Brain and muscle chemistry in ME/CFS and long COVID: a 7T magnetic resonance spectroscopy study, 2025, Godlewska et al

Wyva

Wyva

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Full title: Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study

Beata R. Godlewska, Amy L. Sylvester, Uzay E. Emir, Ann L. Sharpley, William T. Clarke, Stephen R. Williams, Ana Jorge Gonçalves, Betty Raman, Ladislav Valkovič & Philip J. Cowen

Abstract

Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is a common debilitating medical condition, whose main symptoms - fatigue, post-exertional malaise and cognitive dysfunction – are also present in many cases of long COVID. Magnetic resonance spectroscopy (MRS) allows the insight into their pathophysiology through exploration of a range of biochemicals putatively relevant to aetiological processes, in particular mitochondrial dysfunction and energy metabolism.

24 patients with ME/CFS, 25 patients with long COVID and 24 healthy controls (HC) underwent brain (pregenual and dorsal anterior cingulate cortex, respectively, pgACC and dACC) and calf muscle MRS scanning at 7 Tesla, followed by a computerised cognitive assessment. Compared to HC, ME/CFS patients had elevated levels of lactate in both pgACC and dACC, while long COVID patients had lowered levels of total choline in dACC. By contrast, skeletal muscle metabolites at rest did not significantly differ between the groups.

The changes in lactate in ME/CFS are consistent with the presence of energetic stress and mitochondrial dysfunction. A reduction in total choline in long COVID is of interest in the context of the recently reported association between blood clots and ‘brain fog’, and earlier animal studies showing that choline might prevent intravascular coagulation. Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations, may differ. An important implication is that patients with ME/CFS and those with fatigue in the course of long COVID should not be studied as a single group, at least until the mechanisms are better understood.

Open access: https://www.nature.com/articles/s41380-025-03108-8
 
The discussion on interpretations and limitations seems to be better than most of what we usually read here. Part of it:
When interpreting these data, it needs to be considered that biochemical abnormalities may be consequences, rather that the cause, of prolonged inactivity. In the current study there was no correlation between the abnormal neurochemical findings and the length of illness in ME/CFS. In the long COVID group there was a correlation of the length of illness with dACC and total choline (r = 0.605, p = 0.01). This, however, is a non-a-priori correlation, not corrected for multiple comparisons, and therefore should be viewed with caution. Useful for this discussion is a recent meta-analysis of MRS studies, which found that physical activity, rather than sedentary lifestyle, is related to higher brain lactate [81].

While our findings of neurochemical abnormalities in the pgACC and dACC, in ME/CFS and long COVID patients are intriguing, they must be viewed with caution given the limitations of the study. One of them is the small number of patients, which may lead to false positives, especially as we made no correction for multiple comparisons, given the exploratory nature of this study. The possibility that neurochemical changes in the patient group may not be specifically related to the presence of fatigue also needs to be considered. Physical health problems and diversity of medications used, including antidepressants, were difficult to control for. In particular, long COVID patients had symptoms of ill physical health as a consequence of the acute Sars-Cov-2 infection, even if not diagnosed as a separate condition (such as ongoing difficulties breathing). Medications and comorbidities are detailed in Supplementary Table 1.

Another important issue was that only people with mild to moderate symptom severity were included in the study, as participants had to be able to travel for their scan. This unfortunately means that we were unable to get insights into biological processes in patients whose symptoms were more severe, in whom the underlying pathologies might be more accentuated. Also, patients with ME/CFS commonly employ careful symptom management through planning their activities and rest. This is crucial for their well-being but might restrict what can be observed during testing, especially in cases of milder symptom severity. One potential research strategy might be accentuating the differences through functional challenges, such as exercising the muscle in the scanner (a strategy used by Finningan et al. [82] in long COVID), or measuring brain metabolites while participants perform a cognitive task or experience a physiological stimulus such as pain or photostimulation [83].
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I can't read the full abstract, let alone the full paper, but I wonder how many neuroimaging studies with relatively similar results it will take for this to be taken more seriously and maybe more importantly for larger patient samples to be used. Elevated lactate levels have been observed in people with ME for quite some time (20ish years?) and by different teams/labs.
 
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It's a potentially interesting finding, considering I was just reading this hypothesis paper on the role of adenosine accumulation in the anterior cingulate cortex as an important mediator of "mental fatigue" for both cognitively and physically demanding tasks. (I'm still making up my mind on what I think about the hypothesis, though some of the individual findings referenced in it are familiar to me).

Extracellular adenosine has been shown to build up in stimulated neurons as a byproduct of cellular metabolism (adenosine being "ATP" minus the tri-phosphates), and its dual role as an inhibitory transmitter seems to suppress neural activity in brain regions that were recently active, potentially as a way to protect neurons from getting into a damaging metabolic state. Failure of this mechanism seems to be associated with neural damage in epilepsy (thread discussing these findings and possible interpretations here). Caffeine is also thought to work by blocking adenosine binding to receptors.

I don't know for sure, but I would expect adenosine and lactate buildup in these regions of the brain correlate with each other, both being byproducts of metabolic "exertion" (i.e. ATP production and usage that outpaces steady state rates of substrate replenishment).

I also wonder how much the commute to this medical imaging center and all that testing would effectively count as "mental exertion" for the ME/CFS participants. So their "baseline" comparison of mental exertion might not actually be baseline for the ME/CFS group if there is some underlying issue in brain metabolic efficiency. Unfortunately it would probably be extremely logistically difficult to recreate this imaging in participants who were provided lodging nearby so they didn't have to travel and were exposed to minimal sensory stimulation.
 
Made this social media summary of the study:


1) Scientists from Oxford University used one of the most powerful brain scans (7 tesla MRI) and found different results for ME/CFS and Long Covid.

2) In the 24 ME/CFS patients, there were increased levels of lactate in the anterior cingulate cortex (ACC), a brain region involved in emotional and cognitive processing.

3) Increased lactate in the cerebrospinal fluid (the fluid that surrounds the brain and spinal cord) has been reported previously in ME/CFS.
See for example:
https://pubmed.ncbi.nlm.nih.gov/29308330/
https://pubmed.ncbi.nlm.nih.gov/20661876/
https://pubmed.ncbi.nlm.nih.gov/22281935/

4) There was no increased lactate in Long Covid patients but lower levels of choline in the dorsal ACC.

5) The authors also did the first scan of this type (H MRS at 7T) to asses muscle chemistry in ME/CFS and Long Covid, but nothing stood out.

6) They found no difference in acetyl-carnitine in the muscle, suggesting a good usage of fatty acids as energy source. The authors suspect that the problem lies in oxidative respiration and the glycolytic pathway. (A popular hypothesis in ME/CFS research).

7) Some important caveats: the groups (n= 24) were small and not properly matched for sex and age.
The authors tested multiple metabolites without statistical correction for multiple comparisons. Difference may therefore likely to be false positives.

8) In a previous 7 Tesla MRI study, the same authors found lower levels of creatine in ME/CFS which was not replicated here.

9) There were also no correlations between lactate and fatigue scores and the results of cognitive testing. The authors also mention that lactate is difficult to measure in the brain, so the results must be treated cautiously.

10) Link to the study:
https://www.nature.com/articles/s41380-025-03108-8
 
I'll also note, as the authors themselves noted in the discussion, that metabolic pathways in the brain are different since lactate is often fed back into oxidative metabolism as a fuel source rather than simply being a byproduct of glycolysis that has to be cleared.

So increased lactate in the brain doesn't necessarily mean the same thing that it would indicate in the muscle, though differences in brain lactate bw ME/CFS and control would indicate that something is different metabolically.
 
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