PEM - What do physical and mental exertion have in common?

[MeSci]

In light of this thread :

http://forums.phoenixrising.me/index.php?threads/does-anything-besides-activity-give-you-pem.34829/

perhaps I need to ask what do physical and mental activity, migraine and certain foods have in common that could trigger PEM?

We would need to look at what happens in migraine - is it similar in some way to mental activity?

Maybe this paper could help - I haven't time to look at it right now.

Or are we looking for a connection that doesn't exist?

 

[Marco]

We would need to look at what happens in migraine - is it similar in some way to mental activity?

Maybe this paper could help - I haven't time to look at it right now.

Or are we looking for a connection that doesn't exist?

Maybe so. But at least one PWME reports PEM following migraine and studies link migraine to glucocorticoids and leptin (and glutamate) so maybe? I seem to remember seeing something about elevated rates of migraine in ME/CFS.

 

[Elph68]

As I understand it, our energy reserves are low. When we increase activity (physical or mental) energy is shunted towards NADH (ATP) production, and away from NADPH. This will cause ROS and lactate to rise. Now, can high ROS and lactate cause PEM? It seems that many are experiencing relief from PEM with bicarbonate. Rest and antioxidants also seems to help with PEM (as they bring down ROS). There are a few threads going on about this at the moment:

http://forums.phoenixrising.me/inde...ods-and-can-cfs-people-get-really-well.34385/
http://forums.phoenixrising.me/inde...a-sam-e-catalase-no-pem-after-exercise.34446/

Chronic lactic acidosis results in soft tissue calcification. I believe this is a major key to PEM. Calcium does not dissolve very well in solution. In an acidic environment, cells can't effectively remove the calcium build up causing a blockage in the cells ability to consume fuel (trying to simplify this) and repair itself ....

The short answer .... Sodium bicarbonate and magnesium .... magnesium bonds to calcium and transports it back to the storage system (bones). An imbalance between calcium and magnesium means calcium isn't carried away. Resulting in pain and lethargy ..... Sodium Bicarbonate works two fold .... It inhibits lactic acid producing bacteria, and counteracts the acidic environment ......

Cheers.

 

[alex3619]

Which would tie in with leptin?

Our leptin level are normal, they just frequenty move in conjunction with other problems. So the idea is we are too sensitive to normal leptin, I think. This ties in with the microglial hypotheses as they respond to leptin.

 

[Marco]

Our leptin level are normal, they just frequenty move in conjunction with other problems. So the idea is we are too sensitive to normal leptin, I think. This ties in with the microglial hypotheses as they respond to leptin.

I agree Alex. I've a working hypothesis that sensitised microglia are over-reacting to changes in markers of physiological stress/distress within normal parameters. When you think about it many if not all of the stressors which cause us problems are well within the parameters of normal everyday living.

This suggests something that @anciendaze turned me on to. If you consider these markers as danger signals or an early warning system then absolute levels are of little use as an early warning system. Once the level (high or low) has been signalled it may be too late. OK you could argue that you set the levels conservatively but what is conservative depends entirely on the rate of change.

Daily fluctuations in levels within normal parameters may be masking accelerated rates of change which may be interpreted as the danger signal.

I've come across this concept before many years ago in computational vision research where the perception of rotation of a plane object would change when there was an acceleration in one of the angles cast by the object on the visual field.

If neurons or collections of neurons in the visual system operate on this principle then why not the immune system?

 

[Snow Leopard]

I agree Alex. I've a working hypothesis that sensitised microglia are over-reacting to changes in markers of physiological stress/distress within normal parameters. When you think about it many if not all of the stressors which cause us problems are well within the parameters of normal everyday living.

How though, which specific signalling system(s) do you predict are dysregulated?

In the immune system, there are documented effects on various immune cells, that show differences in immediate gene expression, vs responses 3 days later (I remember a study that I think was talking about a T-cell subset).

But then there are also downstream cellular stress pathways and upstream neurological regulation.

I spent a lot of time researching the HPA axis findings in CFS and it is my opinion that the evidence doesn't add up to a (central) problem here. The findings so far in my opinion reflect issues elsewhere.

 

[Marco]

How though, which specific signalling system(s) do you predict are dysregulated?

