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New study hints at biological roots of mental and physical problems in ME/CFS

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by Simon McGrath

5-27brain-blood-flow.jpg


A new study, from Julia Newton's group in Newcastle, UK, has found evidence that reduced blood flow to the brain is associated with muscle abnormalities in CFS patients.

Earlier work by the same group had found that with many CFS patients, muscles don't regulate acid levels properly after exercise. Another study, by Ben Natelson, had shown reduced blood flow to the brain of most in a sample of CFS patients. This new study looked at both muscle acidity regulation and blood flow to the brain in the same people with CFS. They found a strong correlation between the two, both at rest and in response to a challenge.

This is tantalising stuff: there is a marked link between factors that potentially underlie physical fatigue (i.e. flawed acid regulation in muscles) and factors potentially affecting mental fatigue (reduced blood flow to the brain, which has been linked to reduced poor cognitive performance). Unfortunately the study is relatively small and they didn't have the funding to include a control group, so at this stage the findings are tentative.


Links between muscle acidity and brain blood flow at rest

Measurements of brain blood flow and muscle pH were taken for all patients when resting and when challenged. The data from the measurements at rest showed that higher pH (less acid and less ideal) correlated with lower brain blood flow (again, less blood flow is less ideal). The correlation coefficient was 0.67 (on a scale of 0-1.0), which is very high by the standards of CFS research.


Links between muscle acidity and brain blood flow in response to challenge

Many people with ME/CFS find that their problems are provoked when they do something rather than when they are at rest. Using an exercise challenge has proved helpful in revealing abnormalities in CFS patients before, such as the Lights' gene expression work and the Pacific Labs study of Post-Exertional Malaise.


Muscle challenge

Professor Newton's group used a similar approach here, with patients repeatedly exercising a calf muscle while muscle pH was measured using Magnetic Resonance Spectroscopy. Compared with expected results (based on previous studies with healthy controls), the muscle pH didn't recover fully.


Brain blood flow challenge

The 'challenge' to brain blood flow was a little different, using something called the 'Valsalva Manoeuvre'. Here, the patient covers their nose and mouth and tries to exhale hard briefly, before releasing their breath - it's the same trick you would use to clear blocked ears. This simple procedure triggers a surprisingly complex but predictable series of changes in blood pressure and heart rate as the body brings things back to equilibrium by, for example, contracting blood vessels to raise blood pressure.

Using the Valsalva Manoeuvre as the challenge, researchers measured brain blood flow and found that in CFS patients the final part of the brain blood vessels' response to the Valsalva Manoeuvre was delayed. What's more, this delayed response was strongly correlated with poor recovery of muscle pH after exercise (r=0.65, 0-1 scale).


Future promise?

So: both at rest and in response to a challenge, there was a strong correlation between brain blood flow and muscle pH. And in both cases the worse outcome for muscle (higher muscle pH) correlated with the worse outcome for brain blood flow (lower flow/delayed response to challenge).

More on Julia Newton's work
Phoenix Rising articles: Feeling Old? You May be and The Wolf in ME/CFS.

The previous findings of reduced brain blood flow and muscle dysfunction are interesting, but the new result indicating a strong relationship between the two makes it an area of real promise.

Of course, this is a small study and possibly a similar strong correlation exists in healthy people (albeit at more normal levels of pH/blood flow). What’s needed to advance this area is replication of the findings in studies including matched healthy controls – and Julia Newton is hoping to get funding for just such a study.

Simon McGrath has a biochemistry degree from Oxford University. He later worked for Oxfam, a UK charity. After having ME/CFS for nearly 20 years, he takes a very keen interest in the latest research.



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Just to point out the funders of the study*:
"This work was funded by the Myalgic Encephalomyelitis (ME) Research UK Irish ME Trust, and the John Richardson Research Group."

Yet again showing the value of the money ME/CFS charities raise for research.

