ME/CFS Science Blog
Senior Member (Voting Rights)
I wanted to make a thread to discuss the theory that ME/CFS is a signaling problem, located in the synapses of neurons in the brain. I think it fits and would help explain the few findings and observations that we have about the illness.
The clinical picture
First of all, there is no clear pathology in ME/CFS. No signs of inflammation (CPR and cytokines show no differences), no traces of ongoing infection, no deformities or neural damage, no notable increases in antibodies, no mitochondrial dysfunction, no organ damage, etc. I think this is the first important characteristic about the illness: not what we see, but what we don’t see.
The second point is that the disability and symptoms in ME/CFS are often greater than those in other chronic diseases, where there is clear pathology. Studies have compared ME/CFS patients to those with multiple sclerosis, rheumatoid arthritis, congestive heart failure, and renal disease and found that ME/CFS patients generally report more disability and impairment. Even terminal cancer patients can do much more than ME/CFS patients.
So, this poses a conundrum. Perhaps there is some pathology that we cannot yet detect: a hidden reservoir for the virus, antibodies that we don’t see, etc. The question, however, is: why would this ‘hidden’ pathology cause much more disabling symptoms than diseases where the pathology is all over the place? Why would it result in greater disability than in cases where we know there are tumors, inflammation, antibody responses, organ failure, etc? To me, the most plausible explanation is that ME/CFS pathology is in the signaling of symptoms itself.
Evolutionary, one can see symptoms as a response of the body to pathology. The organism retracts and avoids energy expenditure so that its focus can be on healing the disease. I think this explains why fatigue and malaise are part of almost all chronic illnesses. It’s simplistic, I know, but let’s call this the ‘symptom signal’. The hypothesis I’m exploring is that ME/CFS is mainly a pathology of this signal.
New illnesses are often studied by focusing on their most extreme manifestations, and only later is it found that milder and more subtle cases (forme frustre) exist. Let’s apply this and focus on (very) severe ME/CFS for a moment. These patients are so disabled by symptoms that they look like locked-in syndrome patients. They are bedbound, almost totally isolated from the outside world, and can hardly communicate or move. Yet from what we hear and the limited data that we get, there are still no clear signs of pathology. Blood work is largely normal. If we assume a different pathology, like a virus, an antibody, or blood flow problems, then in its severe form, this would, in some cases get out of control, show itself or cause tissue damage. If blood cloths, for example, are part of the pathology, we would perhaps expect to see more thrombosis. Blood flow problems would mean we are more likely to have brain or organ damage, etc. For most pathologies, this would again be a challenge to explain: the symptom/disability keeps increasing to a maximum while biological dysregulation remains elusive. For the signal theory, this is what we would expect with increasing severity: the volume knob for symptoms has been turned to 11, but the rest of the body seems relatively fine and functioning.
Let’s move on to symptoms. I’ll discuss PEM in the next section. The other characteristic ME/CFS symptoms, such as fatigue, malaise, pain, unrefreshing sleep, cognitive dysfunction, light and sound sensitivity, all clearly point to a neurological problem. But it’s not the kind of neurological problem that suggests brain damage. This forum is a good example that there is no retardation in ME/CFS, and specific memory loss has not been picked up in various cognitive tests. The main cognitive problems are brain fog, difficulty concentrating, slower reaction times, etc. Similarly, the sleep problem that is most reported is waking up unrefreshed. So, I would say these fit the ‘symptom signaling’ theory well and do no suggest other problems that require further explanation.
Orthostatic intolerance (needing to lie down, not POT or hypotension) and gut problems (not tolerating certain foods, poorer digestion) could also be viewed/explained from a neurological angle. So, the theory not only fits the most characteristic ME/CFS symptoms well but might also better account for the broad range of symptoms reported. Other theories have more difficulty with this. If you start with endothelial dysfunction or connective tissue, you have to make a lot more connections to come out to photophobia. I think that’s why so many documents say that ME/CFS is a complex multisystem disease. Theories often need to assume multiple pathologies in different body systems and complex connections between them to account for the many symptoms seen. I think this can be more easily explained by ME/CFS being a neurological problem of symptom perception.
Next: post-exertional malaise (PEM). A key observation is that patients can exceed their limit but then get payback and deterioration in symptoms afterwards. This means there is no hard physiological limit that stops patients, like in muscle or mitochondrial pathologies. ME/CFS patients don’t fall during CPET because their muscles stop working or they don’t quit because they can’t breathe enough. They are usually able to finish the test relatively ok but get much more ill afterwards. What stops them is the severity of symptoms, not a biological dysregulation. The mechanisms seem central (in the brain) rather than peripheral (in the muscle). Various studies have tested patients during PEM (e.g., after an exercise test), but overall, these show no clearer signs of pathology than before it. There is e.g., no clear buildup of lactate or detectable immune response during PEM. So, this is another tricky phenomenon to fit into a theory. Why would exertion make things worse?
In the symptom signaling theory, it would make sense. The main problem is that neurons get info that something is horribly wrong in the body, so the organisms must be told to rest and retract. If we do activities, these might give a different signal telling the nervous system that the organism isn’t listening. There might be signs of high energy expenditure that it cannot afford at this time, such as muscle breakdown or a stress response. When the neurons get this info, they interpret this as the body being very naughty so the volume of the symptom signal is increased to induce the appropriate response (feeling awful and not doing anything anymore). The delay in PEM would then be explained by the various signals coming through, communicating, and finding the right response.
