Hypothalamus Link between Stress, Insomnia and Immune Activation

[Wishful]

https://newatlas.com/science/brain-circuit-stress-insomnia-immune-system/

I thought this might be a factor for some ME symptoms. It seems that a small clump of cells (possibly altered in function by ME?) can switch us into insomnia and mess up our immune system. Maybe ME researchers can monitor the state of those cells during different severities of ME symptoms, or use of of those tools for manipulating brain cells (focused ultrasound, light, whatever) to see if that affects ME symptom severity.

This certainly fits my belief that ME involves an alteration of just a small portion of the brain.

 

[HABS93]

"I'm really interested in how we can manipulate distinct circuits in the brain to control not just the immune system at baseline, but in disease states like inflammatory bowel disease or in cancer or in psoriasis—things that are associated with systemic inflammation,”
I'm interested as well lol.

 

[Wishful]

I still think that glial cells are a major part of ME. This from https://www.frontiersin.org/articles/10.3389/fnmol.2019.00258/full (for Huntington's disease, which has similarities):

"Microglia and astrocytes are critical in regulating neuronal activity and maintaining an optimal milieu for neuronal function. Previous studies provide evidence that activated microglia and reactive astrocytes contribute to HD pathology through transcriptional activation of pro-inflammatory genes to perpetuate a chronic inflammatory state. Reactive astrocytes also display functional changes in glutamate and ion homeostasis and energy metabolism. Astrocytic and microglial changes may further contribute to the neuronal death observed with the progression of HD. Importantly, the degree to which these neuroinflammatory changes are detrimental to neurons and contribute to the progression of HD pathology is not well understood. Furthermore, recent observations provide compelling evidence that activated microglia and astrocytes exert a variety of beneficial functions that are essential for limiting tissue damage and preserving neuronal function in the HD brain."

I see it as something activating the body's immune system, which releases cytokines which in turn activates glial cells. This alters the functioning of some critical neurons, which then perpetuate the immune activation state. Thus, after the trigger, we get stuck in this chronic neuroinflammatory state. Which sets of neurons are affected to which degree determines what symptoms we experience. I think the hypothalamus and insula could account for most of our symptoms directly, and most of the rest indirectly.

This theory fits my experiences with temporary remission. In at least the early stages, we might manage to trigger a temporary switch back to the normal state, but some parts of this feedback loop are more persistent, so we switch back into the ME state. Glial cells react quickly, so they could probably switch state in minutes, allowing neurons to resume normal function...and switch back to inflamed/malfunctioning in minutes.

I expect it would fit with gut issues too, since gut permeability and other factors are controlled by neural function. Spinal problems (CCI, or the sacrial dimple mentioned recently) might cause damage to neurons that is exacerbated by glial malfunction. Infections, viral or other, might add to the neuroinflammatory burden, and removing that infection might allow improvement. (Side question: do patients who recovered after antiviral treatments temporarily get ME symptoms again when they get a cold or flu virus?)

Can anyone offer a good reason for why a feedback loop involving glial cells doesn't fit ME?

 

[ljimbo423]

Can anyone offer a good reason for why a feedback loop involving glial cells doesn't fit ME?

I can't.

It's possible. I just don't understand how the glia cells could get stuck in an inflammatory feedback cycle without some kind of autoimmune activation or some other kind of chronic stimulation.

 

[lenora]

HI....Well, I need some help, and perhaps you folks can take your minds off glial cells long enough to lend me your thoughts.

I haven't slept properly (apart from 2 hrs. each max. /24 hr. days), and last night's sleep, my 6th wk. of this, this trial, was only 1 hr., if that. I'm truly a zombie today and, not only that, but all my old symptoms of swollen glands and sore throat are returning. (And I'm sure that's just the beginning.) I'm beyond exhausted and don't know what to do, what to try as I've been battling this additional illness for 34 yrs. (more or less, I forget) now, and sleep has always been a problem for me. (I'm now well over 73 yrs. old)

In the beginning it was that funky sleep of most people with FM. You know, you're asleep but you recall every rustle and sound of people talking, even if it's in the hallway outside the bedroom. You're asleep; but not really.

Fast forward a no. of years, and things changed again to approx. 4 hrs. of decent sleep, no sleeping pills as I find they only work for one or two nights max., so what's the point? I'd rather stay off as many meds as possible. Things like melatonin, valerian (worst of all), and other natural sleep aids don't help either. This I learned to accept and deal with 4 hrs. of sleep per night. Then there would be at least 3 with no sleep, and then the pattern repeats itself. I learned to live a satisfying life with it...and just decided I didn't need much sleep.

