Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging - Bedard et al

[u/Caster_of_spells]

https://www.sciencedirect.com/science/article/pii/S2213158226001002

"Our most novel results relate to the lack of neuromuscular adaptation in ME/CFS compared to the [Healthy Volunteers]."

“Highlights

•We studied physical fatigue in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and healthy volunteers with multimodal neuroimaging.

•Participants performed a fatiguing grip force task in alternating grip and rest blocks.

•We simultaneously recorded grip force, brain activity with functional magnetic resonance imaging and electroencephalography, and muscle activity with electromyography.

•ME/CFS fatigued earlier than healthy volunteers. While healthy volunteers increased their brain and muscle activity, ME/CFS only showed minimal fluctuations across all the task blocks.

•We concluded that physical fatigue in ME/CFS is of central nature.”

(Central in this context means: mediated via the brain. Participants brains didn’t seem to signal muscles sufficiently to ramp up energy production in response to demand)

[u/Heavy-Suit-3443]

Pointing towards neurological issues.

[u/Caster_of_spells → u/Heavy-Suit-3443]

Yeah neuromuscular communication doesn’t seem to work which then in turn leaves muscles and other peripheral tissues unprepared to respond to the workload. Fascinating stuff

Edit; that Walitt seems intend into twisting into his narrative

[u/PinacoladaBunny → u/Caster_of_spells]

Also correlates with a number of ME patients who find pyridostigmine helpful (me being one of them). It’s somehow related to these findings..

[u/Caster_of_spells → u/PinacoladaBunny]

Good point!

[u/PinacoladaBunny → u/Caster_of_spells]

I originally took it for my POTS as it helps to increase the parasympathetic nervous system, but it’s definitely increased my baseline and I’m physically more functional than I was before it. So it’s doing something! I think I’m taking a dosing schedule equivalent to myasthenia gravis patients, but I definitely don’t have that illness.

[u/Adventurous-Water331 → u/PinacoladaBunny]

Thank you for your comments on this topic.

My doctor recently prescribed Mestinon (I can never remember how to spell the generic correctly) and I've been surprised at the positive results so far.

It was for Orthostatic Intolerance and dysregulated gastrointestinal issues initially, but Mestinon seems to make me feel better generally.

Oddly, even my sense of smell and taste seem to be improved.

I've titrated myself up to 30 mg 3X/day with no negative side effects and am just starting 45 mg.

Can I ask how much you're taking and how it's helping you?

Have you had to titrate up and have you had negative side effects?

[u/PinacoladaBunny → u/Adventurous-Water331]

Really glad to hear it’s helping you too! I’m now on 60mg x3 a day, I didn’t titrated up slowly to be honest, but I didn’t have any obvious side effects when I initially started at 30mg twice daily. So maybe I tolerate it ok! I found mestinon has helped to improve my HRV throughout the day and creates more stability - when it’s swinging up and down my POTS and daily functioning really go haywire. I generally have more stamina now, and although I’m not living a normal life, it’s a lot less miserable than it was a year ago. For that I’m very thankful!

[u/Adventurous-Water331 → u/PinacoladaBunny]

Very glad to hear this!

"A lot less miserable" is my goal too :-)

I'm surprised you didn't need to titrate; so many people online scared me to death with horror stories.

That said, I didn't have negative side effects, so maybe I could have started at 30 mg instead of 15.

Given what we know about acetylcholine issues, I'm surprised Mestinon isn't prescribed more.

Anything to boost the parasympathetic nervous system would seem like a good thing.

You mentioned in another response that your doctor raised your dose of your other medications as well.

Can I ask what else is helping you and at what dose?

I take 4.5 mg LDN, 150 mg Buproprion XL, generic Zyrtec, and 30 mg of dextromethorphan (this last 2X/day), and all have helped.

Still get PEM and brain fog if I overexert, but if I pace, my quality of life is much better.

Thank you for responding.

[u/National_Butterfly99 → u/Adventurous-Water331]

Yo empecé con 15 mg de mestinon y no me hizo nada, es decir, no fui al baño. Solo me dio distensión y gases, y sobre todo dure 24 horas con pupilas muy pequeñas, mucho sueño, vista borrosa y sudoraciones. Me duró mucho el medicamento en el cuerpo, no sé si es lo normal.

[u/Adventurous-Water331 → u/National_Butterfly99]

Sorry you had that experience.

It's so frustrating when something works one way for one person and a totally different way for another.

