Discussion in 'Latest ME/CFS Research' started by SpecialK82, Apr 24, 2012.
Very interesting - thank you all - as they say certainly on to something here.
This study doesn't tell us much, in my view. The same problems are found in depression:
Aberrant functional connectivity of cortico-basal ganglia circuits in major depression.
Marchand WR, et al.
Neurosci Lett. 2012 Apr 11;514(1):86-90. Epub 2012 Feb 28.
George E. Wahlen Veterans Affairs Medical Center, 500 Foothill Drive, Salt Lake City, UT 84148, USA; University of Utah, 201 Presidents Circle, Salt Lake City, UT 84112, USA.
There is considerable evidence of functional abnormalities of the cortico-basal ganglia circuitry in affective disorders. However, it has been unknown whether this represented primary pathology within these circuits or altered activation as a result of aberrant input from other brain regions. The aim of this study was to test the hypothesis that cortico-basal ganglia circuit dysfunction represents primary pathology in unipolar depression. Eighteen male subjects with recurrent unipolar depression and eighteen controls without psychiatric illness were studied using functional MRI and functional connectivity analyses. All unipolar subjects were unmedicated and without current psychiatric comorbidity. Compared to controls, unipolar subjects exhibited altered connectivity between bilateral subcortical components of the circuitry (putamen-thalamus) and left hemisphere input and output components. Results provided evidence that functional abnormalities of these circuits represent primary pathology. Further, we found that age of onset but not duration of illness impacts circuit function. These findings suggest that the cortico-basal ganglia circuitry is likely one of several loci of primary pathology in major depression. Additionally, early age of onset is associated with greater circuit abnormality and as such may impact clinical characteristics and/or treatment response through a mechanism of decreasing functional connectivity of some circuit segments. Finally, altered cortico-basal ganglia circuit connectivity with cortical regions (anterior cingulate, inferior frontal gyrus and sensorimotor) may contribute to the emotional dysregulation, impaired emotional recognition and psychomotor symptoms associated with unipolar illness.
I agree that this study (like most CFS studies) need a 'sick' control group as well as a healthy one. Thanks for digging out the depression study, adreno, but note that it isn't looking at the same thing as the Unger study. Unger looked at basal ganglia activity while the Depression study looked a conectivity between the basal ganglia and the hemispheres so they aren't really comparable.
Hi Sean, maybe they should be researching how to give CFS to gambling addicts? I wonder if it cures OCD and ADHD too? Bye, Alex
Just because the Unger study looked at the basal ganglia in isolation, doesn't mean that it works that way. The reality is that brain function works in circuits, and that it is pretty meaningless to look at isolated areas.
Here's another study that found decreased reward (hypoactivity in the striatum) in depression. The striatum is part of the basal ganglia.
"Functional magnetic resonance imaging (fMRI) data indicated that the MDD group was characterized by reduced activation of striatal reward regions during reward selection, reward anticipation, and reward feedback, supporting previous data indicating hyporesponsivity of reward systems in MDD."
Meaningless in what way?
The extent of the lowered basal ganglia activtion correlated very well each patient's level of fatigue. This is pretty remarkable, because not only did they finally find a possible biological mechanism/marker, but it also shows the basal ganglia is probably involved in a linear way (lowered activation/fatigue severity). Wether this is a cause or a consquence of ME/CFS I don't know, but earlier research suggests it's a cause rather than a consequence.
And how does this differ from the lowered basal ganglia activtion seen in depression? What makes it specific to ME?
I don't think we can conclude much from this study, but we can speculate that inflammation causes decreased reward (and fatigue). But this is hardly surprising.
It could be that this study was more thorough than it sounds, but from what we've heard so far, it doesn't sound that exciting to me. (But it could lead on to something?)
One other thing is that 'depression' can include all sorts of different conditions - it could be that some people with depression and some with CFS have similar problems with certain types of inflammation, and it manifests differently.
I wonder if these changes are thought to be secondary or primary in depression? It could be that these sorts of changes in the way our brain's reward mechanisms operate occur in all groups of people having to manage unexplained reductions in capacity (or maybe explained too).
Good question. I'm not a neuroscientist, so I have no idea honestly.
Well, we can conclude the basal ganglia is probably involved in ME/CFS. This is a pretty remarkable milestone in this disease with no known biological marker. Interestingly, this study was already announced at the Ottawa IACFS/Conference in 2011. Cort wrote a report about it where one of the authors speculates why the basal ganglia seems to be less effective in ME/CFS. (http://forums.phoenixrising.me/content.php?548-Ottawa) It definetely opens a whole new area of research which may ultimately lead to understanding the pathophysiology of ME/CFS and possibly a cure.
I don't find it that remarkable. We now know that the basal ganglia is involved in ME (also). But that is true of a range of disorders, and is not specific to ME.
High inflammation is likely to cause fatigue and anhedonia. This is also known as sickness behavior. The fatigue and reduced reward (through reduced interest) will lead you to rest, which is what your immune system "wants". And since reward is mediated by the basal ganglia, these structures are necessarily involved. These are common findings in depression (that is inflammation, anhedonia and fatigue). So it is not surprising to see these findings in ME, as this is a disorder characterized by high levels of inflammation.
The CDC seem to be about 10 years behind the game. The study below below used MR spectroscopy and found elevated levels of choline in the L basal ganglia. That's along the lines of the Puri hypothesis.
The CDC study seems to be an abstract from a conference presentation and not a peer-reviewed paper. I'm not going to take much away from it, as it's very easy to do bad brain imaging studies.
Unless you're completely sure the basal ganglia is involved in the exact same way in both ME/CFS and other disorders, I find your statement highly speculative. Most of this research is way above my head, but I suppose there is a reason why the authors refer to the similarities in ME/CFS and interferon-alpha induced sickness symptoms and not to MDD or another disorder.
