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Article: Light on ME/CFS I: Bad Reception: A Key to ME Uncovered? The Light Gene Expression Studies

Pardon me if this shows ignorance of something that has been previously demonstrated, but I am puzzled. How does propranolol, which blocks activities of the sympathetic nervous system (preventing elevation of heart rate and constriction of blood vessels are two important ones) help people who "had decreased (this is not a typo: not increased, but decreased) sympathetic nervous system receptor activation"? I think I've seen this reported before, that beta blockers help POTS, but I don't understand why. I completely get why midodrine would help: by increasing blood vessel tone to return blood to the heart and brain. But propanolol does pretty much the opposite. Anyone in the know?

You're right! This is a really complex issue. Dr. Light discussed this on this page. He believes that dosage is critical http://aboutmecfs.org.violet.arvixe.com/Trt/Propranolol.aspx

In an email, fatigue and pain researcher Dr. Light, reported an experience he had with Propanolol.

"Theoretically, beta and alpha blockers should actually make CFS patients worse, because the prevailing theory (with some pretty good evidence) is that vascular smooth muscle alpha and beta receptors are DOWN regulated (are effectively non-functional) due to an overdrive of the sympathetic nervous system. Activation of these receptors is essential for proper control of blood flow in skeletal muscles and perhaps also the brain. Without proper control, the amount of metabolites signaling fatigue and muscle pain could swing wildly, leading to the sensation of fatigue with even modest movement, and even at rest. Worse, it could lead to orthostatic hypotension (a very common symptom in CFS patients) that could cause the patient to faint when standing, or even sitting upright.

What we found is that there are also alpha and beta receptors on both the muscle sensory neurons that signal fatigue and also those that signal muscle pain, as well as on circulating immune cells. We further found that the receptors on the sensory neurons and immune cells were blocked at lower doses (1 tenth the dose) than is necessary to block alpha and beta receptors on vascular smooth muscle.

This means that low doses of propranolol (again 1/5 to 1/10 the dose that is prescribed for blood pressure control) can block the sensory receptors, reducing the total signal to the sympathetic nervous system, allowing the normal sympathetic reflexes to be re-established, leading to much more normal control of metabolite levels in muscle and brain.

(Much of this last section is still speculationonly inferred from the data we have on blood pressure and vascular control in FM patients, published in Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. Light KC, Bragdon EE, Grewen KM, Brownley KA, Girdler SS, Maixner W.J Pain. 2009 May;10(5):542-52.)."
 
Not a full validation

As others have said, these results need validating by an independent group, not something that happens very often in the world of CFS research, XMRV excepted.

However, this study is not a straight validation by the Lights of their original pilot, as 19 of the 48 CFS patients in this study are are from the pilot itself. In fact, it appears that they just rolled the pilot data into this new study, so we don't get to see what would be the ideal comparison: the new study, with new patients, vs thier original pilot.

A couple of other points:
- 96% of CFS patients met the Canadian Criteria
- The study looked at cytokines themselves, rather than cytokine receptors (though this doesn't affect the findings).
 
Thanks for the excellent description of the Lights' study, Cort.

What follows is from a thread discussing this paper:

I really like what the authors are trying to do here - look at how gene expression in CFS patients differes from controls after moderate exercise - but I think the results are compromised by the fact that the exercise was not always moderate for CFS patients. Here's what they tried to do:
We elected to use a sustained moderate exercise rather than a maximal exercise test (which typically last only 5-9 min in CFS patients) because of closer similarity to the natural exercise experiences reported to exacerbate CFS symptoms in patients daily lives
...
We attempted to adjust for fitness level mismatches by exercising all patients and controls at the same relative exercise intensity, to 70% of age predicted, maximal heart rate.
The problem with this approach is that for the most severely affected patients (bedbound/housebound) 70% of max heart rate for 25 mins is way, way more than moderate exercise and is vastly more than "natural exercise experiences reported to exacerbate CFS symptoms in patients daily lives". I would be in the second most severe category, 'could live alone with occasional help' and know from trying in the past that I could only manage 70% of max heart rate for a few minutes - my problems are caused by activity way below this.