In the immune system, there are documented effects on various immune cells, that show differences in immediate gene expression, vs responses 3 days later (I remember a study that I think was talking about a T-cell subset).

But then there are also downstream cellular stress pathways and upstream neurological regulation.

I spent a lot of time researching the HPA axis findings in CFS and it is my opinion that the evidence doesn't add up to a (central) problem here. The findings so far in my opinion reflect issues elsewhere.

By immune I was referring to glia. As for which specific signalling that was the initial question I asked and don't know the answer to. Which signals would be activated by both physical and mental exertion?

 

[beaverfury]

I'm still trying to get my head around your model, Marco. It's very hard to discuss this when we don't yet have unique terms for the unique physiology of me/cfs. Plus, I just plain can't understand much !

I agree Alex. I've a working hypothesis that sensitised microglia are over-reacting to changes in markers of physiological stress/distress within normal parameters. When you think about it many if not all of the stressors which cause us problems are well within the parameters of normal everyday living.

This suggests something that @anciendaze turned me on to. If you consider these markers as danger signals or an early warning system then absolute levels are of little use as an early warning system. Once the level (high or low) has been signalled it may be too late. OK you could argue that you set the levels conservatively but what is conservative depends entirely on the rate of change.

The tipping point for me, mentally or physically, is in the signalling, "I am exerting myself". (If I can anthropomorphisize it like that, without knowing the physical substrates).

I can calmly and slowly wash dishes for ages, but if I put my elbow into it and scrub with effort I exhaust myself immediately.
I can think, daydream and read, but if I try to solve a tricky problem or learn a new skill I exhaust myself immediately.
I can feel my heart contract and my head starts to feel swollen (microglia?)
It's exertion or effort that harms me, more than endurance or slow expenditure of energy.

It's like the HPA axis is pre-emptively switching me off before I get a chance to get into the PEM state.
I can't see how I would run out of glucose or get actual fatigue in a matter of seconds, though both these things would happen later if I tried to push through.

After 5 years I have trained myself to stay in a, "I am not exerting myself" state. Though this means that I am missing out on the good stuff like getting excited about things, jumping around, concentrating heavily etc etc

 

[Snow Leopard]

Which signals would be activated by both physical and mental exertion?

The point where the pedal hits the metal... You don't really have a hypothesis until you pick out specific factors and investigate.

I don't really have a formalised system on how to do this, but you can pick out particular signalling systems, trace them upstream and downstream until you come across something that reminds you of other findings or you have intuition that it might be involved. Look at the kinetics of the signalling, outcomes of removing this signalling in knockout mice etc and generally get a feel for it. Then you can start to form hypotheses on direct consequences of this in patients - have those signals been measured directly, gene expression etc, look upstream and downstream, are levels high or low, does this make sense in terms of the symptoms and the underlying system?

I use both Wikipedia and journal articles (through Google Scholar) heavily when doing this sort of investigation. I know you have multiple degrees, but I'm not sure if you still have institutional access to articles? (often through a university library webproxy)

Plus there are tons of interesting diagrams out there when you search for things like "microglia cell signalling" in Google images.

 

[nandixon]

In light of this thread :

http://forums.phoenixrising.me/index.php?threads/does-anything-besides-activity-give-you-pem.34829/

perhaps I need to ask what do physical and mental activity, migraine and certain foods have in common that could trigger PEM?

All of these potentially share increased brain serotonin levels in common.

I noted on the other thread @Marco gave that I think this serotonin excess may possibly be what's going on in my case. And it might be applicable to a small subgroup of other ME/CFS people too.

The theory I have is a sort of an "inverse" corollary of the research that was published earlier last year by Bruce Ames, entitled Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism (http://www.ncbi.nlm.nih.gov/pubmed/24558199/)

The key part of Ames' work is that it was discovered that Vitamin D (calcitriol) regulates the two different tryptophan hydroxylases differently. (These are the enzymes for the first - and key - step in serotonin synthesis.) It was found that calcitriol upregulates TPH2 (found in the brain) while it downregulates TPH1 (found in the gut), via VDRE's.

