Everything is in The Vagus Nerve: What is The Relationship Between Chronic Fatigue Syndrome (CFS) and Coronavirus?, 2020, Selma

[ME/CFS Science Blog]

There was this 2023 study with autopsies of 27 people with COVID-19.

The authors claim to have found signs of inflammation at the vagus nerve. Axonal mRNA analysis showed upregulation of interferon signalling but no signs of axonal damage. Sars-Cov-2 RNA correlated with these signs of inflammation while there was inverse correlation with genes regulating "trans-synaptic signaling or assembly of the neuronal transport machinery."

Discussion here:
Vagus nerve inflammation contributes to dysautonomia in COVID-19, 2023, Woo et al. | Science for ME

So one idea might be that in Long Covid or ME/CFS, this local vagus nerve irritation or inflammation keeps sending viral infection signals to the brain without overt damage or other immune activation that would be visible on tests. And the genetics of DecodeME and the Snyder study on synapses and neural transport assembly might point to this neural aspect of the vagal nerve communication to the brain.

 

[ME/CFS Science Blog]

Perhaps the virus infection and immune irritation of the vagus nerve is gone in ME/CFS but the viral signalling fails to shut itself off due to some defect in this pathway?

 

[Jonathan Edwards]

I just think talking of 'vagus nerve' here is unhelpful. It is a bit like the channel tunnel, carrying both rail and road freight in all directions and no particular reason to think that it carries the cocaine bags any more than any other road or railway.

If they were looking for inflammation they should have done tissue histology, not mRNA counts. I think you can get evidence for whatever you want out of this sort of analysis.

 

[jnmaciuch]

There was this 2023 study with autopsies of 27 people with COVID-19.

I think it's quite likely that those findings are attributable to acute infection, and I agree with the comments in that thread that it's a leap to attribute certain symptoms during acute infection to this specific finding. If there was permanent structural damage to the nerve causing weird firing then maybe that could explain some persistent symptoms, but it doesn't seem to really fit the clinical picture of ME/CFS or many LC cases for that matter.

If they were looking for inflammation they should have done tissue histology, not mRNA counts.

They found increased HLA-DR staining and CD8+ infiltrates in the brain stem, but that's about it. I assume both are just driven by the presence of SARS-CoV-2 virus in the same area. The RNA-seq analysis is confusing to me.

Perhaps the virus infection and immune irritation of the vagus nerve is gone in ME/CFS but the viral signalling fails to shut itself off due to some defect in this pathway?

And the genetics of DecodeME and the Snyder study on synapses and neural transport assembly might point to this neural aspect of the vagal nerve communication to the brain.

I think it just brings us back to the same issue as cytokine-specific signaling in DRG/other sensory neurons. It's not a matter of an IL-1b specific neuron being induced to fire and triggering symptoms, its a matter of neurons that pass along many different signals being internally modulated in a very specific way by downstream cascades of the cytokine receptor. So if you're trying to explain how that can be maintained long term in the absence of the actual cytokine, you have to explain how the intracellular component is maintained long term without [edit: cytokine stimulation]--what happens at the synapse doesn't really matter if you don't have this piece first.

 

[ME/CFS Science Blog]

you have to explain how the intracellular component is maintained long term without stimulation--what happens at the synapse doesn't really matter if you don't have this piece first.

Thanks for spelling this out.

So in ME/CFS one key area to study might be how neurons are activated intracellularly by cytokines that signal viral infection and induce (certain types of) sickness behavior.

Then we would have to compare those pathways in ME/CFS and controls. Suspect this would have to be through autopsy or PET scans.

I'm an amateur but I get the feeling that we don't really understand much about the intermediary steps between those cytokines and actually feeling sick: how neurons translate that signal into their own language. Most papers aren't very specific about this.

Could it be more than just intracellular changes but also how neurons are wired and interconnected?

 

[Jonathan Edwards]

I'm an amateur but I get the feeling that we don't really understand much about the intermediary steps between those cytokines and actually feeling sick: how neurons translate that signal into their own language. Most papers aren't very specific about this.

