Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (M... (Baraniuk, 2022)

Consul

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Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS and Gulf War Illness (GWI) share features of post-exertional malaise (PEM), exertional exhaustion, or postexertional symptom exacerbation. In a two-day model of PEM, submaximal exercise induced significant changes in activation of the dorsal midbrain during a high cognitive load working memory task (Washington 2020) (Baraniuk this issue). Controls had no net change. However, ME/CFS had increased activity after exercise, while GWI had significantly reduced activity indicating differential responses to exercise and pathological mechanisms. These data plus findings of the midbrain and brainstem atrophy in GWI inspired a review of the anatomy and physiology of the dorsal midbrain and isthmus nuclei in order to infer dysfunctional mechanisms that may contribute to disease pathogenesis and postexertional malaise. The nuclei of the ascending arousal network were addressed. Midbrain and isthmus nuclei participate in threat assessment, awareness, attention, mood, cognition, pain, tenderness, sleep, thermoregulation, light and sound sensitivity, orthostatic symptoms, and autonomic dysfunction and are likely to contribute to the symptoms of postexertional malaise in ME/CFS and GWI.

The study: https://www.mdpi.com/2076-3425/12/2/132/htm
 

Pyrrhus

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Thanks for posting @Consul !

For those trying to understand the abstract:

1) The midbrain is a part of the brainstem:
1642622747396.png



2) The "ascending arousal network" is a part of the "Reticular Activating System (RAS)", which plays a crucial role in maintaining arousal and consciousness. The network is represented by the red arrows below:
1642623082074.png
 

HTester

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Those of you with long memories will remember that Pyrrhus' second diagram of "the ascending arousal network" is the same network that led to some of the hypothesized consequences of the IDO1 metabolic trap in the Raphe nucleus. But that's not why I'm writing this post. The combination of recent successes 1) from surgical correction of CCI and, 2) from stellate ganglion block, have drawn me back to the midbrain. I'm still working on the itaconate metabolic trap as my day job, but there's a useful concept called night-science when you are free to work on something new that feels important - and right now, my night-science is focused on the possibility of bistabilities in brainstem neural circuits. I could use some help. What I want to find is the best, most detailed diagram of the brainstem connectome that's available. I've been to the Allen Brain Institute site and got lost somewhere around the hypothalamus. Modern neuroscience appears fixated on the cerebral cortex, but there is a lot that we (or at least I) do not understand about the organization of the brainstem, what neurons project where, and what neurotransmitters are crossing those synapses. If all the smart people on PR would send me the one or two best diagrams they can find in an hour of searching, I'd really appreciate your help. Thanks.
 

Hutan

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The combination of recent successes 1) from surgical correction of CCI and, 2) from stellate ganglion block have drawn me back to the midbrain
Hi @HTester, I'm wondering what you are basing that statement on.

As far as I can see the story of CCI in ME/CFS is anecdotal, and very muddy anecdote at that. And the evidence for the utility of the stellate ganglion block in ME/CFS/Long covid that I have found seems to consist of a paper written by the owner of a company in Alaska that sells the SGB treatment, and is just case study reports for two women.

I'm guessing that you have more evidence around those treatments on which to start building an hypothesis on?
 
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bread.

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Hi @HTester, I'm wondering what you are basing that statement on.

As far as I can see the story of CCI in ME/CFS is anecdotal, and very muddy anecdote at that. And the evidence for the utility of the stellate ganglion block in ME/CFS/Long covid that I have found seems to consist of a paper written by the owner of a company in Alaska that sells the SGB treatment, and is just case study reports for two women.

I'm guessing that you have more evidence around those treatments on which to start building an hypothesis on?
I would like to second that.

I would hope that inquiry that stands on such "weak evidence" is not funded by the OMF. Still a fan of @HTester and grateful for his help and effort for finding answers obviously.

Does this "shift" also indicate that IDO metabolic trap is not being worked at anymore?
 
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HTester

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As far as I can see the story of CCI in ME/CFS is anecdotal, and very muddy anecdote at that. And the evidence for the utility of the stellate ganglion block in ME/CFS/Long covid that I have found seems to consist of a paper written by the owner of a company in Alaska that sells the SGB treatment, and is just case study reports for two women.
Definitely anecdotal. To me, an anecdote is a clue. Some clues strike a chord for me, and I follow them. Just for clarification, that small company in Alaska is a medical practice specializing in pain medicine and run by a patient-centered physician with whom I have spoken directly. Obviously, this is very early days, but if we ignored clues like this, we would not be doing our best for PWME. In the detailed patient stories, there is a strong hint of recovery from bistability. Naturally, a guy who thinks ME/CFS might be a bistability disease is interested. There is a lot going on in and around the stellate ganglion and lidocaine turns off everything neural so it's terribly non-specific. The stellate is known as a sympathetic ganglion, but there are decades of arguments about whether it projects to the brain or if there are other afferent neurons passing through on their way to the brain. I thought it might be a good idea to crowd-source scientific diagrams of stellate neuroanatomy in case something I didn't know has been added since I studied it in grad school, a very long time ago. I have seen the circular fan-shaped connectome diagrams like the ones posted by @SNT Gatchaman , but at least for a non-neuroscientist like me, it's difficult to extract a mechanistic view from them. Long before there is a randomized double-blind clinical trial, there is a clue. I listen to and read ME patient stories all the time. There are clues in those stories.
 

HTester

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Does this "shift" also indicate that IDO metabolic trap is not being worked at anymore?
The theory side of the IDO1 metabolic trap is published, so my modeling work has shifted to a new idea I call the itaconate metabolic trap. I do not have a lab, so the IDO1 trap experimental work is done at Stanford, where it is very much still being worked on.
 

HTester

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Hello @HTester

Would it be possible for you to provide an update on the itaconate metabolic trap


Much appreciated.
Jaybee - I'd love to do this. Probably too speculative for PR at this point. :) It's based on my collaboration with Chris Armstrong in Melbourne. It's a trap in mitochondrial central carbon metabolism that purports to account for the "hypometabolic" phenotype of ME. Also seems, so far, to be consistent with Chris's longstanding ME hypothesis centered on amino acid catabolism.
 

bread.

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Jaybee - I'd love to do this. Probably too speculative for PR at this point. :) It's based on my collaboration with Chris Armstrong in Melbourne. It's a trap in mitochondrial central carbon metabolism that purports to account for the "hypometabolic" phenotype of ME. Also seems, so far, to be consistent with Chris's longstanding ME hypothesis centered on amino acid catabolism.
That is definitely far less speculative than CCI, why do I say that?

Because I know that my Urea cycle is overburdened, I know I have raised MSUD metabolites that should not be there, and I have too much of deamination going on. It can be seen in my blood, reliably tested over and over again.

Thank you for your work!