Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), 2021, Xia Li et al

Xia Li 1
Per Julin 2
Tie-Qiang Li 1, 3,4

1 Institute of Information Engineering, China Jiliang University, 258 Xueyuan Street, Xiasha Higher Education Zone, Hangzhou 310018, China
2 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, S-17177 Stockholm, Sweden
3 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, S-17177 Stockholm, Sweden
4 Department of Medical Radiation and Nuclear Medicine, C2-76, Karolinska University Hospital, Huddinge, S-14186 Stockholm, Sweden

Interesting to see the Chinese and Swedish Collaboration.

This comment about Per Julin by Mango suggests we are not dealing with a BPS proponent. Maybe our Swedish members can tell us more?
A google of Xia Li produces a lot information about a Chinese female wrestler in WWE - possibly they do brain research in their spare time, but probably that's a different Xia Li.
Tie-Qiang Li, based at the Karolinska Institute, has an extensive publication record related to brain imaging.

So, there's no obvious red flags with the authors and the study is of a good size.

 

This is my interpretation of that:
Arterial spin-labelling (ASL) is a brain imaging technique; pseudo-continuous spin-labelling (PCASL) is a version of ASL that has some advantages e.g. whole brain coverage.

A study using ASL in healthy controls found that they could predict levels of fatigue caused by cognitive tasks by measuring the cerebral blood flow in the thalamus and right middle frontal gyrus before the fatiguing task started. So, the idea is that cerebral blood flow at rest in those parts of the brain might be a marker of fatigue.

If that's true, then maybe we will find a difference in cerebral blood flow in people with ME/CFS, compared to healthy controls. But, a study of people with ME/CFS and controls found that global brain perfusion was similar at rest. (But, the title of that study makes me wonder about their patient selection, among other things.
Gherardi, R.K.; Crépeaux, G.; Authier, F.-J. Myalgia and Chronic Fatigue Syndrome Following Immunization: Macrophagic Myofasciitis and Animal Studies Support Linkage to Aluminum Adjuvant Persistency and Diffusion in the Immune System. Autoimmun. Rev. 2019,)

So, this study is to look at the question again - i.e. is there a difference in cerebral brain perfusion at rest between ME/CFS and healthy controls, and is the difference related to the severity of ME/CFS fatigue symptom. And they'll use this technique that they think is very good for the task - PCASL MRI.

 

The ME/CFS subjects met all of the criteria you would want them to (CCC, ICC, IOM).

The imaging found that there was hypoperfusion in the limbic system of the ME/CFS subjects. Cerebral perfusion in these brain regions was reduced by about 34% in comparison with the HC group. That seems quite a lot. ROI is a region of interest. The charts below show results for 4 regions of interest, with each circle being a trial participant. There is overlap, but there does look to be a difference. And this is presumably lying down, the posture where people with ME/CFS typically most feel like a healthy person. It seems to support that finding of cerebral hypoperfusion in ME/CFS in tilt testing.



(There were two different ways of analysing/grouping the data - according to known brain regions, and according to the individual bits of data (the voxels). It probably doesn't matter too much - they found roughly the same thing. Some of the clusters found using the voxels didn't match perfectly to named brain regions, but instead overlapped. It does mean that sometimes a region of interest from a brain atlas won't be found to be different, because only part of the region of interest is different, and part of the neighbouring region of interest is also different.)

The cerebral blood flow of the people with ME/CFS was found to be significantly related to the EQ-VAS scores - a measure of overall health. There was a trend towards a relationship between the fatigue scores as measured by the Fatigue Severity Scale (FSS), but it wasn't statistically significant. The authors suggest that maybe the FSS isn't actually that great at measuring fatigue - there was just a small range of scores.

They conclude that:

Obviously I'm not a brain imaging expert but I thought this was a nice study. The authors don't get in to cherry picking the various functions of the limbic system in the astrology sort of way that BPS brain imaging studies typically do. Given the wide range of roles the limbic system is involved with, I think it's reasonable to assume that thinking and moving is harder in a state of hypoperfusion. The finding fits well with my feeling that living with ME/CFS is like operating at a very high altitude.

