Mij
Senior Member (Voting Rights)
Are you referring to migraine?
From what I've read is that migraine had a slight increase in the number of lesions but that there was no evidence of neurological impairment related to these changes.
-
New Forum Software Installed (Still a few issues but reopening the forum) More details.
The symptom signaling theory of ME/CFS involving neurons and their synapses
- Thread starter ME/CFS Science Blog
- Start date
Are you referring to migraine?
From what I've read is that migraine had a slight increase in the number of lesions but that there was no evidence of neurological impairment related to these changes.
Hoopoe
Senior Member (Voting Rights)
@ME/CFS Science Blog I want to make sure that I understand what is being proposed. Is the model one where
That sounds similar to a biological version of the psychological model that has been applied to ME/CFS.
I don't have objections. I suspect there are variations of this idea that also make sense. We need evidence. We should avoid repeating the error of making a conclusion that it must be a faulty perception because we cannot identify the thing that the body is responding to.
I've often thought that PEM is a bit like an emergency brake used by a body in response to some problem that it is perceiving and that we cannot yet identify.
But why is PEM often delayed?
I'm wondering if the delay exists because could be a fault in the repair mechanisms involved in fixing the wear and tear of the exertion, so that exertion becomes something that causes alarms to go off hours or a day later as the brain realizes something is wrong and the body is not ready for more exertion, and the purpose of the symptoms is to force us to do only the minimum. The recovery time would also be prolonged because of the faulty repair mechanisms.
PEM is telling us that the issue is not during exertion but later. Yet most studies focus on other points in time, without controlling for exertion, because that's how things are usually done. A lot of ME/CFS research is like the person at night searching for his keys under the lamp post and not where he lost them.
Why is exertion in particular perceived as problematic, and not for example, an ordinary flu? If the signal triggered by the flu received by the brain was as amplified in a similar way as the effect of exertion, even ordinary infections would be horrible experiences. If the problem is a distorted signal then it must be a signal that has a specific meaning and isn't involved in say, infections. It would be good to know how much various things contribute to PEM because it would help understand what kind of signal is involved. I sudpect it's metabolic because that seems to fit based on my superficial amateur knowledge.
- a part of the brain that integrates information on the body's health to understand the overall level of sickness/injury/functional capacity/energy reserves/etc. is receiving distorted signals
- this part of the brain is also involved in creating various awful and unpleasant feelings, in response to sickness/etc. that also alter the behaviour of the person.
That sounds similar to a biological version of the psychological model that has been applied to ME/CFS.
I don't have objections. I suspect there are variations of this idea that also make sense. We need evidence. We should avoid repeating the error of making a conclusion that it must be a faulty perception because we cannot identify the thing that the body is responding to.
I've often thought that PEM is a bit like an emergency brake used by a body in response to some problem that it is perceiving and that we cannot yet identify.
But why is PEM often delayed?
I'm wondering if the delay exists because could be a fault in the repair mechanisms involved in fixing the wear and tear of the exertion, so that exertion becomes something that causes alarms to go off hours or a day later as the brain realizes something is wrong and the body is not ready for more exertion, and the purpose of the symptoms is to force us to do only the minimum. The recovery time would also be prolonged because of the faulty repair mechanisms.
PEM is telling us that the issue is not during exertion but later. Yet most studies focus on other points in time, without controlling for exertion, because that's how things are usually done. A lot of ME/CFS research is like the person at night searching for his keys under the lamp post and not where he lost them.
Why is exertion in particular perceived as problematic, and not for example, an ordinary flu? If the signal triggered by the flu received by the brain was as amplified in a similar way as the effect of exertion, even ordinary infections would be horrible experiences. If the problem is a distorted signal then it must be a signal that has a specific meaning and isn't involved in say, infections. It would be good to know how much various things contribute to PEM because it would help understand what kind of signal is involved. I sudpect it's metabolic because that seems to fit based on my superficial amateur knowledge.
Last edited:
Yann04
Senior Member (Voting Rights)
Agreed that the theory focuses on symptoms but needs to explain disability unrelated to symptoms as well. Ie. lowering PEM threshold.
Jonathan Edwards
Senior Member (Voting Rights)
Not really. A synapses is a junction between two cells at micron scale with a gap at 20-40 nanometre scale. Other cells can interfere with the sensitivity of a receiving cell through other means but probably not at an existing synapse.
Control of 'gain' at synaptic junctions is a hugely complex and poorly understood field. Perhaps more importantly, there are very few situations where we can correlated neural events like this directly to symptoms. We know that the brain collates data and makes inferences and builds perceptions out of this but how exactly this is achieved at the cell level is pretty much a closed book beyond some experiments done 50 years ago by Hubel and Wiesel on how cells detect moving lines.
I think that means that we are not going to be in a position to build theories that make precise predictions based on what we know of synaptic use. But that does not prevent us from making suggestions about blocking certain neurotransmitters or whatever at a high level of description.
To me, synaptic involvement simply provides a means by which the disease error can be 'remembered' or learnt' or 'acquired' within brain itself.
