ME Hypothesis- Noradrenergic Neuron Dysfunction

Murph said:
I'm always interested in any hypothesis with an adrenergic connection. beta blockers have been very useful for me, as has midodrine, an alpha agonist. I think vasomotor control by adrenergic receptors is part of the symptom set and we could certainly use upstream explanations of that.

You note that norepinephrine is made of phenylalanine, and there's been lots of findings of phenylalanine levels being out of line in patients. Some studies find it high, some low! I'd like to see some more detailed longitudinal examinations of that.

One more point on the POTS side of things: lots of POTS sufferers note that supermarkets are their kryptonite, that's a kind of low-adrenaline ambling around. I can be upright longer in more exciting circumstances where there's presumably more adrenaline coursing around.
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Re the supermarket I was always the person that was running late or getting in there just before closing so it wasn’t the ambling for me. And it was always the checkout I collapsed at - although of course if I felt rubbish that was where I had to head and pass through (I think I’ve only ‘abandoned trolley’ a few times)

I’m aware of the irony of supermarkets being the exertion curve at the end because of the checking out then unpacking into car

but I suspect as I’ve had to be told in post offices to wait in a chair not the queue (after me looking ill and having to do so once) and gave up other eg clothes shopping before that (but at least there there are more places to sit or lie but further to get home if feeling awful) it’s just the standing , lights, exertion. But .. with the added barriers to getting to a chair you might have in other situations- they should add emergency chairs round the store or on trolleys.
 
TamaraRC said:
The NIH Intramural ME study indicated a norepinephrine and dopamine deficiency, in particular DOPAC & DHPG were low.
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Did it? I thought they only discovered correlation between the performance and DOPAC and DHPG in MECFS patients while there was no such correlation in healthy controls. In other words, low level of catechols didn't effect the performance in healthy people while it did in MECFS patients.
 
wabi-sabi said:
I've heard a CGM is ore accurate than random fingersticks. How low did your sugar get? (If that's not too personal.)
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It would usually go to between 3mmol/l and 4mmol/l , never lower than 2.8mmol/l. There is a picture of my CGM chart at 18.48 in the video.
 
TamaraRC said:
It would usually go to between 3mmol/l and 4mmol/l , never lower than 2.8mmol/l. There is a picture of my CGM chart at 18.48 in the video.
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The endocrinologist I saw said that my hypos of 3.4 (or something) on my finger prick tests were not hypoglycemia because "in non-diabetic individuals, blood sugar levels under 2.5 mmol/L are considered hypoglycemic", I found this interesting because I had read otherwise...
 
poetinsf said:
Did it? I thought they only discovered correlation between the performance and DOPAC and DHPG in MECFS patients while there was no such correlation in healthy controls. In other words, low level of catechols didn't effect the performance in healthy people while it did in MECFS patients.
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They found norepinephrine correlated with time to failure, and cerebrospinal fluid DHPG, DOPAC and DOPA were all lower. There is a slide on the video that talks about the difference between healthy controls and ME at 9.43.

I actually think normetanephrine levels would be a good indicator of neuronal dysfunction as they may give a clearer indication of how much norepinephrine is being reuptaken. If norepinephrine levels are measured in CSF it might be measuring a persons COMT speed more than anything else.
 
bobbler said:
But .. with the added barriers to getting to a chair you might have in other situations- they should add emergency chairs round the store or on trolleys.
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Another irony is that stores can dump temporary displays anywhere that will nicely prevent wheelchair access, but chairs? No way: fire hazard. We weren't allowed to put them out, on pain of disciplinary action, in the public building where I worked for the same reason.

I doubt you'd get public liability insurance for a fold-down chair on a wheeled trolley, but the option to collect a lightweight folding one you could suspend from the trolley with hooks—great idea.

My nan had the best idea for Post Office queues. She took off her shoes, sat on the chair looking like an exhausted little old lady, and whoever joined the queue next would shove them forward with their foot until they got to the front. Thinking about the dates, she couldn't have been more than 55 when she started this oh-I'm-so-old-and-frail act. :D
 
wabi-sabi said:
I've heard a CGM is ore accurate than random fingersticks. How low did your sugar get? (If that's not too personal.)
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Most CGMs are calibrated for key accuracy between the target set point of 5-8 , lower end ( 3 and lower) you need to check with a fingerprint. Higher than 15 the accuracy can tail off .
Based on Libre 2 .
 
bobbler said:
What made you think of neuron and it being if I’ve interpreted right about the amount of something released there ? Or uptake?

