Opposite white matter abnormalities in post-infectious vs. gradual onset chronic fatigue syndrome revealed by diffusion MRI, 2024, Yu et al

[John Mac]

Now published - see Post #6

Preprint
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex and debilitating illness with an unknown pathogenesis. Although post-infectious (PI-ME/CFS) and gradual onset ME/CFS (GO-ME/CFS) manifest similar symptoms, it has long been suspected that different disease processes underlie them. However, the lack of biological evidence has left this question unanswered.

In this study, we recruited PI-ME/CFS and GO-ME/CFS patients based on consensus diagnoses made by two experienced clinicians and compared their diffusion MRI features with those of rigorously matched healthy controls (HCs) with sedentary lifestyles.

PI-ME/CFS patients showed significantly higher axial diffusivities (ADs) in several association and projection fibres compared to HCs.
Higher AD values in PI-ME/CFS were significantly related to worse physical summary scores.

In contrast, GO-ME/CFS patients exhibited significantly decreased ADs in the corpus callosum. Lower AD values in GO-ME/CFS patients were significantly associated with lower mental summary scores in commissural and projection fibres.

Distinct patterns of AD alterations in PI-ME/CFS and GO-ME/CFS provide neurophysiological evidence of different disease processes and highlight the heterogeneities of ME/CFS.
These results also help explain inconsistent findings in previous ME/CFS studies and guide future intervention design.

https://www.medrxiv.org/content/10.1101/2024.08.04.24311483v1

 

[boolybooly]

Interesting first pass study suggesting subtypes based on changes to neurological structures.

143 participants, including 76 patients with ME/CFS (mean age, 42.64 ± 12.71 [standard deviation]; 64 women) and 67 HCs (mean age, 37.51 ± 11.57 [standard deviation]; 52 women).

Requires replication to be sure and corroboration by other studies like Decode ME.

Increased AD (axial diffusivities) in PI-ME/CFS patients might be related to acute inflammatory responses following an infection, whereas decreased AD in GO-ME/CFS patients may reflect chronic neurodegenerative processes.

We hypothesise that inconsistencies in findings across studies may arise from differences in sample characteristics, patient criteria, or statistical methodologies.

Diagnostic criteria once again proving imprecise. Meanwhile methodology has no standard.

Even if the reported neurological differences between infectious vs gradual onset ME patients were proved consistent, we still dont know whether their underlying disease mechanism is the same, or different.

For discussion, is it two manifestations of an immune related mechanism gone awry, one due to infection of the nervous system by say HSVs and the other due to slower acting infection of other tissues like immune cells by other viruses say EBV? Or is it two entirely different mechanisms which both happen to cause fatigue?

The decades roll past and still we have no clue because studies like this are done, go on the pile, are ignored, more studies done and ignored, rinse repeat. There is no deductive overview at work requiring replication, seeking certainty and identifying questions arising then tracking down answers. Its just "lets start here" over and over again.

 

[Deanne NZ]

Have there been any previous studies that differentiated between post infection & gradual onset?

 

[Ravn]

Possibly results from this grant?

https://www.s4me.info/threads/australian-me-cfs-neuroimaging-project-receives-1-2m-govt-grant.12748/

See also this study

https://www.s4me.info/threads/absen...-by-task-functional-mri-2024-schönberg.39688/

On a quick glance this looks to be a good-sized cohort by ME standards, carefully diagnosed, and with well matched controls - notably including for activity

Maybe someone with relevant expertise can comment on the quality of the method and the interpretation of the results?

 

[Ravn]

Have there been any previous studies that differentiated between post infection & gradual onset?

I believe so. Not scans, something else. But for the life of me I can't recall what or who or when

 

[SNT Gatchaman]

Published in July —

Distinct white matter alteration patterns in post-infectious and gradual onset chronic fatigue syndrome revealed by diffusion MRI

Spoiler: Authors

Yu, Qiang; Kwiatek, Richard A; Del Fante, Peter; Bonner, Anya; Calhoun, Vince D; Bateman, Grant A; Yamamura, Takashi; Shan, Zack Y

While post-infectious (PI-ME/CFS) and gradual onset (GO-ME/CFS) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) manifest similar symptoms, it has long been suspected that different disease processes underlie them. However, the lack of biological evidence has left this question unanswered.

