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Neurometabolites in anterior cingulate cortex in CFS:magnetic resonance spectroscopy study @ 7 Tesla

Discussion in 'BioMedical ME/CFS Research' started by Dolphin, Oct 31, 2017.

  1. Dolphin

    Dolphin Senior Member (Voting Rights)

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    From: Dr. Marc-Alexander Fluks


    Source: University of Oxford
    Date: September 22, 2017
    URL: https://ora.ox.ac.uk/objects/uuid:60ff242e-2ccd-4f23-ac7d-16553d864e8b
    https://ora.ox.ac.uk/objects/uuid:60ff242e-2ccd-4f23-ac7d-16553d864e8b/datastreams/content01



    Neurometabolites in anterior cingulate cortex in chronic fatigue syndrome: A magnetic resonance spectroscopy study at 7 Tesla
    ----------------------------------------------------------------
    Chi Chen - St Hugh's College, Department of Psychiatry, University of Oxford

    Abstract

    Background

    Chronic fatigue syndrome (CFS) is a disorder characterized by prolonged physical and mental fatigue that cannot be explained by another established medical diagnosis.

    The anterior cingulate cortex (ACC) and putamen are two regions involved in frontal-striatal neural circuitry, which may be related to the pathophysiology of CFS.

    The aim of this study was to investigate the concentrations of neurometabolites, including glutamate, gamma-aminobutyric acid (GABA) and glutathione, in the ACC and putamen, using magnetic resonance spectroscopy (MRS) at 7 Tesla (7T).

    In addition, this study also aimed to evaluate resting-state functional connectivity in CFS with functional magnetic resonance imaging (fMRI).

    Methods

    This study involved 12 patients who met the Oxford criteria for CFS and 25 healthy controls.

    Participants rated themselves on the Chalder Fatigue Questionnaire (CFQ) and the Beck Depression Inventory (BDI).

    All participants had a single proton (1H) MRS and resting-state fMRI scan with a 7T Siemens MAGNETOM scanner (Siemens, Erlangen, Germany) with a Nova Medical 32 channel receive array head coil.

    Spectra were measured from voxels in the ACC (20x20x20 mm), putamen (10x16x20 mm) and occipital cortex (20x20x20 mm).

    Spectra were analysed with LCModel to obtain absolute concentrations of the neurochemicals.

    Differences in functional connectivity between CFS and healthy participants were tested using multivariate exploratory linear optimized decomposition into independent components (MELODIC) and dual regression.

    Results

    Concentrations of putamen glutamate and glutamate+glutamine (Glx) were increased in CFS while that of ACC GABA was decreased.

    Putamen Glx and ACC glutamine were negatively associated with the severity of self-reported fatigue.

    There were main effects of CFS diagnosis on glutathione (GSH) and total creatine, indicating decreases of these neurometabolites in all the regions studied in CFS patients.

    In addition, the CFS patients demonstrated elevated functional connectivity between the default mode network and right supracalcarine cortex, precuneus cortex and dorsolateral prefrontal cortex.

    Conclusions

    The increased putamen glutamate, decreased ACC GABA and elevated resting state functional connectivity of the default mode network suggest a hyperactive brain status in CFS.

    The global decrease of GSH and total creatine also suggest that CFS patients may have an abnormal bioenergetic status with higher oxidative stress.

    -------- (c) 2017 University of Oxford



     
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  2. Cheshire

    Cheshire Senior Member (Voting Rights)

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    Small cohort and poor criteria. Does that mean anything?
     
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  3. Trish

    Trish Moderator Staff Member

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    What a wasted opportunity - so they used Oxford Criteria, Chalder Fatigue scale and a depression measure. So what condition(s) were they actually studying.

    I hope people more expert than me will interpret. @Woolie can you help?

    Edit to add: Looks like it's a Masters' degree thesis.
     
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  4. Trish

    Trish Moderator Staff Member

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    CFQ fatigue (Mean ± SEM) control: 11.0 ± 0.2 cfs: 24.3 ± 1.2 p<0.001**
    BDI depression (Mean ± SEM) control: 0.5 ± 0.2 cfs: 9.3 ± 2.9 p<0.011*

    So the patients were statistically significantly fatigued and significantly depressed.

    I haven't read the whole thesis and don't intend to, but I glanced through the bit about CBT and GET as current treatments. The student appears to have swallowed PACE and the BPS model uncritically, not surprising given he's a student in the psych department at Oxford, which is Michael Sharpe's base.
     
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  5. ivorin

    ivorin Established Member

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    Still seems to show what we'd expect. Higher levels of excitatory transmitters that contribute to a "wired but tired" state. Is it really that bad? I almost feel encouraged that they got these results even from a badly defined patient cohort. Am I completely off here?
     
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  6. Trish

    Trish Moderator Staff Member

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    You may well be right, @ivorin . I think I'm being so negative because it makes me angry that a potentially promising young ME researcher is being so grossly misled by his supervisors about what ME actually is, and the whole BPS model. Let's hope he/she reads more widely if they move on to do a PhD in the same field.
     
