Understood - and I certainly did not mean to argue against your own experience or to suggest that my experience in any way carries more weight than your own when it comes to figuring any of this out. This is, of course, one of the many frustrating things about even beginning to trace the origins of whatever has ruined us: our experiences are all so very different, sometimes profoundly so. I regularly read of experiences here and elsewhere that leave me questioning whether I could actually have the same condition at all.
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The symptom signaling theory of ME/CFS involving neurons and their synapses
- Thread starter ME/CFS Science Blog
- Start date
Mij
Senior Member (Voting Rights)
@leokitten
My illness is the reverse from yours. My immune system was ok for years except for the virus PVFS I had. during onset.
My overly activated immune system started 13 years after ME onset and it's getting even worse in the last 5 years.
My illness is the reverse from yours. My immune system was ok for years except for the virus PVFS I had. during onset.
My overly activated immune system started 13 years after ME onset and it's getting even worse in the last 5 years.
BrokenBeaktheBrave
Established Member
Nor did I. In fact I initially put it down to drastically reducing my usual exercise routine. I thought perhaps that's what happens when you go from exercise 6 days a week to viritually nothing. The stiffness was there but it was the least of my problems so I easily overlooked it.
It wasn't until I started taking TUDCA (off the back of Hwang's study showing ER stress in 2023) that my lactic acid reduced (I measured this with a lactate acid monitor) and my general muscle fatigue and muscle strength reduced drastically. I went from not being able to open a bottle of water to popping them open willingly. I've been taking it for a year and a half now and although it's made a discernible difference with grip strength and muscle endurance unfortunately it hasn't touched the general fatigue.
BrokenBeaktheBrave
Established Member
Mine too. Specifically in my armpits.
Snow Leopard
Senior Member (Voting Rights)
I can tell you haven't done a true maximal CPET because it is absolutely the muscles being unable to continue/the heart reaching its limits that causes cessation of CPETs. Treadmill CPETs are not conducted with ME/CFS patients due to the risk of falling. I literally had my vision black out when I knew I had reached a true VO2Max, but some patients cannot get that far because their muscles just cannot do the work.
The main criticism of the hypothesis is that it is disconnected from all of the research we know about how fatigue is sensed and the effects on the brain. Central fatigue is not a mystery, it is not a mistake, it is a carefully tuned feedback system between muscle afferents, spinal efferents and feedback on the motor cortex. Central fatigue signalling mechanisms helps maintain endurance performance of animals. Fact is that peripheral sensitisation mechanisms DO follow the kinetics that matches PEM, whereas central mechanisms don't.
The brain cannot misperceive fatigue out of thin air, because peripheral and central systems are deeply intwined.
Say it was a broken neurological feedback loop. I just cannot believe that any drug currently available that affects anything in the brain would not be able to shift symptoms in ME/CFS people. Surely there would be one psychiatric, narcolepsy or neurological drug that would have gained a reputation as shifting something by now for us people.
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Jonathan Edwards
Senior Member (Voting Rights)
I don't see it that way, and I spend most of my time that is not on ME/CFS of central perception mechanisms in the field of consciousness research. I don't think a brain solution is necessarily further away than an immunological one. I think the examples of epilepsy and migraine may actually be very relevant. I also think that even if the shift in dynamic state is in the brain that manipulating input from immune signals may still be useful.
I can apprecaite that people don't like the idea of the problem being in the brain but as @ME/CFS Science Blog /CFS says, the evidence for pathology in other tissues is very inconsistent.
chillier
Senior Member (Voting Rights)
I think we shouldn't exclude the possibility that there is damage occurring, a few reasons why:
1) As has been alluded to ME/CFS like fatigue is also seen in CNS injury:
2) I wasn't keen on the idea of there being mitochondrial dysfunction before but I think decode has made this seem much more likely due to decode gene FBXL4. Combined with decode gene PRDX6 I think you could plausibly link these to oxidative damage. Oxidative damage does seem to be a part of other neurological diseases like motor neuron disease (with its genetic hit for super oxide dismutase 1 SOD1) - and of course SOD3 was the most significant protein hit in beentjes blood biomarker paper. We have some evidence of protein degradation problems too (from decode: CCPG, RABGAP1L, PEBP1, KLHL20, from HEAL2: proteasome). MND also has genes related to protein degradation issues.
From a google I think neurons expressing interferon stimulated genes might be more prone to excitotoxicity.
1) As has been alluded to ME/CFS like fatigue is also seen in CNS injury:
Yes, and also post stroke fatigue.
2) I wasn't keen on the idea of there being mitochondrial dysfunction before but I think decode has made this seem much more likely due to decode gene FBXL4. Combined with decode gene PRDX6 I think you could plausibly link these to oxidative damage. Oxidative damage does seem to be a part of other neurological diseases like motor neuron disease (with its genetic hit for super oxide dismutase 1 SOD1) - and of course SOD3 was the most significant protein hit in beentjes blood biomarker paper. We have some evidence of protein degradation problems too (from decode: CCPG, RABGAP1L, PEBP1, KLHL20, from HEAL2: proteasome). MND also has genes related to protein degradation issues.
I am thinking this too. We have two apparently downregulated decode genes (ARFGEF2 and CCPG1) supposedly involved in recycling GABA receptors to the post synaptic membrane. Combined with other genes involved in the post synaptic density I wonder if this could lead to excessive calcium influx when the glutamate neurotransmitter is received at the synapse, causing excitotoxicity and damage partially mediated through ROS production, and then leading to synapse loss. The neuron itself need not be fully killed.