In this study, how white matter microstructural changes in PI-ME/CFS and GO-ME/CFS patients were investigated. PI-ME/CFS and GO-ME/CFS patients were recruited based on consensus diagnoses made by two experienced clinicians and compared their diffusion MRI features with those of rigorously matched healthy controls (HCs) with sedentary lifestyles.

PI-ME/CFS participants showed significantly higher axial diffusivity (AD) in several association and projection fibres compared to HCs. Higher AD in PI-ME/CFS was significantly related to worse physical health. In contrast, GO-ME/CFS participants exhibited significantly decreased AD in the corpus callosum. Lower AD in GO-ME/CFS was significantly associated with worse mental health in commissural and projection fibres. No significant group differences were found for fractional anisotropy, mean diffusivity, or radial diffusivity.

Distinct patterns of AD alterations in PI-ME/CFS and GO-ME/CFS provide neurophysiological evidence of different disease processes and highlight the heterogeneities of ME/CFS.

Web | DOI | PDF | Nature Scientific Reports | Open Access

 

[Hutan]

My set point for brain imaging studies is skepticism, dialled up higher than my usual level of skepticism, so, that's pretty high. But this is a decent sized study and they have made a good effort to match the controls. Also, this work has been led by Zack Shan in Queensland, Australia and he has a strong track record.

And, I note that they have identified increased axial diffusivity in the post-infectious group in the right superior longitudinal fasciculus and right uncinate fasciculus.

Higher AD in PI-ME/CFS participants than HCs
Figure 2 illustrates the TBSS AD results between the HCs and PI-ME/CFS patient groups in MNI 152 standard space. As shown in Fig. 2, the ADs in the PI-ME/CFS patient group were significantly higher than those in the HCs in the following fibre tracts: association fibres (right superior longitudinal fasciculus, right uncinate fasciculus, and right external capsule), and projection fibres (left inferior cerebellar peduncle, middle cerebellar peduncle, left superior cerebellar peduncle, right superior corona radiata, right posterior corona radiata, right sagittal stratum, corticospinal tract, and left medial lemniscus).

There's a small 2013 study
Increased Brain White Matter Axial Diffusivity Associated with Fatigue, Pain and Hyperalgesia in Gulf War Illness, Rayhan et al
where they found that

Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus.

Does the right inferior fronto-occipital fasciculus have anything to do with the right superior longitudinal fasciculus and right uncinate fasciculus? I have no idea but some of the words are the same.

Also, that 2013 study was by Baraniuk and ... Walitt. And there was some wittering about the identified sites being linked with emotional and reward processing (yes, Walitt was doing that even back then in 2013).

 

[Hutan]

This is AI generated, about the three association fibre locations mentioned by the 2025 study:

• Right Superior Longitudinal Fasciculus (SLF): The SLF is a large association tract that connects the frontal lobe with the parietal and occipital lobes. It runs in the white matter lateral to the centrum semiovale, arching around the insula. The SLF has multiple components (SLF I, II, and III) with distinct pathways and cortical terminations. It is situated superior and parallel to the arcuate fasciculus (AF).
• 
  
• Right Uncinate Fasciculus (UF): The UF is a hook-shaped bundle of fibers that connects the anterior temporal lobe (including the amygdala and parahippocampus) with the inferior frontal gyrus and orbitofrontal cortex. It passes through the temporal stem and is located in the ventral external capsule, just posterior to the limen insulae.
• 
  
• Right External Capsule (EC): The external capsule is a thin sheet of white matter located between the putamen (medially) and the claustrum (laterally). It contains association fibers, including parts of the inferior occipitofrontal fasciculus and the uncinate fasciculus, as they pass through the region.

It says that the Right External Capsule includes parts of the right inferior occipitofrontal fasciculus. I'm willing to bet that that is the same as the right inferior fronto-occipital fasciculus that the 2013 Baraniuk study mentioned.

So, it does sound as if the findings of the 2025 ME/CFS study do overlap with the findings of the 2013 Gulf War study.

I guess I should have finished reading the 2025 study, they may well have noted this connection. Edit - no, I don't think they did, I couldn't see the paper in the reference list.

