From ME Research UK: Brain fog. Part 2: Cognitive function and ME/CFS

This is the second article by Dr Eleanor Roberts looking at brain fog, the range of cognitive difficulties experienced by people with ME/CFS.

Read part 1 here, which introduces cognitive function and the areas of the brain involved.

Cognitive dysfunction can be one of the most distressing symptoms for people with ME/CFS. This includes decreases in working memory, attention, ability to monitor errors, organisational skills, problem solving, verbal fluency and reasoning.


There are a number of tests and techniques used to assess brain structure and function, and some of these were discussed in a previous article.

There is clearly cognitive dysfunction in ME/CFS, and a 2010 meta-analysis revealed significant differences in information processing, working memory and attention in people with ME/CFS compared with healthy control subjects.

However, unlike a focused injury (such as occurs with a stroke), with ME/CFS no single brain region has been found to be disrupted in all people. Damage and changes leading to cognitive dysfunction may involve not only the grey matter, where neuronal cell bodies sit, but also the white matter, where axons send signals between different brain areas.

In addition to neuronal structural changes, problems may also arise due to changes in function. Furthermore, abnormalities may relate to problems in areas of the brain directly involved in cognition and/or other brain areas that influence these through the connections between them (as discussed in part 1).

In this article, we look at a few of the many brain studies conducted in people with ME/CFS, concentrating on those that have examined areas of the brain directly involved in cognitive function: the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex (dlPFC) and the lateral orbitofrontal cortex (lOFC).

Brain structure

To start with, a study that examined how brain structure is changed in people with ME/CFS showed a significant reduction in grey-matter volume in all of these frontal-lobe areas, as well as a correlation between the amount of this reduction and patients’ ‘performance status.’ Volume reductions in the dlPFC (which is involved in problem solving, working memory and cognitive flexibility) were significantly correlated with fatigue scores.

Another study examined the microstructure of brain tissue and how the small projections of neurons called dendrites and neurites were aligned and dispersed (imagine a field of wheat which should stand up straight but is squashed down and/or mowed in parts). This study found structural decreases in the ACC, which is involved in cognitive processes such as attention, cognitive flexibility and emotional regulation, along with other parts of the frontal and parietal lobes.

The authors suggested that their findings indicate shrinkage of neurons and of the density of axons and the myelin sheath that helps convey cell signals. They also found changes in the number and pattern of neurites in other areas of the cingulate, temporal and occipital lobes, suggesting a decrease in neuronal function as they are less able to pick up neighbouring cell signals.

Also shown in this study were decreases in the superior longitudinal fasciculus pathway, which is a large bundle of axons from many neurons that conveys signals from the frontal lobe to other parts of the cortex involved in many cognitive processes, including emotional processing, attention and memory.

Metabolic and chemical changes

Studies have also investigated metabolic and chemical changes in the areas of the brain involved in cognitive function. One examined the molecule acetylcarnitine (which is thought to be involved in brain energy production and utilisation) as well as assessing blood flow (which is a marker of brain activation). Analysis showed a decrease in both of these factors in the ACC, which could reflect a disturbance in signals conveyed by the neurotransmitter glutamate.

Another study found a decrease in a serotonin transporter in the ACC (the mechanism that helps serotonin be recycled by a neuron so it’s available to pass on a signal), which could also affect cognitive processing.

Electrical activity

Another way of looking at how the brain works is to assess electrical activity and connectivity inside and between brain regions. A study using electroencephalography found deficits of neuronal activity in people with ME/CFS in several cerebral areas. These areas included the cingulate, parietal and occipital lobes, which are associated with attention, memory, concentration and information processing.

The study also found reduced connectivity in cognitive networks involved in focused attention, input interpretation, goal-directed behaviour and working memory, including in our three key areas – the ACC, dlPFC and OFC.

Abnormal functional connectivity in another study was found both locally, within the ACC, and between this area and the right insula, a part of the cerebral cortex involved in perception, cognitive functioning, emotion and consciousness. The authors suggested that this decreased connectivity might be associated with neuropsychological deficits.

Connectivity was also reduced between the ACC and the hippocampus, an area involved in memory, and between the hippocampus and other parts of the frontal lobe including the dlPFC and OFC, the latter of which is involved in cognitive initiation, problem solving, interference control and sensory integration. A further study showed abnormal functional connectivity between areas inside the cingulate cortex, which, they hypothesised, “may result in deficits of cognition and emotion” in people with ME/CFS.

Support and immune cells

Even if neurons are structurally and functionally sound, they may be affected by what is happening in the brain’s ‘support’ cells, astrocytes and immune-system cells (the microglia). Activation of these cells is associated with inflammation in the brain, as was found in a study of people with ME/CFS where inflammation correlated with the severity of cognitive impairment as well as fatigue and pain. Specific regions affected included the ACC as well as other regions involved in cortical functioning, such as the thalamus, hippocampus, midbrain and pons.

The authors postulated that the neuroinflammation they found may be due to neurons having to ‘overexert’ themselves to compensate for functional loss. Indeed, another study that examined mental fatigue during cognitive tasks found ratings were significantly predictive of increased brain activity in regions including several areas of the cingulate cortex as well as regions in the frontal, temporal and parietal lobes, and sub-cortical areas such as the cerebellum and hippocampus.

These authors concluded that their results “suggest that acute mental fatigue has widespread effects on attention, working memory and executive control processes and it is plausible that feelings of fatigue could affect a person’s ability to efficiently attend to, store, manipulate and retrieve information”. These are all circumstances that people with ME/CFS can greatly relate to.


While these are just a few of the studies looking at cognitive dysfunction in ME/CFS, this snapshot shows that what people experience under the banner of ‘brain fog’ may be associated with actual changes in the structure of the brain, dysfunction of neurons, and activation of support and immune-system cells within the brain.

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