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British Journal Radiology: CFS/ME Structural Brain Changes

Firestormm

Senior Member
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5,055
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Cornwall England
29 November 2011: http://bjr.birjournals.org/cgi/content/abstract/93889091v1 Abstract ahead of print. Requires membership to read in full.

Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3-T MRI study

B K Puri, PhD, FRCPsych1, P M Jakeman, MSc, PhD2, M Agour, MB, MRCPsych3, K D R Gunatilake, MD, MRCPsych4, K A C Fernando, MBBS, MRCPsych5, A I Gurusinghe, MBBS, PGDPsych6, I H Treasaden, MRCS, FRCPsych7, A D Waldman, PhD, MRCP1,8 and P Gishen, DMRD, FRCR1

1 Department of Imaging, Hammersmith Hospital, London, UK 2 Department of Physical Education and Sport Sciences, University of Limerick, Republic of Ireland 3 University of Hertfordshire, and Care Principles, Rose Lodge, Langley, West Midlands, UK 4 The Ridge Hill Centre, Dudley, UK 5 Brooklands Hospital, Birmingham, West Midlands, UK 6 Broadmoor Hospital, Berkshire, UK 7 Three Bridges Unit, WLMHT, Middlesex, UK 8 National Hospital for Neurology and Neurosurgery, Queen Square, London, UK

Objective:

It is not established whether myalgic encephalomyelitis/chronic fatigue syndrome (CFS) is associated with structural brain changes. The aim of this study was to investigate this by conducting the largest voxel-based morphometry study to date in CFS.

Methods:

High-resolution structural 3-T cerebral MRI scanning was carried out in 26 CFS patients and 26 age- and gender-matched healthy volunteers. Voxel-wise generalised linear modelling was applied to the processed MR data using permutation-based non-parametric testing, forming clusters at t > 2.3 and testing clusters for significance at p < 0.05, corrected for multiple comparisons across space.

Results:

Significant voxels (p < 0.05, corrected for multiple comparisons) depicting reduced grey matter volume in the CFS group were noted in the occipital lobes (right and left occipital poles; left lateral occipital cortex, superior division; and left supracalcrine cortex), the right angular gyrus and the posterior division of the left parahippocampal gyrus. Significant voxels (p < 0.05, corrected for multiple comparisons) depicting reduced white matter volume in the CFS group were also noted in the left occipital lobe.

Conclusion:

These data support the hypothesis that significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness; they also suggest that subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS.

Without access to the full paper it is always difficult to read too much into research, but I think this is another piece of welcome news. Only 26 patients (don't know criteria) but the important part is the conclusion. This isn't the first time I have read about brain abnormalities being observed, but it is the most recent study; and one that points to cognitive dysfunction and related symptoms as being a possible result.

If anyone can gain full access and is unable to post (due to copyright) would they PM me perhaps? I would really like to read it in full. If I obtain a copy and can repost I will. :cool:
 

Marco

Grrrrrrr!
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Near Cognac, France
Hi Firestormm

I can't help you with the full paper but did find this on a European site :


Structural MRI
Testing a brain (lipid) hypothesis


It is instructive to review a brain (lipid) hypothesis put forward by the late Professor David F. Horrobin (6th October 1939 1st April 2003) regarding the aetiology and potential treatment of post-viral fatigue syndrome, which nowadays would be subsumed under the heading of myalgic encephalomyelitis (or chronic fatigue syndrome). Horrobin suggested that abnormalities in fatty acids played a key role in the pathophysiology of this disorder (Horrobin, 1990). Indeed, a randomized, double-blind, placebo-controlled three-month trial of fatty acids (including gamma-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid and linoleic acid) by Behan, Behan and Horrobin, in 63 adults suffering from post-viral fatigue syndrome, gave positive results in favour of the PUFA supplementation (Behan et al., 1990)). Unfortunately structural brain MRI changes were not assessed during this randomized, double-blind, placebo-controlled trial, but subsequently a pilot study has indicated that eicosapentaenoic acid-rich PUFA supplementation in myalgic encephalomyelitis may be associated with beneficial brain changes, with a reduction in the size of the lateral ventricles (Puri et al., 2004). The question of whether, at baseline, myalgic encephalomyelitis is associated with changes in brain structure compared with unaffected age- and gender-matched controls has been addressed by a number of studies; the most recent and largest voxel-based morphometry study of 26 patients and 26 matched controls has shown that this disease appears to be associated with reduced grey matter in the occipital lobes, right angular gyrus and left parahippocampal gyrus, and reduced white matter in the left occipital lobe (Puri et al., 2011).
 