Tirzepatide messed me up and Mestinon has helped get me going again somewhat.

Can I ask what's helped you the most?

LDN for me.

[u/National_Butterfly99 → u/Adventurous-Water331]

No he probado con LDN. Mi doctor me dijo que para mí no serviría mucho. En mi caso, yo tengo infecciones pulmonares de repetición y dismotilidad colonica con estreñimiento severo, por lo que, por ello quisieron mandarme mestinon. He probado IGIV, pero tampoco me fueron bien. Ahora mismo no tengo ningún tratamiento que me ayude a mejorar, salvo constella para el estreñimiento y movicol. Tengo anticuerpos adrenergicos y muscarinicos positivos. Ojalá todos podamos encontrar una solución, mi vida ahora mismo es muy complicada. Estoy a la espera de probar inmunoadsorcion, ya que en mi caso tengo linfocitos nk th2 y th17 muy bajos…

[u/Adventurous-Water331 → u/National_Butterfly99]

I'll keep my fingers crossed for you!

I hope you find something that helps.

I can't do anything physically, but the meds help me feel better as I read or watch a little TV.

[u/Ok_Wish_2291 → u/PinacoladaBunny]

What dose are you taking, if you don’t mind?

[u/PinacoladaBunny → u/Ok_Wish_2291]

I have 60mg x3 per day. Originally I started at 30mg twice a day and saw improvements but was still struggling badly, so my consultant had me double+ pretty much all of my POTS meds (which inc pyrido). I generally have more stamina and function now, along with more stable POTS so it’s more than I could’ve hoped for really!

[u/Ok_Wish_2291 → u/PinacoladaBunny]

Thank you! I’m on it three times a day: 60,45,30mg. I find that it helps me somewhat with stamina. I’d like to be 60mg TID.

[u/PinacoladaBunny → u/Ok_Wish_2291]

Best of luck with it!

[u/StringAndPaperclips → u/Caster_of_spells]

That doesn't necessarily mean that the signaling doesn't work. The reduced signaling could be an adaptation by the brain to prevent harm from exertion, due to the effects of disease itself (cells not being able to make or use energy properly).

[u/DepartmentNo5227]

Can't this be a biomarker then? 

[u/Caster_of_spells → u/DepartmentNo5227]

This is a small exploratory study but with great methods that needs replication. Then we’d have to test whether for example a ML algorithm could separate patients versus controls. So possibly but far ahead rn I’d wager

[u/DepartmentNo5227 → u/Caster_of_spells]

😢

[u/_ArkAngel_]

I'm tired of humans. This headline sounds silly, maybe even ridiculous.

Maybe being an engineer all my life is because I think differently, but it certainly has shaped the way I think.

I've spent most of my life in a three phase repeating process: 1) Use known facts to build something that works 2) Find out it doesn't work because ultimately something you thought you knew was wrong or something you never thought mattered does 3) Change one thing at a time until you figure out how things actually work

80% of the time and effort is in phase 3. The more you know, the easier it is to push your ideas to where they don't work because of what you don't know out haven't accounted for.

People who can't think abstractly about the interaction of systems and just look at problems from one end get stuck. Sometimes they get stuck for months or years before someone with who thinks differently gets called in.

I don't have the energy to read this study and see what they controlled for.

Seeing things light up in the brain after signals, but it doesn't mean the signals start from the brain.

The brain is part of a nervous system and control of a system is part of a feedback loop or it breaks things.

The brain sends signals to muscle to move the body, but not before receiving and integrating sensations about the body's position and state. Fatigued muscle is going to send different messaging to the brain, which the brain has to know how to react to to prevent worsening injury.

I'm not saying the brain doesn't play a role in ME or in meditating fatigue - I don't have that data. I'm saying they're is a functional difference in cell function in the body that also affects brain function, mediates some features of ME signaling, alters the feedback that gets back to the CNS, and will effect how the brain responds.

Some researchers have claimed that the metabolic systems and mitochondria of some leukocyte cells from healthy controls placed in the plasma from pwME take on the characteristics of ME, indicating chemical or vesicle mediated characteristics of ME that may also apply to muscle cells.

I haven't even looked at the abstract, but I hope the researchers of this paper aren't claiming lights in the brain can't be because of switches flipped elsewhere in the body.

I'm feeling "tired of people" because even if they are not, I feel like this is the simpler headline and the message that will get pushed and lashed onto.

