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

[Dolphin]

Link to the published paper here
*****************************************


This is a preliminary presentation:

https://academic.oup.com/ijnp/article/28/Supplement_1/i60/8009437
https://academic.oup.com/ijnp/article-pdf/28/Supplement_1/i60/61854477/pyae059.104.pdf

Journal Article
MECHANISMS OF MYALGIC ENCEPHALITIS/CHRONIC FATIGUE SYNDROME (ME/CFS) AND LONG COVID WITH PREDOMINANT FATIGUE: A MAGNETIC RESONANCE SPECTROSCOPY STUDY OF THE BRAIN AND MUSCLE AT 7 TESLA

*Beata Godlewska1, Uzay E Emir2,4, Ann L Sharpley1, Stephen Williams3, Ana Jorge Gonçalves5, Betty Raman6, Ladislav Valkovič6,7, Philip J Cowen1

1Department of Psychiatry, University of Oxford, Oxford, UK, 2Wellcome Centre for Integrative Neuroimaging, University of Oxford, UK, 3Division of Informatics, Imaging and Data Science; Faculty of Medicine, Biology and Health; University of Manchester, UK, 4School of Health Sciences, Purdue University, USA, 5Wolfson Molecular Imaging Centre, Faculty of Biology, Medicine and Health, University of Manchester, UK, 6Oxford Centre for Clinical MR Research (OCMR), RDM Cardiovascular Medicine, University of Oxford, UK, 7Department of Imaging Methods, Institute of Measurement Science, Slovak Academy of Sciences, SVK

International Journal of Neuropsychopharmacology, Volume 28, Issue Supplement_1, February 2025, Pages i60–i61, https://doi.org/10.1093/ijnp/pyae059.104
Published:

12 February 2025

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Abstract

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating condition, which core symptoms are fatigue not caused by exertion and not alleviated by rest, post- exertional malaise, decline in functioning, and cognitive symptoms, often described as 'brain fog’ (1). Similar symptoms are also present in 'long-COVID’, a sequela of the acute infection with the SARS-CoV- 2 virus (2). While underlying pathogenetic processes are still largely unknown impaired mitochondrial function and energy metabolism in both conditions, and clotting problems in long-COVID, have been suggested.

Aims & Objectives
the aim was to investigate differences in the biochemistry of the brain and muscle between patients with ME/CFS, long-COVID and healthy volunteers (HV), using the state-of-art ultra- high-field proton magnetic resonance spectroscopy (H1-MRS) at 7 Tesla (7T). In particular, we aimed to assess metabolites involved in energy processing (creatine and lactate). Additionally, we aimed to explore the relationship between MRS findings with the cognitive function. Method: 24 CFS/ME patients, 25 long-COVID patients with predominant fatigue, and 24 healthy volunteers underwent H1-MRS scanning of the brain and calf muscle at 7 Tesla. Voxels were positioned in the pregenual and dorsal ACC (pgACC and dACC, respectively). Participants completed the Stroop Color and Word Test, testing ability to inhibit cognitive interference, related to the ACC function. Other cognitive functions tested included verbal memory and learning, working memory, verbal fluency and executive function.

Results
Compared to HV, participants with ME/CFS had increased levels of lactate in both pgACC (ME/CFS 1.52 mM, HV 1.22; p=0.003) and dACC (ME/CFS 1.45 mM, HV 1.40 mM; p=0.005), while participants with long-COVID had decreased concentrations of total choline in dACC as compared to healthy individuals (long-COVID 2.25 mM, HV 2.77 mM; p=0.0002). In the ME/CFS group, we observed a negative correlation between verbal fluency and both pgACC and dACC lactate concentrations (pgACCr=-0.614, p=0.01; dACC r=-0,623, p=0.008), while in the long-COVID group we observed a correlation between total choline concentrations and executive function (r=-0.592, p=0.005). There were no significant between-group differences in terms of muscle metabolites.

Discussion & Conclusions
In ME/CFS, increased levels of lactate suggest dysfunction in energy metabolism, with lactate accumulation suggesting ill mitochondrial health and a shift towards anaerobic metabolism (3). Low levels of total choline in long-COVID patients are interesting in the context of the recently reported association between blood clots and 'brain fog’ in long COVID (4), and reports of neuroprotective effects of choline in animal models, preventing disseminated intravascular coagulation (5). Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations with fatigue and brain fog, may differ. This has implications for future research, suggesting 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, and that different treatments may be needed despite similarity of symptoms.

