1. Sign our petition calling on Cochrane to withdraw their review of Exercise Therapy for CFS here.
    Dismiss Notice
  2. Guest, the 'News in Brief' for the week beginning 18th March 2024 is here.
    Dismiss Notice
  3. Welcome! To read the Core Purpose and Values of our forum, click here.
    Dismiss Notice

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

Discussion in 'ME/CFS research' started by Sly Saint, Nov 1, 2021.

  1. Sly Saint

    Sly Saint Senior Member (Voting Rights)

    Messages:
    9,574
    Location:
    UK
    Abstract
    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS.

    In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner. Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement.

    The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor. In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area.

    For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis

    https://www.mdpi.com/2379-139X/7/4/56
     
    Fizzlou, Simone, boolybooly and 30 others like this.
  2. Ash

    Ash Senior Member (Voting Rights)

    Messages:
    1,105
    Location:
    UK
    I don’t have the physical capacity to read or the education to assess this.

    So I look forward to all your interpretations.

    Every time I see one of these I think something solid or another melter?

    Science moves on so slowly with such inadequate funding.

    I fear I may have strayed from topic apologies. This one appealed cause my brain certainly ‘feels’ deprived of perfusion.
     
    Simone, cfsandmore, Samuel and 16 others like this.
  3. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    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.
     
    Last edited: Nov 2, 2021
    Simone, sebaaa, oldtimer and 7 others like this.
  4. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    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.
     
    Last edited: Nov 2, 2021
  5. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    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.

    Screen Shot 2021-11-02 at 2.08.17 PM.png

    (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.
     
    Last edited: Nov 2, 2021
  6. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    rainy, Barry, NelliePledge and 3 others like this.
  7. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights)

    Messages:
    4,256
    Location:
    Aotearoa New Zealand
  8. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    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?
     
    Last edited: Nov 2, 2021
  9. Woolie

    Woolie Senior Member

    Messages:
    2,918
    You don't see the term "limbic system" very much these days.

    What they say is right about the anterior cingulate. There's a portion of it (the rostral ACC or midcingulate cortex) which communicates heavily with the anterior insula. Its been suggested that the insula is important for integrating and evaluating input about internal bodily states, and that it projects this information to the ACC, which then signals if a bodily response is needed. The two are believed to work hand-in hand in the pain response, and some say the ACC component, which is more response-oriented than the insula, is the more aversive component (there's even a form of surgery to relieve pain that involves cutting some tissue within the ACC).

    One of the main jobs of the ACC is to initiate ANS changes that may be help to meet some situation or challenge. This is not adjusting to cold by shivering, or low level things like that, its more about explicit goals and intentions. Like gearing yourself up to win a race, even though you're tired.

    My stab in the dark guess is that people with MECFS learn to downregulate the activity in this network as a form of adaptive strategy. The ACC initiates autonomic changes, and the dysregulation of the ANS in MECFS might mean that engaging it makes people feel sicker.
     
    Last edited by a moderator: Nov 2, 2021
  10. Annie

    Annie Established Member (Voting Rights)

    Messages:
    31
    This is way beyond my scientific capacity but I wondered if this could be related to the micro-blood-clots currently being treated in Germany, mainly on LongCovid patients though I gather a few ME patients have been successfully treated there?
     
  11. Woolie

    Woolie Senior Member

    Messages:
    2,918
    PS I don't think reductions in rCBF indicate anything wrong with blood supply to the brain. rCBF is an index of which regions of the brain are active during a particular task or at a particular time.

    The brain takes up blood oxygen according to need, and these measures are an index of that level of need.
     
  12. Peter Trewhitt

    Peter Trewhitt Senior Member (Voting Rights)

    Messages:
    3,637
    Forgive me if this is a stupid question, but is this suggesting it is not possible with this study to distinguish between reduced blood supply to an area and reduced oxygen uptake for other reasons in that area?
     
  13. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    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?

     
    Last edited: Nov 2, 2021
  14. Levant

    Levant Established Member (Voting Rights)

    Messages:
    59
    Fizzlou, Perrier, FMMM1 and 1 other person like this.
  15. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    13,278
    Location:
    London, UK
    Per Julin has published with Jonas Blomberg which suggests a serious biomedical interest.
     
    Mithriel, sebaaa, Grigor and 14 others like this.
  16. Barry

    Barry Senior Member (Voting Rights)

    Messages:
    8,385
    Are we saying that the more active an area of the brain is, the more oxygen 'flow' it needs to service that need, and thereby higher blood flow to that area?

    And so a lower blood flow to an area of the brain could be due to either:
    • That area of the brain demanding / needing a higher blood flow, but something preventing that for some reason? Or ...
    • That area of the brain for some reason not demanding / needing a higher blood flow, even though it should?
     
    ahimsa, boolybooly, Michelle and 8 others like this.
  17. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

    Messages:
    13,278
    Location:
    London, UK
    Probably yes, either.
     
    ahimsa, boolybooly, MEMarge and 8 others like this.
  18. CRG

    CRG Senior Member (Voting Rights)

    Messages:
    1,857
    Location:
    UK
    My thoughts are that the whole process of the MRI -preparing for the day, getting to the facility, answering all the protocol questions, being in the machine, would place far higher physical and cognitive demand on the ME subjects and that any difference in perfusion would involve at least some measure of adaptive response, - I think I'm just saying less clearly what @Woolie wrote above,
    but provoked specifically by attending for the MRI. So the MRI would be a proxy for any physical or cognitive challenge, but the perfusion measure is not as the authors suggest evidence of an underlying pathology, but of an adaptive response to that pathology
     
    JemPD, Michelle, oldtimer and 4 others like this.
  19. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    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.
     
    Last edited: Nov 2, 2021
    Michelle, Woolie, oldtimer and 3 others like this.
  20. Hutan

    Hutan Moderator Staff Member

    Messages:
    26,534
    Location:
    Aotearoa New Zealand
    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'.
     

Share This Page