Could it be more than just intracellular changes but also how neurons are wired and interconnected?

I think that is a very pertinent question.
Sickness behaviour seems to be explained by some well known cytokine activators but in reality you can have all sorts of different patterns of the various features in different proportions and time courses. There is probably a ot more to know.

 

[jnmaciuch]

I'm an amateur but I get the feeling that we don't really understand much about the intermediary steps between those cytokines and actually feeling sick: how neurons translate that signal into their own language. Most papers aren't very specific about this.

Could it be more than just intracellular changes but also how neurons are wired and interconnected?

Yep, it's not very specific since we're only at early stages of trying to figure that out. The paper looking at cytokine-specific firing patterns is probably the most interesting leap forward so far. This recent paper seems to be a good marker of where we're at currently--trying to sort out if some sensory neurons in a "mosaic cluster" are slightly more responsive to one cytokine over another. It seems in contradiction to some other recent findings so I suspect that this paper will probably be both contested and validated several times before we figure out an answer.

From the discussion:

Our findings reveal that the sensing of cytokines through the vagus nerve in the body-brain axis is not a simple linear relay. Instead,
nodose ganglia neurons create real-time, dynamic representations of specific cytokines before transmitting this information to the brain. We
found that while some nodose ganglia neurons respond selectively to particular cytokines, others detect multiple cytokines yet maintain distinct activity patterns for each, suggesting a coding logic for immune signaling that is more complex than dedicated lines

And you're absolutely right that interconnected neurons probably factor into how things ultimately manifest as symptoms. It's just a question of how much we could feasibly expect a problem at a downstream step to recognizably mimic a whole suite of symptoms if the structure of the whole cytokine-->symptoms process seems to increase in complexity/number of moving parts at every step.

 

[ME/CFS Science Blog]

Hundreds of thousands of people had their vagus nerves cut for treatment of peptic ulcer in the 1970s. Nobody noticed any dramatic effects beyond delayed gastric emptying as far as I remember. If vagus nerves were to blame for anything like ME/CFS I think someone might have noticed.

Counterpoint: I assume it was only cut at the stomach or abdomen, so it wouldn't disrupt the vagal nerve's function of picking up inflammation or damage signals elsewhere in the body and passing it on to the brain?

ME/CFS might most often be caused by local inflammation of the vagal nerve at different locations than the stomach. Even so, cutting it as a treatment for peptic ulcer might have slightly reduced the risk of ME/CFS. At a time when the syndrome wasn't properly defined in the medical literature, this would be nearly impossible to notice.

 

[Jonathan Edwards]

Counterpoint: I assume it was only cut at the stomach or abdomen, so it wouldn't disrupt the vagal nerve's function of picking up inflammation or damage signals elsewhere in the body and passing it on to the brain?

It was cut as the nerve enters the abdomen. The vagus only connects to internal viscera as far as I know. So the connections to heart and lungs would remain. But what inflammation or damage are we talking about? We have not found any. Maybe signals still come from heart or lung, but what signals and why? It is all a bit vague!

ME/CFS might most often be caused by local inflammation of the vagal nerve at different locations than the stomach. Even so, cutting it as a treatment for peptic ulcer might have slightly reduced the risk of ME/CFS. At a time when the syndrome wasn't properly defined in the medical literature, this would be nearly impossible to notice.

So now this is a different scenario I guess - inflammation of the nerve - but why would there be segmental inflammation of nerve trunk? Why not other nerves as well or whatever? If the nerve was important for ME/CFS surely a few people who already had ME/CFS would have suddenly got better even if it was called neurasthenia at the time.

I guess my point is that you could propose just about any theory with as much reason as we have here - that ME/CFS is due to dysregulation of the left adrenal or hyperactivity of the right ankle joint. It might be, but we haven't the slightest reason to choose those anatomical categories - any more than 'vagus nerve'.