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Brain imaging reveals clues about chronic fatigue syndrome

Discussion in 'General ME/CFS News' started by Firestormm, May 23, 2014.

  1. Firestormm

    Firestormm Guest

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  2. Esther12

    Esther12 Senior Member

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    Here's an old Cort article which mentions some of this stuff: http://phoenixrising.me/archives/8707

    Doesn't sounds that exciting to me - but maybe there's fun stuff waiting to be revealed. The brains of people who experience a lot of fatigue/pain/laughter/depression/anything are likely to show some differences to health controls.
     
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  3. Roy S

    Roy S former DC ME/CFS lobbyist

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    Color me cynical about studies coming out of Emory University financed by the CDC; but I'm wondering what the potential news stories titles could be. How about --

    "Chronic Fatigue Patients Lack Motivation"
     
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  4. alex3619

    alex3619 Senior Member

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    I think we need to read the published study to draw conclusions on this.

    Emory does not have a good reputation with us, if I recall correctly. However the devil is in the details. We need to see how many devils dance in their publication. Maybe we will be pleasantly surprised. I have my doubts though.
     
  5. WillowJ

    WillowJ Senior Member

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    if I remember right the Georgia cohort is Reeves criteria, so whatever they find probably doesn't apply to any one particular disease. However if they can find biomarkers for fatigue that could potentially help patients with lots of diseases. (They just should use a generic fatigue term as the title.)
     
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  6. Valentijn

    Valentijn Activity Level: 3

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    The article is pretty good at least. So odd to see a behavioral psychiatrist speaking about purely neurological issues, plus the treatments listed as examples are physiological, instead of CBT/GET, etc. Looks like progress!
     
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  7. Wildcat

    Wildcat Senior Member

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    "The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents."

    .
    Would that be the Georgia telephone survey which was the foundation for the Reeves Criteria?
    .
     
  8. Ren

    Ren Primum Non Nocere

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    Once again the lack-of-motivation stereotype rears its ugly head. I assume though that some researchers will include statements like this, as they transition from their failed theories to actual science - and as they grab at straws, to justify their years of abuse and negligence.

    I do not have a legal background, and I just skimmed this article*, but it would be interesting to know if researchers/psychiatrists/etc. who make such generalizations/allegations could be held accountable for defamation and negligence (at the very least).

    "Psychiatrists often believe that they are protected from liability when conducting third-party evaluations..."

    "Case law has demonstrated otherwise..."

    *http://www.jaapl.org/content/35/2/200.full

    When psychiatrists generalize that 17 million individuals - whom they have not examined - lack motivation, is this not a third-party evaluation?

    What about when healthcare providers (individuals) author biased secondary-source texts (for the State), knowing that such texts will be used as evidence (in legal settings) to deny individuals with ME/CFS access to entitlements, such as proper medical care and social services support, etc.?

    ----
    edit:
    @justinreilly - Any immediate thoughts regarding traction with this for the ME/CFS community? (In your personal, non-legal-advice opinion).

    ---
    edit:
    Also of interest: http://www.behaviorismandmentalheal...-psychiatric-diagnoses-defamatory-statements/
     
    Last edited: May 24, 2014
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  9. Bob

    Bob

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    So this must be the paper?

    Decreased Basal Ganglia Activation in Subjects with Chronic Fatigue Syndrome: Association with Symptoms of Fatigue
    Andrew H. Miller, James F. Jones, Daniel F. Drake, Hao Tian, Elizabeth R. Unger, Giuseppe Pagnoni.
    May 23, 2014
    DOI: 10.1371/journal.pone.0098156
    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0098156

    Free access.

    "Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects.
    These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks."
     
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  10. Countrygirl

    Countrygirl Senior Member

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    This reminds me that when I had a CT scan following a suspected stroke, it revealed lesions through the basal ganglia that had calcified. Has anyone else received a similar result and could this possibly be a result of inflammation? Would this be a common finding in ME?

    The scan also revealed lesions through the falx but perhaps that just means I am getting close to falling off my perch and is not associated with ME. :)
     
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  11. SDSue

    SDSue Florida

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    My personal experience at Emory ranks second only to Mayo Clinic in horrific treatment as an ME patient. I was told "we don't believe in that" at the former, and "we don't care about that" and "have a glass of wine" at the latter. Notice the "we" in both instances - it's an attitude that starts at the top and is forced on the providers as they learn to play by the rules.

    Unfortunately, those rules are in place at large corporate clinics for two reasons: 1. to maximize profits by minimizing chair time; and 2. to keep statistics of successfully treated patients high.

    So while this abstract may sound promising, I believe it will be a LONG time before we see a resultant change in attitudes of caregivers at Emory (or elsewhere) regardless of the details. After all, it is coming from the psychos, who believe that the basal ganglia are mostly responsible for psychiatric problems associated with conditions such as Parkinson's. These include depression, anxiety, affective disturbances, apathy, cognitive impairment, and hedonistic behaviors.