Also, such a level of exercise is likely to be more than moderate for someone who was very inactive and so deconditioned but was otherwise healthy. The paper gives very little info on the healthy controls but it doesn't even claim they are sedentary - in other words they are not well matched to the CFS patients on activity levels.

The mean score for self-rated exertion for the control group was 3.1, which is just right as a score of 3 equates to moderate exertion. For the CFS group the mean was 5.0 ('hard' exertion) but would have been substantially higher than this for some patients. [from other data given, the exertion for the 21 most exhausted patients can be calculated as 6.5, equivalent to 'very hard' exertion]

This matters, because the genes chosen for study have increased expression for strenous exercise in healthy controls:
Initial experiments with normal subjects indicated that mRNA for [genes in this 2011 study] was upregulated at 8 and 24 hours after strenuous exercise. (from 2009 pilot study) mRNA did return to normal at 48 hours

Worryingly, data in the paper shows that the biggest increases by far for gene expression are in the two most severely affected groups whose exercise level is likely to be far above moderate. It could be argued this is exactly as expected for individuals exercising very hard, not evidence for a specific disease process.

Now, as noted elsewhere in the thread, the authors do address this point by an analysis that only looked at patients and controls with similar exertion levels:
This comparison examined 15 controls with the highest RPE (mean 3.89) matched with 27 patients with overlapping RPEs (mean 3.87). Even though this reduced our sample size and statistical power substantially, 6 of the 7 genes AUCs were still significantly greater in CFS patients than controls [P2X4 (p<.05), TRPV1 (P<.02), -2A (P<.03), -2 (P<.03), COMT (P<.04), and IL10 (P< .01)]. The only gene not reliably different was P2X5 (P=.12)
This is an important finding. However, the statistical significance is much less impressive than for the full study (no doubt due to losing the patients with the biggest differences, as well as the inevitably smaller sample size) and the sample size is small. We don't know if the alpha-2a subgroup exists in this smaller sample.

What this leaves us with is effectively a pilot-study type result (15 controls/27 patients vs 49/48 in the full study), rather than a confirmatory result. It's still very interesting, but it's not nearly as convincing.

Well, that's my take. I'm happy for anyone to point out flaws in my logic. Otherwise, to be convinced I'd like to see rersults for a much larger study and ensure that exertion/exercise levels are appropriate for the level of severity experienced by each CFS patient.
 
Interesting analysis, Oceanblue. I hardly ever read a full paper, so i would miss such points. I also hope another group will try to replicate these results in a different and larger cohort. I think it was interesting that they also compared ME/CFS subjects to Fibromyalgia ones. I don't know much about Fibromyalgia, but maybe in this group you would be more likely to find people with a similar lifestyle to people with ME/CFS, as compared to healthy controls.
 
Judith Shapiro noted that Sophia Mirza's autopsy revealed inflammation in the sensory ganglia - which are the dorsal root ganglia (DRG). As I remember she also had inflammation in the brainstem. One paper I read said that once a virus is settled in the DRG and the sensory nerves then it has a pathway to the brain.

Herpes simplex virus, for instance, established latency in the DRG and when it gets to the brain causes the most severe form of encephalitis known.

And, iirc, the London outbreak where M.E. got it's name form, 2 or 3? folk died in year or so afterwards and were autopised. Those showed inflammation of the base of the brain and brain stem (if my creaky memory serves me right)
hence "Encephalomyelitis": corroborative proof of CNS involvement hence NEUROLOGICAL illness of the W.H.O.

wish we could get the findings of those original investigations, as grounds for forcing acceptance in UK of M.E. being a purely biological disease based on prior knowledge that has been deliberately ignored, prior accepted testimony, prior accepted legal documentation (death certificates)...nice to have a civil court case, even if it cannot force medical authorities to change, it can force Parliament to take note and thus, kick the Medical Establishment up the arse!
And thus have the "Weasel Gang" put on trial for fraud, on top of everything else :victory: ;)
 
Thanks for the excellent description of the Lights' study, Cort.