Holmsey

Senior Member
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286
Location
Scotland, UK
Obvious question first, anyone know how they picked the test subjects, it would be nice to know if we're looking at results for a nurological condition or depression? Correct me if I'm wrong but trying to find an e-mail address for Puri I found that Hammersmiths part of Royal College London, which if I'm not mistaken is also where Mr. Wessely hangs out.

Assuming we're taking us, are they suggesting this leads to the illness or is a symptom of the illness, and more importantly, does this reflect pemanent damage or is it likely that post illness this damage can be repaired?
 

kaffiend

Senior Member
Messages
167
Location
California
I can't access this through the UC system but emailed a couple of people who can get it for me. 26 patients is a large sample for an MRI study (it's extraordinarily expensive research).

Finding structural differences in visual cortical regions and the angular gyrus could go a long way in legitimizing this disease and distinguishing it from psychiatric conditions. Keep in mind, however, that brain imaging studies don't uncover causes or lead directly to improved treatments.
 

HowToEscape?

Senior Member
Messages
626
"subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements,"

That's interesting. When I'm in an impaired state but still mobile I've had a few occasions of bumping into people or things. I one case I sat on bench but missed the spot, and hit someone's arm. Fortunately I was using a cane that day and it was understood to be an accident... could have gotten ugly.
 

oceanblue

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UK
Yes, 26 is very big by MRI standards but it is, still, a small sample. I know other, smaller, studies have also found changes in white and grey matter but I think the changes were in different areas to this study.

Puri's big interest seems to be in phospolipds/fatty acids, has published quite a bit on CFS, including a 2002 paper finding differences in choline - also in the occipital cortex.
 

snowathlete

Senior Member
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5,374
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UK
and more importantly, does this reflect pemanent damage or is it likely that post illness this damage can be repaired?

I worry about this too. Somewhat reasuringly, my father suffered from migrains very badly for about 30 years and in the end it affected his speech quite badly - he would often come out with gobbeldy-goop - but then he found a cure and now he is better. He then went to see a specialist who ran a bunch of tests on his brain and how he used it, and the results showed high scored across the board, which he told him was very unusual, something he said never happened. Most people score high only in one or two areas. So he told him that had his migraines caused damage, then in fact he would not have got those results.

Obviously, migraines and ME are different illnesses but the point is that damage doesnt always occur even though you would think it would - lets hope we are so lucky!

Also, from a testing point of view, its not a fair test. People with ME typically dont work because they are ill, and perhaps, you might argue, are therefore less stimulated mentally, and therefore the brain doesnt need to be as 'big' (if thats the right word here). If the healthy controls stayed at home, unable to engage their brains in much interesting then who is to say their brain wouldnt also react like this?
 

Dolphin

Senior Member
Messages
17,567
A Dutch (Nijmegen) study claimed to show CBT increased Grey Matter Volume in CFS. Here's a letter that challenged that Nijmegen paper:

Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy. Brain. 2009 Jul;132(Pt 7):e119; author reply e120. Epub 2009 Jan 29.
Kindlon T.

-------

Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy

Tom Kindlon

Received November 19, 2008.
Accepted December 14, 2008.

Sir, In their reply to Dr Bramsen, De Lange et al. (2008) use a type of circular reasoning: cognitive behavioural therapy (CBT), they say, has previously been shown to be effective for chronic fatigue syndrome (CFS) so the change they measured must be due to CBT.

First, it needs to be pointed out that CBT is far from a panacea for CFS. A recent meta-analysis (Malouff et al., 2008) of the efficacy of CBT in treating CFS found an effect size of d = 0.48 (95% CI 0.270.69).

In their letter, De Lange et al. (2008) refer to a review by Whiting et al. (2001) as part-evidence for their claim that CBT is effective for CFS. However, this review recommended the use of objective outcome measures e.g. Outcomes such as improvement, in which participants were asked to rate themselves as better or worse than they were before the intervention began, were frequently reported. However, the person may feel better able to cope with daily activities because they have reduced their expectations of what they should achieve, rather than because they have made any recovery as a result of the intervention. A more objective measure of the effect of any intervention would be whether participants have increased their working hours, returned to work or school, or increased their physical activities.

