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Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with CFS

Discussion in 'Latest ME/CFS Research' started by Kati, Jul 1, 2017.

  1. Kati

    Kati Patient in training

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    Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome
    Shan, Kwiatek, Burnet, Del Fante, Staines, Marshall-Gradisnik, Barnden

    http://dx.doi.org/10.1002/nbm.3757

    Abstract:

    Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS).

    This study examined brain structure variations associated with sleep quality in patients with CFS.

    38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited.

    All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires.

    Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities.

    We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure.

    In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE < 0.05) and between PSQI and T1w intensities (PFWE < 0.05).

    In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001).

    This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS.

    This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.
     
  2. shannah

    shannah Senior Member

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    "This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS."

    Does anyone understand how they reached the conclusion that the differences are due to unrefreshing sleep and not some other reason such as, for example, an infection?
     
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  3. RogerBlack

    RogerBlack Senior Member

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    They did neither.
    They found that those with worse sleep have more changes in that brain area.
    They did not find that this was caused by anything, or if the brain changes caused worse sleep, or if the worse sleep caused brain changes.
     
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  4. shannah

    shannah Senior Member

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    With your elaboration, I can plainly see now @RogerBlack what seemed hidden before.
    I should have paid more attention to that word "correlate".
    Thanks for the well worded explanation.
     
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  5. CFS_for_19_years

    CFS_for_19_years Hoarder of biscuits

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  6. Manganus

    Manganus Senior Member

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    Thanks!

    Sympathetically written! Between the lines, one can see the scientific urge.
    Nice! :)

    The methods with different kinds of modern "x-raying" are impressive.
    ...one has to hope that Someone Else understands the matter and can say if the study's methodology is good or bad.

    I started reading in a rather critical mode, but have to give credit for using the Canadian Consensus Criteria! :thumbsup:

    As the authors conclude, the importance of studies like this is that they contribute to the heap of evidence, that the illness is followed by (or, less likely, caused by) brain damage.

    The idea is intriguing, that the bad sleep is correlated with disappearing axons in a distinct area of the brain!

    Strange!

    That's an interesting enigma to ponder on, how to explain that specifically neurons in that area have given up!
     
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  7. CFS_for_19_years

    CFS_for_19_years Hoarder of biscuits

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    From the full text article http://sci-hub.cc/10.1002/nbm.3757

    The parts I could understand are in italics.:nerd:
     
  8. MEMum

    MEMum Senior Member

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    Where are the knowledgeable science members when you need them? If in Europe they're probably out partying, unless they have ME.
     
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  9. CFS_for_19_years

    CFS_for_19_years Hoarder of biscuits

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    I think @Woolie or @Research 1st might be knowledgeable when it comes to brain science.
     
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  10. RogerBlack

    RogerBlack Senior Member

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    I don't want to quite say this is useless, but it's pretty close to it.
    (in a rational world, where 'refutation of patients are liars' is not valuable of itself)

    It is an interesting study, but there is absolutely no way a treatment can come from this - we have no way of 'stimulating' an under-active area of the brain.

    To make a car analogy, this is sort of like saying 'if you look in the joins at the bottom when you open the door, you can see if it's likely to be rusted out'.

    It makes no progress towards finding which particular spots in this car are affected, no way to treat the rust, ...

    The changes in the brain are not due to a disease process specific to that area of the brain.
    That area of the brain may be slightly more vulnerable to systemic processes, but that doesn't help you nail down what those processes are.

    Would I like - academically - a better understanding of brain physiological changes - sure.
    This could also perhaps be useful for selecting interesting areas for analysis at autopsy. But that requires considerable work and funds.
     
  11. Kati

    Kati Patient in training

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    Biomarkers are a beautiful thing for a disease that has been relying on case definition/ reports of symptoms. This paper is a first report. Further papers could possibly correlate disease severity with worse imaging (just an example).

    I welcome biomarkers, further research on brain imaging and further understanding of what exactly is going on with us.
     
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  12. trishrhymes

    trishrhymes Save PR. Sack the President of the Board.

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    I agree it's not useless in the sense that it's another nail in the BPS coffin. I'd be pleased to be able to show evidence to doctors that my chaotic sleep patterns are reflected in my brain and not just down to me not trying hard enough to establish sleep hygiene.

    Though as has rightly been said, it neither explains why not offers treatment. It is simply an interesting correlation.
     
  13. RogerBlack

    RogerBlack Senior Member

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    https://www.ncbi.nlm.nih.gov/pubmed/26449441
    Was a similar form of study, findings from MRIs that correlated with patient reports of fatigue severity, and significant differences from controls.

    I haven't properly dug into the properties of each study, and found if it would be a usable individual test, it's quite possible it may not.

    It may for example miss 20% with a variant of CFS that are just as disabled, but do not have a response in this portion of the brain. Or it may just miss 20% of people at random.
    This is just fine for doing correlational studies of even small groups (20s), but pretty useless as a test.
     
    Last edited: Jul 2, 2017
  14. Snow Leopard

    Snow Leopard Hibernating

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    I too am a bit skeptical about this sort of imaging and what it means in terms of underlying biology or treatment.

    I understand the point about biomarkers, but well, these sorts of findings never have the sensitivity and specificity to be useful (for almost any disease).
     