What follows is from a thread discussing this paper:

I really like what the authors are trying to do here - look at how gene expression in CFS patients differes from controls after moderate exercise - but I think the results are compromised by the fact that the exercise was not always moderate for CFS patients. Here's what they tried to do:
The problem with this approach is that for the most severely affected patients (bedbound/housebound) 70% of max heart rate for 25 mins is way, way more than moderate exercise and is vastly more than "natural exercise experiences reported to exacerbate CFS symptoms in patients daily lives". I would be in the second most severe category, 'could live alone with occasional help' and know from trying in the past that I could only manage 70% of max heart rate for a few minutes - my problems are caused by activity way below this.

I don't see a problem with the Lights using a protocol that more severely afflicted people with CFS could not comply with - in a sense I think it buttresses their claims - since it shows that even relatively well-off patients still show remarkably different levels of gene expression - altho I see you have something to say about this below.

Also, such a level of exercise is likely to be more than moderate for someone who was very inactive and so deconditioned but was otherwise healthy. The paper gives very little info on the healthy controls but it doesn't even claim they are sedentary - in other words they are not well matched to the CFS patients on activity levels.

I agree that sedentary groups are often used in exercise studies and that suggests it would have been good to have one here. On the other hand the healthy controls and CFS patients exhibited similar results at rest - which indirectly infers some similarities? - although not in exercise. Would sedentary controls exhibit the same results as the CFS patients? I would guess not but I think the research community will want to see that at some point.

The mean score for self-rated exertion for the control group was 3.1, which is just right as a score of 3 equates to moderate exertion. For the CFS group the mean was 5.0 ('hard' exertion) but would have been substantially higher than this for some patients. [from other data given, the exertion for the 21 most exhausted patients can be calculated as 6.5, equivalent to 'very hard' exertion]

This matters, because the genes chosen for study have increased expression for strenous exercise in healthy controls:

I think I see what you're saying...the self rated expression for the controls should have been higher in order to get increased gene expression levels. I suppose you can argue that the CFS patients were more deconditioned and because of that they worked harder and because of that they had greatly increased gene expression levels. It comes back to the need for sedentary controls.

Worryingly, data in the paper shows that the biggest increases by far for gene expression are in the two most severely affected groups whose exercise level is likely to be far above moderate. It could be argued this is exactly as expected for individuals exercising very hard, not evidence for a specific disease process.

Now, as noted elsewhere in the thread, the authors do address this point by an analysis that only looked at patients and controls with similar exertion levels:
This is an important finding. However, the statistical significance is much less impressive than for the full study (no doubt due to losing the patients with the biggest differences, as well as the inevitably smaller sample size) and the sample size is small. We don't know if the alpha-2a subgroup exists in this smaller sample.

What this leaves us with is effectively a pilot-study type result (15 controls/27 patients vs 49/48 in the full study), rather than a confirmatory result. It's still very interesting, but it's not nearly as convincing.

Well, that's my take. I'm happy for anyone to point out flaws in my logic. Otherwise, to be convinced I'd like to see rersults for a much larger study and ensure that exertion/exercise levels are appropriate for the level of severity experienced by each CFS patient.


It was good to see that 6 of the 7 genes were still significant in the smaller set but it sounds to me like you're making some good points.
 
Hi Cort

thanks for taking the trouble to look at my rather long and technical post.

I think I see what you're saying...the self rated expression for the controls should have been higher in order to get increased gene expression levels. I suppose you can argue that the CFS patients were more deconditioned and because of that they worked harder and because of that they had greatly increased gene expression levels. It comes back to the need for sedentary controls.

More the other way around. The exercise levels for controls were just right ie moderate as the experiment was based on gene expression being unchanged by moderate activity but enhanced by strenous activity in healthy controls.