Nevertheless, I am interested in the phenomenon of unrefreshing sleep and have wondered if an ongoing problem with updating/deleting daily data (via synapses) may be part of the origin of symptoms in ME/CFS.
Jonathan Edwards
Senior Member (Voting Rights)
No, but we are not seeing any support for that from DecodeME much.
mariovitali
Senior Member (Voting Rights)
Would glutamate dysregulation and excitotoxicity fit here ?
Sasha
Senior Member (Voting Rights)
.
Would you like to expand on that? I noticed on another thread, you said:
And here are a few of your quotes from that thread:
Does this imply that tackling our sleep should be a priority? Does it suggest that some ways of tackling our sleep might be better than others (given that people here will be trying all sorts of stuff)?
leokitten
Senior Member (Voting Rights)
Can this theory also explain how so many of us have peripheral immune symptoms and comorbidites after getting ME? MCAS, worsening of preexisting autoimmune or autoinflammatory disorders, sudden new autoimmunity. Could central signaling issues directly trigger these?
Kitty
Senior Member (Voting Rights)
Yep. Part of what makes it interesting is that sleep seems poorly understood. If you wanted somewhere to hide a process or a cycle from view, it would be a good place.
My physically-induced PEM had a consistent 24 hr delay, and it seemed to be triggered by muscle damage rather than energy consumption. To me, the obvious conclusion is that the delay was due to immune system involvement, which is known to have a consistent delay mechanism. My ME started as a type IV food sensitivity, with a precise and consistent 48 hr (+/- a few minutes) delay, and gave the same pattern of symptoms that I later experienced from PEM.
Also, I couldn't tell the difference between physically-induced PEM and the increase in ME symptoms due to a viral infection, so my conclusion is that PEM is a response to an immune response. That response causes activation of glial cells, which results in ME symptoms. Cognitive exertion triggered my PEM in a much shorter and inconsistent delay, and I think depended on the type and magnitude of cognitive exertion. I see that as involving glial cells or neurons directly, bypassing the immune cell mechanisms.
Any theory about ME involving synapses also involves glial cells, since those are directly involved in synaptic function. Do the glial interactions with synapses change when the glia are activated by immune signals? My guess is that this is an area that hasn't been studied well enough.
For those who feel that glutamate in the brain is involved with ME, glial cells are critical for glutamate management. How is that affected by glial activation? Do even small increases in chemokines make a significant difference in glial interaction with neurons, and thus how we feel?
The interaction of glia and synapses (and neurons in general) varies with the type and location of neurons. I expect it also depends on brain development, so personal experiences (stress, developing a talent, etc) would affect responses in different brain areas differently. So, in one PWME, their PEM involves muscle weakness, while in another, hypersensitivity to noise, and in another, digestive system abnormalities.
So to me, PEM is a response to glial response to immune activation. However, some people report feeling better in response to viral infection, rather than guaranteeing PEM-like symptoms. So it's not as simple as PEM being a response in all PWME to IL-whichever. The immune system is complex, so maybe it's some subtle ratio of some molecules involved in the immune activation or deactivation mechanism that is critical.
Jonathan Edwards
Senior Member (Voting Rights)
The only immune symptoms that seem to have got into the clinical description of ME/CFS are tender lymph nodes and sore throat. Those are common enough anyway and have never been formally documented but it is quite plausible that they might appear as a result of CNS events, either lowered sensory thresholds or through autonomic signals to lymphoid tissue. The latter is not well documented and it would be nice have better information on whether or not it really occurs.
The 'comorbidities' are not reliably documented and I am doubtful that we have good evidence of any association. When people have looked for autoimmunity they not found much.
My first impression is that I think it may be quite hard to construct a testable theory from this, given the vast complexity of the brain and that "something faulty in neurological signaling related to synapses" still seems quite vague for the beginning. Suppose one had all the hypothetical and unethical possibilities available to test this theory, including things such as cutting open the brains of live humans, how would one go about testing this theory?
My layman understanding is that a single synapse is usually categorised as excitatory or inhibitory, but my layman understanding is that these separations are quite contextual (they can switch or be both depending on the context and in particular some synapses can have an altered role in pathological states). Do we expect the problem to be more likely in one department than the other or do we expect it to be a mix of both?
Would we expect to see effects from something like TMS?
Neuroreceptor drugs have not shown to be an instant solution to ME/CFS, what can this tell us? Suppose ME/CFS is similar to a ongoing sickness response in acute infection, does one then see if one can characterise a sickness response in mice and see which drugs can elevate this response?
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.
My layman understanding is that a single synapse is usually categorised as excitatory or inhibitory, but my layman understanding is that these separations are quite contextual (they can switch or be both depending on the context and in particular some synapses can have an altered role in pathological states). Do we expect the problem to be more likely in one department than the other or do we expect it to be a mix of both?
Would we expect to see effects from something like TMS?
Neuroreceptor drugs have not shown to be an instant solution to ME/CFS, what can this tell us? Suppose ME/CFS is similar to a ongoing sickness response in acute infection, does one then see if one can characterise a sickness response in mice and see which drugs can elevate this response?