*the ME Association and Action for ME are also funding some of Julia Newton's research
 
One step closer to reality: ME/CFS is probably related to a mechanical defect in circulating blood to the brain. The body reacts in shock, tries to shut down over over-exertion, HPA axis becomes screwed up. Plus OI/ POT/ NMH. and all those other symptoms result too.

In other words, ME/CFS is probably just a symptom of a genetic condition. That gets triggered by periods of stress or excess inflammatory cytokines. The lactic acid build up she noted is just the body's reaction to a shortage of circulating blood. It is probably a side issue. The strips, and not the zebra.

She didn't consider the other big elephant in the living room: weak connective tissue disorders, most importantly, weak and bulging arteries and veins. The best reason so far why blood is slow to make to the brain. But any progress in the right direction is appreciated. Kudos to Dr. Newton.
 
One step closer to reality: ME/CFS is probably related to a mechanical defect in circulating blood to the brain. The body reacts in shock, tries to shut down over over-exertion, HPA axis becomes screwed up. Plus OI/ POT/ NMH. and all those other symptoms result too.

In other words, ME/CFS is probably just a symptom of a genetic condition. That gets triggered by periods of stress or excess inflammatory cytokines.

I wish I thought it was that simple. I think things with this illness go further then it just being a genetic condition as that doesnt explain the big ME outbreaks enough when they occur. Genetics I think are only a part of the answer.

She didn't consider the other big elephant in the living room: weak connective tissue disorders, most importantly, weak and bulging arteries and veins. The best reason so far why blood is slow to make to the brain. But any progress in the right direction is appreciated. Kudos to Dr. Newton.

But what about the actual low blood volume in many of us? It takes more then weak, bulging arteries and veins to be causing the body to have actually less blood. Laying a lot or low gravity can affect blood volume if Im remember the studies from astronaunts correctly.. but I think it may be more then just that making our blood volume less in some of us . Ive come to that conclusion as nowdays Im not laying down much at all and are upright "most" of the time (as long as I havent been standing too much).. but I still seem to have actual very low blood volume (indicated by my need to be drinking a lot still and that helps.. and I need to take Florinef for it too).

I agree that connective tissue disorder is probably involved too..but once again. I think that is only a part of the whole thing going on. This illness I think is going to turn out to be a very complex one (A ..genetics + B immune fault?? + C ???some bacteria, virus, fungi, vitamin/mineral deficiency or something = D (ME/CFS) .
 
I think there's a problem with this sort of study, in that it only looks at 'fatigue', and not 'malaise'. And it seems to almost suggest that a lactic acid build up is a cause of CFS. It's too simplistic, IMO. That's not to say that it couldn't be helpful research, but I'm not convinced that it's the best route to finding answers. I'm not yet up to date with all of Julia Newton's most recent research though, so I've got some reading to do, and I might not yet fully understand the implications or possibilities of this research.
 
I wish I thought it was that simple. I think things with this illness go further then it just being a genetic condition as that doesnt explain the big ME outbreaks enough when they occur. Genetics I think are only a part of the answer.

I can easily see the outbreaks coexisiting with the low blood flow/ weak tissues theory of ME/CFS. The outbreak or clusters could have originated in a very bad virus that happened to kick off the cascade of nasty immune cytokines. Which caused a higher percentage of vulnerable people to fall into long-term ME/CFS illness. I don't think one theory precludes the other.

Or the outbreaks could have been explained by some exotic, never-seen virus that came and went. The symptoms of our illness are so vague and far flung, as we know, that even doctors have had hard time discerning what is what. Many diseases start with flu-like symptoms; like the flu, for example, or AIDS.

But what about the actual low blood volume in many of us? It takes more then weak, bulging arteries and veins to be causing the body to have actually less blood. Laying a lot or low gravity can affect blood volume if Im remember the studies from astronaunts correctly.. but I think it may be more then just that making our blood volume less in some of us . Ive come to that conclusion as nowdays Im not laying down much at all and are upright "most" of the time (as long as I havent been standing too much).. but I still seem to have actual very low blood volume (indicated by my need to be drinking a lot still and that helps.. and I need to take Florinef for it too).

