Brain on Fire: Widespread Neuroinflammation Found in ME/CFS by Jarred Younger

[CFS_for_19_years]

I always feel feverish and my head is burning, so I usually wear a cold pack 24/7 except in the rare occasions I feel better.

How does one attach a cold pack to one's head?

 

[pamojja]

How does one attach a cold pack to one's head?

 

[alex3619]

Sounds like you cannot detoxify paracetamol properly.

Most people, including doctors, do not realise that this is a prodrug, not a drug. Its not active until the liver activates it. Then the liver has to detox it. If its not activated, or activated too slowly, it wont work. It requires glycine for activation if I recall correctly. It requires glutathione for detox.

 

[edawg81]

How does one attach a cold pack to one's head?

I have a mini fridge full of these things, they got velcro, they go on sale every few months:

https://www.thebodyshop.com/en-au/body-care/accessories/cooling-gel-eye-mask/p/p000375

 

[Murph]

Cort has published a follow-up post. It covers the entry of immune cells into the brain. There's a separate thread on it here:

https://forums.phoenixrising.me/ind...n-in-me-cfs-follow-up-to-brain-on-fire.61600/

 

[Mel9]

I vote for it being a brain problem. I don't have any non-neurological symptoms, and have a definite increase in symptom severity when tryptophan transport into the brain increases. To me that says that it's a brain problem, most likely involving microglia. The physical limitations experienced by most ME victims is more likely a secondary response to neurological changes.

I agree that I ‘feel’ it is a brain problem. But how does all this tie in with PEM? Why delayed? And how do the mitochondria tie in?

 

[FMMM1]

We do have to be careful in interpreting inflammation. We now have consistent results, in the same brain structures, in multiple studies, and more are on the way. However we still do not understand the processes driving all this. There are some hypotheses, but we need more research. These findings give me some hope that more breakthroughs will be made.

Now if it is inflammation then research into antiinflammatories that cross into the brain, as Cort comments on, is one way to go.

Regarding the process which is driving this. This study appears to support a switch in metabolism i.e. switch from using glucose, to amino acids, as energy source.
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

Ron Davis has been trying to identify the substances in blood plasma which are causing this metabolic switch i.e. upstream cause.

 

[Wishful]

I agree that I ‘feel’ it is a brain problem. But how does all this tie in with PEM? Why delayed? And how do the mitochondria tie in?

I can give one plausible hypothesis for delayed PEM: Physical exertion causes muscle damage, which triggers the immune cells (to clean up the damaged cells), which results in an increase in IFN-g 24 hrs later, which increases production of indole oxidase (IDO) in the microglia, which converts more tryptophan into kynurenines, some of which are neurotoxic and produce the symptoms you feel. The mitochondria are involved because they produce the superoxide required for TRP catalysis, and for the deactivation of IDO (through peroxynitrite). Changing the levels and ratios of superoxide and peroxynitrite logically should affect KYN levels.

I'm not sure why cerebral activities can trigger my PEM within a few hours, but it seems plausible that cerebral activity can affect microglia too, resulting in improper levels of kynurenines. Why does cuminaldehyde block my physically-induced PEM (but not the cerebrally-induced PEM)? I have no idea; too many possible chemical reactions.

For @ljimbo423 , BCAAs use the same molecular system that carries tryptophan into the brain, and have much greater priority than TRP, so taking BCAAs blocks TRP transport into the brain, reducing KYN production. See if that fits your theories.

 

[ljimbo423]

For @ljimbo423 , BCAAs use the same molecular system that carries tryptophan into the brain, and have much greater priority than TRP, so taking BCAAs blocks TRP transport into the brain, reducing KYN production. See if that fits your theories.

I have read that BCAA's blocks or competes with tryptophan for entry into the brain. I don't really know how it fits into my theory, if at all.

I haven't really looked too much into neurotransmitters. Although I have noticed that I need much less 5htp now to give me the same relief in anxiety, about 1/2 of what I needed before I started taking the BCAA's.

Which don't make a lot of sense from a neurotransmitter perspective I don't think. What's your take on why I would need less 5htp, when BCAA's actually lower tryptophan in the brain?

I think you have done much more research in this area than I have. One reason BCAA's could give people more energy is because is does reduce tryptophan in the brain and tryptophan can cause fatigue, which you probably already know.

 

[Wishful]

There's a danger in looking for overly simple theories, such as 'TRP gets converted to 5-HTP and beneficial neurochemicals, so less TRP should mean more anxiety'. Maybe the TRP level isn't involved (since only 5% or so of TRP goes down the 5-HTP pathway). Maybe the BCAAs are enhancing some cell function or protein synthesis which multiple steps later results in lowered anxiety. The body is way too complex to rely on simplistic theories. You need more information (experimental results) to be able to figure out why BCAAs are having an effect.

 

[ljimbo423]

There's a danger in looking for overly simple theories, such as 'TRP gets converted to 5-HTP and beneficial neurochemicals, so less TRP should mean more anxiety'. Maybe the TRP level isn't involved (since only 5% or so of TRP goes down the 5-HTP pathway). Maybe the BCAAs are enhancing some cell function or protein synthesis which multiple steps later results in lowered anxiety. The body is way too complex to rely on simplistic theories. You need more information (experimental results) to be able to figure out why BCAAs are having an effect.

Good points. I agree that the body is profoundly complex. Often the best I can do is try simplify a very profound, complex theory or idea into something that might make sense.

