Brain Studies of MECFS: A Primer

Neuroimaging Studies of MECFS: A Primer​

If you look for neuroimaging studies of MECFS, you will come across four different types of methods that are used. What you can conclude from each study depends hugely on the method that was used, so it’s important to know the basics.

The first three methods in this list are primarily used by psychologists: they are used to make inferences about psychological (cognitive and emotional) functioning. They are not aimed at documenting neurological problems - specific physiological abnormalities or other disease processes that may impact on brain functioning more generally.

1. Task-related fMRI:

​

In these studies, participants view a stimulus or are asked to complete a task. For example, they might see some emotional pictures, or be given an uncomfortable stimulus, like having their hand placed in cold water. There’s usually a control condition too, where they might see something unemotional or experience some stimulus that isn’t uncomfortable. The objective is to see whether the brain regions that are most active in condition of interest (compared to the control task) are different for MECFS patients than they are for controls.

This kind of study attempts to demonstrate that MECFS patients process certain tasks/stimuli ‘abnormally’ – that is, they show cognitive or psychological abnormalities.

In principle, you could use this method to study the cognitive consequences of having MECFS. You could ask patients to do mental tasks they find challenging and examine their brain responses. However, it is rarely used in this way. Usually, it is used to explore the psychological factors believed to cause or perpetuate the illness. Most studies focus on how patients process emotional or painful stimuli, and aim to show that we respond abnormally to these things. Hence confirming our psychopathology.

2. Resting state fMRI:

​

This is similar to above, except instead of giving the participants tasks to do, the researchers simply measure the activity of different parts of the brain during rest/eyes closed. When at rest, some brain regions tend to ‘resonate’ together (that is, activity in those regions is correlated). These resonation patterns have enabled researchers to identify ‘networks’ of regions that seem to work together. The most well-known of these is the default mode network, a network that appears to be active when we are at rest and our mind is wandering freely. This network includes some regions important for re-experiencing autobiographical memories.

Other networks include the salience network, which includes the anterior insula (believed to play a role in evaluating one's emotional or bodily state), and the anterior cingulate (believed to be involved in preparing the body and brain for important and challenging mental or physical tasks). The salience network has shown to be overactive in anxiety disorders, so it is often a target for those wishing to explore the ‘psychopathology’ that causes MECFS.

3. Grey/white matter volume analysis (structural MRI):

​

This is a different technique altogether. It involves using automated methods to quantify the volume of grey and/or white matter in different parts of the brain, based on how it appears in a high resolution structural MRI scan. Generally speaking, white matter contains lots of axons, which are the parts of neurons that act as "wires" to transmit signals across different bits of cortex. Grey matter contains lots of cell nuclei, so it looks darker.

Use in Neurology. Neurological populations, such as Alzherimer's patients, tend to show massive reductions in both white and grey matter volume. This makes sense because most neurological disease processes affect neurons generally, both long and short, and all parts of the neuron, both axons and nuclei. Exceptions to this general rule are things like MS, which are known to selectively affect myelin, which is the substance wrapped around the axons which makes it look white in the first place. So in this disease, you get a disproportionate reduction in white matter volume.

Use in Psychology. The majority of recent studies of grey/white matter volume focus on populations without any known neurological damage, and use it as an indirect measure of learning and overall psychological functionality. For example, one recent study showed that after participants underwent intensive training in juggling, grey matter volume increased in regions associated with visual processing. In other words, your grey matter volume in particular areas can change with your experience. These changes are much smaller than those seen in neurological disease.

However, the reasons for these changes are not fully understood. It is unlikely that that you actually gain new neural cells. More likely, blood flow to that area just gets more efficient.

You can also use this technique to compare some clinical group with normal controls. For example, kids with ADHD show some areas of increased and some of reduced grey matter volume relative to non-ADHD kids. This is also not surprising, because any group that behaves differently from another, will probably think and process information differently, and all these things can influence grey matter volumes.

Another problem is that the abnormalities in grey matter are often positive in some areas and negative in others. They also often affect brain areas that don’t appear to have much to do with the disorder in question. So again, researchers often cherry-pick: they focus on the differences that make some sort of sense and ignore the others.

In MECFS, researchers often look for increases in grey matter volume as a way of gaining insight into our psychological function. They look for increases in areas associated with emotional and pain processing - which might suggest pathological and prolonged focus on these things. The idea is usually that such changes play a causal role in perpetuating our illness.

4. Methods that track specific substances in the brain

This fourth class of methods enable the researcher to track the uptake of a particular substance in different regions of the brain, or to measure the concentration of some substance within a particular region. These methods are often used in a genuine attempt to examine pathology within the brain which might be the result of a disease process happening elsewhere in the body - they're used less often to make inferences about the person’s Psychology. However, having said that , there are some examples of studies using these methods in MECFS that seem to have managed to explain their findings in psychological terms alone.

Examples of these methods in the MECFS area include one recent study that used PET to measure the concentration of a particular marker of brain inflammation in different brain regions. Another recent study used a slightly more recent technique -MR spectroscopy - to measure the concentration of various neurotransmitters and substances indicative of inflammation in different brain regions.

 

Problems to watch out for in brain studies of CFS
​

Unreliability. Brain methods generally involve performing many thousands of individual comparisons between the group of interest and the control group. This means that there's a much higher chance than usual of obtaining some significant findings by chance alone. Normally, to reduce the number of spurious findings they obtain, researchers apply a correction, so that only differences that are really large are considered secure. However, corrections do not completely solve the problem. Really, the only way to be sure a result from any neuro study is robust is to show that if you take another sample of MECFS patients and another sample of controls, you get the same outcome. Often neuroimaging studies of MECFS use sample sizes that are way too small, so some of the differences we see may just be quirks of the individuals that were chosen for the samples, not real effects due to the MECFS.

Cherry picking. This is kind of related to the point above. Most neuroimaginig studies will yield lots of differences between the two groups, but the researchers will tend to focus on those differences that “make sense” within their framework of what causes the illness. So the study can turn into nothing more than a belief confirmation exercise.

Reverse Inference. We can never be sure what region X is actually doing. For example, some researchers have suggested the anterior insula is involved in evaluating emotional states, so some have suggested high levels of activation in that area may indicate pathologically high emotional processing. But we simply don’t know enough at this point to make such an inference. Some ideas we had have turned out to be pretty wrong.

Overprocessing or compensation? The same area might be contributing very different things in different situations. For example, in some situations, greater activation in an area might mean people are particularly engaged in or focussed on some aspect of the task. In others, it might mean they are having particular problems with that aspect, and the high levels of activation reflects an attempt to compensate for their inadequacies.

Poor causal reasoning. Perhaps the biggest problems with neuro studies of MECFS is that too much speculation goes on as to what causal role the neuro abnormalities might play in the disease. Researchers commonly start with the assumption that the brain is playing a major role in perpetuating the symptoms. Then when they find abnormalities, they readily jump to the conclusion that these abnormalities are what's causing the MECFS. I think its far more likely to be the other way around: MECFS is a systemic illness that affects a lot of body systems, including the brain.

 

Some key brain studies of MECFS​

Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: an 11C-(R)-PK11195 PET study.
Nakatomi Y et al.
Journal of Nuclear Medicine. 2014 Jun 1;55(6):945-50.