    IMHO, anything coming from the psychos won't result in good things for us.

    Now, if you'll excuse me, I've got to get back to my "hedonistic behaviors" lol.
     
  12. alex3619

    alex3619 Senior Member

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    23. Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, et al. (2005) Chronic fatigue syndrome–a clinically empirical approach to its definition and study. BMC Med 3: 19.

    Reference 23 in the paper confirms this. They are vague as to what specific criteria were actually used, but the reference is clear.
     
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  13. Firestormm

    Firestormm Guest

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    From the paper: http://www.plosone.org/article/info:doi/10.1371/journal.pone.0098156

    Acknowledged deficiencies in the cohort:
     
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  14. Firestormm

    Firestormm Guest

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  15. Simon

    Simon

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    Commentary

    Summary
    Bit of a 'hey ho, not much to write home about' study. The biggest weakness is the use of empiric criteria so these are probably mostly chronic fatigue cases rather than CFS. The biggest strength is that they pursued a specific (and plausible) hypothesis that the problem was in the basal ganglia, and used a gambling test that had already been shown to activate the basal ganglia - so this wasn't a fMRI fishing trip looking for random differences between patients and controls. The correlation between a clinical feature - fatigue - and brain differences during the gambling test also adds weight to the findings.

    However, the differences they found were small and patchy, which, combined with the broad empiric criteria makes this study, in my view, of limited interest. Even though these findings are consistent with an inflammatory model of mecfs, which has growing evidence for it.

    Background biology
    The basal ganglia are a set of structures deep in the brain that have been implicated in fatigue both in neurological diseases and in response to inflammation (eg after administration of the cytokine interferon-alpha as treatment of Hepatitis C patients). The basal ganglia are also a site of reward processing, and this study looked at changes in basal ganglia during a gambling test, a classic test of reward processing.

    The basal ganglia has three components, as you can see in this wikimedia pic: the caudate (long, tail-like structure) the putamen and (hidden behind the putamen) the globus pallidus. As for much of the brain, this structure is symmetrical, with left and right caudate, putamen and globus pallidus. This fMRI study looked at each structure separately
    [​IMG]

    Gambling test
    Unbeknown to the subjects the test was rigged:they started with $16 and all ended with $23 at the end so they had a consistent 'gambling' experience.

    Weak definition of CFS
    As @alex3619 and @Valentijn have pointed out, this study uses the empiric criteria, which in a poplulation study found a rate of 2.5% for CFS, compared with around 0.3% for a similar earlier study using the Fukuda criteria. The particular issue with the empiric criteria is it uses very 'soft' thresholds: in this sample the average SF36 Physical Function score of 64/100, compared with around 40/100 in outpatient clinic trials. Additionally the sample only had 4.6 CDC symptoms (8.1 total symptoms) suggesting this might be a group of people with general health problems inc fatigue rather than even Fukuda CFS.

    Oh, to add to the fun, 39% had done post-graduate study, showing this sample to be somewhat unrepresentative.

    Patchy results and Statistical issues
    I know, stats are so dull, but so important too, especially in fMRI studies that generate shed-loads of data and so are prone to finding false positive.

    Looking at the whole of the basal ganglia there was a difference between patients and controls, but it wasn't big (p=0.02). Figure 2 shows data for individual areas within the basal ganglia and as you can see there is substantial overlap between patient and control scores.
    [​IMG]
    As the authors point out:
    Back to the detail, and the study found:
    Again, not hugely significant results. They also found differences for these structures using bilateral data (combined left and right): p=0.047 for caudate and p=0.036 for globus pallidus. However, note no differences in the left caudate or globus pallidus, and no differences anywhere in the putamen. So these results are a bit patchy.
    [correction: - bilateral data was in fact significant, but I'm trying to establish if appropriate statistical corrections for multiple comparisons were made].

    Also, why was the effect seen in the right structures but not the left? The authors did not predict this, and while they speculate as to why it might be, I suspect if they'd found the reverse pattern they could have happily speculated in the opposite direction too.

    Looking at correlation between fatigue and fMRI-measured response to reward - the most interesting part of the study - the results were again patchy. The authors only looked where they'd found results above and found correlations found in the right globus palllidus, but not the right caudate - and didn't mention the bilateral pallidus or caudate. However, they have said that the effects they found in the right globus pallidus were large effects.

    The correlations that were found, in the right globus pallidus, were that increased fatigue was correlated with decreased response to reward (the direction that would be expected). It was strongest for mental fatigue (as opposed to general or physical), which again makes sense and the correlation of r-squared = 0.49 (p=0.001) is pretty impressive: equivalent to a correlation coefficient r of 0.7 (0-1.0 scale). This one result does look very good and suggests they might be on to something.

    Fatigue vs motivation
    Another slightly odd aspect of this study is that it sets out to investigate fatigue and the basal ganglia role in fatigue, but focus on motivation (measured by the gambling test), which ain't quite the same thing.