From a google I think neurons expressing interferon stimulated genes might be more prone to excitotoxicity.
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OrganicChilli
Senior Member (Voting Rights)
But do we know much about post-concussion syndrome? My impression is it gets treated like ME/CFS by doctors along the lines of "There's no visible damage in your brain and you just need more exposure to light/noise/any other triggers and it's all just anxiety."
Hoopoe
Senior Member (Voting Rights)
One problem we have in ME/CFS research is that we agree exertion and activity of any kind can cause PEM, but it's hard to define what exertion and activity means.
Could the "exertion" that causes PEM be excitement, and eventually, overexcitement of the nervous system? Any physical activity, any exposure to sensory stimuli, any emotions that must be processed, any mental activity, would all lead to excitement of the nervous system.
I noticed that my brain can get overstimulated and overexcited in various ways (this precedes my ME/CFS). This may also be a link to autism.
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chillier
Senior Member (Voting Rights)
I guess the two levers I'm imagining that could lead to that would be exertion leading to an increase in neuron firing rates in some circuits in a given time period, or exertion leading to an increase in the fragility of the neurons via some indirect method (hormonal?)
ME/CFS Science Blog
Senior Member (Voting Rights)
But wouldn't CNS injury be relatively easy to see on scans?
And wouldn't we have the same discrepancy as explained in the introduction: that the fatigue in CNS injury is often less than in ME/CFS and if CNS injury was involved wouldn't it eventually be visible as ME/CFS severity increases to more extreme levels?
Yann04
Senior Member (Voting Rights)
Abilify kinda has that reputation among bits of the patient community. But we have no studies and the fact most people get worse after a while is suspect. But that could also be an interesting clue. Assuming abilify does improve function and then taper off as often reported. Why that happens could be interesting.
Of course, It’s likely all just placebos.
jnmaciuch
Senior Member (Voting Rights)
These were thoughts from people studying epilepsy, chronic pain, and major depression, respectively. The former is doing some of the most advanced epilepsy research with brain organoids, which would not be possible here. [Edit: advances in migraine are limited to prophylaxis for spreading depolarization, which is a brief phenomenon that is not the causal mechanism mediating actual migraine symptoms besides maybe aura. Everything that happens before and after that point is still a black box of “maybe it’s glial activation or something with neural mitochondria”, same as ME/CFS].
I appreciate you might see a way forward for “just the brain” theories, but I must admit that after several discussions going into the details, I don’t see a path forward besides trying drug after drug. I’m quite thankful to see other viable theories
I do agree with @chillier that we can’t ignore the mitophagy angle as well.
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jnmaciuch
Senior Member (Voting Rights)
Vyvanse did move me to mild, though I’m certainly still sick. I must have tried about 13 other drugs as well over the course of my illness. Not exhaustive, sure, but given how willing most doctors (in the US, anyways) are to put us on every and any psychiatric medication, we have a pretty decent sampling already across all of us and only a handful of anecdotes about things helping but not fixing.
As @Yann04 notes abilify has the most traction, and even then doesn't seem to work all that well for more than a handful. It would be great if there’s some shelved drug that fixes everything, but my own perspective is to focus on other promising peripheral-mechanism-acting-on-the-brain-amongst-other-things theories rather than jump to a brain-only theory right away.
Snow Leopard
Senior Member (Voting Rights)
Not necessarily, unless the injury is severe. SFN in particular is hard to see without a biopsy.
But imaging of peripheral nerve/dorsal root ganglion is almost never done in ME/CFS.
And the reply to JE, few tissues have actually been investigated in ME/Patients
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chillier
Senior Member (Voting Rights)
I'm not sure, but I'm not suggesting there would be big chunks of damage like you'd surely see with stroke. It would be a mosaic of neurons or even just parts of neurons, maybe just the dendrites. Still enough perhaps to prime or activate microglia in some way. Would that be visible on the kind of brain scans that have been done so far? I know next to nothing about brain imaging so you could be right.
I think in general more brain scanning would be good, especially if there are synapse tracers we can use. Have there been pre and post cpet brain scans?
ME/CFS Science Blog
Senior Member (Voting Rights)
But isn't that a peripheral neuropathy, one that wouldn't explain any of the core ME/CFS symptoms?
And why would a injury that is not severe cause much more debilitating fatigue symptoms than the severe CNS injuries that are already known?
If it is possible, it will probably have this special connection with the neural pathway that produces symptoms, so we're back to where we started.
Ok, but a pathology of neurons that is hard to see on brain scans is quite similar to what the theory proposes. I don't see why it has to go to the microglia and then back again to the nervous system. Seems like this step isn't really necessary?
I have the feeling that in trying to understand ME/CFS, a peripheral pathology doesn't add much explanatory power.
Mij
Senior Member (Voting Rights)
This would also include vestibular system fatigue which includes physical and overstimulation mental fatigue. I've had this for 5 years. It's more exhausting than my ME/CFS fatigue short term.
Managing energy levels through pacing and rest, and addressing underlying causes like infections or neurological conditions is part of therapy treatment.
chillier
Senior Member (Voting Rights)
You said there were no signs of neural damage and I don't think that's necessarily the case.
Doesn't have to be microglia that was a bit of a throwaway comment. The rationale was that it provides a link for how maybe both stroke and excitotoxicity could cause fatigue - while also providing a time delay for PEM as it would take a while for them to get going. Another idea is global upscaling (takes about 1-2 days) of firing rate after input loss.
EDIT: I don't mean to be sounding critical by the way, I can get on board with the thrust of the argument you're making in your main posts
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