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  7. Dolphin

    Dolphin Senior Member (Voting Rights)

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  8. ivorin

    ivorin Established Member

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    And let's hope she does pursue a PhD in the field :)
     
  9. Dolphin

    Dolphin Senior Member (Voting Rights)

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    Beck's Depression Inventory
    This depression inventory can be self-scored. The scoring scale is at the end of the questionnaire.

    1.
    0 I do not feel sad. 1 I feel sad 2 I am sad all the time and I can't snap out of it. 3 I am so sad and unhappy that I can't stand it.

    2.
    0 I am not particularly discouraged about the future. 1 I feel discouraged about the future. 2 I feel I have nothing to look forward to. 3 I feel the future is hopeless and that things cannot improve.

    3.
    0 I do not feel like a failure. 1 I feel I have failed more than the average person. 2 As I look back on my life, all I can see is a lot of failures. 3 I feel I am a complete failure as a person.

    4. 0 I get as much satisfaction out of things as I used to. 1 I don't enjoy things the way I used to. 2 I don't get real satisfaction out of anything anymore. 3 I am dissatisfied or bored with everything.

    5. 0 I don't feel particularly guilty 1 I feel guilty a good part of the time. 2 I feel quite guilty most of the time. 3 I feel guilty all of the time.

    6. 0 I don't feel I am being punished. 1 I feel I may be punished. 2 I expect to be punished. 3 I feel I am being punished.

    7. 0 I don't feel disappointed in myself. 1 I am disappointed in myself. 2 I am disgusted with myself. 3 I hate myself.

    8. 0 I don't feel I am any worse than anybody else. 1 I am critical of myself for my weaknesses or mistakes. 2 I blame myself all the time for my faults. 3 I blame myself for everything bad that happens.

    9. 0 I don't have any thoughts of killing myself. 1 I have thoughts of killing myself, but I would not carry them out. 2 I would like to kill myself. 3 I would kill myself if I had the chance.

    10. 0 I don't cry any more than usual. 1 I cry more now than I used to. 2 I cry all the time now. 3 I used to be able to cry, but now I can't cry even though I want to.

    11. 0 I am no more irritated by things than I ever was. 1 I am slightly more irritated now than usual. 2 I am quite annoyed or irritated a good deal of the time. 3 I feel irritated all the time.

    12. 0 I have not lost interest in other people. 1 I am less interested in other people than I used to be. 2 I have lost most of my interest in other people. 3 I have lost all of my interest in other people.

    13. 0 I make decisions about as well as I ever could. 1 I put off making decisions more than I used to. 2 I have greater difficulty in making decisions more than I used to. 3 I can't make decisions at all anymore.

    14. 0 I don't feel that I look any worse than I used to. 1 I am worried that I am looking old or unattractive. 2 I feel there are permanent changes in my appearance that make me look
    unattractive 3 I believe that I look ugly.

    15. 0 I can work about as well as before. 1 It takes an extra effort to get started at doing something. 2 I have to push myself very hard to do anything. 3 I can't do any work at all.

    16. 0 I can sleep as well as usual. 1 I don't sleep as well as I used to. 2 I wake up 1-2 hours earlier than usual and find it hard to get back to sleep. 3 I wake up several hours earlier than I used to and cannot get back to sleep.

    17. 0 I don't get more tired than usual. 1 I get tired more easily than I used to. 2 I get tired from doing almost anything. 3 I am too tired to do anything.

    18. 0 My appetite is no worse than usual. 1 My appetite is not as good as it used to be. 2 My appetite is much worse now. 3 I have no appetite at all anymore.

    19. 0 I haven't lost much weight, if any, lately. 1 I have lost more than five pounds. 2 I have lost more than ten pounds. 3 I have lost more than fifteen pounds.

    20. 0 I am no more worried about my health than usual. 1 I am worried about physical problems like aches, pains, upset stomach, or constipation. 2 I am very worried about physical problems and it's hard to think of much else. 3 I am so worried about my physical problems that I cannot think of anything else.

    21. 0 I have not noticed any recent change in my interest in sex. 1 I am less interested in sex than I used to be. 2 I have almost no interest in sex. 3 I have lost interest in sex completely.

    INTERPRETING THE BECK DEPRESSION INVENTORY
    Now that you have completed the questionnaire, add up the score for each of the twenty-one questions by counting the number to the right of each question you marked. The highest possible total for the whole test would be sixty-three. This would mean you circled number three on all twenty-one questions. Since the lowest possible score for each question is zero, the lowest possible score for the test would be zero. This would mean you circles zero on each question. You can evaluate your depression according to the Table below.

    Total Score____________________Levels of Depression

    1-10____________________These ups and downs are considered normal

    11-16___________________ Mild mood disturbance

    17-20___________________Borderline clinical depression

    21-30___________________Moderate depression

    31-40___________________Severe depression over

    40__________________Extreme depression

    A PERSISTENT SCORE OF 17 OR ABOVE INDICATES THAT YOU MAY NEED MEDICAL TREATMENT. IF YOU HAVE ANY CARDIAC CONCERNS, PLEASE CONTACT CARDIOVASCULAR INTERVENTIONS, P.A. at 407-894-4880
     
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  10. Valentijn

    Valentijn Not a moderator

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    Or not depressed, since they don't meet the threshold for a diagnosis.
     