 

[Utsikt]

This study has some limitations that should be acknowledged. First, the significant associations of AD-PCS in PI-ME/CFS and AD-MCS in GO-ME/CFS groups were lost when the multiple regression analyses were conducted in the patient group.

What are the implications of this?

 

[DHagen]

These findings suggest that a one-size-fits-all treatment approach is unlikely to be effective. Instead, further investigation into the relationship between clinical manifestations and these neurobiological profiles could inform the development of personalised interventions. For instance, patients with post-infectious onset and evidence of neuroinflammation-related white matter changes may benefit from therapies targeting immune dysregulation or neuroinflammation. In contrast, individuals with gradual onset ME/CFS who show signs of possible chronic axonal damage or metabolic stress may require strategies focused on neuroprotection, mitochondrial support, or cognitive rehabilitation.

While I am very aware of my limited ability to evaluate a study such as this, and that matching up one's own subjective symptoms with an imperfect study and extrapolating from minimal information is obviously quite foolish... I must say that, as a person with gradual onset ME and a lot of cognitive issues (indeed, I would characterize my symptoms as primarily cognitive), this is pretty damn discouraging, especially as reading about the sort of damage associated with low axial diffusivity seems to match up pretty damn well for me.
Not that it matters.

 

[PageofME]

Why do these researchers think that post-infectious and gradual-onset are mutually exclusive? If we have learned something form the Covid pandemic it certainly is that Covid can trigger both gradual-onset and severe fast-onset.

My guess is that if we looked at what explains the difference between gradual onset and seriously sick fast we'd find out that the first group rested during their first ME episode because they thought or were told that they were sick while the latter thought or were told that they're healthy and just needed to push through their lingering symptoms. And genetical immunological differences would account only for a low percentage of that difference.

By the way, I think that ME/CFS is itself infectious. I think that I got ME from dating a mild gradual-onset and undiagnosed ME patient who complained at the time about feeling recurrently flu-like, fatigued, and with a sore throat after running.

This is just one more piece of evidence in my personal ME puzzle why I belive that Jaqueline Cliff with her HHV-6B hypothesis is on the right track!

Also, there aren't just many families where there are several ME patients and which seems to lead some researchers to believe that there is an important genetic component. I think that there is also strikingly high number of couples where both have ME which rather hints at ME being infectious itself too.

 

[PageofME]

While I am very aware of my limited ability to evaluate a study such as this, and that matching up one's own subjective symptoms with an imperfect study and extrapolating from minimal information is obviously quite foolish... I must say that, as a person with gradual onset ME and a lot of cognitive issues (indeed, I would characterize my symptoms as primarily cognitive), this is pretty damn discouraging, especially as reading about the sort of damage associated with low axial diffusivity seems to match up pretty damn well for me.
Not that it matters.

I feel for you, DHagen.

For myself, I have already decided that ME has left me brain injured and have joined a brain-injury self-help group recently.

I find it helpful because it helps me to begin to accept being chronically ill with some irreversible damages.

 

[DHagen]

For instance, patients with post-infectious onset and evidence of neuroinflammation-related white matter changes may benefit from therapies targeting immune dysregulation or neuroinflammation. In contrast, individuals with gradual onset ME/CFS who show signs of possible chronic axonal damage or metabolic stress may require strategies focused on neuroprotection, mitochondrial support, or cognitive rehabilitation.

If the findings and interpretation are accurate (and they may not be), this section in particular seems to suggest that post-infectious ME/CFS may be treatable, while those with gradual onset will be left with the same bullshit we already have (i.e. sweet FA). I suppose I commented mostly because this has been a persistent fear of mine.

 

[ScoutB]

The MRI cross-sections are useful to understand *where* they found significant differences, but I wish we also had scatter plots to see how much the patients and controls overlap. (Assuming that's a meaningful question to ask in this context, idk much about MRI results.)

I must say that, as a person with gradual onset ME and a lot of cognitive issues

In the same boat here. Have we ever polled on S4ME if gradual onset seems more associated with cognitive symptoms (and infectious or sudden onset with physical symptoms)? Would be interested in hearing from others.