 

[heapsreal]

I agree that I ‘feel’ it is a brain problem. But how does all this tie in with PEM? Why delayed? And how do the mitochondria tie in?

If you look into the hypothalamus and pituitary gland in the brain, look at all the functions they have and things that can occur down stream from that. Hypothalamus issue could cause a hormone to be less than optimal and this could lead to increased inflammation. Theres just a snowball effect of many things thats possible.

 

[FMMM1]

If you look into the hypothalamus and pituitary gland in the brain, look at all the functions they have and things that can occur down stream from that. Hypothalamus issue could cause a hormone to be less than optimal and this could lead to increased inflammation. Theres just a snowball effect of many things thats possible.

Jonas Bergquist has been funded to do a hormone study in ME/CFS. Can't remember which hormones. He's giving a presentation at the OMF symposium tomorrow.

 

[Emily Taylor]

Jonas Bergquist has been funded to do a hormone study in ME/CFS. Can't remember which hormones. He's giving a presentation at the OMF symposium tomorrow.

Thanks for sharing that, FMMM1. The Solve ME/CFS Initiative funded Dr. Jonas Bergquist in the Ramsay Award Class of 2017. You can read more about his team's work here:

https://solvecfs.org/ramsay-2017-meet-research-team-1/

Interim updates from the Class of 2017 will be shared in Research 1st. Dr. Eran Segal just shared his team's first update in yesterday's issue of Research 1st.

http://go.solvecfs.org/webmail/1926...ffe4d9de93da8e3f71c0e077a67417eba10cbd269ccb1

Dr. Younger's work on brain imaging and inflammation was also funded by a 2016 Ramsay Award grant.

 

[FMMM1]

Thanks for sharing that, FMMM1. The Solve ME/CFS Initiative funded Dr. Jonas Bergquist in the Ramsay Award Class of 2017. You can read more about his team's work here:

https://solvecfs.org/ramsay-2017-meet-research-team-1/

Interim updates from the Class of 2017 will be shared in Research 1st. Dr. Eran Segal just shared his team's first update in yesterday's issue of Research 1st.

http://go.solvecfs.org/webmail/1926...ffe4d9de93da8e3f71c0e077a67417eba10cbd269ccb1

Dr. Younger's work on brain imaging and inflammation was also funded by a 2016 Ramsay Award grant.

Thank you for this.

Here's a potential blood based diagnostic test. It's based on the measurement of phenylalanine in blood cells. It appears to support Chris Armtrong's, and Fluge and Mella's, findings that there's a switch in cellular energy production i.e. from the (normal) use of glucose to amino acids [such as phenylalanine].
1) abstract: https://pubs.rsc.org/en/content/articlelanding/2018/an/c8an01437j/unauth#!divAbstract;
2) full paper: https://sci-hub.se/10.1039/C8AN01437J.

I've written to the European Union "Committee on the Environment, Public Health and Food Safety (ENVI)" to see if they would lobby for European Union funding to validate this.
https://forums.phoenixrising.me/ind...ch-theyre-working-for-you.61516/#post-1001161

Possibly this potential diagnostic test could be considered for a Ramsay Award grant.

 

[Deepwater]

Most people, including doctors, do not realise that this is a prodrug, not a drug. Its not active until the liver activates it. Then the liver has to detox it. If its not activated, or activated too slowly, it wont work. It requires glycine for activation if I recall correctly. It requires glutathione for detox.

Now I never knew that. Paracetamol has never worked on me. It didn’t work for my mother either. It didn’t work on my daughter when she was small, though she says it does now.

 

[Wishful]

People should try at least the three main pain relievers, since which one is most effective varies with the individual. Ibuprofen is supposed to work better for males than for females. Acetaminophen works best for me. I do hope that's not an actual measure of my masculinity...

 

[percyval577]

I agree that I ‘feel’ it is a brain problem. But how does all this tie in with PEM? Why delayed?

I think this is exactly the right question. And then the appearance of pem differs quite remarkebly in different persons, not only in time but also in the abilities/feelings that are affected.

I now think it like so: The brain needs to proceed/learn every time again, and all new experiences (walking through a wood, reading a newspaper) need to be compared to older experiences, and everything will get readjusted. And this might probably happen with a lot different timeframes, minutes, hours, days.

A commonly accetpted guess for the mechanism of learning is the "NO-system", and microglia (the immunesystem!) contribute to it. Here something could go wrong.

A long term influence on the microglial NO-productionj is manganese, high manganese will elevate the production, remarkebly under infectious circumstances. I am improving on the (very) long run, years, from a diet with reduced manganese.


A lot of questionmarks remain, but in normal life as well as in science this can not be avoided and needs to be dealed with. Why wouldn´t the huge amount of the immunesystem (microglia account for 10% of all brain cells, and then there are as well 20-40% astrocytes), influence all the lerning-processes in the same manner, in us? Somehow, because it is so complex.

 

[alex3619]

Sounds like you cannot detoxify paracetamol properly.

I would argue its likely the opposite. The liver cannot activate it properly, or there is far too much detox leading to high clearance rates. If there were a slow detox then it would rapidly lead to paracetamol overdose problems, and it should work as a pain reliever very well until the damage accumulated.

 

[bertiedog]

I would argue its likely the opposite. The liver cannot activate it properly, or there is far too much detox leading to high clearance rates. If there were a slow detox then it would rapidly lead to paracetamol overdose problems, and it should work as a pain reliever very well until the damage accumulated.

Yes that makes sense perhaps because of certain SNPs in CYP2E1?

Pam