    If the authors had used a better sample, these results would have been more interesting, especially as I think other studies have indicated difference between basal ganglia in CFS patients v controls. But fMRI is a field noted for its false positives so I think a lot more work is needed before too much weight can be put on the role of basal ganglia in mcfs.
     
    Last edited: May 27, 2014
  16. Valentijn

    Valentijn Activity Level: 3

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    So it sounds like a decent fatigue study, but not an ME study at all. And it might (or might not) have found an interesting anomaly that could indicate subgroups, possibly even the ME subgroup. Hence not completely useless, despite the horrible CFS definition.

    No conclusions to really be reached from it, but potential direction for future investigation.
     
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  17. alex3619

    alex3619 Senior Member

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    @Simon , is it anywhere clearly cited as to what SF-36 PF scores are typically seen in clinics or outpatient studies? Has anyone reviewed the CFS and ME studies to determine what is commonly found (while acknowledging that most of these studies are primarily on mild patients). This would help us put studies like PACE into perspective.
     
  18. user9876

    user9876 Senior Member

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    I was wondering how this study would relate to ideas of the lack of blood flowing to the brain. From my very limited understanding the fMRI scan is detecting changes in the flow of oxygenated blood. I think the oxygenated blood affects the magnetic field more than once the oxygen has been released. Then they make an assumption that areas of the brain where processing is happening require oxygen and hence they look for the change between oxygenated and non-oxygenated blood.

    So my assumption (although I've not yet read the paper) is that what they are detecting is less blood flow and less oxygen being metabolized in areas of the brain where people have fatigue. It made me wonder if this may relate to work that Julia Newton is doing at Newcastle finding increased acidosis in muscles which I believe is due to the lack of oxygen available to turn something (glucose?) into energy.
     
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  19. N.A.Wright

    N.A.Wright Guest

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    The study used the Reeves 2005 population but remember that included assessment as:

    The clinical visit included detailed medical history, physical examination, laboratory tests, psychiatric screen, and questionnaires to measure functional status, impairment and symptoms, and was completed by 783 persons. Participants were classified as: i) CFS cases, according to the 1994 case definition[22], [23]; ii) non-fatigued controls; iii) insufficient symptoms or fatigue for CFS; or iv) exclusionary medical or psychiatric condition.
    and
    The follow-up clinic evaluated 751 participants and classified them in the manner described above. Following clinical and laboratory assessments, 71 persons met criteria for CFS, and 212 were determined to be controls.

    Further the current study had an extensive exclusion process which included:

    Subjects with a score >60 on the 20-item, self report Zung Self Rating Depression Scale (Zung SDS)(indicating more than mild depressive symptoms) were also excluded [25]. All subjects were required to be free of psychotropic medications including antidepressant, antipsychotic, mood stabilizer or anti-anxiety medications for at least 4 weeks prior to brain imaging procedures. No subjects were taken off psychotropic medications for the purposes of the study.

    One of the criticism of Reeves work is that it didn’t distinguish between ME and depression, but it would appear that this study went to some lengths to avoid conflation. So as I read it, the study CFS cohort was Fukada, but with identifiable depression or other psychiatric confounders allowed by Fukada removed – so not a bad proxy for a wider ME/CFS population. That said I’d agree that the results are not overwhelming – another study that shows there’s ‘stuff going on’ but that the ‘stuff’ is all over the place. Some discussion about articulating the problems of definitions in the P2P context here: http://www.occupycfs.com/2014/05/22/p2p-agenda-fatigue/#comments
     
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  20. RustyJ

    RustyJ Contaminated Cell Line 'RustyJ'

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    Not so odd. I am pretty sure they were pinning their hopes on finding supporting evidence for a behavioral cause for ME. They failed and I think they tried to spin the study results a slightly more positive way.

    The real story here is that the suggestion of a behavioral cause of ME was not supported by the findings.

    This study reminds me of the recent Wyller clonidine study, which attempted to prove a behavioral cause of ME. Ironically that study didn't pan out either, thus sorta supporting a biophysical cause.

    Okay, I may be a tad cynical here, mainly because of the players involved and where this study was carried out. I think they set out to prove that inflammation in ME was a behavioral response, ie due to the altered reward mechanism, as they have tried to do previously in linking depression and inflammation.

    I know on the surface it looks as though they toughened up the Fukuda selection criteria to focus on physical causes. But it's likely they filtered the patients to rule other possible behavioral mechanisms so they could isolate motivation as a defining cause of inflammation in ME.

    The positive to come out of the study is that the fatigue inflammation correlations were strong, adding to support for a biophysical cause.

    The other positive was that the inflammation motivation correlations were quite poor. So that's good for us too.

    What I find personally confronting, with the Wyller study and this one, is that the researchers actually believed they were onto something (ie ME has a behavioral cause) and appeared genuinely surprised with their results. Both teams went ahead and published their findings, despite their failures, so it's not as if they were trying something dodgy.
     
    Last edited: May 27, 2014
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