The clinical picture
First of all, there is no clear pathology in ME/CFS. No signs of inflammation (CPR and cytokines show no differences), no traces of ongoing infection, no deformities or neural damage, no notable increases in antibodies, no mitochondrial dysfunction, no organ damage, etc. I think this is the first important characteristic about the illness: not what we see, but what we don’t see.
The second point is that the disability and symptoms in ME/CFS are often greater than those in other chronic diseases, where there is clear pathology. Studies have compared ME/CFS patients to those with multiple sclerosis, rheumatoid arthritis, congestive heart failure, and renal disease and found that ME/CFS patients generally report more disability and impairment. Even terminal cancer patients can do much more than ME/CFS patients.
So, this poses a conundrum. Perhaps there is some pathology that we cannot yet detect: a hidden reservoir for the virus, antibodies that we don’t see, etc. The question, however, is: why would this ‘hidden’ pathology cause much more disabling symptoms than diseases where the pathology is all over the place? Why would it result in greater disability than in cases where we know there are tumors, inflammation, antibody responses, organ failure, etc? To me, the most plausible explanation is that ME/CFS pathology is in the signaling of symptoms itself.
Evolutionary, one can see symptoms as a response of the body to pathology. The organism retracts and avoids energy expenditure so that its focus can be on healing the disease. I think this explains why fatigue and malaise are part of almost all chronic illnesses. It’s simplistic, I know, but let’s call this the ‘symptom signal’. The hypothesis I’m exploring is that ME/CFS is mainly a pathology of this signal.
New illnesses are often studied by focusing on their most extreme manifestations, and only later is it found that milder and more subtle cases (forme frustre) exist. Let’s apply this and focus on (very) severe ME/CFS for a moment. These patients are so disabled by symptoms that they look like locked-in syndrome patients. They are bedbound, almost totally isolated from the outside world, and can hardly communicate or move. Yet from what we hear and the limited data that we get, there are still no clear signs of pathology. Blood work is largely normal. If we assume a different pathology, like a virus, an antibody, or blood flow problems, then in its severe form, this would, in some cases get out of control, show itself or cause tissue damage. If blood cloths, for example, are part of the pathology, we would perhaps expect to see more thrombosis. Blood flow problems would mean we are more likely to have brain or organ damage, etc. For most pathologies, this would again be a challenge to explain: the symptom/disability keeps increasing to a maximum while biological dysregulation remains elusive. For the signal theory, this is what we would expect with increasing severity: the volume knob for symptoms has been turned to 11, but the rest of the body seems relatively fine and functioning.
Let’s move on to symptoms. I’ll discuss PEM in the next section. The other characteristic ME/CFS symptoms, such as fatigue, malaise, pain, unrefreshing sleep, cognitive dysfunction, light and sound sensitivity, all clearly point to a neurological problem. But it’s not the kind of neurological problem that suggests brain damage. This forum is a good example that there is no retardation in ME/CFS, and specific memory loss has not been picked up in various cognitive tests. The main cognitive problems are brain fog, difficulty concentrating, slower reaction times, etc. Similarly, the sleep problem that is most reported is waking up unrefreshed. So, I would say these fit the ‘symptom signaling’ theory well and do no suggest other problems that require further explanation.
Orthostatic intolerance (needing to lie down, not POT or hypotension) and gut problems (not tolerating certain foods, poorer digestion) could also be viewed/explained from a neurological angle. So, the theory not only fits the most characteristic ME/CFS symptoms well but might also better account for the broad range of symptoms reported. Other theories have more difficulty with this. If you start with endothelial dysfunction or connective tissue, you have to make a lot more connections to come out to photophobia. I think that’s why so many documents say that ME/CFS is a complex multisystem disease. Theories often need to assume multiple pathologies in different body systems and complex connections between them to account for the many symptoms seen. I think this can be more easily explained by ME/CFS being a neurological problem of symptom perception.
Next: post-exertional malaise (PEM). A key observation is that patients can exceed their limit but then get payback and deterioration in symptoms afterwards. This means there is no hard physiological limit that stops patients, like in muscle or mitochondrial pathologies. ME/CFS patients don’t fall during CPET because their muscles stop working or they don’t quit because they can’t breathe enough. They are usually able to finish the test relatively ok but get much more ill afterwards. What stops them is the severity of symptoms, not a biological dysregulation. The mechanisms seem central (in the brain) rather than peripheral (in the muscle). Various studies have tested patients during PEM (e.g., after an exercise test), but overall, these show no clearer signs of pathology than before it. There is e.g., no clear buildup of lactate or detectable immune response during PEM. So, this is another tricky phenomenon to fit into a theory. Why would exertion make things worse?
In the symptom signaling theory, it would make sense. The main problem is that neurons get info that something is horribly wrong in the body, so the organisms must be told to rest and retract. If we do activities, these might give a different signal telling the nervous system that the organism isn’t listening. There might be signs of high energy expenditure that it cannot afford at this time, such as muscle breakdown or a stress response. When the neurons get this info, they interpret this as the body being very naughty so the volume of the symptom signal is increased to induce the appropriate response (feeling awful and not doing anything anymore). The delay in PEM would then be explained by the various signals coming through, communicating, and finding the right response.
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