The problem is the level of exercise for CFS patients who are inevitably badly deconditioned - I think they need to find a more appropriate (and lesser) exercise regime for the level of deconditioning. The formula used to estimate 'moderate' exercise was 70% of age-based maximal heart rate, which would be fine for normal individuals but not for severely deconditioned but otherwise healthy people.

What we are trying to establish is: is the change in gene expression due to deconditioning (a secondary affect of the illness) or due to the underlying illness itself?
 
Hi Oceanblue,

I wanted to thankyou for your 'long' post on the Light paper. I don't have any sort of science background and I thought you made really important points, which give me a much more informed perspective on it.

Its so important to look at ALL research papers critically, not just the psycho ones, and it is a great help that you (and others) are giving to your fellows..

OTH
 
I'm pretty sure at least some of the controls were sedentary and deconditioned, and they didn't get any kind of gene expression the way we do. I also was really concerned about not being able to do their 25 minutes of exercise beforehand because at the point when I did the exercise study in March I was so ill I could only get out of bed about 3 hours a day. Dr. Light reassured me that it wouldn't be as hard as I thought, and indeed I made it through okay. I did get really bad PEM, but of course that's the point.

I'm really excited about the work they are doing, because it seems like it could really lead somewhere.
 
Hi Cort

thanks for taking the trouble to look at my rather long and technical post.

More the other way around. The exercise levels for controls were just right ie moderate as the experiment was based on gene expression being unchanged by moderate activity but enhanced by strenous activity in healthy controls.

The problem is the level of exercise for CFS patients who are inevitably badly deconditioned - I think they need to find a more appropriate (and lesser) exercise regime for the level of deconditioning. The formula used to estimate 'moderate' exercise was 70% of age-based maximal heart rate, which would be fine for normal individuals but not for severely deconditioned but otherwise healthy people.

What we are trying to establish is: is the change in gene expression due to deconditioning (a secondary affect of the illness) or due to the underlying illness itself?

Alan's really been great. I gave him your post and here is his response. I was struck by how many studies he's involved in now - he seems to be engaged in a comprehensive quest. I was also amazed that he appears to be finding unique fatigue signatures in different disorders with severe fatigue including post-prostate cancer patients and MS...

I know this doesnt answer all ofthe questions, but hope it helps, as we had worried about all of the samepoints this person brought up.

Of course, we would like to include everything in one paper, but the current JIM paper is already too much for many people.

We have tested controls at a much higher intensity (80% max heart rate), and still saw almost no increases in the geneswe saw that increased in The CFS patients (material still to be written up).

We have a paper about to come out, wherewe also tested MS patients with unexplained fatigue at 70% max heart rate, andsee only two of the 6 genes increased.

We also have a study in progress thatlooks at normal subjects at three different levels of exercise. A VO2 max test,a full cycling time trial, and a full cycling time trial with their core temperature increased by 2 degrees C. So far, with these max tests, most ofthe sensory genes actually go down in these normal subjects. AD2A does go up,but not as much as in patients, and Beta 2 actually goes down in all but the VO2 max test.


In the original pilot, we also had asubgroup of very sedentary controls that we examined for changes in geneexpression. They had small increases in some of the same genes as the patients,but only a few, and these were very small increases.

All of this argues against the geneexpression differences being caused by de-conditioning.

However, some of the gene expressionincreases may still be an effect of lack of exercise. In our experience, anyone that is as sedentary as a class 1 or 2 CFS patient is by no means normal, and mayhave a pathological condition that has not been diagnosed. I dontbelieve we could find normal control subjects that we could matchwith these patients.

We are in the process of comparing CFS patients with severely fatigued patients with prostate cancer. So far, this group also does not show the pattern of gene expression increases seen in CFS patients. However, this study is not yet completed. These patients may function as one of the control groups that can demonstrate that the gene expression pattern we have observed in CFS patients is unique.

