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

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by Simon McGrath

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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Dr Simpson was one of the blood cells shape people. I remember him from a talk he once gave to a group in London. Know he went around the world talking about this test.

Les Simpson's work was largely about RBC flexibility iirc. The membranes were stiff and not able to flex to get through small capillaries easily. This would stuff up microcirculation, but not be obvious in major blood vessels.

 

How does this explain Cluster Outbreaks and spouse to spouse transfer?
I still say the answers are in the gut!

 

Thank you Simon for this.
I would assume that this finding is just one piece of the large puzzle. Nevertheless, any piece found, gets us that much closer to the mystery solved.

 

Simon,

I thank you for posting the article and explaining it in "laymen's" terms as much as possible as well as posting the original publications so that those who can understand it can read it.

Whenever I go to the actual publications, I cannot mentally get past the "abstract" much less remember what I just read. (Hmmm... maybe I should be laying down when I read...)

And, thanks to the many comments that dissect the research. Although, I am still waiting for the one article that says "CURE FOR ME/CFS HAS BEEN FOUND!" (not holding my breath), I am still fascinated that there are researchers, Dr's, scientists and others who are working on finding the clues to the puzzle. And I am very pleased to know there are people like Julia Newton still looking for correlations even if they are not causations.

To me, any research is worth noting so ME/CFS patients don't feel like this illness is completely being ignored.

 

I want to comment on the article: Les Simpson ('Blood Viscosity Factors - the Missing Dimension In Modern Medicine', 'Ramsay's Disease - ME (Myalgic Encephalomyelitis and the Unfortunate Creation of CFS', and contribution to 'A Beginner's Guide to ME/CFS' has done years of research on the way that non-deformable erythrocytes are responsible for the symptoms in muscles, cognition, and endocrine regulation in ME - For some reason his work has up to now been bypassed by the ME research community, although several are familiar with his work. It seems that some fruitful synergy could be created here, and it is very good news that this new work is being done!

Nancy Blake

 

Les Simpson's work was largely about RBC flexibility iirc. The membranes were still and not able to flex to get through small capillaries easily. This would stuff up microcirculation, but not be obvious in major blood vessels.

Alex,
I seem recall some of the patients had the following. Don't know if it was in line Simpson's research. My group's patients had other variations in blood shapes too, i can't recall them:

Anisocytosis

Anisocytosis is a medical term meaning that a patient's red blood cells are of unequal size. This is commonly found in anemia and other blood conditions. False diagnostic flagging may be triggered by an elevated WBC count, agglutinated RBCs, RBC fragments, giant platelets or platelet clumps.
The red cell distribution width (RDW) is a measurement of anisocytosis[1] and is calculated as a coefficient of variation of the distribution of RBC volumes divided by the mean corpuscular volume (MCV)

 

I got the opportunity to look at my blood cells under the microscope. They were very ugly.
Mishapen, stuck together, and bits of debri between cells. I was ashamed of them.

I am 42 and considered myself quite fit and in good health before falling to the invisible peril.

They attributed b12 deficiency to some of the mishapen cells.

 

Just realised the heading refers to "mental problems" - just never had - a jump ahead of those around me when slow as I was could point out a water leak to those around me who failed to notice or grasp the implications. Cognitive problems ......slow processing of information only. Intelligence is unimpaired.

 

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).

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

Erythrocyte oxidative damage in chronic fatigue syndrome. [full text link added by me]
...
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.

Hi Research 1st

Interesting paper on CFS vs erythrocyte metabolism/shape. I just checked the full text, and turns outit too uses Fudkuda, ie the same criteria as the Julia Newton study I've written about here - PEM not mandatory:

Patients with chronic fatigue syndrome were recruited through the Chronic Fatigue Syndrome Society, and their diagnosis confirmed by a clinician according to established criteria (16).
[16: Fukuda]

I'm not wild about the Fukuda criteria but they are very widely used and I'm not inclined to dismiss all research out of hand because of using Fukuda. Personally, what I would most like to see is some validated criteria developed i.e. taking a large group of patients diagnosed by a range of criteria and looking at clustering of symptom and biological data. From what I can tell, this is very much what is being planned by the Open Medicine Institute.