I’m intrigued why you’ve gone for starting here (it might be your background, or something you’ve noticed in your experiences etc)?

and the 3types idea came from?

and also get that these models are important to model out to be able to rule in and rule out by testing hypotheses of what should happen/be seen if … and so are useful even if they just indicate there is more to it etc.
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It mostly came from my experiences of bad reactions to medications and the glucose issues. The researcher Karl Tronstad did a metabolic study showing 3 subtypes, and I have always been curious why some ME patients have POTS and some don't so I tried to come up with the most plausible explanation for that.
 
TamaraRC said:
I have always been curious why some ME patients have POTS and some don't
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Except that the POT part of POTS may be something of a red herring, but nearly everyone would seem to have reduced cerebral blood flow on ortho-stress, regardless of normality or abnormality in the general cardiovascular system. So the symptoms may relate more to failures in the mechanisms of cerebral vascular regulation.

Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation (2021, Physiological Reviews)

Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography (2020, Clinical Neurophysiology Practice)

The cardiac output - cerebral blood flow relation is abnormal in most ME/CFS patients with a normal heart rate and blood pressure response during a tilt test. (2024, Preprint: MedRxiv)
 
SNT Gatchaman said:
Except that the POT part of POTS may be something of a red herring, but nearly everyone would seem to have reduced cerebral blood flow on ortho-stress, regardless of normality or abnormality in the general cardiovascular system. So the symptoms may relate more to failures in the mechanisms of cerebral vascular regulation.

Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation (2021, Physiological Reviews)

Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography (2020, Clinical Neurophysiology Practice)

The cardiac output - cerebral blood flow relation is abnormal in most ME/CFS patients with a normal heart rate and blood pressure response during a tilt test. (2024, Preprint: MedRxiv)
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The reduced cerebral blood flow could have different causes. If someone has excessive vasodilation of blood vessels, blood can pool in the lower part of body and the blood flow to the brain is affected. However excessive cerebral vasoconstriction can reduce cerebral blood flow as well.

These differences may give us hints to differences between subtypes, although they could also be red herrings.
 
The blood pooling can be variable in an individual. I dont know if it is normal, but there are times when my son can lower his hands and you can see his veins begin to bulge then he raises them and they drain. The same with his feet & lower legs although they also become red very quickly. Then there are other times when this does not happen.
 
Looking back on my OAT test results and assuming this theory is correct then I think my test results co-operate (???) the idea the NET is reduced.

If NET is reduced then norepinephrine just sits in the synapse meaning it doesn't get broken down in the cell as much and doesn't get produced as much (as the post synapse is already getting stimulated with enough norepinephrine). This is why my VMA (a breakdown product of norepinephrine) is low, yet my HVA (breakdown of dopamine) is normal (dopamine extracellular transporters are working).

@TamaraRC Is that what you would expect to see in a ME2 subgroup?

Could also explain why my sympathetic nervous system is constantly jacked up and takes ages to respond to changes in positon / activity levels. If I walk up stairs then stop my heart carries on beating extra hard like I'm still walking up the stairs for minutes after when it should stop almost instantly. Extra norepinephrine is released into the synapse when I'm walking up stairs to deal with the challenge then when I stop, the NET don't remove the, now unnecessary, norepinephrine from the synapse anywhere near fast enough so my heart continues to beat out of my chest.

Also I should add that it is not just insulin resistance that can lead to NET dysfunction. ChatGPT says chronic stress, inflammation, hypoxia, pathogens, COMT mutations and more can also do it.
 

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sb4 said:
Looking back on my OAT test results and assuming this theory is correct then I think my test results co-operate (???) the idea the NET is reduced.

If NET is reduced then norepinephrine just sits in the synapse meaning it doesn't get broken down in the cell as much and doesn't get produced as much (as the post synapse is already getting stimulated with enough norepinephrine). This is why my VMA (a breakdown product of norepinephrine) is low, yet my HVA (breakdown of dopamine) is normal (dopamine extracellular transporters are working).

