A recent brain imaging study investigated whether there are distinct brain differences between individuals with post-infectious ME/CFS (PI-ME/CFS), where symptoms begin shortly after an infection, and those with gradual-onset ME/CFS (GO-ME/CFS), which develops slowly over time without a clear infectious trigger.
The research team, which included Dr Zack Shan (currently funded by ME Research UK on another project), used a specialised MRI technique known as diffusion tensor imaging (DTI) to examine axial diffusivity (AD) – a marker of the structural integrity of axons (the long, connecting portions of neurons (brain cells)) which are part of brain white matter. Changes in AD can indicate axons are damaged.
The study found that PI-ME/CFS and GO-ME/CFS patients showed opposite patterns of abnormalities, suggesting these subtypes may involve different disease mechanisms. This raises the possibility that onset type could influence treatment approach in ME/CFS.
Study Overview
Aim
The study focused on two clinically observed ME/CFS onset patterns:
- Post-infectious ME/CFS: Rapid symptom onset following a viral or bacterial infection (e.g., Epstein-Barr virus, Q fever, influenza, or coronaviruses).
- Gradual-onset ME/CFS: “Slow, progressive development of symptoms over months or even years, without a clear infectious trigger.”
The researchers hypothesised that these two onset types would show distinct patterns of white matter disruption in the brain.
Methods
The study involved 43 participants with post-infectious ME/CFS, 33 participants with gradual onset ME/CFS, and 67 healthy controls. Participants with ME/CFS met the Canadian consensus criteria.
All participants underwent DTI brain scans to measure axial diffusivity. They also completed questionnaires that included assessment of physical and mental health.
Key Findings and Interpretation
Opposite Patterns of Axial Diffusivity:
Post-infectious ME/CFS:
- Increased AD compared to healthy controls.
- Affected brain areas were in regions associated with motor control and emotional regulation.
- The increase in AD may reflect axon swelling, injury, or disrupted axonal transport (process of transporting essential cargo along neurons), possibly due to immune activation or neuroinflammation (inflammation of brain and/or spinal cord) following infection.
Gradual-onset ME/CFS:
- Decreased AD compared to controls.
- Affected brain areas were in regions associated with communication between brain hemispheres.
- This reduction in AD may indicate axonal degeneration and could contribute to cognitive and information deficits often reported in ME/CFS.
Symptom Correlations:
- PI-ME/CFS: Increased AD was associated with worse physical health.
- GO-ME/CFS: Decreased AD was associated with worse mental health.
The paper states, “Unlike the immune-triggered pathology hypothesised in PI[post infectious]-ME/CFS, gradual onset cases may involve long-term dysregulation of the central nervous system, including mitochondrial dysfunction, impaired cerebral perfusion, or altered autonomic regulation mechanisms that have been proposed I previous ME/CFS research.”
Interestingly, no other significant changes were found in other DTI metrics, as reported in other studies. The researchers state that “the inconsistencies in findings across studies may arise from variations in sample characteristics, patient criteria, or statistical methodologies” and suggested that there methods of data collection and statistical analysis were more rigorous.
Limitations
The authors acknowledge several major limitations. There were several confounding factors, such as comorbidities, which could affect the observed relationships. The paper seems to suggest that the statistical significance of correlations noted in relation to axial diffusivity amongst the ME/CFS subgroups was lost following further analysis (which involve only the patient groups). The researchers suggest that this loss of significance may have been related to a small sample size. The researchers suggest that future studies should aim to address these issues.
It should also be noted that there may not be such a clear distinction between post-infectious and gradual onset ME/CFS, as some people consider that their ME/CFS-related symptoms seemed to develop gradually following an infectious trigger.
Conclusion
The researchers state that this study “provides significant insights into the white matter alterations in ME/CFS, distinguishing between those with post-infectious (PI-ME/CFS) and gradual onset (GO-ME/CFS) … These results suggest different white matter microstructural abnormalities between the two subtypes of ME/CFS and indicate that AD may serve as a sensitive indicator of white matter pathology.”