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.
At least for the symptom cluster I am a part of - heavy neurological symptoms and most notably getting a sore throat immediately after mental exertion - I definitely think that neuronal signalling plays a significant role, although I doubt it is everything that's going on. But for at least this symptom HAS to be a signalling issue in the brain. And if the sore throat from mental exertion is brain mediated, why shouldn't the sore throat from physical exertion be too?
Regarding the no evidence for mitochondrial dysfunction, no autoantibodies etc.: I believe the underlying assumption is that ME/CFS is homogenous and has a single cause for all patients. I doubt this is the case, or if it is we would still see vastly different treatment responses anyways. It is likely that many research results got diluted due to throwing all patients into one pot. I have almost nothing in common with the immune suppressed, fatigue-heavy phenotype except for PEM. I doubt that in the end there will be a treatment to which every patient will respond.
How would you explain the 'something in the blood findings' though?
How would you explain for example the recent finding of significantly lower lumen radius and higher ECM collagen deposition?
Lastly, I want to share this paper that Herbert Renz-Polster mentioned, describing a sort of immunological switch in the brainstem, with pro- and antinflammatory cytokines changing very significantly when these circuits are modulated.
Summary:
Involved circuits (activated by immune cells, eg when stimulated with LPS):
@ME/CFS Science Blog you put into words what I was thinking of but couldn't articulate, thank you!
Regarding the no evidence for mitochondrial dysfunction, no autoantibodies etc.: I believe the underlying assumption is that ME/CFS is homogenous and has a single cause for all patients. I doubt this is the case, or if it is we would still see vastly different treatment responses anyways. It is likely that many research results got diluted due to throwing all patients into one pot. I have almost nothing in common with the immune suppressed, fatigue-heavy phenotype except for PEM. I doubt that in the end there will be a treatment to which every patient will respond.
How would you explain the 'something in the blood findings' though?
How would you explain for example the recent finding of significantly lower lumen radius and higher ECM collagen deposition?
Lastly, I want to share this paper that Herbert Renz-Polster mentioned, describing a sort of immunological switch in the brainstem, with pro- and antinflammatory cytokines changing very significantly when these circuits are modulated.
A body–brain circuit that regulates body inflammatory responses
https://www.nature.com/articles/s41586-024-07469-ySummary:
Involved circuits (activated by immune cells, eg when stimulated with LPS):
- Caudal nucleus of the solitary tract (cNST), containing dopamine beta hydroxylase (its activation is highly anti-inflammatory)
- Which receives anti-inflammatory signals from TRPA1-expressing vagal neurons and pro-inflammatory signals from CALCA expressing neurons in the vagal ganglia
@ME/CFS Science Blog you put into words what I was thinking of but couldn't articulate, thank you!
That would tell us that ME's mechanism most likely doesn't depend on the molecular interaction affected by those drugs. The list of other possibilities seems vast. Maybe the difference between feeling clear-headed rather than brainfogged is how many times an astrocyte sticks a process into the synaptic gap per second, or how long or thin that process is, or whether the process membrane has a 17/3 ratio of palmitic acid vs butyric acid rather than 19/3. All sorts of possibilities that won't be obvious from taking a blood sample or even a CSF sample or a general MRI scan. Some possible factors are highly localized or very short-lived.
"This mouse is grooming only 12 times per hour rather than the usual 15 times. This mouse has ME! Let's write some research papers based on this proven model of ME."
ChronicallyOverIt
Established Member (Voting Rights)
I don’t know for you but unrefreshing sleep was the first thing I noticed. Absolute 180 even when I was very mild in the beginning, I wonder if the build up over time of poor sleep makes everything worse. Slowly as we aren’t able to reset the other symptoms appear due to a “clog” from our sleep….
I remember my first few weeks of CFS feeling weird and noting “wow I haven’t gotten real sleep in ages this is hell”. I was still sleeping 8-10hrs, but it just wasn’t the same. I quickly forgot the feeling of waking up satiated from sleep.
I'm unconvinced that there's a problem with our sleep not being refreshing. I think we have a symptom that feels like we didn't get enough sleep, but it has nothing to do with sleep. It's just a symptom that's there all the time, unaffected by sleep.
So if I'm understanding things correctly DecodeME hints clearly at the brain and likely at neurons, and possibly at synapses but we're not quite sure yet (that is largely coming from the Zhang et al study and some analysis done by @forestglip , but perhaps some caution is warranted). So perhaps based on DecodeME postulating a problem related to ion channels creating too much ion channel noise leading to faulty signalling or something leading to a destruction of refractory periods and faulty signalling or any other scenario would be quite plausible as well?
While the synapse-related gene sets weren't bonferroni-corrected significant in the DecodeME MAGMA test I did (which I hope to redo with the standalone MAGMA instead of FUMA so that no conversion/data loss is needed), it's striking that it's one of the top gene sets and matches Zhang's finding.
Technically neurons weren't significant either after Bonferroni correction of the five cell-type datasets I tested.
Brain is the only really clear tissue finding from the paper.