I found mention of "low axial diffusivity in the corpus callosum" in a study of children with Developmental Coordination Disorder. Their symptoms remind me a bit of the motor control issues I get when I'm feeling worse. In that study they say:

Given that we did not find any differences in radial diffusivity or mean diffusivity, we can likely rule out demyelination or dysmyelination (driven by radial diffusivity changes) or membrane density (driven by mean diffusivity) as potential factors in the pathophysiological process of DCD. We suggest that the low fractional anisotropy and low axial diffusivity observed in children with DCD are potentially manifestations of impaired microstructure associated with altered axonal development.

Which might be relevant as this thread's ME/CFS study also found no differences in radial or mean diffusivity.

 

[Utsikt]

Why do these researchers think that post-infectious and gradual-onset are mutually exclusive? If we have learned something form the Covid pandemic it certainly is that Covid can trigger both gradual-onset and severe fast-onset.

They might just be looking to see if there are any differences. I don’t think it’s uncommon for diseases to have different variations, and type of onset seem like something that might at least be plausible.

By the way, I think that ME/CFS is itself infectious. I think that I got ME from dating a mild gradual-onset and undiagnosed ME patient who complained at the time about feeling recurrently flu-like, fatigued, and with a sore throat after running.

I think we’d see a lot more evidence of carers of pwME/CFS getting ME/CFS themselves then. And for it to be infections, it would have to be caused by an «ME/CFS pathogen», and that doesn’t match with people getting ME/CFS following pretty much and kind of infection, or seemingly without any infection at all.

It seems much more likely that ME/CFS is caused by one or more flaws in the immune system rules that makes it possible to randomly get stuck in some kind of ME/CFS state. That would be more likely to happen following immune activation from an infection, but could by chance happen without infections as well.

 

[Mij]

@PageofME you might be interested in reading this story This is where I live and became ill from sudden viral ME onset in 1991. It's very interesting with the recent studies that show EBV could have a strong link to MS.

"Dutrisac wants to know why 14 former neighbours — all about the same age, all from the small suburban enclave of Elmvale Acres — were also diagnosed with MS as adults."

"Dutrisac said three of his childhood playmates from Plesser Street were later diagnosed with MS, including Diane Ladouceur. Dutrisac first heard about Ladouceur's diagnosis about a month after his own in 1991.

"And then a few weeks later, I found out that one of our neighbours … who was a few years younger than us, well she was diagnosed with MS. So I'm saying, 'This is kind of strange,'" said Dutrisac."

 

[PageofME]

They might just be looking to see if there are any differences. I don’t think it’s uncommon for diseases to have different variations, and type of onset seem like something that might at least be plausible.

I think we’d see a lot more evidence of carers of pwME/CFS getting ME/CFS themselves then. And for it to be infections, it would have to be caused by an «ME/CFS pathogen», and that doesn’t match with people getting ME/CFS following pretty much and kind of infection, or seemingly without any infection at all.

It seems much more likely that ME/CFS is caused by one or more flaws in the immune system rules that makes it possible to randomly get stuck in some kind of ME/CFS state. That would be more likely to happen following immune activation from an infection, but could by chance happen without infections as well.

Reactivation of herpesviruses in Myalgic Encephalomyelitis

Human Herpesvirus 6B in Myalgic Encephalomyelitis pathogenesis: temporal analysis of viral reactivation and immunity toelucidate cause vs effect

www.brunel.ac.uk

Everything you say is compatible with the hypothesis that HHV-6B reactivation is the cause of ME. Check out Jaqueline Cliff's research under the link above.

 

[PageofME]

@PageofME you might be interested in reading this story This is where I live and became ill from sudden viral ME onset in 1991. It's very interesting with the recent studies that show EBV could have a strong link to MS.

"Dutrisac wants to know why 14 former neighbours — all about the same age, all from the small suburban enclave of Elmvale Acres — were also diagnosed with MS as adults."

"Dutrisac said three of his childhood playmates from Plesser Street were later diagnosed with MS, including Diane Ladouceur. Dutrisac first heard about Ladouceur's diagnosis about a month after his own in 1991.

"And then a few weeks later, I found out that one of our neighbours … who was a few years younger than us, well she was diagnosed with MS. So I'm saying, 'This is kind of strange,'" said Dutrisac."

Yes, I know of the MS - EBV relation.

