Brain function characteristics of chronic fatigue syndrome: A task fMRI study, Shan et al, 2018

Indigophoton

Indigophoton

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Highlights
CFS patients recruit larger BOLD activation areas for the Stroop task.

BOLD signal complexities in CFS are lower in ten activated regions while complexities of heart rate and pulse pressure are similar.

The BOLD signal complexity is correlated with the SF-36 health score across all subjects.

The BOLD signal complexity explains more than 40% of variance in the health score across all subjects.
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Abstract
The mechanism underlying neurological dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is yet to be established. This study investigated the temporal complexity of blood oxygenation level dependent (BOLD) changes in response to the Stroop task in CFS patients.

43 CFS patients (47.4 ± 11.8 yrs) and 26 normal controls (NCs, 43.4 ± 13.9 yrs) were included in this study. Their mental component summary (MCS) and physical component summary (PCS) from the 36-item Short Form Health Survey (SF-36) questionnaire were recorded. Their Stroop colour-word task performance was measured by accuracy and response time (RT). The BOLD changes associated with the Stroop task were evaluated using a 2-level general linear model approach. The temporal complexity of the BOLD responses, a measure of information capacity and thus adaptability to a challenging environment, in each activated region was measured by sample entropy (SampEn).

The CFS patients showed significantly longer RTs than the NCs (P < 0.05) but no significant difference in accuracy. One sample t-tests for the two groups (Family wise error adjusted PFWE < 0.05) showed more BOLD activation regions in the CFS, although a two sample group comparison did not show significant difference. BOLD SampEns in ten regions were significantly lower (FDR-q < 0.05) in CFS patients. BOLD SampEns in 15 regions were significantly associated with PCS (FDR-q < 0.05) and in 9 regions were associated with MCS (FDR-q < 0.05) across all subjects. SampEn of the BOLD signal in the medioventral occipital cortex could explain 40% and 31% of the variance in the SF-36 PCS and MCS scores, and those in the precentral gyrus could explain an additional 16% and 7% across all subjects.

This is the first study to investigate BOLD signal SampEn in response to tasks in CFS. The results suggest the brain responds differently to a cognitive challenge in patients with CFS, with recruitment of wider regions to compensate for lower information capacity.
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Graphical abstract
The sample entropy (a measure of amount of information encoded in a temporal signal) of BOLD response to Stroop tasks in seven areas are significantly lower in patients with chronic fatigue syndrome (CFS) and significantly correlated health scores across all subjects, suggesting that the brain operates differently in CFS patients.

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The Stroop test (the one where you have to identify that RED is saying 'red') seems like a good test to find differences in brain function between people with and without ME/CFS. Even just thinking about the effort of doing that test makes me groan.

This is an interesting study from the Australian NCNED team - although I don't understand it all yet. @Woolie

Would the participants have been lying down when they did the fMRI/Stroop test? If so, I expect that might have had an impact on blood flow.
EDIT: Although I guess reducing the impact of orthostatic intolerance might help to illuminate what else is going on. But differences in cognitive function under real life conditions would be underestimated.
 
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Interesting study.

I'm not familiar with the SampEn measure they used, but from what they say, it appears to be a measure of neural processing efficiency.

The main conclusion of the study was that CFS patients are less efficient at recruiting neural resources to accomplish a challenging task (the Stroop task) than are controls. The two findings that led them to this conclusion are:

1. CFS patients showed more widespread brain activation than healthy controls during the task, suggesting a lack of efficiency.
2. SampEn measures in some regions were lower in CFS patients than in controls, which (I think) they interpreted as less coherent, synchronous activity. Most of these regions are ones that are not normally associated with the the Stroop task.

They conclude that the brain recruits wider regions in CFS patients to compensate for the lower processing capacity.

Its important to remember that fMRI indexes blood flow, so its hugely affected by a person's cardiovascular health. However, these authors do not think these abnormalities are due to cardiovascular factors because: 1) the CFS patients' heart rate and pulse pressure during the task were not different from controls'; and 2) if it were all down to cardiovascular factors, then the SampEn measures would be higher in all brain areas, not just in the few they found (I don't think this necessarily follows, but its what they said).