The erythrocyte paper concludes:

Further research that has recently commenced in our laboratory will determine whether there is a correlation between erythrocyte form and antioxidant levels

Not sure this was ever published? Pity.

 

Just realised the heading refers to "mental problems" - sorry never had - not bonkers a jump ahead of those around me like slow as I was could point out a water leak to those around me who failed to grasp - COGNITIVE/PERCEPTUAL problems only.
Ah now who had the mental problems like capacity to ignore the implications - they had I did not. Strange though so incapacited to be brighter.........more intelligent.

Ah, probably should have said cognitive! Changed from mental fatigue, as that wasn't strictly accurate but maybe went out of the frying pan into the fire.

 

Important comments made years ago by Dr. Simpson about abnormally shaped RBCs, hyper-viscous blood in ME patients, and also slowed cerebral blood flow. According to Dr. Newton, there is some kind of impaired blood circulation. The question is why?

Dr. Les Simpson – Rethinking the Pathogenesis of CFIDS

The NZ biologist’s research career began in 1964, studying the New Zealand black mouse as a model for human illnesses such as systemic lupus erythematosus. Shortly after an outbreak of ME (Myalgic encephalomyelitis – the name for CFS most frequently used in New Zealand) in the early 80’s, his attentions began to focus more on the role of blood rheology in ME. He explains, “In the early 1980s, a percipient country doctor recognized an unusual pattern of sickness in his region - which became known as "Tapanui Flu”.

About that time, I became interested in blood rheology [the study of blood flow] using blood filtration and blood viscometry. I was using a filtration technique to assess red cell stiffness. When Dr. Campbell Murdoch was appointed Professor of General Practice, he was soon involved with ME and through his good offices was able to assess ME blood filterability.”

Simpson continues, ”I found that ME blood filtered poorly - implying that they had a problem with blood flow, particularly at capillary level. In a paper published by New Jersey Medicine, I suggested that ME people might have the anatomical feature of smaller than usual capillary diameters. Such a proposal would help to explain the great variety and variation in distribution of the symptoms reported by ME people.”

Other models for the illness have struggled to fit the distinct features of CFIDS, such as exertion intolerance and circulatory dysfunction. Simpson feels impaired blood flow offers a unifying thesis that can explain many of these distinct symptoms. He vividly recalls the unique response to exercise of a patient referred to him. “Two scans were done [SPECT scans] -- pre and post exercise. While the pre-exercise scan showed reduced cerebral blood flow, this was much worse in the post-exercise scan. At that time, the effects of physical activity on red cell shape had not been reported. This shows the extent of ignoring blood rheology factors as determinants of blood flow.”

“When you crank up activity levels, symptoms re-surface. Physical activity changes the shape populations of red cells in an additive fashion.” We published a controlled study of the effects of pulling the trigger of a model pistol on red cell shape in ME and controls. The study showed that ME people could not pull the trigger as long as controls before the onset of fatigue - and this was associated with a greater change in the shape populations of red cells. "

While shape changes of red blood cells occur in healthy controls, Simpson says it is the proportion of different types of red blood cells, as well as lower capillary diameter in subsets of patients that may play a large role in undermining proper blood distribution. He does not believe CFIDS is an anemia (a lack or deficiency of red blood cells). “Red cell number is the major determinant of blood viscosity - the main feature of blood rheology. In polycythaemia rubra vera, the high value for red cells is recognized clinically as a cause of the associated increase in blood viscosity.”