Given one of the aims of CBT (for CFS) has been said to be increased confidence in exercise and physical activity (ODowd et al.), we cannot have complete confidence that the improvements recorded in CBT trials thus far represent objective improvements [such as improvements in grey matter volume (GMV)], rather than simply being due to altering how patients answer questionnaires. An INAMI report (2006) on the use of CBT (combined with GET) in over 600 CFS patients in Belgium found that while patients reported improvements on their fatigue scores, there was negligible change on the tests of exercise capacity and there was actually a worsening of their employment status (as measured by the amount of hours worked per week), both at the end of the intervention and at follow-up.

CFS is not generally a progressive conditionimprovement often occurs (Nisenbaum et al., 2003; Cairns et al., 2005). Indeed, in a recent uncontrolled study of CBT (Scheeres et al., 2008), co-written by one of the authors (Bleijenberg), a spontaneous recovery rate of 5% was assumed over a similar period as this study. Thus the authors have not proven that the 12% improvement in GMV in CFS was due to CBT. If their logic was applied throughout medicine, control groups would only be required to test if an intervention was effective as measured by one or a limited number of outcome measures. After that, if a positive change in any other outcome measure was recorded in any uncontrolled study, it would be acceptable for pharmaceutical companies and others to claim that this must be due to their effective intervention!

References

- Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond) 2005;55:20-31.
? de Lange FP, Koers A, Kalkman JS, Bleijenberg G, Hagoort P, Meer JW, et al. Reply to: can CBT substantially change grey matter volume in chronic fatigue syndrome? Brain 2008. doi: 10.1093/brain/awn208 [Epub ahead of print 30 August 2008].
? Malouff JM, Thorsteinsson EB, Rooke SE, Bhullar N, Schutte NS. Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: a meta-analysis. Clin Psychol Rev 2008;28:736-45.
? Nisenbaum R, Jones JF, Unger ER, Reyes M, Reeves WC. A population-based study of the clinical course of chronic fatigue syndrome. Health Qual Life Outcomes 2003;1:49.
- O'Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technol Assess 2006;10:1-121. iii-iv, ix-x.
- Rapport dvaluation (20022004) portant sur lexcution des conventions de rducation entre le Comit de l'assurance soins de sant (INAMI) et les Centres de rfrence pour le Syndrome de fatigue chronique (SFC). 2006. http://www.inami.fgov.be/care/fr/doctors/specific-information/sfc-cvs/sfc-cvs04.htm (10 September 2008, date last accessed).
? Scheeres K, Wensing M, Bleijenberg G, Severens JL. Implementing cognitive behavior therapy for chronic fatigue syndrome in mental health care: a costs and outcomes analysis. BMC Health Serv Res 2008;8:175.
? Whiting P, Bagnall AM, Sowden AJ, Cornell JE, Mulrow CD, Ramirez G. Interventions for the treatment and management of chronic fatigue syndrome: a systematic review. JAMA 2001;286:1360-8.
 

Annesse

Senior Member
Messages
164
Here is some recent research on the brain and low B12 levels. I believe in autoimmune disease and CFS the problem lies partially in the metabolism of B12. No matter how much we take in supplement form, with certain nutrients, we will not be able to bind or transport them. I will find and post some additional studies on MS and the inabililty to metabolize B12. MS is also associated with white matter lesions.
http://www.medpagetoday.com/Neurology/GeneralNeurology/28740
 

Enid

Senior Member
Messages
3,309
Location
UK
Very interesting indeed - thanks Firestorm - I always wanted to know more about the "high spots" on my MRI brain scan and reported by my Neurologist 10 years ago. Looking as if this too is being unravelled. And yes the processing of perceptual information was very much impaired. The research findings now (with Norway) finally remove the W school from ME.
 

kaffiend

Senior Member
Messages
167
Location
California
I just read the paper. Not much can be taken away other than some structural differences were found in the areas reported in the abstract. They don't do a very thorough job of reporting the results and I'm guessing this is their first attempt at this type of brain imaging analysis.

It is however the first and largest study of its kind in ME/CFS and so hopefully will encourage follow up studies that correlate structural changes with behavioral scores from perceptual and movement tests.

I found the discussion interesting. I have significant problems with performing intended actions and also lose a sense of where I am in space...how close or far away things are (kind of a fun-house effect as I walk around).

From the discussion...

