Trial Report Distinct white matter alteration patterns in post-infectious and gradual onset chronic fatigue syndrome revealed by diffusion MRI, 2025, Yu et al

[John Mac]

Abstract​

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.

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

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...

www.nature.com

 

[Creekside]

I can't judge whether these are valid findings or just seeing patterns in random noise, but I certainly expect there to be differences in brain architecture after long-term suffering from symptoms. Perhaps there would be similar patterns from other chronic diseases or body damage. With the right technology, you might be able to look at brain scans and say "This person has a foot injury. That person has chronic constipation." etc.

 

[Utsikt]

Activity levels for all participants were monitored by the Actigraph GT3X-BT device (ActiGraph LLC., United States) for 14 days, seven days before and after MRI scans.

I can’t find the data for this when I search for «activ». Has anyone spotted it somewhere?

 

[forestglip]

I can’t find the data for this when I search for «activ». Has anyone spotted it somewhere?

It's the MET rate metric:

Furthermore, the metabolic equivalents (MET) rate of the task from the Actigraph data was calculated using the Freedson Adult (1998) algorithm by ActiLife® software to measure the activity level for each participant.

There are no significant differences in age (p = 0.67), BMI (p = 0.82), MET rate (p = 0.10), or MRI scan time (p = 0.55) between the PI-ME/CFS patients and HCs.

There are no significant differences in age (p = 0.75), BMI (p = 0.27), MET rate (p = 0.09), and MRI scan time (p = 0.57) between the GO-ME/CFS patients and HCs.

Supplementary Table S7 (Appendix B.1) shows that PI-ME/CFS and GO-ME/CFS patients are effectively equivalent in terms of demographic characteristics and behavioural assessments, with no significant differences observed in sex, age, BMI, MET rate, or any clinical scores.

 

[Utsikt]

It's the MET rate metric:

Thank you!

I wonder what they actually measured.

And I’m always surprised when I see that moderate patients do as much physical activity as unfit, sedentary healthy people. But I started at the lower end of moderate and got worse, so my perspective might be very skewed.

 

[ME/CFS Science Blog]

Social media summary:


This brain scan study from Australia found differences between #ME/CFS patients with post-infectious (PI-ME/CFS) versus gradual onset (GO-ME/CFS). In the first group, axial diffusivity was increased compared to controls, while it was decreased in the latter.

The researchers used a special type of MRI called Diffusion Tensor Imaging (DTI). It measures the the directional flow of water in along he length of axons and can provide insights into white matter pathology.

Several small (n < 30) ME/CFS studies have used this DTI technique before to study white matter in the brain but results have been inconsistent. Some references:
https://pubmed.ncbi.nlm.nih.gov/25353054/
https://pubmed.ncbi.nlm.nih.gov/30430664/
https://pmc.ncbi.nlm.nih.gov/articles/PMC9291819/
https://pubmed.ncbi.nlm.nih.gov/37331007/

This study had a larger sample size (86 ME/CFS participants) and it divided them into PI-ME/CFS and GO-ME/CFS to account for heterogeneity.

It's not so clear what increased axial diffusivity in the PI-ME/CFS group means. The authors speculate that it "may reflect a state of axonal swelling or disrupted axonal transport, possibly resulting from immune activation or neuroinflammation following infection."

Patients with gradual onset had decreased axial diffusivity in the corpus callosum (the structure that connects the two brain hemispheres). The authors think this might contribute to cognitive and information processing deficits that ME/CFS patients often report. Decreased axial diffusivity has been found in multiple neurological conditions where it is linked to axonal degeneration and white matter loss.

While previous ME/CFS studies reported differences in other measures such as fractional anisotropy, mean diffusivity or radial diffusivity, this was not the case in this study. The authors speculate this may be due to heterogeneity and stringent correction for significance.

The study was funded by the NMHRC and the Mason Foundation

 

[Deanne NZ]

I’m not sure what to make of this study. @SNT Gatchaman , if I recall correctly you have questioned if Gradual Onset is valid given the prevalence of asymptomatic viral infections. What do you make of this study?
If funding wasn’t an issue you could run the same scans on PwME and not pre-disclose if the individuals were PI or GO and see if the results were able to accurately determine which group each patient was in.