References
1) Prins, J.B., van der Meer, J.W., Bleijenberg, G. (2006) 'Chronic fatigue syndrome.’ Lancet, 367, pp.346–355.

2) Kelly, J.D., Curteis, T., Rawal, A., et al. (2023) 'SARS-CoV-2 post-acute sequelae in previously hospitalised patients: systematic literature review and meta-analysis.’ Eur Respir Rev, 32, pp.220254.

3) Brooks, G.A. (2018) 'The Science and Translation of Lactate Shuttle Theory.’ Cell Metab, 27, pp.757- 785.

4) Taquet, M., Skorniewska, Z., Hampshire, A., et al. (2023) 'Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization.’ Nat Med, 29, pp.2498-2508

5)Blusztajn, J.K., Slack, B.E. and Mellott, T.J. (2017) 'Neuroprotective actions of dietary choline.’ Nutrients, 9, p.815.

Short Communications (Oral Abstracts)

https://twitter.com/user/status/1890404377740906937

 

[Utsikt]

(5). Importantly, differences in findings between ME/CFS and long COVID suggest that the underlying neurobiological mechanisms, while leading to similar clinical presentations with fatigue and brain fog, may differ. This has implications for future research, suggesting 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, and that different treatments may be needed despite similarity of symptoms.

Were the ME/CFS patients pre-pandemic? And did they check them for covid-antigens?

Could different illness durations explain the differences?

 

[forestglip]

Another study finding high brain lactate in ME/CFS using brain imaging. Most of the previous studies are from Dikoma Shungu's lab, so good to see another group studying this.

Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder: an in vivo 3.0 T 1H MRS imaging study (Shungu et al, 2009, NMR in Biomedicine)

Mean lateral ventricular lactate concentrations measured by 1H MRSI in CFS were increased by 297% compared with those in GAD (P < 0.001) and by 348% compared with those in healthy volunteers (P < 0.001), even after controlling for ventricular volume, which did not differ significantly between the groups. Regression analysis revealed that diagnosis accounted for 43% of the variance in ventricular lactate.

Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder (Shungu et al, 2010, NMR in Biomedicine)

we sought to assess the specificity of this observation for CFS by comparing ventricular lactate levels in a new cohort of 17 CFS subjects with those in 19 healthy volunteers and in 21 subjects with major depressive disorder (MDD) [...] Ventricular CSF lactate was significantly elevated in CFS compared to healthy volunteers [...] Ventricular lactate measures in MDD did not differ from those in either CFS or healthy volunteers. We found a significant correlation between ventricular CSF lactate and severity of mental fatigue that was specific to the CFS group.

Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology (Shungu et al, 2012, NMR in Biomedicine)

Fifteen patients with CFS, 15 with MDD and 13 HVs were studied using the following modalities: (i) (1)H MRSI to measure CSF lactate [...] We found elevated ventricular lactate and decreased GSH in patients with CFS and MDD relative to HVs. [...]

In exploratory correlation analyses, we found that levels of ventricular lactate and cortical GSH were inversely correlated, and significantly associated with several key indices of physical health and disability.

Multimodal and Simultaneous Assessments of Brain and Spinal Fluid Abnormalities in Chronic Fatigue Syndrome and the Effects of Psychiatric Comorbidity (Shungu et al, 2017, Journal of the Neurological Sciences)

proton magnetic resonance spectroscopy (1H MRS) was performed to measure ventricular lactate [...]

lower GSH and CBF and higher ventricular lactate and rates of spinal fluid abnormalities in CFS patients compared to healthy controls.

Elevations of ventricular lactate levels occur in both chronic fatigue syndrome and fibromyalgia (Shungu et al, 2017, Fatigue: Biomedicine, Health & Behavior)

Ventricular lactate was assessed in vivo with proton magnetic resonance spectroscopic imaging (1H MRSI) [...] Mean CSF lactate levels in CFS, FM and CFS + FM did not differ among the three groups, but were all significantly higher than the mean values for control subjects.