Still, even if the basal ganglia is involved in the exactly (or even partly the) same way in ME/CFS as other conditions, there still is a huge possiblity that the causes or different.
Do you have any research to support your last notion? As far as I know, ME/CFS has only slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF)
The existence of CFS remains in question... I wish everyone, who claims that CFS is not real, would suffer from this illness for the rest of his life. Luckily these people are and will remain a minority. This study is interesting but as most other studies always raises the question, which was first, decreased Basal Ganglia activation or CFS. I find it interesting that they bring up inflammation as possible culprit. In the end however, nothing changed, we don't have diagnostics and we don't have efficient treatment.
We can argue about the level of inflammation involved in ME, but the fact remains that inflammation is involved.
This study found inflammation to be significantly higher than healthy controls, and although they do term it "low grade" in the conclusion, it is still speculated to account for the symptoms seen:
"CONCLUSIONS: The findings show that ME/CFS is characterized by low-grade inflammation and activation of CMI. The results suggest that characteristic symptoms of ME/CFS, such as fatigue, autonomic symptoms and a flu-like malaise, may be caused by inflammatory mediators, e.g. IL-1 and TNF?."
I very much suspect that the inflammation can account for anhedonia, as well, and so can account for the decreased activity in the reward center seen on the brain imaging.
Since they used fMRI, like the study you quoted, presumably they looked at the whole brain not just at the basal ganglia (all the other fMRI studies I've seen scan the whole brain and look at differences between patients and controls). Assuming they did - I guess we'll have to wait to see the published paper to finbd out - then their findings appear to be different to the depression study.
Thanks - this study looks altogether more relevant. I wonder if the Unger study excluded depressed patients from their sample? And what case definition was used (though I'd be surprised if they used the wacky Empiric criteria as Unger seems to be backing off that one).
re inflammation, I'd like to see the Maes study replicated before getting to excited (NK cytotoxicity is about the only robustly replicated biomarker I know of). Also, if real, that would show inflammation in blood markers, which may or may not correspond to inflammation in the brain,
See also this summary by Cort:
And Betty Dowsett was talking about this area of the brain (among others) back in the 1990s.
Do current researchers take any notice of research and debates that were around decades ago?
Sore Winner Syndrome?
The CDC has recently gone on record as stating...that when we understand the disease better the name will change by itself:
Low Brain Activity Seen in Chronic Fatigue
By Charles Bankhead, Staff Writer, MedPage Today: http://www.medpagetoday.com/Neurology/GeneralNeurology/32379
Published: April 26, 2012
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- This study found that patients with chronic fatigue syndrome (CFS) had significantly less activation of the basal ganglia in response to a known stimulus compared with a control group.
- In the CFS group, reduced activation in the right globus pallidus correlated significantly with mental fatigue, general fatigue, and reduced activity.
- Patients with chronic fatigue syndrome (CFS) had significantly less activation of the basal ganglia in response to a known stimulus compared with a control group, investigators reported.
Brain imaging during a simulated reward task showed reduced activation in the right caudate and right globus pallidus of patients with CFS. Decreased activation in the globus pallidus correlated significantly with multiple domains on a validated fatigue scale.
The findings suggest that reduced neural activation in the basal ganglia may have a role in the etiology in CFS, Elizabeth Unger, MD, PhD, reported at the Federation of American Societies for Experimental Biology meeting in San Diego.
"Given similar findings in patients treated with the antiviral cytokine interferon-alpha, inflammatory cytokines might be involved in chronic fatigue syndrome," Unger, of the CDC, and colleagues concluded in a poster presentation.
"Because dopamine is the primary neurotransmitter in basal ganglia, dopamine metabolism may be important in CFS," they added.
Despite intensive study, the origin of CFS remains unknown. Infection, inflammation, and chronic stress all have supporting evidence for a role in CFS. Inflammatory cytokines might constitute a common trigger for factors linked to CFS, the investigators noted in the background of their presentation.
Fatigue is a common feature in neurologic disorders that involve the basal ganglia, such as Parkinson's disease and multiple sclerosis. The basal ganglia, which mediate motor activity and motivation, are vulnerable to the effects of pro-inflammatory cytokines, and the effects of interferon-alpha on the basal ganglia correlate with fatigue.
Given the suggestive background information, Unger and colleagues hypothesized that activation levels in the basal ganglia of CFS patients would correlate with fatigue.
To test the hypothesis, they conducted a study involving 18 patients with CFS diagnosed in accordance with the 1994 case definition. For comparison, the investigators studied 41 age-, sex-, and race-matched individuals with no history of significant clinical depression and no current use of medication affecting immune or cognitive function.
All study participants underwent functional MRI scans while participating in a reward task involving simulated gambling. The brain scans measured blood flow, and activation of the basal ganglia was determined by signal differences associated with winning and losing. The amount won was the same for all participants.
The MRI results showed significantly less activation of the right caudate nucleus (P=0.014) and right globus pallidus (P=0.019) in the patients with CFS versus the control group.
In the CFS group, reduced activation in the right globus pallidus correlated significantly with mental fatigue (P=0.001), general fatigue (P=0.011), and reduced activity (P=0.02). Basal ganglia activation did not correlate with any of the fatigue domains in the control group.
"The reduction in activity (in the CFS group) correlated with measures of fatigue; the greater the fatigue, the greater the reduction in activation," Unger and colleagues stated in their presentation.
The investigators had no disclosures.
Primary source: Federation of American Societies for Experimental Biology
Source reference: Unger ER, et al "Decreased basal ganglia activation in chronic fatigue syndrome subjects is associated with increased fatigue" FASEB 2012. Abstract 4833.
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