We originally thought the pattern would not be unique, but rather would just be a sign of the fatiguestate of the patients. We are actually more than a bit surprised to find that itmay be unique.

We have very few of the most severely affected CFS patients in this study. We know this is a potential problem and are working on finding genes that are different even atrest in CFS patients, so we
dont have to put them through the exerciseprotocol to see differences, and can therefore, look at more of the most severely affected patients.

We would actually like to avoid doing amuch larger study of CFS patients in the exercise protocol because we believe it is very stressful for the patients. We will do it if we cannot find a geneprofile that works with just a baseline blood draw. We believe the publishedstudies we have provided are sufficient to demonstrate that at least some genes that are involved in fatigue detection and immune cell modulation are dysregulated in CFS, and that this may contribute to some of their symptoms. Whether this dysregulation is a cause of effect of their de-conditioning is another questionthat would be
interesting to answer at some point.
 
Very interesting, Cort, thanks. What might help could be to to test ME/CFS patients that don't live a typical ME/CFS lifestyle. There are patients that are working or studying and have never had any deconditioning, as they have not stopped these activities so far. Probably these are mostly patients who haven't had ME/CFS for very long, but for long enough to fit the diagnosis criteria. I would like to see this data.
 
Thanks again, Cort, for summarizing complex issues. You do a great job. My intention is never to shoot the messenger. But i have some observations.

Firstly, identifying the herpes inflammation in a certain part of the brain still leaves the state of knowledge pretty much-- no where. They have known about the part of the brain implicated in Parkinson's for decades. Ask Michael J. Fox how much that has helped him. I'm just going to forget that I read about that. It is a false hope.

If you are an ME/CFS patient and have benefitted from Lyrica, neurontin, or other off-label anti-seizure/anti-convulsive meds, then don't read any further.

But everything I've heard from CFS patients about these drugs has been negative. Especially the part about coming off the drugs, after you have become completely habituated. The honeymoon phase for Lyrica or neurontin lasts about six months or a year. Then it stops working, or you begin experiencing frightening neurological disturbances. Genuine pyschosis seems to be common symptom. The paranoid part of me says-- Bright and Bateman will "isolate the gene" that makes you a genuine beneficiary of this therapy. Then the screws will start to tighten in the GP's office to take the stuff.

Lets make no mistake-- the ordinary doctors out there push these new drugs very hard. I'm not saying it's all about the money-- but that's sure part of it. Saying "no, no, no" to all of the latest off-label wonder drugs puts you at risk of becoming an "uncooperative patient." I'm sure we've all had that experience-- where the doctor scampers into the back room, coming back with a handful of free samples, with a look of gleeful anticipation in his eyes. Saying no at that point creates a wall of frustration. After all, the efficacy of these drugs are backed by "hard science." I'm not sure Bright and Bateman have done me any favors by adding to their legitimacy.

I have a personal relation who took Neurontin on the word of a highly respected neurologist, who swore it had absolutely no side effects. This drug will cause psychosis in a very rational, otherwise sane individual. If you are indeed having seizures, then it is probably warranted. Giving it to ME/CFS patients or MS patients is not warranted. Another big money pot is Cymbalta. I can't imagine the detox from crack cocaine being any worse than what I've read about Cymbalta. And I've gotten the squeeze several times to take that one also. It was like being on a used car lot.

Just one last thing-- I would like Klimas, Bateman, Light, et al, themselves, to all go on a course of beta blockers for six months. Then report back to us what the real side affects were. If you didn't have chronic fatigue before the BB, you will most certainly have it after. I have been given Florinef, as a supposed relief for POTS, but have never heard of anybody who actually benefitted from it. The doc is extremely insistent I take the damn things; so I lie and say I took them. Terrible isn't it. There was a phase early on in my illness when I believed the "it can't hurt, so you might as well try it" philosophy that so many ME/CFS docs seem to adhere to. Not any more.
 