Evidence of widespread metabolite abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Assessment with whole-brain Magnetic Resonance Spectroscopy. (Younger et al, 2019, Brain Imaging and Behavior)

Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed [...] whole-brain echo-planar spectroscopic imaging (EPSI). [...] Choline (CHO), myo-inositol (MI), lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR). [...]

We found increased LAC in ME/CFS patients in the bilateral insula, bilateral parietal cortex, left hippocampus, left middle cingulate gyrus, left precuneus, right thalamus, right rolandic operculum, left temporal cortex, right calcarine sulcus, right fusiform gyrus, right lingual gyrus, and cerebellum. [...] we note that three out of the five regions with elevated brain temperature in individuals with ME/CFS also contained elevated lactate: the right insula, right thalamus, and cerebellum.

Not yet published study found elevated MRS-measured lactate in gulf war illness (though not significant by my calculation).

 

[Creekside]

I'm not convinced that it's not just a difference between healthy, active people and inactive people who feel lousy all day. They need some inactive non-ME/LC subjects, and maybe some subjects fighting viral infections.

 

[Eddie]

I'm not convinced that it's not just a difference between healthy, active people and inactive people who feel lousy all day. They need some inactive non-ME/LC subjects, and maybe some subjects fighting viral infections.

It could be that both viral infections and ME involve higher lactate levels in the brain. So I am not sure what that would rule out other than suggesting that perhaps they involve some of the same features.

24/25 subjects and controls seems pretty decent for this kind of study. Interesting that lactate levels seem to negatively correlate with some of the test scores.

 

[forestglip]

This study is interesting. 15 people with gulf war illness did two exercise tests separated by 24 hours. They did an n-back cognitive test before the first exercise then again immediately after the second exercise test.

The group of participants where cognitive score decreased after exercise had significantly higher brain lactate before exercise than the opposite group. (After exercise, they had similar levels.)

Prefrontal lactate predicts exercise-induced cognitive dysfunction in Gulf War Illness (Baraniuk et al, 2013, American Journal of Translational Research)

We performed single voxel 1H MRS to evaluate brain metabolic differences in the left anterior cingulate cortex and the changes associated with exercise.

Results: Eight GWI subjects increased their 2-back scores after exercise (labelled increasers) and seven GWI subjects decreased their 2-back scores after exercise (labelled decreasers). [...]

Decreasers had significantly elevated prefrontal lactate levels compared to Increasers prior to completion of the exercise stress tests.

 

[Turtle]

My first reaction to lactate in the brain was: Bad news. No medical knowledge, that shows.
A quick search showed that lactate in the brain has many functions. Fuel and protection among them..
What caught my eye was; lactate as protection of the BBB.

Question: Could a high fever disrupt the Blood Brain Barrier?

 

[Wyva]

Now published

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

 

[Utsikt]

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].

 

[butter.]

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.

 

[jnmaciuch]

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.

 

[ME/CFS Skeptic]

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

 

[jnmaciuch]

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.

 

[Utsikt]

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.

Could it just be that pwME/CFS are working harder at baseline?

 

[arnoble]

Given baseline uncertainty, would it be more informative for MRS studies to measure differential metabolites, before and after some task?

 

[jnmaciuch]

Could it just be that pwME/CFS are working harder at baseline?

lt depends on what “worker harder” means biologically. Either the same sensory input ends up triggering comparatively more neural firing which uses more ATP to reset, or the same amount of neural firing is simply more “costly” in ME/CFS due to faster accumulation of those metabolic byproducts. Or a combination of the two. I don’t know of any findings that would indicate the first option is more likely but I also haven't comprehensively looked

 

[wigglethemouse]

Given baseline uncertainty, would it be more informative for MRS studies to measure differential metabolites, before and after some task?

Betty Raman, one of the authors on this study did just that as part of the following study in Long Covid. Maybe the equipment in this study didn't allow for that as it seems from this other study that metabolites can change fast.
1H and 31P MR Spectroscopy to Assess Muscle Mitochondrial Dysfunction in Long COVID

 

[arnoble]

Betty Raman, one of the authors on this study did just that as part of the following study in Long Covid. Maybe the equipment in this study didn't allow for that as it seems from this other study that metabolites can change fast.

In metabolics studies, do best-practise protocols prefer to measure changes in response to some challenge, rather than just snapshot an unknown set of baselines?