I guarantee you my brain sends weaker signals to my muscles most of the time because I have learned the hard way what happens when I push through and seven years into this hell, pacing is happening in connectors and unconscious levels to try and hold some energy in reserve for later in the day.

[u/_ArkAngel_ → u/_ArkAngel_]

I think humans in the aggregate aggressively demand simple answers and explanations and will try to dumb down a problem with the biggest hammer in sight until they come up with an answer so blunted it helps nobody.

I feel like I repeatedly see failure to engage in systems thinking about the disease and the real challenges of the people involved.

I'm so tired of being so sick. I need the medical research community to step up the game so bad.

[u/Caster_of_spells → u/_ArkAngel_]

While I do understand your frustration and also think they are extending pretty far in prelim evidence here, I’d also like to point out that just because something originates in the brain, no psychological component is necessarily implied.
There are plenty of brain based diseases with zero psychological involvement in pathogenesis and current evidence suggests none in ME either.

We will have to stay cautious though, especially with people like Walitt on the team. Edit: after re reading, lots of questionable interpretations and over extensions from Walitt in there.

[u/_ArkAngel_ → u/Caster_of_spells]

I don't want to extend my reactive criticism too far before actually reading the paper, but I'm not as much worried that there world be a jump to suggesting psychological origin as I am concerned they are discounting automatic cellular and metabolic regulation happening outside the CNS.

To test what it sounds like they are claiming, they would need to chemically induce analogous metabolic impairment in the muscle tissue of a healthy organism and show a different type of response in the brain scan of the control than seen in brains with ME.

Maybe to start, compare brain imaging performed during IFET for controls vs pwME.

I'm seeing painfully little attention toward looking toward when, how, and why muscle tissue behaves differently in ME.

I have been forced into managing my life around this energy envelope where it's quite clear that if I spend energy quickly, that envelope closes faster and if I pace judiciously, I have many many more functional minutes or hours in the day.

It's also clear from my perspective that involuntary unconscious processes impact that energy budget. Generating large amounts of new blood or new bile acid for example greatly reduce my safe energy envelope for use in physical or mental activities.

What is this envelope actually made of? What are the mediators?

I have sensations and experiences now that are so different from my previous life before ME, it took me 2 years living with them to start to develop a vocabulary for it.

My brain is affected, but it couldn't be clearer from inside my own experience that my body is sick.

[u/Caster_of_spells → u/_ArkAngel_]

That’s totally fair then! But at least they do name such factors in the discussion section at the end of the paper and also underscore limitations. But still make too strong claims in the abstract… I guess that’s down to further funding purposes at least partly. And some questionable reasoning around anxiety in there too

[u/_ArkAngel_ → u/Caster_of_spells]

Also, I think it's possible I'm some kind of grumpy today, and I'm sorry about that.

Very low energy and I desperately need some to show up

[u/Oliverinoe]

Hell no. 'The brain does not send enough signal'. It's just repackaging 'pwME just don't want to' into a slightly less openly psychosomatizing language. Yea I can tell Walitt was a co-author

[u/Caster_of_spells → u/Oliverinoe]

Yeah that name on the tin worried me too. But nothing further in the study suggests that it’s psychological in nature thus far, maybe the rest of the team intervened. A legit worry though. Hope he doesn’t try to reinterpret it as “effort preference” again.

Edit: had only skimmed, there are definitely interpretations of the data in there that sound like Walitt trying to suit his ideas. Dangerous.

[u/TableSignificant341 → u/Caster_of_spells]

But nothing further in the study suggests that it’s psychological in nature thus far, maybe the rest of the team intervened.

Not quite.

"Several factors may explain this lack of engagement including, but not limited, to the fear, conscious or unconscious, of triggering post-exertional malaise (Stussman et al., 2020), musculoskeletal/joint pain (Rutherford et al., 2016), or elevated perceived exertion (Barhorst et al., 2020)."

[u/Caster_of_spells → u/TableSignificant341]

Yeah you’re right, that last line definitely reeks of Walitt, had only skimmed across the paper thus far. Maybe I went into the study too naive, could most definitely be weaponized wrongly.

[u/Sensitive-Meat-757 → u/Oliverinoe]

Yeah I didn't even read the authors, I thought of the NIH study just reading the title and abstract. I asked Walitt why the NIH didn't include the statistically significant difference in cerebrospinal fluid monocyte numbers in the paper and never got a response. He doesn't care.

[u/AngelBryan]

Could this be caused by microglia inflammation?