Yes, it is true, the astronauts did get low blood volume by traveling in low gravity environments. But they were all strong, healthy guys who did not have weak tissue structures. But if our bodies go through a period of stress, and the genetically weak tissues and veins weaken even more, due to cytokines or cortisol, that could be the initiating event for us. The sickness slows the supply to the brain.

When the brain stops receiving the blood, the HPA axis goes into a panic and probably signals for all kinds of other changes, to restore homeostasis. One of the signals could be to slow production of red blood cells. Why produce more cells when it thinks it is not making it to the brain.

BTW Tania, have you ever had your blood cells examined, where they look at the shape of red blood cells? We had several people at the support group meetings back in the 90s who said they had their blood analyzed, and the docs told them their platelets were old, mis-shapen and worn out looking.

At that time, I thought it was just another wishful thinking hooey, sketchy doc making things up to keep the patients coming back. Now i think they might have been on to something. Our bodies are probably not regenerating blood cells at the same rate as a normal person.

Hence, the ones we have get old and worn out looking. An outcome of having perpetually low blood volume. The people who told these stories did seem compelling and believable. I wonder why nobody ever gets that test done anymore? It used to be very popular among CFS patients. I wonder if any of the readers ever had this testing done?
 
One step closer to reality: ME/CFS is probably related to a mechanical defect in circulating blood to the brain. The body reacts in shock, tries to shut down over over-exertion, HPA axis becomes screwed up. Plus OI/ POT/ NMH. and all those other symptoms result too.

An important thing to keep in mind is that the study is showing correlation, not causation. I think both this article and the study did a good job of keeping that in mind.

For example, if the blood circulation problem was causing other ME symptoms, then those symptoms might disappear when blood circulation to the brain improves, such as while lying down. This doesn't generally help with muscular symptoms, though it does help with cognitive symptoms. Also, a fair number of ME patients get their circulatory issues medically treated to some extent, but this doesn't improve muscular issues either.

I think it's more likely that the correlation between muscular and brain dysfunction comes from an unknown common underlying factor. That is, something could be causing both the deficit in brain circulation and the muscle dysfunction, and potentially other sets of symptoms as well (sleep, GI, etc). Thus when one set of symptoms is successfully treated, there's little effect upon the other symptom sets. This would also explain why some people, even when untreated, could have ME with symptom sets missing, including PEM, if their body is somehow able to compensate in that one area.
 
Thanks Simon for doing this work. I hadn't been able to review the latest Cardiac paper. Appreciate it. Exciting and hopeful times ahead I think. It might not result in answers and treatment for everyone - or to everyone's satisfaction - but I think it has rightly shined a spotlight on the great prevalence of cardiac and especially autonomic nervous system dysfunction in patients with our diagnosis; and that has to be a good thing.
 
Thanks Mark and Simon - very interesting .....thinking personally it would explain why at one stage the nurses had great difficulty finding veins to draw blood samples as if they were "collapsed"....vascular problems. One could even speculate that the "patchy high signal changes" on my brain MRI scan had to do with reduced bloodflow.

Interesting pieces of the puzzle - hope more funding given.
 
Thanks Mark and Simon.
Thanks Simon for doing this work.... I think it has rightly shined a spotlight on the great prevalence of cardiac and especially autonomic nervous system dysfunction in patients with our diagnosis; and that has to be a good thing.
Thanks both! (edit: and Enid)

The paper I've written about here has its own thread: New article by the Newcastle team, the thread you mention cover Julia Newton's work more widely, based on her presentation to the AfME AGM. Both recommended.
 
