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

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.

Fig. 1. Voxel placement and representative spectra from the pregenual anterior cingulate cortex (pgACC, green) and dorsal anterior cingulate cortex (pgACC, blue).

Lac lactate, tCho total choline, Glu glutamate, Gln glutamine, GSH glutathione, Cr creatine, PCr phosphocreatine, myoIns myo-inositol, NAA N-acetylaspartate.

Fig. 2. Voxel placement and representative spectra from the calf muscle.

IMCL intramyocellular lipids, EMCL extramyocellular lipids.

Fig. 3. Lactate concentrations in the pregenual anterior cingulate (pgACC) and dorsal anterior cingulate (dACC) by group.

In ME/CFS, lactate concentrations (in mmol/kg) were significantly higher in both pgACC (p = 0.004) and dACC (p = 0.006) as compared with healthy controls. Number of participants: pgACC, CFS - 22, long COVID - 19, HC 22; dACC, CFS - 22, long COVID - 16, HC - 17. * indicates significant results with p value > 0.01 and ≤ 0.05, ** indicates highly significant results with p velue ≥ 0.0001 and < 0.01.

Fig. 4. Total choline concentrations in the dorsal anterior cingulate (dACC by group).

In long COVID, total choline concentrations were lower in dACC as compared with healthy controls (p = 0.0002). The between-group differences in pgACC were non-significant. Number of participants: CFS - 23, long COVID - 17, HC 21. * indicates significant results with p value 0.01 and ≤ 0.05, ** indicates highly significant results with p velue ≥ 0.0001 and 0.01.