@TamaraRC Is that what you would expect to see in a ME2 subgroup?

Could also explain why my sympathetic nervous system is constantly jacked up and takes ages to respond to changes in positon / activity levels. If I walk up stairs then stop my heart carries on beating extra hard like I'm still walking up the stairs for minutes after when it should stop almost instantly. Extra norepinephrine is released into the synapse when I'm walking up stairs to deal with the challenge then when I stop, the NET don't remove the, now unnecessary, norepinephrine from the synapse anywhere near fast enough so my heart continues to beat out of my chest.

Also I should add that it is not just insulin resistance that can lead to NET dysfunction. ChatGPT says chronic stress, inflammation, hypoxia, pathogens, COMT mutations and more can also do it.
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I don't think you can work out what subtype you are based on VMA levels alone. That's because the norepinephrine that's broken down from inside the neuron is also converted to VMA, just like the norepinephrine outside the neuron. Also there are other factors like the breakdown rate of COMT and MAO. It could indicate a dysregulation of norepinephrine, but not what subtype. Norepinephrine is also released from adrenal glands as well as sympathetic nerves which also complicates things.

It's possible that the DHPG level and normetanephrine level could be an indication of norepinephrine transporter function, but genetic variants of COMT and MAO would still need to be taken into account, and I don't think DHPG test is even a test the public can access, more for medical research. Also the DHPG and normetanephrine levels could be affected by recent activity giving inconsistent results.

I am planning to do some more research and try to figure out a better way to discern subtypes. If anyone has any ideas, let me know.
 
@TamaraRC has your hypothesis on the adrenergic components changed with your newer pre-print?

Wondering if there's been any recent study replicating this one on clonidine and CFS in adolescents? Here, clonidine was deemed useless in CFS. Wonder if it might be different in adults, or whether guanfacine would have showed improvements in the adolescents.
 
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rapidboson said:
@TamaraRC has your hypothesis on the adrenergic components changed with your newer pre-print?

Wondering if there's been any recent study replicating this one on clonidine and CFS in adolescents? Here, clonidine was deemed useless in CFS. Wonder if it might be different in adults, or whether guanfacine would have showed improvements in the adolescents.
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The new hypothesis still includes the concept of downregulated norepinephrine transporters leading to high extracellular norepinephrine, causing downregulation of beta 2 adrenergic receptors.

In the study, they were given clonidine for 9 weeks. However for me, the treatment I took to correct my dysfunction- for 10 weeks I saw no difference at all (I nearly gave up at 8 weeks) and then suddenly I improved at the 10 week mark. Beta 2 adrenergic receptors can take months to upregulate.

Also, I think it would be better to get to the root cause of the increased neuronal insulin receptor sensitivity, for example if it is caused by a phospholipid deficiency, then correcting that would make more sense than targeting norepinephrine regulation directly.

However it is possible that even if my hypothesis is accurate, it may only describe what is happening in a small subtype, and this subtype may not have been included in the clonidine study. The early onset adolescence subtype may have some differences to later onset subtype that I have had.
 
TamaraRC said:
The new hypothesis still includes the concept of downregulated norepinephrine transporters leading to high extracellular norepinephrine, causing downregulation of beta 2 adrenergic receptors.

In the study, they were given clonidine for 9 weeks. However for me, the treatment I took to correct my dysfunction- for 10 weeks I saw no difference at all (I nearly gave up at 8 weeks) and then suddenly I improved at the 10 week mark. Beta 2 adrenergic receptors can take months to upregulate.

Also, I think it would be better to get to the root cause of the increased neuronal insulin receptor sensitivity, for example if it is caused by a phospholipid deficiency, then correcting that would make more sense than targeting norepinephrine regulation directly.

However it is possible that even if my hypothesis is accurate, it may only describe what is happening in a small subtype, and this subtype may not have been included in the clonidine study. The early onset adolescence subtype may have some differences to later onset subtype that I have had.
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Following your experience, it might be interesting to see a study over 12 or 16 weeks then.
Agree that a2 agonism is downstream in your hypothesis and not the root cause (which would be "better" to tackle).

Thanks!
 
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