I think there's a problem with this sort of study, in that it only looks at 'fatigue', and not 'malaise'. And it seems to almost suggest that a lactic acid build up is a cause of CFS. It's too simplistic, IMO.
Hi Bob

I'm probably guilty of using artistic licence by including 'fatigue'in the title; the study itself just looks at muscle pH and brain blood flow. I don't think they have yet correlated these to fatigue. The incomplete pH recovery in muscles could potentially lead to PEM as well as fatigue itself.Will try to get the blog title changed.

As for lactic acid, it is a little more complicated than that, as they have looked at pH withing muscle cells, not at blood pH, though the plan to do so in detail in future

The Study said:
We postulate that a compromised skeletal muscle cellular membrane function may lead to the equalisation of the pH between the skeletal muscle intracellular environment and blood, where an increase in intracellular pH (more alkaline) and decrease in blood pH (acidosis) take place, triggering hyperventilation to buffer the pH change in the blood.
...
However, blood acidosis may also affect cellular membrane function, hence the underpinning mechanism of CFS cannot be fully resolved directly in this work, and extensive further work with detailed blood composition analysis is necessary to validate the pathophysiological model implicated here. Nevertheless, our results point to a disease mechanism outside of the CNS, with a peripheral cause.
The evidence for muscle membrane problems in this study is rather limited, but Julia Newton's group have some fascinating work in the pipeline where they have cultured and grown muscle cells from CFS patients (therefore free of e.g. deconditioning and autonomic nervous system problems) - and found defects there too. However, this work has yet to be finalised and published. More about it in Firestormm's transcript of Julia Newton's talk (on page 8 of the pdf).
 
Very interesting article, Simon.

Could you say something about the diagnostic criteria used to select the participants? I'm wondering how close they would be to CCC/ICC and whether PEM was necessary for inclusion.
 
Hi Bob

I'm probably guilty of using artistic licence by including 'fatigue'in the title; the study itself just looks at muscle pH and brain blood flow. I don't think they have yet correlated these to fatigue. The incomplete pH recovery in muscles could potentially lead to PEM as well as fatigue itself.Will try to get the blog title changed.

As for lactic acid, it is a little more complicated than that, as they have looked at pH withing muscle cells, not at blood pH, though the plan to do so in detail in future

The evidence for muscle membrane problems in this study is rather limited, but Julia Newton's group have some fascinating work in the pipeline where they have cultured and grown muscle cells from CFS patients (therefore free of e.g. deconditioning and autonomic nervous system problems) - and found defects there too. However, this work has yet to be finalised and published. More about it in Firestormm's transcript of Julia Newton's talk (on page 8 of the pdf).

Thanks for the info, Simon.
I've got a lot of reading to catch up with, including @Firestormm's transcript.
 
Very interesting article, Simon.
Could you say something about the diagnostic criteria used to select the participants? I'm wondering how close they would be to CCC/ICC and whether PEM was necessary for inclusion.
Thanks. They used Fukuda, so PEM would have been one of the 8 symptoms, but any 4 of these are needed, none are mandatory apart from fatigue.

An important thing to keep in mind is that the study is showing correlation, not causation. I think both this article and the study did a good job of keeping that in mind.

For example, if the blood circulation problem was causing other ME symptoms, then those symptoms might disappear when blood circulation to the brain improves, such as while lying down. This doesn't generally help with muscular symptoms, though it does help with cognitive symptoms. Also, a fair number of ME patients get their circulatory issues medically treated to some extent, but this doesn't improve muscular issues either.

I think it's more likely that the correlation between muscular and brain dysfunction comes from an unknown common underlying factor. That is, something could be causing both the deficit in brain circulation and the muscle dysfunction, and potentially other sets of symptoms as well (sleep, GI, etc). Thus when one set of symptoms is successfully treated, there's little effect upon the other symptom sets. This would also explain why some people, even when untreated, could have ME with symptom sets missing, including PEM, if their body is somehow able to compensate in that one area.
Yes, it's seems quite likely that both muscle pH and brain blood flow (if confirmed) have a common cause. Though as I metioned in my reply to Bob, the authors speculate that everything else flows from a primary defect in muscle function:
It is possible that CFS is driven by a primary peripheral abnormality that is associated with secondary central sequelae, where a compromised skeletal muscle cellular membrane function underpins the observed abnormalities.
Good point about how one set of symptoms can be tackled independently - i too find lying down makes a big difference to my mental energy, though doesn't have such a big impact on physical fatigue.