“ I never use the word "misshapen" with regards to red cells. The red cells in normal blood fall into 6 different shape classes, and alteration in the cell environment leads to shifts in the proportions of the different cell shapes. Biconcave discocytes (the textbook "normal" red cell) are the most deformable of cells due to the "spare" membrane of the biconcavities. The loss of the concavities when other shapes occur is associated with a reduction in deformability.”
Differing proportions of different shapes of red blood cells can affect blood flow and viscocity. Higher proportions of flat cells ( F-above) may contribute to the high viscocity of blood in CFIDS.

He continues, “Because many capillaries are much smaller than the diameter of the red cell, red cells must change shape to pass through the capillary bed. But shape-changed red cells are stiffer than usual and poorly deformable and they will pass through small capillaries very slowly, or even block the capillary.”

While circulatory dysfunction and post-exertional muscle fatigue are hallmarks of the illness, the symptom set of neurological dysfunction varies widely among sufferers. Simpson believes impaired blood flow can provide a reasonable explanation for the widely varied neurological set of symptoms among individuals with CFIDS/ME.

“As blood flow with normal rates of delivery of oxygen to nerves is essential for normal nerve function, it is very likely that dysfunction of autonomic nerves (as in orthostatic intolerance) could be expected in conditions with changed populations of red cell shapes.

In a 1992 paper published by New Jersey Medicine, I suggested that ME people might have smaller than usual capillary diameters in those parts of the body expressing symptoms. Such a proposal would help to explain the great variety and variation in distribution of the symptoms reported by ME people. ”

At the moment, no education institutions have dedicated programs on haemorheology (study of blood viscosity). He would like to see courses on haemorheology taught at medical schools. “There is a very large medical literature concerning haemorheology - yet the topic is not taught at medical schools - nor is the published information utilized clinically.”

Simpson believes that a body of new ideas on how to more effectively study red blood cells has been published, but this information is yet to be applied properly. Haematologists, he says, “have failed to make the transition from light to electron microscopy. When they use electron microscopy, they do not use immediately fixed red cells - and the textbook concept of a red cell simply shows the effects of treatment prior to fixation.”

Since retiring in 1985, Simpson has sacrificed a large amount of his own time and personal resources to uncover more information about CFIDS/ME. “Since my earliest days with ME, my objective has been to try and improve the well-being of patients.” An attempt by Simpson to establish a clinic to test red blood cells did not survive due to lack of funds, a problem experienced by many researchers interested in CFIDS.

If Simpson’s ideas are correct, agents which improve blood viscosity/flow may relieve symptoms in CFIDS patients. He hopes to someday see placebo-controlled studies conducted “with the primary objective of determining which agent [haemorheological], if any, has the ability to improve patient well-being.” He continues, “Because it is not possible to increase the diameter of a capillary, treatments should be aimed at increasing red cell flexibility. There is published information which reports that TRENTAL (pentoxifylline), fish oil, and oil of evening primrose taken in sufficient amounts (4000mg) improved red cell flexibility.”

 

I've read about decreased blood flow to the brain before, but I was wondering if I take supplements that increase blood flow to the brain such as Ginkgo Biloba, Vinpocetine, Resveratrol, Grape Seed Extract, Pterostilbene, etc. would that increase the chance of mercury reaching the brain if a person was mercury toxic? I've avoided these supplements since recent troubles with an amalgam, but I'm wondering if I'm being overly cautious.

 

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):

Hi Research 1st, thanks for this, very interesting.

I had the 'Live Blood Analysis' a number of years ago. I, too, had many misshapen RBCs. The 'cure' was to eat more protein. Not very helpful, but it was fascinating to see the little buggers on the microscope video monitor. I also have chronic inflammation, but no knows exactly where or why, and they have no interest in finding out.

The mention of oxidative stress make me think of Martin Pall's work on nitric oxide, the "NO/ONOO" stuff, or something like that, and Rich Van K's methylation theories.

