Trial Report Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI, 2024, Thapaliya et al

https://www.sciencedirect.com/science/article/pii/S000293432400216X

Imbalanced Brain Neurochemicals in long COVID and ME/CFS: A Preliminary Study using MRI

Kiran Thapaliya, PhD 1*, Sonya Marshall-Gradisnik, PhD 1 , Natalie Eaton-Fitch, PhD 1 , Zeinab Eftekhari BSc (Honours)2 ,Maira Inderyas MSc.1 , and Leighton Barnden, PhD 1

1 National Centre for Neuroimmunology and Emerging Diseases (NCNED), Griffith University, Australia

2 Centre for Advanced Imaging, The University of Queensland, Australia

CofI: None

Author’s contribution: KT: conceptualization, formal analysis, and writing–original draft. KT and ZF: methodology. KT, LB, NE-F, ZF, MI, and SM-G: writing–review and editing. KT, MI: Data curation, LB and SM-G: supervision. LB, KT, SM-G, NE-F; funding acquisition.

All authors contributed to the article and approved the submitted version.
open access

Abstract
Purpose
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures.

Methods
Magnetic resonance spectroscopy (MRS) data was acquired with a 3T Prisma MRI scanner. We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n=17), ME/CFS (n=17), and healthy controls (n=10) using Osprey software. The statistical analyses were performed using SPSS version 29. Age and sex were included as nuisance covariates.

Results
Glutamate levels were significantly higher in long COVID (p=0.02) and ME/CFS (p=0.017) than in healthy controls. No significant difference was found between the two patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (p=0.012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS.

Conclusion
Our study identified significantly elevated Glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the two patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.

Keywords
long COVID
ME/CFS
glutamate
N-acetyl-aspartate (NAA)
brain neurochemicals
and MRI


Clinical Significance

• People with long COVID and ME/CFS have elevated glutamate and N-acetyl-aspartate levels compared to healthy controls in the posterior cingulate cortex, potentially causing multiple symptoms in both conditions.
  
  
• Similarities in brain neurochemicals between long COVID and ME/CFS provide further evidence for a significant link between the two conditions.
  
  
• Associations between brain neurochemicals and severity measures in long COVID and ME/CFS, may highlight the role of neurochemicals in these conditions.

Funding
This research is funded by ME Research UK (SCIO Charity Number SC036942) with the financial support of The Fred and Joan Davies Bequest. Other funding bodies include The Stafford Fox Medical Research Foundation (489798), the National Health and Medical Research Council (1199502), Talei Foundation, Buxton Foundation (4676), Henty Community (4879), Henty Lions Club (4880), Blake Beckett Trust Foundation (4579), Alison Hunter Memorial Foundation (4570), and the Change for ME Charity (4575).

 

Interesting to see this. I cannot comment on the method etc used but if replicated could make a lot of sense regarding patients symptoms especially the cognitive dysfunction.

I suspect that this is an effect of something else resulting in raised cerebral glutamate and NAA. Infection? Antigen? Multiple causes resulting in same/similar bodily defensive response?

Info from Cleveland Clinic website re glutamate:
"Glutamate plays a major role in shaping learning and memory. Glutamate needs to be present at the right concentrations in the right places at the right time. Too much glutamate in your brain, in the wrong place, in too high of a concentration and for too long can cause brain cell damage or death. Some neurodegenerative diseases associated with having too much glutamate exciting nerve cells include Parkinson’s disease, Alzheimer’s disease and Huntington’s disease."

 

I think that's the crucial point. From what I've seen if history is anything to go by we won't be seeing a meaningful replication of this work.

 

And that would be sad.

Can anyone comment on the method and cost of such a study? And whether this is something a neurologist would take interest in?

 

"In ME/CFS, we found a positive association between glutamine and Cr+PCr levels and ‘physical activity’, indicating that lower physical activity is associated with reduced levels of these neurochemicals."

Perhaps another clue regarding the inability of pwME to maintain activity and exercise. And why GET is contraindicted.

 

Could this be a clue as to why benzodiazepines seem to increase capacity/functionality acutely?

This is anecdotal of course but it seems to at least be true for other patients as well.

“Thus, in vivo low concentrations of benzodiazepines may reduce synaptic glutamate concentrations by increased uptake, providing an additional mechanism to modulate neuronal excitability.”

https://pubmed.ncbi.nlm.nih.gov/10582598/

 

I've very little knowledge but my understanding is that "Magnetic resonance spectroscopy (MRS)" or "MRI" is considered a reliable technique - just wondering why e.g. Jonas Bergquist wouldn't have picked this up in his CSF studies?

 

Jarred Younger is another person who may have MRS/MRI data re Glutamate levels, or at least would be able to check these findings.

 

Ah, but our friends could interpret this as indicating that lower physical activity is causing the reduced neurochemical levels rather than the other way around.

 

Hmmm, the glutamate and NAA levels were found to be raised in pwME and LC so that kinda kicks their theory a bit more, maybe.

I was thinking the more activity and exercise that patients do, the higher these levels might get.... or have I got that back to front

 

I haven't looked at the paper but I don't understand why they are just reporting on the posterior cingulate cortex.

If their findings are specific to the PCC I am sceptical that they would be telling us something about the cause of the problem. I would expect abnormal signalling causing symptoms to be mediated through hypothalamus or brain stem.

Cingulate has a lot to do with mood and self-aware thinking. I wouldn't be surprised if wearing a 40Kg rucksack led to changes in glutamate in the PCC but the changes wouldn't explain any sense of exhaustion.

To be much use I think measurements like these need to be compared with other illnesses, other time points, time of day and all sorts.

 

First, dopamine and norepinephrine in NIH paper. Now, glutamate. All these chemicals are involved in excitatory response to novel stimuli. Tiny cohorts notwithstanding, the positive correlation to symptom reduction is interesting to me because of my experience with becoming symptom-free when living on the road in my car, as I'm doing right now. But then, nicotine patch didn't prevent my PEM when I'm home, so maybe there is nothing to it. Just a non scientific observation with n=1.

 

I'm referring to NIH paper on deep phenotyping which showed positive correlation between catechol level and the performance. This paper on glutamate, as understand, also showed association of the functioning and glutamate level in PCC. Understood, it's tiny study that doesn't mean much. I was just reflecting it on my personal experience of being able to get away with doing more when I'm in a novel environment and my brain is wide awake.

 

I'm not totally sure how to ask this in a sensible way, but is there any reason to think that the disease process / biomarkers may be somewhat different between milder and more severe forms of ME? As in, it's not that it's straightforwardly "this molecule is causing problems, and the severity of your problems is correlated to the level you have of this molecule" but more something like: a normal process in your body has gone awry, and there are a couple of backup processes that the body can use to sort of get around it and survive. And maybe one of them involves producing more glutamate, but there's a cap on how much of that is possible, and the sicker you are the more you use up that glutamate? So that perhaps the highest levels of glutamate would be found in moderately ill pwME, because those who are milder would produce less and those who are severe would produce more but also use it up more? (Just using glutamate as an example because that's what's reported by this paper, my question is about the shape of findings.)