"The right angular gyrus has now been shown to have a critical role in perceptual sequence learning [15]. It also computes action awareness representation; in particular, it is associated with both awareness of discrepancy between intended and movement consequences, and awareness of action authorship [16]. Farrer et al have proposed that the right angular gyrus is involved in higher-order aspects of one's own action; specifically, it processes discrepancies between intended action and movement consequences in such a way that these will be consciously detected by the subject: this joint processing is at the core of experiences used to interpret one's actions [16]. On the basis of our results in the occipital lobes and right angular gyrus, we would suggest that subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movement, should be investigated in CFS patients."
 

allyb

Senior Member
Messages
127
Location
yorkshire/lancashire border, England
Obvious question first, anyone know how they picked the test subjects, it would be nice to know if we're looking at results for a nurological condition or depression? Correct me if I'm wrong but trying to find an e-mail address for Puri I found that Hammersmiths part of Royal College London, which if I'm not mistaken is also where Mr. Wessely hangs out.

Assuming we're taking us, are they suggesting this leads to the illness or is a symptom of the illness, and more importantly, does this reflect pemanent damage or is it likely that post illness this damage can be repaired?

Proff Basant Puri, is a research psychiatrist he specialises in magnetic resonance studies. He has published extensively. Good question Holmsey, since he writes prolifically on both.
I recognised his name from a book that I'd had recommended and read whilst on a course in London in 2004 called The Natural Way to Beat Depression, (you can buy it on Amazon for a penny) This was long before I became ill and I was interested in his work on EPA.

I have just realised that he also wrote Chronic Fatigue Syndrome: A Natural Way to Treat M.E. in the same year. Interesting reviews on Amazon. Also the same year he wrote a book; Revision Notes in Psychiatry and in 2008 an E-book Pocket Essentials of Psychiatry.
Maybe he is looking at damage limitation or repair through 'eicosapentaenoic acid?' EPA.


Puri's big interest seems to be in phospolipds/fatty acids, has published quite a bit on CFS, including a 2002 paper finding differences in choline - also in the occipital cortex.
Oceanblue, this does seem to be his area.
--------------------------------------------------------------------------------
 

Snow Leopard

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5,902
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South Australia
Has anyone compared this directly to the 2011 Barnden et al study? It is also funny how they do a 26/26 study and then proclaim it is the largest yet (the Barnden study was 25/25).
 

kaffiend

Senior Member
Messages
167
Location
California
Has anyone compared this directly to the 2011 Barnden et al study? It is also funny how they do a 26/26 study and then proclaim it is the largest yet (the Barnden study was 25/25).

The study in this thread (Puri) didn't look at the brainstem so they can't be compared.
 

Marco

Grrrrrrr!
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2,386
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Near Cognac, France
These preliminary results are being reported in the media today :

Eating baked or grilled fish at least once a week was associated with larger grey matter volume 10 years later in certain brain structures that are important in memory and learning. These structures included the hippocampus, precuneus, posterior cingulate and orbital frontal cortex.


This report looks as if it has been sourced from our old friends the Science Media Centre with (this time) appropriate comments and caveats :

http://www.halifaxcourier.co.uk/news/health/can_eating_fish_prevent_alzheimer_s_1_4019974
 

Holmsey

Senior Member
Messages
286
Location
Scotland, UK
Proff Basant Puri, is a research psychiatrist he specialises in magnetic resonance studies.

I have just realised that he also wrote Chronic Fatigue Syndrome: A Natural Way to Treat M.E. in the same year. Interesting reviews on Amazon. Also the same year he wrote a book; Revision Notes in Psychiatry and in 2008 an E-book Pocket Essentials of Psychiatry.
Maybe he is looking at damage limitation or repair through 'eicosapentaenoic acid?' EPA.

Read a paper posted on the ME Associations site regarding endothelial dysfunction in ME/CFS, again no indication of the cohort used and no reply from any of the authors when I enquired. Reason I mention it is that in scanning for endothelial dysfunction I find that there's also been conclusive studies involving depressives. Yesterday I scanned for reduced grey / white brain matter and find there's also been longitudinal studies attempting to match depression to that reduction.

On first seeing both papers my thoughts were, great, someone's proving physical abnormalities, but now I'm wondering if it's simply, 'oh, this shows up for depression, lets see if it shows up under ME/CFS', I'd hate to think that was the driver for the research.

