Trial Report A Multimodal Magnetic Resonance Imaging Study on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Feasibility and Clinical Correlation, 2024, Kaur

So, magnetic resonance spectroscopy only in three regions of interest: anterior cingulate gyrus (ACC), left dorsolateral prefrontal cortex (L-DLPFC) and the brain stem (BS).

Patient selection looks to have been fine - i.e. from a registry, diagnosis confirmed by physician interview, PEM required. The age range of the patient participants was very wide (24-68 years) and there were only 5 healthy controls, so, that's not ideal; the authors acknowledge that this study was only preliminary. What isn't okay though is that there is no mention of blinding the assessment of the imaging. That's a problem, as there is quite a lot of processing where bias could creep in. Hopefully they can fix that in their next study - perhaps it was done and just wasn't mentioned.

So, it doesn't sound as though they found very much in terms of brain metabolite differences, perhaps hampered by the small size of the healthy control cohort.
NAA is N-acetyl aspartate, which they noted earlier was a marker of neuronal viability and the DLPFC is the left dorsolateral prefrontal cortex - it was found to be higher in the ME/CFS group. I guess the fact that they didn't find differences in the metabolites they looked for is useful information. Table 2 gives results for 10 metabolites in each of the three brain regions. And yes, of the 30 comparisons, the NAA in the DLPFC is the only one remotely significant.

Googling about NAA, it does seem to be recognised a measure of neuronal health and function, and is correlated with common measures of cognitive intelligence (higher levels = higher cognitive intelligence). The DLPFC is involved in complex thinking, abstract reasoning, executive function. So, what could be happening here is that we are just seeing a sampling bias. The type of people who are more likely to sign up to a patient registry and participate in research are more likely to be of above average intelligence. The difference with the small healthy control cohort wasn't huge and there were overlaps, but may reflect differences in selection, and so mean intelligence.

The researchers correlated findings with all sorts of measures. There did seem be some correlation between measures of symptoms e.g. fatigue and NAA, but that might just be the result of an even stronger selection bias for cognitive intelligence in people with worse fatigue. That seems possible: people who understand the importance of research are likely to be more motivated to participate. (Actually, looking at the charts, the correlation is mostly the result of the healthy controls tending to have lower NAA and lower symptom burden.)

So, I'm not really seeing any finding here that can't be explained by a participant selection bias. If there really was a difference in average cognitive abilities in the two groups, then it does create problems for comparisons with fMRI cognitive investigations such as the n-back studies.

The authors don't seem to have considered this obvious possible explanation (that their patient sample had better mean inherent cognitive capacity and therefore neuronal integrity than the controls), instead offering a vague hand-wavy "it is likely that the NAA level may represent a potentially negative downstream effect of ME/CFS patholophysiology".

They go on to note that another small study actually found lower levels of NAA in the CFS cohort, but in a different brain region, while another study found a high NAA level in yet another brain region.

So, of the 'group differences in metabolites' in the three parts of the brain that were examined, I don't think there is really any difference that we can point to and say 'this is implicated in ME/CFS pathology'. I guess more studies with bigger and better matched cohorts might be useful, especially if other parts of the brain were examined.

 

Yes, that paper:

was the one I was looking at too. And they did find a relationship between the cerebral NAA and cognitive abilities, as the title suggests. With respect to actual measured IQ, the abstract goes on to say:

I haven't looked further into the paper, but it sounds as though they finessed things with respect to those 'outlying values'. And of course, IQ measurement is horribly biased and problematic. Putting measured IQ aside though, I think the core point remains - there is a likely relationship between cerebral NAA levels and cognitive ability (i.e. intelligence) in broad terms, and there is also a likely bias in the cognitive ability of participants volunteering for research studies. I think that cerebral NAA:cognitive ability relationship is particularly likely to be true when the part of the brain that is being assessed is involved in higher-level cognitive tasks. This ME/CFS study did not find differences in the NAA levels in the brain stem, which isn't known for its involvement in higher-level cognitive tasks.

Of course, it may well be just a random result, but I do think that these authors should have at least noted that the higher NAA in the DLPFC may be a result of a bias in the cognitive abilities of the participants in their sample when they were hypothesising about what the finding might mean.

I think the finding is good news for people with ME/CFS. Good levels of cerebral NAA are not suggestive of damage to the brain.