They suggest instead that the problem in the CFS patients is to do with neurovascular coupling. So in healthy people, activating a part of the brain initiates a chain of events, which result in increased dilation of the blood vessels supplying that area. These authors suggest that something is going wrong in this chain of events, so the blood isn't getting where it needs to efficiently.

On the whole, its pretty true to the results (in fact, frustratingly so, there's not much speculation about how this might all fit in with the clinical picture in CFS). I only spotted one instance of clear cherry picking:

The results said (my bold):
paper said:
There were 93 brain areas activated exclusively in the CFS group. They included regions in the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, parahippocampal gyrus, posterior superior temporal sulcus, superior parietal lobule, inferior parietal lobule, precuneus, postcentral gyrus, insular gyrus, cingulate gyrus, lateral occipital cortex, amygdala, hippocampus, basal ganglia, and thalamus (Supplementary Table S1)
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The conclusion said:
paper said:
This current study observed that CFS patients recruited the additional subcortical structures of amygdala, hippocampus, basal ganglia, and thalamus in response to the Stroop task.
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Also, I have absolutely no idea why they chose the Stroop task, and I'm not sure they do either. I think they just thought it was "hard".
 
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I guess sticky blood may effect blood flow to the brain?

Putting aside the dubious reasoning, I think it’s good to have a study that shows the cognitive challenges we face, even if it drifts off into the complicated when a more simple physiological explanation may exist...although it may be complicated of course?

The challenge with repeating this on a larger sample is the variance within the sample I guess. It would be interesting to look at other measures alongside as a way of predicting poor cognitive function. Perhaps using the test after being laid down, or perhaps expose the subject to stimulus and measure before and after for controls and patients? Stimulus could be watching a debate on tv or something similarly challenging ?
 
The following is my understanding - it may be wrong.

BOLD - Blood Oxygenation Levels
alktipping said:
hypoperfusion is the same cause of cognitive difficulties mentioned by dr ramsey and dr Byron hyde a very long time ago before expensive mri testing was possible
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If I'm understanding things correctly, this study actually found more regions to be perfused rather than hypo-perfused in people with CFS as compared to the controls. They call it 'BOLD activated' which indicates a raised blood oxygenation level. The authors are saying that having more areas of the brain working to do a task is indicative of an inefficient brain that is using more energy than it should be. However, they found the differences weren't statistically significant.

They quote a study (Mizuno 2015) that also found more regions to be BOLD activated in people with CFS - so there may well be a real (but small?) trend.

SampEn of BOLD
The other measure they talk about is SampEn (the temporal variability) of the blood oxygenation levels. For this measure, temporal variability is good. I'm assuming it's a bit like a computer with the 0's and 1's - the quicker the 0's and 1's get sent, the more information is being processed. Another study found that SampEn of BOLD was lower in old people.

This study found ten regions of the brain where SampEn was lower (statistically valid) in people with CFS. And they found that in seven of these regions, the SampEn was significantly correlated with the health scores of the participants (with lower SampEn values being correlated with lower health scores).
 
Hutan said:
If I'm understanding things correctly, this study actually found more regions to be perfused rather than hypo-perfused in people with CFS as compared to the controls. They call it 'BOLD activated' which indicates a raised blood oxygenation level. The authors are saying that having more areas of the brain working to do a task is indicative of an inefficient brain that is using more energy than it should be. However, they found the differences weren't statistically significant.
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Since this is a task-related fMRI study, what you're seeing in the maps is not absolute blood oxygen uptake, but a difference score (task minus control).

So you're seeing how much additional oxygen the brain is taking up during the key (interference) condition of the task, over and above what you see in the control condition.

This pattern - of more diffuse, less "targeted" activity - is observed in a lot of clinical populations, and you see it even in normal ageing. Its like a marker of how efficient you are at performing a task.

