetic studies. Various mutations associated with demyelination suggest that myelin health requires intact lipid pathways with a steady equilibrium between lipid synthesis and degradation.

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

 

[livinglighter]

@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.

 

[Mij]

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

 

[SNT Gatchaman]

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

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).

 

[Art Vandelay]

Moved post

An article about the recent Griffith MRI study.

Griffith University researchers identify similar brain structure changes in both chronic fatigue syndrome and long COVID

In a world-first study, Queensland researchers have identified similar changes in brain structure among people who have long COVID and chronic fatigue syndrome.

Griffith University scientists used a high-powered magnetic resonance imaging scanner to compare the brains of 28 adults.

Eight had long COVID, 10 people had been diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and 10 were healthy volunteers.

The researchers, from Griffith's National Centre for Neuroimmunology and Emerging Diseases, found the brainstem was significantly larger in long COVID patients and those with ME/CFS compared to people who had never been diagnosed with either ailment.

"Structural changes in the brain stem of ME/CFS and long COVID patients could result in severe and varied deficits in brain function," they wrote in a study published in the journal, Frontiers in Neuroscience.

'Scary' impact of long COVID
Disability support worker Sue Murphy developed long COVID after contracting the pandemic virus in January last year.

The 63-year-old, who welcomed research into the malady, has been off work since then with debilitating symptoms, including fatigue, heart problems, breathlessness, migraines and muscle pain.

She's had brain fog so bad she had to pull over on the way home after having some blood tests and scans because she "could not recognise where I was".

"It was absolutely scary," Ms Murphy recalled.

"I had to actually put my home address in my phone in Google maps to get home."

 

[Andy]

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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