Dr Ames' main theory, I think, is that in autism TPH2 is not being sufficiently induced to increase serotonin production in the brain (and TPH1 is not being sufficiently suppressed to decrease serotonin production in the gut), due to a vitamin D deficiency from an early age. (For a layperson's summary of the article, see: http://www.timeforwellness.org/blog-view/solving-autism-vitamin-d-and-serotonin-synthesis-380)

Perhaps someone else has already thought of this, but based on that work, and on a lot of gene SNP analysis I've done, I think it's possible that a subgroup of ME/CFS may have essentially the inverse issue, i.e., "overly upregulated" TPH2 and "over suppressed" TPH1.

In this "inverse autism theory," the main problem for these ME/CFS people would be too much serotonin being generated in the brain that's not eliminated quickly enough (and possibly not enough serotonin being produced in the GI tract).

(Note that because serotonin does not cross the blood brain barrier, the amount of serotonin or its metabolites that one sees in blood or urine is not related to brain serotonin content.)

Importantly, serotonin increases with exercise, with emotions, with certain foods and supplements (e.g., vitamin D, fish oils), and note that some migraines are due to high brain serotonin levels (i.e., the cause and effect for PEM may be reversed in the case of migraines).

I'm guessing that an additional defect, e.g., a down-regulation in the serotonin transporter (SLC6A4), and/or a defect in tryptophan catabolism (i.e., the kynurenine pathway, e.g., IDO1), etc, may also be needed to have a serotonin excess problem, in addition to perhaps a necessary SNP upregulation in TPH2.

This theory may apply more broadly, but it seems most applicable to individuals who are intolerant (e.g., have increased fatigue) to vitamin D and who have higher than normal calcitriol levels. (The latter is a relatively common finding among individuals who are genetically predisposed to kidney stones, and can be due to an otherwise benign renal phosphate leak, for example.)

(Note that some of the people who have attempted to follow the "Marshall Protocol" may have the issue of vitamin D intolerance due to possibly excessive brain serotonin under this theory.)

I first tried to address what I think is the problem of excess serotonin in my own case by attempting to lower my calcitriol levels, but my natural setpoint is too high (I'm at the very upper limit of the normal range even at a minimal 500 iu vitamin D3/day).

The next option, that I hope to try soon, is to use a TPH2 inhibitor. (Any serotonin receptor antagonists are likely going to be too far downstream, and SSRI's are exactly the wrong modality under this theory, of course.)

I can't go into it here but serotonin has a profound impact on the HPA, so dysregulated serotonin is likely to mean a dysregulated HPA, which fits for ME/CFS of course.

To test this theory out experimentally one could do spinal taps for serotonin in patients and controls following exercise (after a suitable delay, since PEM should be required). That's not going to happen of course, but an MRI brain study similar to what was done for lactate should be possible, if it's not already been done.

 

[adreno]

Interesting, @nandixon.

Did you consider tianeptine for this? You might also consider 5-HT1A agonists, as activating the autoreceptors will reduce 5-HT release.

 

[alex3619]

We have a fair amount of data regarding PEM after muscle based activity. We have very limited data on PEM after cognitive or emotive activity. Let me also point out that an activated immune system, ramping up for any reason, is immunological activity.


The CDC multisite study might finally give us some data on changes after brain activity.

 

[beaverfury]

If activated microglia are a commonality in both mental and physical PEM, what is the insult they are reacting to ?

What is the benefit of setting off inflammation in the brain after physical exertion ?

 

[soxfan]

I have no idea what the answer to your question is but for me....I do not get PEM from physical exertion at all. I never have in the 10 years I have been sick. It is definitely the mental exertion or mental stress/emotional that wipes me out.

It can even be good mental stress like socializing but for some reason when I have to listen to conversation from several people and respond it totally wrecks me for the next 24 hour or longer.

I can take 4-5 mile walks...snorkel...hike...bike...all with no problems afterwards. I have even run in 5K's...well maybe jogged a 5K but have no issues later.

I know after all this time what triggers the horrible crashing after mental exertion and I either do the activity anyway and know that I will suffer afterwards or I don't. I still go to family holidays because I want to see them but I know that night when I go to bed there will be hell to pay...hours of my body so overstimulated that I can't sleep. My body vibrating inside...shaking...pounding heart and the next day I will feel like a truck hit me....heavy...tired...worn out.

