Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging, 2026, Singh et al

[forestglip]

Microstructural alterations in brain tissue of ME/CFS and long COVID using diffusion tensor imaging and diffusion kurtosis imaging

Singh, Tanoj Bahadur; Marshall-Gradisnik, Sonya; Barnden, Leighton; Eaton-Fitch, Natalie; Huynh, Tuong Hieu; Inderyas, Maira; Thapaliya, Kiran

Introduction
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID have overlapping symptoms, such as profound fatigue, cognitive impairment, post-exertional malaise, pain and sleep disturbances that are debilitating and reduce quality of life. While Magnetic Resonance Imaging (MRI) techniques, specifically Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI), have been used to investigate brain tissue microstructure in ME/CFS or long COVID, no study has yet combined these modalities to directly compare tissue microstructural differences between people living with ME/CFS and long COVID.

Methods
We recruited 37 ME/CFS participants (Age: 43.56 ± 12.5), 19 long COVID participants (Age: 47.92 ± 13.3), and 27 healthy controls (Age: 37.9 ± 10.4). Data were acquired using a 3 Tesla (3T) Prisma MRI scanner. DTI and DKI metrics were determined using MRtrix v3.0.7 and Designer V2.0 software, respectively. Voxel-based statistical analysis of cohort differences was performed using the Statistical Parametric Mapping (SPM12) toolbox in MATLAB. Correlation analysis was performed between DTI, DKI metrics and clinical measures such as duration of illness, fatigue severity, SF36 domains and WHODAS domains.

Results
Compared with healthy controls, individuals with ME/CFS showed microstructural alterations in the cingulum, supplementary motor areas, and parts of the corpus callosum (all p < 0.05). Long COVID participants demonstrated microstructural alterations in regions including the fusiform and precentral gyrus and in major white matter tracks (all p < 0.05). Direct comparisons between ME/CFS and long COVID revealed difference in the left corona radiata ( p = 0.001).

Conclusion
This study identifies distinct tissue microstructural alterations in ME/CFS and long COVID and offers a vital insight into the neuropathological basis of shared symptoms in both conditions.

Web | DOI | PDF | Frontiers in Medicine

 

[Creekside]

Arrrgh! Why can't scientists understand that they need matched controls rather than healthy ones? Whoever is providing funding for ME or LC research should reject proposals that use healthy controls.

 

[InitialConditions]

"19 long COVID participants were recruited after meeting the WHO working case definition."

You can meet this criteria if you developed a couple of symptoms that did not resolve and you think they likely had something to do with a covid infection. It doesn't matter what the symptoms are, and no proof of infection is needed.

Plus, is it not statistically more likely than not that some participants in this group have ME/CFS?

 

[TiredMathematician]

Plus, is it not statistically more likely than not that some participants in this group have ME/CFS?

If the long COVID sample was drawn randomly from a population where at least 3.6% of people have ME/CFS, then it is more likely than not that at least one person in the sample of 19 has ME/CFS (assuming my maths is right).

 

[SNT Gatchaman]

The introduction notes the lack of consistency in recent neuro MR diffusion studies. Reformatted —

Thapaliya et al. has demonstrated the microstructural changes in the brainstem region using DTI where AD and MD were significantly decreased whereas RD was increased in people with ME/CFS compared to healthy controls.

Yu et al. reported ME/CFS individuals with post-infectious onset showed increased AD, whereas those with gradual onset exhibited reduced AD.

Zeineh et al. reported increased FA in the right anterior arcuate, while

Kimura et al. observed significantly lower FA in the genu of the corpus callosum and in the anterior limb of the internal capsule of ME/CFS compared to healthy controls. […]

Liang et al. reported increases in FA in several white matter regions and in MD in the left amygdala. Studies have also reported significantly decreased FA, MD, RD and AD in long COVID compared to healthy controls. […]

Thapaliya et al. demonstrated significantly higher FA value in the right superior longitudinal fasciculus in long COVID compared to COVID-recovered healthy controls and significantly lower AD and MD in the left caudate in COVID-recovered healthy control compared to non-COVID-healthy controls.

Using the DKI method, Kimura et al. found a significant decreases in the DKI metric MK in the right frontal area, anterior cingulate cortex, superior longitudinal fasciculus and left parietal areas. Yuan et al. also found reduced MK and RK in the right inferior fronto-occipital fasciculus in recovered COVID-19 patients.

Thread at Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging (2019)

Overall, inconsistencies in ME/CFS DTI findings were driven by varying diagnostic criteria, heterogeneous symptoms, sample size, data processing pipelines and the scarcity of DKI studies in ME/CFS and long COVID, limits the robustness of the current conclusions.

I suspect a lot of these conflicting reports also reflect noise with diffusion techniques.

For diffusion kurtosis, see eg Toward more robust and reproducible diffusion kurtosis imaging (2021, Magnetic Resonance in Medicine)

Spoiler: Abstract

PURPOSE
The general utility of diffusion kurtosis imaging (DKI) is challenged by its poor robustness to imaging artifacts and thermal noise that often lead to implausible kurtosis values.

THEORY AND METHODS
A robust scalar kurtosis index can be estimated from powder-averaged diffusion-weighted data. We introduce a novel DKI estimator that uses this scalar kurtosis index as a proxy for the mean kurtosis to regularize the fit.

RESULTS
The regularized DKI estimator improves the robustness and reproducibility of the kurtosis metrics and results in parameter maps with enhanced quality and contrast.

CONCLUSION
Our novel DKI estimator promotes the wider use of DKI in clinical research and potentially diagnostics by improving the reproducibility and precision of DKI fitting and, as such, enabling enhanced visual, quantitative, and statistical analyses of DKI parameters.

This study reports no correlations with clinical measures.

We found significant uncorrected correlations between DTI, DKI metrics and clinical measures in ME/CFS and long COVID. However, we did not find any significant differences between these metrics after adjusting for multiple comparisons. […] Supplementary Table 1–10.

And again, similar to the glymphatic findings, it doesn't really make sense for lateralised findings, ie why one side of the brain would be vulnerable and not the other. More importantly, if there is something important happening in the major fibre tracts on one side of the body, we'd be reporting unilateral problems.

We found significant differences in the DKI metric between ME/CFS and long COVID. There was a significant increase in AK in the left corona radiata, which is the major projection fiber and includes corticospinal, corticopontine and thalamocortical fibers. […] The microstructural alterations observed in the left corona radiata may therefore represent compensatory increases in cellular density or neuroinflammatory processes. […] disruptions in the microstructure of the corona radiata could plausibly contribute to the motor difficulties, altered sensory processing, and cognitive impairment

We don't generally give descriptions of lateralised symptoms, eg weakness in the right arm or hand. If it's neuroinflammatory, why would that only affect one side? And if it's compensatory increase in cellular density, why only compensatory on one side? (All right hand dominant??)

 

[DMissa]

could spending a lot of time lying on one's side have a relationship with lateralised measurements?

 

[Jonathan Edwards]

Very possibly.

It seems as plausible as anything to explain a change in diffusion in corpus callosum.

 

[Creekside]

could spending a lot of time lying on one's side have a relationship with lateralised measurements?

I could certainly see that they might be measuring more time spent in bed plus a statistical difference in people's preferred sleep position. Possibly more time spent on a couch (enforced lateral position) watching TV. Lots of possible factors for differences in measurements.