The symptom signaling theory of ME/CFS involving neurons and their synapses

Many of us would disagree somewhat with this belief, because for us the first couple years or so of ME it felt very, very strongly immune system driven, like our immune system was stuck in some strange chronic activation. Many of my lymph nodes were constantly swollen and hard as a rock and I had many other what felt like immune system dysfunction symptoms. All the neurological symptoms really felt like a direct downstream consequence of this immune system activation.

Now yes as the years have gone by the immune activation symptoms have gradually subsided and the neurological symptoms have stayed or gotten worse and now it feels mostly neurological, but I cant help think that the immune system craziness of the first few years still have something really important to do with it
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.
 
Interestingly I didn’t even register it for the first few years of my illness (just bled into the background of general aches and pains)

I’ve commented on this elsewhere but one specific symptom which leads me to think something must be occurring in the muscle as well as brain is muscle stiffness—much worse after activity but nearly constantly present to some degree.
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.
 
ME/CFS patients don’t fall during CPET because their muscles stop working or they don’t quit because they can’t breathe enough.

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.
 
If it does turn out to be a broken neurological feedback loop, we’d more or less end up in a “throw psychiatric medications at a wall and see what sticks” scenario.
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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It’s far off in a way that most other biomedical research isn’t—a fact that I didn’t fully comprehend until I was walked through the limited set of neurological phenomena that could be measured [edit: especially without an animal model] and the even more limited conclusions that could be drawn from any of it. The few examples of successes with migraine and epilepsy are mostly due to the triggering phenomena in both cases being substantially different to the sort of “broken loop” mechanism proposed here.

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.
 
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:

Beyond infectious scenarios already mentioned, something that resembles ME/CFS quite well is post-concussion syndrome. Perhaps that is not a bad starting point either.
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.

Would glutamate dysregulation and excitotoxicity fit here ?
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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Beyond infectious scenarios already mentioned, something that resembles ME/CFS quite well is post-concussion syndrome. Perhaps that is not a bad starting point either.

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."
 
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.

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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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 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 like fatigue is also seen in CNS injury:
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?
 
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