The authors talk about improvements in the PCASL technique that they'd like to make. I hope that they get more funding to expand on this work. I wonder if this technique can be applied to upright MRI machines.

 

@Woolie; @SNT Gatchaman - one for you

 

I was wondering what a reduction in cerebral blood flow of the order talked about in this paper might mean. I found this paper:
https://onlinelibrary.wiley.com/doi/10.1111/cns.12780
Advances in chronic cerebral circulation insufficiency

So, this study reported cerebral brain flows in the regions of interest as follows:

58 mL/100 g/min for the healthy controls seems to tie in with the reported normal blood flow of 50-55 mL/100 g/min. The 38 mL/100 g/min for people with ME/CFS is at about the level where there is the disruption of glucose utilisation in the brain i.e. problems with making energy. But it's not at the level of neurological dysfunctions or permanent neuron damage.

That's for lying down doing nothing though. While it looks as though blood flow has to be majorly limited to cause permanent neuron damage, I guess I wonder why we don't see such damage in people with ME/CFS who really push themselves. I don't think we see such damage. I don't think we see people developing dementia at unusually high rates. Is the fatigue and feeling of being dreadfully ill so insistently protective that we always stop well before permanent damage is caused? And/or, is the blood flow in ME/CFS always sufficient to not risk permanent neuron damage?

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999014/
Arterial spin labeling in neuroimaging, 2010, Petcharunpaisan et al

I found this paper by Petcharunpaisan et al useful in understanding the technique. Unlike techniques where a tracer is injected into the person, the imaging labels the person's own blood water, temporarily magnetising it, and recording where it goes. The blood water only stays magnetised for a second or so, so you have to do lots of repeated measurements, which is why it takes so long to get the data. But it gives you a measure of blood flow. I don't think it says anything about oxygen delivery, unlike the BOLD technique that compares the relative magnetic properties of haemoglobin with and without oxygen attached.

So, increased regional blood flow is correlated regional brain activation; decreased regional blood flow is correlated with reduced regional brain activation.

I guess the study that is the subject of the thread found lower perfusion in some parts of the brain, but not all of the brain. So, there's not global hypoperfusion. So, @Woolie, are you telling us that there's nothing here to indicate that there is something wrong with the blood supply system - that we can be fairly confident that it's just that the regions of the brain that the healthy controls are using while lying in the machine aren't being used as much by the people with ME/CFS? And that the lower blood flow to the identified regions is something that the person has learned is helpful e.g because activating the ACC increases an autonomic response that is unpleasant?

Could it be that the people with ME/CFS are, on average, better at lying still thinking of nothing much, as instructed, while the healthy controls are, during the 45 minute scanning session, planning what they are going to make for dinner, and thinking about a social event tomorrow?

Could it be that there is a different level of experience of MRI scans in the two groups? Maybe the ME/CFS patients are more likely to have had an MRI before, and so are calmer about the process, on average, than the healthy controls?

 

Could it be that someone in chronic pain and/or fatigue might adapt over time by down regulating the activity of the ACC? So, we might expect to see the same thing in people with rheumatoid arthritis, for example?

Altered cerebral pain processing of noxious stimuli from inflamed joints in rheumatoid arthritis: An event-related fMRI study
My interpretation of this study is that when people with RA received a painful stimulus on a thumbnail, they reacted the same as healthy controls and blood flow to the prefrontal cortex increased. But when they received a painful stimulus on an inflamed joint, calibrated to be as painful to them as a painful stimulus to the healthy joint of a healthy control, that increase in blood flow didn't happen - the prefrontal cortex was not activated (and so it did not activate the ACC). So, the person with RA had adapted over time, the joint pain was there, but the brain's response of 'you need to do something about this now' was not.

 

I think Ken Lassesen might be making the mistake I made, of seeing 'hypoperfusion' referred to in this study and mixing it up with global hypoperfusion (that still might be a thing, but this paper is not evidence of it).

The levels of 'hypoperfusion' in some regions of the ME/CFS brains that the paper that is the subject of this thread found seem to be at the level of 'the brain region is ok, it's just not being used as much as the healthy controls were using their same bit of the brain'.