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  15. ljimbo423

    ljimbo423 Senior Member

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    When my cfs was at it's worst, I was sleeping 10-12 hours a day and still exhausted all day. As my cfs improved, so did my sleep.

    I'm at the healthiest I have been in years and now only need 7-8 hours of sleep and have good energy throughout the day, most days.:) I see a very clear connection to sleep quality and the degree of my cfs.

    I think the brain plays a big role in sleep quality in cfs, but there is a much bigger picture. More studies are needed for sure.
     
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  16. Alvin2

    Alvin2 If humans were rational...

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    i agree, if the money could be redirected to Ron Davis i would be all for it, or otherwise other researchers who are making real progress, but if not at least its something.
     
  17. Woolie

    Woolie Gone now, hope to see you all again soon somewhere

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    I've just had a chance to read this fully.

    One huge problem I had with it is that unrefreshing sleep, as measured on their self-report scale was positively correlated with self-reported fatigue. And then they went ahead and looked at the sleep measure without factoring out the fatigue one (as far as I can see). So are they really measuring the neural correlates of the unrefreshing sleep? Or of some other factor that's correlated with it, like overall fatigue severity? That's a pretty huge problem imo.

    The findings about the medial prefrontal cortex (mPFC) are a tiny bit interesting. Some people think this area serves as a sort of brain-body interface, it initiates changes to the autonomic nervous system when we need to exert mental effort on things. Sort of goal-driven arousal, if you like. Unlike fear etc., where the arousal is automatic, this area deals more with intentional "gearing up" for a task when the person wants to do well. What happens when its unable to do its job? The brain fog we all know so well.

    I doubt, though, that this brain area is the source of the problem, I suspect the problem is happening further downstream - in other words, the signals sent by the mPFC are probably fine, but various physiological changes it is supposed to initiate are not happening as they should.

    But with this study, there are also a lot of findings that seem quite random. For example, the left and right IFOF's are implicated in some of the analyses (a white matter tract that runs along the base of each hemisphere). But there's absolutely no reason to believe these are at all involved in CFS.

    I would also want to see this sort of study replicated over and over again before I'd be willing to believe its saying anything.

    Plus, I think the brain is only just producing echoes of something else going on elsewhere in the body. I suspect people who try to look for CFS in the brain are looking in the wrong place.
     
    Last edited: Jul 3, 2017
  18. RogerBlack

    RogerBlack Senior Member

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    http://www.nature.com/nature/journal/v445/n7124/fig_tab/445160a_F1.html
    [​IMG]

    Historically, we've looked at the brain in terms of how it looks under the microscope when stained.
    Different parts of the brain absorb different dyes, and are therefore assigned separate names, and it's assumed that the named areas 'do stuff'.

    These are the relatively large areas in solid colours in the above diagram of the mouse brain.
    The dots overlayed are the intensity of activation of one gene (green-red).
    Each area contains multiple cell types, and apparently similar cells under the microscope may have rather different genes turned on.

    It is at least plausible that whatever CFS does impacts certain cell types in the brain more than others, perhaps by direct methods - some protein expressed in the cell type(s) is especially vulnerable to whatever it is CFS mediates, or something more systemic - due to increased oxygen or whatever demand in the type of cell, that particular type of cell is vulnerable.

    Cell types (gene expression patterns cause cell types) are spread over the brain in a more complex manner than the typical graphs with large solid areas of colour indicate.
    There are also lots more cell types, and they do not all localise in one area of the brain.

    To make a bad car analogy. It's not like CFS takes a hammer to a specific part of a car, and causes a simple malfunction. It's like it hammers all parts of the car made in Malaysia on a Tuesday.

    From a functional perspective, some parts may be damaged, and limp on, with not many changes, as they have reserve capacity, or are not 'important' in the ways measured.
    But the damage does not focus on one system of the car, it can be spread throughout the car with various impact.

    In principle, using MRI to select the volume, then comparing gene expression changes and other changes in detail on a per-cell-type basis post-mortem may be interesting.

    It could in principle be one route to working out what is affecting the cells, if you can take 20 types of cells that are affected, 20 types that are not, and compare their genetic expression. This might lead to a handful of proteins differently expressed that could be looked into more closely.

    As others have implied though, this sort of result is vulnerable to poor statistics, and someone with lots more clue would need to go through it in detail to work out if it's at all real.
     
    Last edited: Jul 3, 2017
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  19. nryanh94

    nryanh94

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    I'm new here, and don't know nearly as much about this as the rest of you, nor am I very scientifically inclined. But if this study holds to be true wouldn't this be a negative? If their is structural change to the brain wouldn't that suggest that it is unlikely that we will be able to cure our illness, or am I misinterpreting that?
     
  20. Woolie

    Woolie Gone now, hope to see you all again soon somewhere

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    Luckily, structural change doesn't mean permanent, @nryanh94. The brain's always changing in response to how we use it. If you got cured of your MECFS, then the changes would most likely reverse.

    Besides, the stuff they're reporting here has not yet been replicated, and these kinds of measures are really unreliable. So we're not even sure what they found is real or just an artefact right now.

    If there were structural damage to the brain due to MECFS, our mental function would get steadily worse. This doesn't happen. Instead, our brain fog generally fluctuates along with our other symptoms.
     

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