Very interesting, Cort, thanks. What might help could be to to test ME/CFS patients that don't live a typical ME/CFS lifestyle. There are patients that are working or studying and have never had any deconditioning, as they have not stopped these activities so far. Probably these are mostly patients who haven't had ME/CFS for very long, but for long enough to fit the diagnosis criteria. I would like to see this data.

You know I am right in there - While I don't get much exercise I make sure I go on short walks, am up and about all the time - I have never even remotely been deconditioned......I would be great in that study :)
 
"Very interesting, Cort, thanks. What might help could be to to test ME/CFS patients that don't live a typical ME/CFS lifestyle. There are patients that are working or studying and have never had any deconditioning, as they have not stopped these activities so far. Probably these are mostly patients who haven't had ME/CFS for very long, but for long enough to fit the diagnosis criteria. I would like to see this data."

They can be found Eric.

I have had the inability to tolerate aerobic exercise right from the start of my illness (after being an everyday swimmer) but also 'managed' twenty years of study, work and everyday activities that would leave me no more deconditioned than 80% of the healthy population. Then I took a further downward turn but am even now more physically active than the majority of the population. As long as I don't overdo things or breach the anaerobic threshold I'm fine from that perspective and have the luxury of PEM having no other consequences for me (as I no longer work) than an indefinite period of enforced inacitvity and malaise.

However, I would also add that pain and fatigue have never been my major problems. Other symptoms have been much more disabling for me including IBS/food intolerances; orthostatic intolerance; temperature dysregulation; cognitive problems etc. PEM is also as likely to be triggered by cognitive or emotional effort as by physical exertion.

Any explanation for our pathology has to be able to explain the full range of symptoms plus the fact that they vary by individual and over time. I personally feel that the answer lies, not so much with pain/fatigue receptors, as with the full cytokine storm that produces 'sickness behaviour' of which pain and fatigue are a subset.

What is causing this chronic sickness behaviour is the big issue.
 
So maybe you could ask Dr. Light about this, Cort? If it would make sense to study that kind of ME/CFS person, people who never have had deconditioning.

I agree, Marco, that the cause is the most important issue. But if this work could lead to a diagnostic tool and to validation of what people with ME/CFS experience that would also be a big step forward, i feel. So if they can do this, i think it would be a good milestone on the way to find the cause. It could certainly help us get better recognition, maybe help with cohort selection for studies, subgrouping, etc.
 
So maybe you could ask Dr. Light about this, Cort? If it would make sense to study that kind of ME/CFS person, people who never have had deconditioning.

I agree, Marco, that the cause is the most important issue. But if this work could lead to a diagnostic tool and to validation of what people with ME/CFS experience that would also be a big step forward, i feel. So if they can do this, i think it would be a good milestone on the way to find the cause. It could certainly help us get better recognition, maybe help with cohort selection for studies, subgrouping, etc.

I wasn't suggesting that research that doesn't seek to identify the cause has no value Eric. In fact I'd prefer at this stage that researchers focus primarily on elucidating the exact nature of the pathology and thus establishing once and for all the organic nature of the disease rather than trying to identify the 'one' cause (if there is only one).

The real point I was making is that we won't get any closer to identifying the pathology and ultimately the cause if we continue to circumscribe the problem primarily as an issue of fatigue and pain. While these are important elements (and perhaps more so for other individuals than they are for me) they are not specific to ME/CFs and do not adequately cover the full range of symptoms experienced.

Likewise exercise challenges do not represent the full range of circumstances that provoke PEM. I suspect they are used because they are relatively easy to implement but the danger is that their use leads again to the assumption that it is an aberrant response to physical exercise only and therefore we should look for explanations that start at signals sent from the periphery to the brain.

I would still maintain that sickness behaviour as described following infection best describes the range of symptoms we experience. Acknowledging this would place fatigue and pain amongst the range of symptoms that people experience when they are sick rather than as suggestive of a central role for pain and fatigue in provoking and maintaining the illness.