ME/CFS and fatigue at the level of neurotransmission

[Hoopoe]

This is amateur speculation about ME/CFS, not sure if it's the right place.

What if a big part of ME/CFS is that neurons fail to sustain effective communication over time during repeated or prolonged activity? The emphasis is on failure to sustain... things might be normal for a short time, but for some still unknown reason, sustained use would lead to a rapid decline in effective neurotransmission.

This seems like it would fit with some characteristics of the illness, but not all of them. The marked sensitivity to sensory stimuli suggests something else, maybe a different kind of dysregulation, which could still be at the level of neurotransmission.

Drugs like SSRIs that affect reuptake of neurotransmitters don't seem to be effective in treating ME/CFS, but there are other ways that dysfunction of neurotransmission could occur.

 

[ME/CFS Science Blog]

Interesting but wouldn't a decline in neurotransmission result in muscles or cognitive abilities no longer functioning? In ME/CFS the end results always seems to be feeling awful. So instead of normal functions shutting down, it suspect it involves some feedback signal that is turned on too strongly and isn't cleared. A sustained effort then seems to increase the signal.

 

[Creekside]

What if a big part of ME/CFS is that neurons fail to sustain effective communication over time during repeated or prolonged activity?

That doesn't fit my experience with my symptoms. I don't wake up fully energetic and then decline. I wake up feeling sluggish and groggy, and remain that way (not increasing) even if I do strenuous physical or cognitive activities.

So instead of normal functions shutting down, it suspect it involves some feedback signal that is turned on too strongly and isn't cleared. A sustained effort then seems to increase the signal.

That fits better. Some of the symptoms of PEM might be not an increase in the feedback signal, but a result of an increase in that signal. Those symptoms might trigger at a certain level of that signal, without necessarily feeding back into it.

 

[jnmaciuch]

There is some evidence showing that this is in fact what happens with repeated stimulation of neurons re: adenosine signaling

Thread 'Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity, 2012, Lovatt et al.'

Jun 12, 2025

Neuronal adenosine release, and not astrocytic ATP release, mediates feedback inhibition of excitatory activity​

Ditte Lovatt, Qiwu Xu, Wei Liu, Takahiro Takano, Nathan A. Smith, Jurgen Schnermann, Kim Tieu, Maiken Nedergaard

Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of...

• jnmaciuch
• adenosine brain metabolism
• Replies: 2
• Forum: Other health news and research

• 

 

[Hoopoe]

Interesting but wouldn't a decline in neurotransmission result in muscles or cognitive abilities no longer functioning? In ME/CFS the end results always seems to be feeling awful. So instead of normal functions shutting down, it suspect it involves some feedback signal that is turned on too strongly and isn't cleared. A sustained effort then seems to increase the signal.

It would depend on the severity of the disruption and I suspect on the exact effect on signals.

In myasthenia gravis, antibodies block neurotransmission at the neuromuscular junction. This leads to muscles becoming rapidly fatigued and weak with use. The weakness tends to fluctuate over the course of the day, getting worse with activity and improving with rest, and there is a wide spectrum of severity.

In multiple sclerosis, fatigue is thought to result in part from disrupted neurotransmission resulting from damage to myelin.

In the context of ME/CFS, I'm thinking about neurotransmission in the CNS. That could have all sorts of effects. Migraine affects the brain and makes people feel awful. The feeling of effort and fatigue associated that we often experience might be what poor neurotransmission feels like. Subjective mild weakness in limbs after too much mental activity seems like it's probably a brain problem.

If there is a disruption of neurotransmission in ME/CFS, it must occur via a different mechanism than in MG or MS.

 

[Creekside]

In the context of ME/CFS, I'm thinking about neurotransmission in the CNS.

https://meassociation.org.uk/2025/0...novel-biomarker-and-therapeutic-target-in-me/

I'm guessing that sphingomyelin would affect neurotransmission. It would probably have different levels of effect on different types of neurons. What if there are neurons involved in a certain feedback loop that are unusually sensitive to alterations in this enzyme function?

 

[jnmaciuch]

What’s been shown with adenosine (in that thread/paper I linked) is that repeated neural firing results in a higher concentration of adenosine, which is a byproduct of the metabolic demand of recalibrating membrane potential (adenosine being the “A” in ATP and membrane potential maintenance being the most ATP-demanding function in a neuron by a long shot).

Adenosine also doubles as an inhibitory neurotransmitter. Meaning that the more a neuron fires, the more adenosine leaks into the extracellular space as a byproduct of metabolic activity, and the “harder” it becomes for the neuron to continue to fire.

adenosine receptors are also the target of caffeine. It’s been hypothesized that this is the reason caffeine helps counteract decline in cognitive performance over time. Though caffeine would also target other neurons besides the ones that are in this metabolic state, leading to the unpleasant autonomic nervous system side effects.

Theoretically, anything that affects the rate of adenosine accumulation (which could be metabolic “inefficiency” at any number of points) or which alters the receptor sensitivity for adenosine could result in exactly this dynamic:

So instead of normal functions shutting down, it suspect it involves some feedback signal that is turned on too strongly and isn't cleared. A sustained effort then seems to increase the signal.

 

[Hoopoe]

What’s been shown with adenosine (in that thread/paper I linked) is that repeated neural firing results in a higher concentration of adenosine, which is a byproduct of the metabolic demand of recalibrating membrane potential (adenosine being the “A” in ATP and membrane potential maintenance being the most ATP-demanding function in a neuron by a long shot).

Is there anything that suggests a problem with adenosine at the level of neurotransmission in ME/CFS?

 

[jnmaciuch]

Is there anything that suggests a problem with adenosine at the level of neurotransmission in ME/CFS?

I don’t think it’s really been studied. There’s anecdotal evidence that caffeine can keep some pwME going for longer, provided that they can tolerate the other side effects, though they also often report a crash. But that’s about it as far as “evidence” goes.

My guess is that adenosine might possibly mediate some of the specific phenomena described at the beginning of this thread, but it would be as a downstream effect of something else, rather than a central issue driving the illness as a whole.

 

[Snow Leopard]

Is there anything that suggests a problem with adenosine at the level of neurotransmission in ME/CFS?

I don't think it's a problem with adenosine specifically, but that sensing adenosine is part of the fatigue sensing apparatus of the brain and plays a role in neurovascular coupling, analogous to the afferents that stimulate fatigue sensing muscle afferents.