 

[Spartacus]

According to this, I don't exist. My onset was sudden but not post viral. I went to bed normal and woke up barely able to move my arms and legs. My onset was also gradual, like MS. Sudden repeated attacks of neurological symptoms, with total remission in between.
So a sudden but gradual onset.
Eventually I was misdiagnosed by a neurologist who told me to do vigorous exercise 3 times a week. End result no more remissions, end of life. Diagnosis of ME confirmed by Dr Weir.
Am I the only person with this kind of onset? Are we really just divisible into 2 groups?

 

[Yann04]

According to this, I don't exist. My onset was sudden but not post viral. I went to bed normal and woke up barely able to move my arms and legs. My onset was also gradual, like MS. Sudden repeated attacks of neurological symptoms, with total remission in between.
So a sudden but gradual onset.
Eventually I was misdiagnosed by a neurologist who told me to do vigorous exercise 3 times a week. End result no more remissions, end of life. Diagnosis of ME confirmed by Dr Weir.
Am I the only person with this kind of onset? Are we really just divisible into 2 groups?

I would say I had a gradual onset with the main triggering event being a viral infection.

I think obviously splitting into sudden - viral , gradual - non-viral, is a big oversimplification by the authors, that’s probably just straight up innacurate in many cases.

 

[SNT Gatchaman]

I’m not sure what to make of this study. @SNT Gatchaman , if I recall correctly you have questioned if Gradual Onset is valid given the prevalence of asymptomatic viral infections. What do you make of this study?

I haven't read this paper yet, but yes I question some of the presumed non-infectious triggers which might have been acutely asymptomatic infections, but then retrospectively attributed to things like a period of increased work or family stress. But I would certainly leave open the possibility of things like trauma, surgery, anaesthesia, drugs, vaccines also causing long-term immune dysfunction with this syndromic outcome.

On gradual onset, I do wonder if that's actually the more typical pattern, but that we tend not recognise it until we reach a threshold, which appears to be sudden. See below.

According to this, I don't exist. My onset was sudden but not post viral. I went to bed normal and woke up barely able to move my arms and legs. My onset was also gradual, like MS. Sudden repeated attacks of neurological symptoms, with total remission in between.
So a sudden but gradual onset.
Eventually I was misdiagnosed by a neurologist who told me to do vigorous exercise 3 times a week. End result no more remissions, end of life. Diagnosis of ME confirmed by Dr Weir.
Am I the only person with this kind of onset? Are we really just divisible into 2 groups?

That sounds fairly similar to my experience, with the difference being that I have (admittedly non-conclusive) retrospective evidence of a preceding asymptomatic Covid infection. As far as I knew at the time I was normal / healthy and then suddenly things started to go significantly wrong. I was enjoying a summer sailing cruise in perfect and highly salutary conditions when orthostatic and exertional intolerance appeared out of nowhere. Followed quickly by a few days of crushing fatigue.

But this seemed to resolve completely after a week, only to then find an odd cadence of (I think 3 cycles of) three weeks of feeling "I'm completely fine" with three weeks of "I'm not fine at all". Saw a couple of specialists: one good, one not; with the latter advising to ignore symptoms and stop being "hypervigilant" and go back to the gym. The parting "Be Well." as the only treatment offered by a supposed professor of medicine was jarring. Not all professors are created equal.

Anyhow, there followed a gradual decline over 4-5 months until I fell off the proverbial cliff in mid 2021. I joined S4ME and my medical education proper began. In hindsight though I do recognise that I was going off the boil for ~6 weeks before I first recognised any symptoms.

 

[Snow Leopard]

According to this, I don't exist. My onset was sudden but not post viral. I went to bed normal and woke up barely able to move my arms and legs. My onset was also gradual, like MS. Sudden repeated attacks of neurological symptoms, with total remission in between.
So a sudden but gradual onset.
Eventually I was misdiagnosed by a neurologist who told me to do vigorous exercise 3 times a week. End result no more remissions, end of life. Diagnosis of ME confirmed by Dr Weir.
Am I the only person with this kind of onset? Are we really just divisible into 2 groups?

Yes, they've skipped the relapse-remitting onset pattern and it's disappointing.

 

[Malvaceae]

Yes, they've skipped the relapse-remitting onset pattern and it's disappointing.

Where can one find information about that pattern and other subgroups?

 

[Snow Leopard]

Where can one find information about that pattern and other subgroups?

It's barely studied at all unfortunately. There is some discussion here: https://www.mdpi.com/1422-0067/23/19/11852