I don't know a lot about EBV but I know that it is the only Human Herpes Virus that manages to get itself into the core of the cell to repiclate. It therefore directly changes the chromosomes of cells. The other herpes viruses can't do that. They can only change what's synthesized in the "cell lab" outside of the core.

 

[SNT Gatchaman]

I must say that, as a person with gradual onset ME and a lot of cognitive issues (indeed, I would characterize my symptoms as primarily cognitive), this is pretty damn discouraging, especially as reading about the sort of damage associated with low axial diffusivity seems to match up pretty damn well for me.

Except it may not be damage. (In the same way T cell subset exhaustion markers do not mean globally tired T-cells.)

The changes in diffusivity might not indicate neuroinflammation or cell damage. It could relate to myelin maintenance and even be compensatory, ie increased or decreased to preserve conduction velocities for signalling between brain regions that rely on simultaneous time-of-flight for effective neurological performance. (Perhaps this process might be deficient in FND.) See —

Change of conduction velocity by regional myelination yields constant latency irrespective of distance between thalamus and cortex (2003)

Spoiler: Abstract

The widely spanning sensory cortex receives inputs from the disproportionately smaller nucleus of the thalamus, which results in a wide variety of travelling distance among thalamic afferents. Yet, latency from the thalamus to a cortical cell is remarkably constant across the cortex (typically, ≈2 ms).

Here, we found a mechanism that produces invariability of latency among thalamocortical afferents, irrespective of the variability of travelling distances. The conduction velocity (CV) was calculated from excitatory postsynaptic currents recorded from layer IV cells in mouse thalamocortical slices by stimulating the ventrobasal nucleus of the thalamus (VB) and white matter (WM).

In adults, the obtained CV for VB to WM (CVVB-WM; 3.28 ± 0.11 m/s) was ≈10 times faster than that of WM to layer IV cells (CVWM-IV; 0.33 ± 0.05 m/s). The CVVB-WM was confirmed by recording antidromic single-unit responses from VB cells by stimulating WM. Exclusion of synaptic delay from CVWM-IV did not account for the 10-fold difference of CV.

By histochemical staining, it was revealed that VB to WM was heavily myelinated, whereas in the cortex staining became substantially weaker. We also found that such morphological and physiological characteristics developed in parallel and were accomplished around postnatal week 4. Considering that VB to WM is longer and more variable in length among afferents than is the intracortical region, such an enormous difference of CV makes conduction time heavily dependent on the length of intracortical region, which is relatively constant.

Our finding may well provide a general strategy of connecting multiple sites irrespective of distances in the brain.

Web | PDF | Proceedings of the National Academy of Sciences | Open Access

Myelination and isochronicity in neural networks (2009)

Spoiler: Abstract

Our brain contains a multiplicity of neuronal networks. In many of these, information sent from presynaptic neurons travels through a variety of pathways of different distances, yet arrives at the postsynaptic cells at the same time. Such isochronicity is achieved either by changes in the conduction velocity of axons or by lengthening the axonal path to compensate for fast conduction.

To regulate the conduction velocity, a change in the extent of myelination has recently been proposed in thalamocortical and other pathways. This is in addition to a change in the axonal diameter, a previously identified, more accepted mechanism.

Thus, myelination is not a simple means of insulation or acceleration of impulse conduction, but it is rather an exquisite way of actively regulating the timing of communication among various neuronal connections with different length.

Web | PDF | Frontiers in Neuroanatomy | Open Access

 

[DHagen]

Except it may not be damage. (In the same way T cell subset exhaustion markers do not mean globally tired T-cells.)

The changes in diffusivity might not indicate neuroinflammation or cell damage. It could relate to myelin maintenance and even be compensatory, ie increased or decreased to preserve conduction velocities for signalling between brain regions that rely on simultaneous time-of-flight for effective neurological performance.

This is certainly important to keep in mind (and I think the authors at least allude to this). My dismay (which I understand is likely premature) was more in response to the statement that, in contrast to PI-ME/CFS sufferers, GO-ME/CFS patients would be left with nothing but "strategies focused on neuroprotection, mitochondrial support, or cognitive rehabilitation" in place of, say, an actual treatment. Obviously, more work is needed, and I am certainly hoping they are wrong about this particular part of the equation.