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  11. Dolphin

    Dolphin Senior Member (Voting Rights)

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    Looking over the 21 questions in the BDI, I don't think an average score of 9 is that high for people with CFS.
     
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  12. Trish

    Trish Moderator Staff Member

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    Thanks for putting me straight. So it was a statistically significant difference on depression score, not a clinically significant one. That's reassuring I guess.

    Edit to add: I would score on several of the questions because I physically can't do what I used to be able to do, completely unconnected with my state of mind. That seems an inappropriate questionnaire to use to assess mental state for physically disabled people.

    I think I should cease and desist. I'm being excessively picky and grumpy about this study.
     
    Last edited: Oct 31, 2017
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  13. Valentijn

    Valentijn Not a moderator

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    No, you're completely right. A common BPS trick is using inappropriate questionnaires then pretending that a difference from healthy controls is meaningful - even when patients are well under the threshold.
     
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  14. Wonko

    Wonko Senior Member (Voting Rights)

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    I only got 16, mild mood disturbance - the BPS crew are slipping as previously, on a different test I came in as suffering from severe depression.

    So, it's getting better, but still not reflecting the reality, that I am not, in fact, depressed, let alone suffering from depression.
     
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  15. Woolie

    Woolie Committee member

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    Okay, here goes. The technical aspects of the work are beyond me (how they actually measured the metabolites), but I can comment on what the aims were, and whether the results justify the conclusions.

    First thing to note: the theoretical framework set out in the intro very clearly falls within in category of 'my brain made me do it' . The researchers are proposing that the alterations within the brain actually cause the various other biological and psychological changes associated with the disease.
    What they did was look at the concentration of metabolites of certain neurotransmitters and markers of cell metabolism in three key brain regions: the ACC (anterior cingulate), putamen and OCC (occipital cortex).

    The neurotransmitters they studied were glutamate, GABA glutamine, and a combined measure of glutamate+glutamine. The markers of cell metabolism they studied were GSH, choline, creatine and total N-acetylaspartate.

    They describe it as a pilot study.

    As regards the metabolites, none of the differences they found would survive correction for multiple comparisons (which they didn't do, probably because it would have made all the results non-significant). Probably the result that got closest is the combined measure of glutamate+glutamine, which was higher in the putamen for CFS patients than for controls. However, the finding doesn't look very robust, because within the CFS group considered alone, higher concentrations of this substance tended to be associated with lower self-rated fatigue.

    They go on to overinterpret the findings anyway (which I suppose is reasonable, given its a thesis, but the language could have been more cautious). For example, they suggest that the putamen abnormalities may lead to "an imbalanced perception of costs and rewards" which "could be a potential cause for mental fatigue".

    Although to be fair, they do also consider the possibility that the various trends they found here may be caused by "systemic inflammation, which is a possible factor in CFS aetiology". They also raise the possibility that some changes might be compensatory - they reflect the strategies patients use to overcome fatigue.

    I think its really hard to conclude much at all from these results yet, until there is a bigger study, which is able to yield robust effects that survive corrections for multiple comparisons.
     
    Last edited: Oct 31, 2017
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  16. Woolie

    Woolie Committee member

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    PS. I want to say too that I think its way too early to be looking at the brain. We don't know enough yet to be able to interpret what we see. So there is a huge danger of just fitting whatever we find around a pre-existing model of MECFS.

    If we want to find out what causes this disease, we need to look outside the brain. Once we understand the systemic features of the disease(s), then we can start looking at effects on the brain - and actually have a chance of understanding what they might actually mean.
     
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  17. Aimossy

    Aimossy Established Member (Voting Rights)

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  18. Adrian

    Adrian Administrator

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    I think a number of the depression questionnaires are not reliable when given to people with chronic illness because too many questions are ambiguous. HADS has been commonly used but it is a really bad scale. I suspect this one is a bit better

    I have real issues with it (or any questionnaire) being used as a continuous scale rather than as a set of questions with a heuristic to classify (in this case depressed or not depressed). I'm not convinced that questionnaires could measure the degree of depression and ensure that this is linear especially with other factors (such as chronic illness) also defining question answers.

    Perhaps the interesting thing to do would be to prune out the obvious answers that may relate to chronic disease and redo the calculations.
     
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  19. Valentijn

    Valentijn Not a moderator

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    Or ask patients if they're depressed. And believe them when they answer :rolleyes:
     
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  20. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I absolutely agree with the analysis in @Woolie 's first post. I am not sure I quite agree with the second but I think it is pertinent in this context.

    As a general point, I think MR spectroscopy may have been under-utilised in this illness. MR spectroscopy is where you do not so much try to get a picture of a tissue as to measure the chemical content by looking at 'magnetic resonance signatures' for specific molecules and quantifying them. It is a bit like a Star Trek version of a biochemical analysis. It ought to solve a lot of the queries about muscle metabolism. MR spectroscopy has been around since at least the 1960s but strangely has been rather little used in clinical medicine.
     
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