Glia: the fulcrum of brain diseases

[Wishful]

https://www.nature.com/articles/4402144

I came across this paper. Its slant seems to be brain injury, but what caught my eye was the discussion of how important the greater ratio of glia/neurons and complexity of their processes are in the difference between the human brain and those of less intelligent species. There seems to be a lot of room for subtleties of brain function due to glial function, and thus lots of room for subtle changes in glial function to have large effects on brain function. With that vast network of "helper" cells, how much of a change in glial function would it take to cause brainfog, malaise, hypersensitivity, etc? As the paper shows, there's a lot still undiscovered about brain function at the cellular and molecular level, so it's reasonable to not find a clear biomarker when the difference between PWME and healthy controls is some factor that no one has looked at yet.

Since we don't have a test for ME, we don't know what the prevalence is in other animals or if it's human-only. If it isn't found in other species, maybe it's due to the difference in glial populations.

 

[Wishful]

There are various hypotheses about why some people have a predilection to develop--and sustain--ME: genetics, chronic infections, etc. The paper prompts me to propose another possibility: physical development differences. Whenever a cell divides or sends out projections, it's a random direction. We all have a bunch of neurons connecting the colon to other neurons in the brain, but I expect even identical twins will have different physical pathways for these neurons, and different glial cells connecting or influencing them. In one individual, a specific neural pathway will be next to the pathway for a kidney, and in another, it will be next to the pathway for the left big toe. If each astrocyte connects to ~2 million neurons--and some probably large number of other astrocytes, the individuals will respond differently to different factors. Add in the individual physical locations of the vascular and lymphatic and glymphatic networks. In PWME, maybe the physical placement and interconnection of these different pathways allows and sustains the ME state. In the old phone cable networks (hundreds of individual wires interwoven somewhat randomly), there could be interference between pairs of wires, due to specific physical placement of the wires.

In ME, perhaps some of the neurons and glial cells and blood/lymph plumbing carrying immune system signalling are placed in such a way that allows interference or feedback. At some point, after an immune activation event, the network achieves positive feedback, locking us into the ME state.

Someone with a good grasp of statistics and network theory might be able to figure out whether this hypothesis could explain the observed prevalence of ME, and the prevalence at different ages and for different genders. These various physical location factors change enough over time to explain why ME is more likely to strike at a certain age, but do later changes not explain why ME doesn't just go away on its own? It does pass my test of explaining temporary remissions (chemicals can affect the overall value of the feedback loop).

I don't feel strongly in support of this hypothesis, but I thought I'd put it out there as a thought experiment.

 

[Wishful]

I'd also like to point out that posting this paper isn't a challenge to other theories. The problem is that most of us have seen really simplified models of the brain and body, which directs us to expect simple theories to explain ME. This, and other papers I've posted links to expose just how complex the body really is, and the mechanism of ME might also be very complex, and possibly involve cellular or body functions that are still undiscovered or at least poorly understood, or worse: mistakenly understood.