Increased brain neurochemical levels in ME/CFS and long COVID


Kiran Thapaliya, Sonya Marshall-Gradisnik, Natalie Eaton-Fitch, Zeinab Eftekhari, Maira Inderyas, Leighton Barnden


Griffith University and University of Queensland, Australia


American Journal of Medicine, 2024 April 6; Epub ahead of print


ME Research UK with the financial support of the Fred and Joan Davies Bequest

Key findings

  • Brain MRI scans from people with ME/CFS and long COVID were analysed to measure levels of neurochemicals including glutamate (a neurotransmitter) and N-acetyl-aspartate (NAA; which has a number of functions).
  • Glutamate levels in the brain were increased in ME/CFS and long COVID patients, while NAA levels were increased in long COVID.
  • In both patient groups, neurochemical levels correlated with the severity of symptoms such as physical function, cognitive impairment, unrefreshing sleep and pain.
  • Glutamate and NAA levels may therefore contribute to the complex symptoms experienced by people with ME/CFS and long COVID, while the similar patterns in both diseases support a possible overlap in their underlying pathology.
  • The researchers will follow up this work by tracking progression of these and other brain abnormalities over time.

About the study

Dr Barnden and his team at Griffith University and the University of Queensland have published a series of articles reporting the results of their study looking at brain abnormalities in people with ME/CFS and long COVID.

Many of the symptoms experienced by people with ME/CFS – including problems with concentration, memory, vision and heart-rate control – suggest abnormalities in the brain and nervous system, and previous research has demonstrated changes in brain structure, impairments in the connectivity between different regions of the brain, and disruption to the autonomic nervous system (which regulates many body functions).

Dr Maira Inderyas, Dr Leighton Barnden and Dr Kiran Thapaliya

Using a powerful 7-Tesla MRI scanner, the researchers have uncovered a number of findings which throw more light on these abnormalities, including brainstem volume changes in ME/CFS and long COVID (which correlated with measures of pain and breathing difficulty), as well as impaired functional connectivity between specific brain regions in ME/CFS, and during cognitive exertion in long COVID.

In these further experiments, the team turned their attention to the levels of specific brain neurochemicals in people with ME/CFS and long COVID, in particular glutamate and N-acetyl-aspartate (NAA).

Glutamate is a neurotransmitter, which means it is a chemical messenger responsible for carrying chemical signals from the neuron (nerve cell) to the target cell. NAA has a number of functions in the brain, including controlling fluid balance, contributing to energy production, and in the synthesis of other substances.

Between them, glutamate and NAA are the two most common molecules found in the brain, and are essential in the function of the nervous system.

What did they do

The researchers performed brain MRI scans on 17 people with ME/CFS, 17 people with long COVID and 10 healthy control subjects. ME/CFS was diagnosed based on the Canadian Consensus Criteria and/or the International Consensus Criteria, and information on symptom severity, quality of life and cognitive impairment was obtained from all participants.

The MRI scans were analysed to provide data on the levels of a number of different substances, including glutamate, NAA and several brain metabolites. These substances all respond (or resonate) differently when stimulated with radio waves while the individual is inside the MRI scanner, and this information can be analysed to distinguish between them (a technique called magnetic resonance spectroscopy).

Levels of these brain neurochemicals were compared between the different patient groups, and their relationships with severity measures were also analysed.

What did they find?

Levels of glutamate in the brain were significantly higher in people with ME/CFS than in healthy control subjects, while people with long COVID also had increased glutamate levels. Interesting, glutamate levels were similar between ME/CFS and long COVID.

Brain levels of NAA were significantly higher in people with long COVID than in healthy control subjects, but the same was not true among those with ME/CFS.

All of the other neurochemicals analysed had similar levels in both patient groups, and in the healthy control subjects.

The researchers also found significant correlations between levels of various neurochemicals and symptom severity in both ME/CFS and long COVID patients, including measures of physical function, cognitive impairment, unrefreshing sleep and pain.


The researchers believe that their finding of an imbalance in these two neurochemicals (as well as their association with measures of severity) suggest that glutamate and NAA levels could contribute to the complex symptoms experienced by people with ME/CFS and long COVID.

Furthermore, the similar patterns of brain neurochemicals in both diseases supports a possible overlap in their underlying pathology. However, it is worth noting that is not clear whether these abnormal neurochemical levels are a cause or a consequence of ME/CFS and long COVID.

In a press release from Griffith University, Dr Thapaliya said that, “People with long COVID and ME/CFS have significantly elevated neurochemical levels, compared with healthy controls potentially causing multiple symptoms in both conditions. Long COVID and ME/CFS have a remarkably similar neurochemical signature, providing further evidence for a significant link between the two conditions.”

What does this mean for patients? Well these results do suggest that one therapeutic strategy might be to restore the balance of glutamate and NAA levels. For example, glutamate-modulating therapies have been used to treat obsessive compulsive disorder, while gene replacement therapy has been used to reduce toxic NAA accumulation in Canavan disease. However, it is too early to consider these as options for ME/CFS or long COVID just yet.

In the meantime, Dr Barnden and his team plan to continue this line of research, specifically by tracking progression of the disease over time, including changes in MRI parameters and neurochemical levels. This new ME Research UK-funded study will start in September 2024.

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