Plus note on the longitudinal study though, the conclusion seemed to be that depression begins/intensifies due to the loss of grey/white matter, the study was for otherwise healthy people who were lossing matter due to natural wastage with age, and I think they said all depressions were sub-clinical, I take it that means they're not clinically depressed, but just not as perky as they once were.

So, is it the case that even if they can associate some sub-clinical depression with 'ME/CFS' this is due to the disease itself reducing grey/white matter, or fatiuge / fog reducing use and so natural reduction. If it is then the cascade would be - illness onset leads to a reduction in congnitive ability, leads to a reduction in grey/white matter, leads to mild depressive symptoms, leads to sceptisicm, ignorane, miss diagnossis and the sense your MP is fed up from hearing from you?

Just a thought.
 

Holmsey

Senior Member
Messages
286
Location
Scotland, UK
These preliminary results are being reported in the media today :




This report looks as if it has been sourced from our old friends the Science Media Centre with (this time) appropriate comments and caveats :

http://www.halifaxcourier.co.uk/news/health/can_eating_fish_prevent_alzheimer_s_1_4019974

Marco, do you know what the science behind this is, is it the omega oils in the fish or the whole package? Not a big fish eater, and when I do it's probably the wrong kind, I'm also skeptical about eating anything caught off the coast of a western country given what we pump into the water, not to mention the nuclear power stations sprinkled around the UK coast.
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
I just read the paper. Not much can be taken away other than some structural differences were found in the areas reported in the abstract. They don't do a very thorough job of reporting the results and I'm guessing this is their first attempt at this type of brain imaging analysis.

It is however the first and largest study of its kind in ME/CFS and so hopefully will encourage follow up studies that correlate structural changes with behavioral scores from perceptual and movement tests.

I found the discussion interesting. I have significant problems with performing intended actions and also lose a sense of where I am in space...how close or far away things are (kind of a fun-house effect as I walk around).

From the discussion...

"The right angular gyrus has now been shown to have a critical role in perceptual sequence learning [15]. It also computes action awareness representation; in particular, it is associated with both awareness of discrepancy between intended and movement consequences, and awareness of action authorship [16]. Farrer et al have proposed that the right angular gyrus is involved in higher-order aspects of one's own action; specifically, it processes discrepancies between intended action and movement consequences in such a way that these will be consciously detected by the subject: this joint processing is at the core of experiences used to interpret one's actions [16]. On the basis of our results in the occipital lobes and right angular gyrus, we would suggest that subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movement, should be investigated in CFS patients."

Thank you. This explanation is in part a good reason to gain access to full research papers. Was there any mention of how they determined patient suitability i.e. the criteria for 'CFS'? I know it matters little in terms of the results but it is perhaps important.

I note the concerns expressed above about this possibly being used in relation to 'depression' though I noted also on the MEA Facebook page that Dr Shepherd was thinking along the lines that it might also be used to support the neurological disease case:

'Many thanks for posting this abstract. I have not yet seen the full paper but it looks as though the results should further strengthen the case for neurological classification.'

Personally, I suppose I hope that this research will add further legitimacy to the condition as well as greater understanding and might spawn similar research. Whether or not the reason behind such a change in one's brain and function can be established is for me secondary; I would rather hope they could use this finding to better direct therapy and/or treatment (assuming of course either are indeed possible).

Edit: I wonder if - in the future - such observable physical abnormality could feature in the diagnosis of 'CFS/ME'? I mean it could well increase the argument for a MRI at the point of diagnosis. If the one's doctor suspects 'CFS/ME' along similar lines as they do now, then perhaps a MRI could confirm the diagnosis along similar lines as happens for Multiple Sclerosis (though for MS they do not look at the brain obviously).
 

Marco

Grrrrrrr!
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2,386
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Near Cognac, France
Marco, do you know what the science behind this is, is it the omega oils in the fish or the whole package? Not a big fish eater, and when I do it's probably the wrong kind, I'm also skeptical about eating anything caught off the coast of a western country given what we pump into the water, not to mention the nuclear power stations sprinkled around the UK coast.

I presume that's what its about Holmsey but as its just an abstract at the moment there's no way of telling.
 

Dolphin

Senior Member
Messages
17,567
From paper:
Acknowledgments
We should like to thank the MRC for funding this study. We also wish to acknowledge the involvement of several myalgic encephalomyelitis / CFS charities, including ME Research UK (formerly known as MERGE) and ME Solutions. We are very grateful to the patients, their families and the healthy volunteers who took part in this study.