 

Lotus, when these findings came out people with ME and CFS started experimenting with supplements that are said to have these properties in a big way. It was a big topic of discussion. Can't say that anyone reported any worthwhile success with these things at the time. No idea about mercury.

p.s. Dr Simpson suggested fish oils, evening primrose oil and Pentoxifylline at the time. I didn't get a chance to try the Pentoxifylline.

p.p.s. someone has been in contact with Dr Simpson and made him aware of the new research. He is 89 but still replies to emails.

 

Lotus, when these findings came out people with ME and CFS started experimenting with supplements that are said to have these properties in a big way. It was a big topic of discussion. Can't say that anyone reported any worthwhile success with these things at the time. No idea about mercury.

p.s. Dr Simpson suggested fish oils, evening primrose oil and Pentoxifylline at the time. I didn't get a chance to try the Pentoxifylline.

p.p.s. someone has been in contact with Dr Simpson and made him aware of the new research. He is 89 but still replies to emails.

I found Ginkgo and Vinpocetine to be good for brain fog (although some people have had problems with Vinpocetine) and Resveratrol is good for inflammation. I've also heard good things about Grape Seed Extract and Pterostilbene. They might not solve the problem or even make a huge difference, but I think they're worth trying.

 

Lotus, the problem is that for many of us we have been trying since the research first came out. For some of use we met Dr Simpson and have been trying ever since then. Been over 20 years since I met him.

It's an area that needs better research and not just into the causes but also treatments. Spending hundreds of pounds each year on supplements that make little difference over a very long period of time is a severe finanacial drain. "tryng" isn't possible to do for decades unless one is has an income.

Not only can my finances afford to do this but my stomach packed up in 2005 and I simply cannot digest all the supplements I was swallowing.

 

ph abnormality resonates here...for decades I have thought that the reason some meds/foods/supplements 'help', affect me positively, is their clearly off label effect of changing ph; antibiotics do this, hormones, foods...virtually everything has this potential; one doc actually told me outright that he thought it was the saline vehicle and other properties of the cleocin IV's ( NOT cleocin's antibiotic / microbe killing capacity) that made me feel better for a few hours, and I agree, knowing how unpopular this might be...but hey, its a start..

 

Lotus, the problem is that for many of us we have been trying since the research first came out. For some of use we met Dr Simpson and have been trying ever since then. Been over 20 years since I met him.

It's an area that needs better research and not just into the causes but also treatments. Spending hundreds of pounds each year on supplements that make little difference over a very long period of time is a severe finanacial drain. "tryng" isn't possible to do for decades unless one is has an income.

Not only can my finances afford to do this but my stomach packed up in 2005 and I simply cannot digest all the supplements I was swallowing.

Boy does this ever sound familiar. I would say the most desperate times in post-diagnosis years came when I would spend hour after hour reading about supplements, and walking the isles of health food stores, looking for the one thing that would help me. Both the expense and the disappointment were huge. I took enough supplements over the course of two years to sink a battleship. The only thing that had a "noticeable" effect was vitamin B-12. And even that faded over time. Now looking back, i can say that avoiding certain foods, toxins and eating green vegetables and protein was the only thing that really helps.

 

Ive found Gingko to be of no help at all for my brain. Neither did fish oil or evening primrose oil help any of my ME symptoms. (Fish oil thou helps my osteroarthritis).

Methylation things thou have been a good help for me (methyl B12, active folate) along with things which are antioxidents (selenium/vit C are of use to me) along with molybdenum.

 

Now looking back, i can say that avoiding certain foods, toxins and eating green vegetables and protein was the only thing that really helps.

MishMash.. if you havent done so already.. I suggest to go and have a 2hr glucose test done with the insulin included to get issues there ruled out. Those who have insulin issues feel better on high protein diets (it helps stop the insulin from spiking) along with the avoidance of many other things is needed in those who have this issue. You could have hyperinsulinemia (insulin resistance)... prediabetic state and that can give a lot of symptoms to some of us who have this.