 

[Marco]

If activated microglia are a commonality in both mental and physical PEM, what is the insult they are reacting to ?

What is the benefit of setting off inflammation in the brain after physical exertion ?

That's the question. As for the benefit I would expect it to be an evolutionary behavioural response. In healthy folks its telling you to ease off before you're banjaxed. In sick animals its' part of sickness behaviour telling you to quit because you're already banjaxed. We're pretty obviously already banjaxed.

 

[Marco]

The point where the pedal hits the metal... You don't really have a hypothesis until you pick out specific factors and investigate.

I thought I was doing pretty well to have identified neuroinflammation as the likely central mechanism before anything had been published confirming that having started from a position that fatigue was pretty useless as a clue

Anyway, I'm pretty convinced that neuroinflammation/glial priming/activation explains more than other models but I'm interested in fleshing out peripheral stressors that might maintain and inflame that state. Mental and physical exertion are obvious stressors but via which signalling pathways?

Yes you could do an exhaustive investigation of various pathways one by one but it should be possible to narrow the search field logically by excluding various possibilities. For example the pain pathways found by the Lights' can't apply to mental exertion nor is it likely that pathways signalling muscle fatigue are the same as those signalling mental fatigue. Conversely there is a model of mental fatigue that involves impaired clearance of extracellular glutamate by astrocytes. But this mechanism is unlikely to apply to skeletal muscle.

As @alex3619 says, ramping up for any reason is immunilogical activity so perhaps the particular pathway (be it muscle pain, muscle fatigue, mental fatigue, leptin, glucosteroids or whatever) doesn't matter. The primed glia see them all as 'alarmins'.

It may be a case that we have impaired brainstem 'gating' of sensory input which I'd suggested myself previously but there's evidence (not conclusive) that the problem may be at a higher level involving attentional mechanisms.

@beaverfury talks about the signal being 'I am exerting myself' (presumably regardless of whether physically or mentally). I referred to a similar feeling of 'frustration' on the other PEM thread. Is it likely that there's a particular pathway encoding 'exertion' or more likely to be some higher level cognition involving a judgement that 'this is more exertion than I'm confortable with' - which of course is where the CBT/GET folks think they can step in.

 

[alex3619]

nor is it likely that pathways signalling muscle fatigue are the same as those signalling mental fatigue.

I am not sure about this. Elevated lactate might be a universal marker the body can sense.

 

[alex3619]

As for the benefit I would expect it to be an evolutionary behavioural response.

There may be an evolutionary response that is pushed beyond what it evolved for. Or maybe this is exactly what it evolved for - either to slow us down, or to confer enhanced immunity to specific kinds of things. Or alternatively something is just broken for some reason. Not everything has to have been caused by evolution. Evolution is always something in progress, not a final destination.

 

[Marco]

I am not sure about this. Elevated lactate might be a universal marker the body can sense.

True. In that case thought I was referring specifically to the putative pathways in the Lights' findings (purinergic/vanilloid?).

 

[mermaid]

Maybe so. But at least one PWME reports PEM following migraine and studies link migraine to glucocorticoids and leptin (and glutamate) so maybe? I seem to remember seeing something about elevated rates of migraine in ME/CFS.

It was me and actually I specifically have migraine aura, and rarely have the classic migraine pain that is described in this paper quoted above by MeSci http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690498/

I have 3 very specific triggers for migraine aura (which I have had to some extent through life, but quite rarely until my ME relapse 5 yrs ago, and now at least monthly but recently weekly), and these are pain in my stomach (I have chronic gastritis which I am trying to sort out), overdoing things physically and/or mentally, and when I am fighting off a cold virus.

The after effects seem like PEM but maybe they are not the same (I notice someone else on the other thread describes them as being slightly different). For me it's a loss of both physical and mental function - almost like feeling brain damaged, and I feel a loss of energy especially in my legs. So very similar and it tends to come the day after one, and last for a day or 2.

Apparently recent studies into migraine (especially into those with aura) have shown small lesions in the brain and abnormalities in the white matter. Isn't that what they found (the latter) in a study late last year re ME/CFS people?!