It seems to me that the SampEn measure is sort of capturing the same thing - how much useless activity you're engaging in over and above the useful and targetted activity you're doing to actually accomplish the task. Notice how its all the irrelevant regions that have the abnormal SampEn measures - not the regions people actually need to accomplish the task.
 
Thanks for the explanation, @Woolie

I write a blog about cognitive tests and fatigue a few years ago:
http://phoenixrising.me/archives/16688

I can’t remember all the details of the research, but I think the Stroop test is one of those that has shown differences between patients and controls.

Here’s my intro to the Stroop test:

Do the Stroop & other cognitive tests

The Stroop is a quirky test of attention, with a quirky name. The simplest way to see how it works is just to look at the two lists above. Don’t read them, instead say the color each word is displayed in, as quickly as you can. Not so easy… Try it online!
 
Simon M said:
I can’t remember all the details of the research, but I think the Stroop test is one of those that has shown differences between patients and controls.
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Okay, sure, but this is a task-related fMRI study, they ought to have proper theoretically motivated reason for choosing the task they did. The Stroop is "hard", but then so too are lots of tasks. Why did they pick that? First thing that came to mind? The Stroop is a language control task - its about overriding the language element that's most strongly in your mind in order to produce another one. Is language control what you want to measure? A different sort of "hard" task - for example, a sustained attention task - would likely produce some very different patterns of activation.

I would just have liked to see some sort of justification.
 
Woolie said:
the CFS patients' heart rate and pulse pressure during the task were not different from controls'
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Sorry, I've not read any of the detail but this made me think - wouldn't we expect to see a difference in patients heart rates? I'm assuming, fairly safely I think, that this test will need to be done outside of the patients home, so you have the travel from home to test centre, interacting with those at the test centre, and then taking the test. The only way I could see this avoided would be if a rest period was built in before taking the test.

Woolie said:
I only spotted one instance of clear cherry picking
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Wouldn't be NCNED without some cherry picking ;)
 
Hutan said:
The Stroop test (the one where you have to identify that RED is saying 'red') seems like a good test to find differences in brain function between people with and without ME/CFS. Even just thinking about the effort of doing that test makes me groan.

This is an interesting study from the Australian NCNED team - although I don't understand it all yet. @Woolie

Would the participants have been lying down when they did the fMRI/Stroop test? If so, I expect that might have had an impact on blood flow.
EDIT: Although I guess reducing the impact of orthostatic intolerance might help to illuminate what else is going on. But differences in cognitive function under real life conditions would be underestimated.
Click to expand...

Yes. I was a subject in this study. The tests were conducted lying down in a fMRI machine.
 
I was a subject in this study.

In answer to two of the questions above:
* the test was conducted lying down in an fMRI machine, and took about 45 mins in total for each subject
* the first 15 minutes or so was calibrating the machine for each subject. In one sense, this could be considered a 'rest', but it also allowed time to adjust to being in the machine itself.
 
The difficulty for me with this sort of study is that we would expect patients to have different thoughts from controls while taking part in a test like this. The regions with increased blood flow may simply reflect the different emotional connotations for patients and controls. For a control it might be 'this is better than sorting out that paper work Jenny asked me to do yesterday - hoho!' For a patient it may be 'am I actually doing this right, it is quite stressful thinking that the results of this test will be used to create theories about my illness'.

I think you absolutely need patients with other illnesses as controls and you really need them to think the test is just as relevant to their illness as to ME.
 
Jonathan Edwards said:
I think you absolutely need patients with other illnesses as controls and you really need them to think the test is just as relevant to their illness as to ME.
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Even then there are a vast range of different things that may be thought about including stuff like the stress of getting to where ever the test was. Maybe they should get the patient to write down their thoughts during the test so they could include a coding of that in any cluster analysis they do.

I thought that some fMRI scan work gave people different tests and tasks to think about and compared images between the different tasks for the same patient. That may produce some consistency,
 
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