I wish I thought it was that simple....

...I agree that connective tissue disorder is probably involved too..but once again. I think that is only a part of the whole thing going on. This illness I think is going to turn out to be a very complex one (A ..genetics + B immune fault?? + C ???some bacteria, virus, fungi, vitamin/mineral deficiency or something = D (ME/CFS) .
I agree it's likely to be be very comples, perhaps even more than you suggest if there are actually several distinct illnesses withing ME/CFS.
 
Thanks. They used Fukuda, so PEM would have been one of the 8 symptoms, but any 4 of these are needed, none are mandatory apart from fatigue.


Yes, it's seems quite likely that both muscle pH and brain blood flow (if confirmed) have a common cause. Though as I metioned in my reply to Bob, the authors speculate that everything else flows from a primary defect in muscle function:

Good point about how one set of symptoms can be tackled independently - i too find lying down makes a big difference to my mental energy, though doesn't have such a big impact on physical fatigue.

I agree it's likely to be be very comples, perhaps even more than you suggest if there are actually several distinct illnesses withing ME/CFS.

Yes Simon, PEM is not a required symptom for Fukuda CFS. :(

It remains unknown even from default subjective claims from Dr Newton's patients of having CFS/ME (because they are labelled with CFS/ME), if anyone even did have ME! (Post exertion worsening of symptoms (relapse) being a classic symptom of ME).

This is the only 'advantage' of DOH's CFS/ME over Fukuda CFS. (DOH CFS/ME requires post exertional worsening of symptoms and Fukuda doesn't).
 
I had that test done sometime in the early 90s. I can't remember my exact figures but I know it was over 80% of misshapen red blood cells. It was interesting but nobody came up with any ideas for treatment


Hello, I had the same result as you. The 'scientific' term for this finding is altered morphology (shape). It's a sign of hematological dysfunction, probably caused by chronic inflammation.

Here's a paper with a related topic, on red blood cells also (erythrocytes):

Arch Med Res. 2007 Jan;38(1):94-8. Epub 2006 Nov 3.
Erythrocyte oxidative damage in chronic fatigue syndrome.

Richards RS, Wang L, Jelinek H.
Source

School of Community Health, Faculty of Health Sciences, Charles Sturt University, NSW, Australia. rorichards@csu.edu.au
Abstract

BACKGROUND:

It has been hypothesized that a link exists between erythrocyte metabolism (particularly redox metabolism) and erythrocyte shape and that both are related to erythrocyte deformability. The aim of this research is to confirm the results of earlier studies and to investigate a correlation between erythrocyte morphology and erythrocyte oxidative damage in chronic fatigue syndrome (CFS).
METHODS:

Reduced glutathione (GSH), malondialdehyde (MDA), methemoglobin (metHb) and 2,3-diphosphoglyceric acid (2,3-DPG) were measured in 31 patients suffering from CFS and 41 healthy control subjects. Scanning electron microscopic studies of the erythrocytes from both groups were also carried out.
RESULTS:

There was evidence of oxidative damage in CFS with statistically significant increases in 2,3-DPG (p < 0.05), metHb (p < 0.005) and MDA (p < 0.01). The CFS patients in this study also had significantly more stomatocytes in their blood than the normal subjects (p < 0.005).
CONCLUSIONS:

There is a strong likelihood that the increase in erythrocyte antioxidant activity is associated with the presence of stomatocytes. The results of this study provide further evidence for the role of free radicals in the pathogenesis of CFS and a link between erythrocyte metabolism and erythrocyte shape.