OK, after 8 hospitalizations for 8 separate and serious matters in one year, I'm finally home and doing OK, except for the sleep. I'll probably have to go in for 1-2 more surgeries before the year ends. That means anesthetics, which my body doesn't tolerate (they put me to sleep and then I'm up for days), but at least I shouldn't need the ever-joyful steroids, and their horrid side-effects, including hallucinations. Unless my encephalitis starts up again, that is.

Someone mentioned beef collagen....what do you know about that? If so, could consumme be used or even beef broth until some bones can be purchased? I'm planning to take at least one sleeping pill as I go down tonight & if I awaken for my nocturnal trip to the bathroom, I may just take another one. This has to be broken....somehow. I'm just afraid that some everlasting damage may have been done. Really, it's true....I'm well into my 6th wk. with no decent sleep. SOS to all of you, please!! Thanks, Lenora.

 

[andyguitar]

This might be of interest. There is a lot there but the first couple of paragraphs give a good overview of what NG2 glia cells do.

 

[Mary]

@lenora - have you ever tried Unisom, or its generic equivalent? It's an old anti-histamine, but nothing like benadryl. Benadryl does next to nothing for me and just leaves me feeling yucky.

I've found Unisom however to be very powerful. Actually 1/4 tab in the middle of the night will put me back to sleep for the rest of the night. You may need more than me, but I wouldn't start with more than 1/2 a tab. It's surprisingly effective! Unfortunately, for me at least, if I take it daily it only works for a few weeks and then my body adjusts. But it might give you a few weeks of decent sleep.

One other thing that helps me is grounding - basically sitting outside with my feet on the ground or grass or dirt or cement. I know you sit outside a lot on your porch - would it be possible to move from your porch to the ground, with your feet on the ground? I discovered this a year ago. It really does help. 30 minutes will help a little, an hour is even better. And you could break it up into 2 phases. I've found that the longer I can do it, the better - hope this helps!

Beef collagen or broth wouldn't work for me because of its glutamate content, which caused insomnia for me.

Glycine, however, does help me with sleep. So does inositol, taurine, niacin (the kind that makes you flush) and vitamin C. Taurine and vitamin C both help with excitotoxicity caused by glutamate, which is in almost all processed foods.

 

[andyguitar]

What i've been thinking about recently is that we might be looking at things the wrong way round. So rather than "What causes neuroinflammation?" the question should be "What stops natural processes in the brain from causing neuroinflammation" So more of a failure of control than anything else.

 

[Pyrrhus]

I just don't understand how the glia cells could get stuck in an inflammatory feedback cycle without some kind of autoimmune activation or some other kind of chronic stimulation.

A very good point. The only situation that I can think of relates to traumatic brain injury. In the case of traumatic brain injury, the tissue-resident macrophages (microglia) activate to repair the tissue damage. But, repairing tissue damage in the brain requires a lot of specialized nutrients. If the diet doesn't include sufficient nutrients or the nutrients can't cross the blood-brain barrier, the tissue-resident macrophages might end up in an activated state, constantly trying to repair the damage.

Ian Lipkin was involved in a classic experiment where pregnant mice were subjected to an immune insult at a specific stage of pregnancy, designed to injure the fetus's brain, to see if the fetus's brain would recover before birth. The baby mouse was born with what appeared to be lasting neuroinflammation. (Although I don't know how long it lasted.)

 

[Wishful]

perhaps you folks can take your minds off glial cells long enough to lend me your thoughts.

The point was that malfunctioning neural cells in the hypothalamus can cause insomnia, and that glial cells might affect the hypothalamus. Unfortunately, this theory doesn't come with a simple way to fix it.

It's certainly possible that your insomnia is at least partly due to the stress of surgery and the immune system activation as your body cleans up the damaged cells. IIRC, the researchers in the link were able to switch off the insomnia causes by stress, but that was in rat brains, using techniques not considered acceptable for human patients. When I try to remember if I've read about any sleep induction techniques, all that comes to mind are science fiction stories. I want a sleep induction helmet too.

 

[Wishful]

I just don't understand how the glia cells could get stuck in an inflammatory feedback cycle without some kind of autoimmune activation or some other kind of chronic stimulation.

I skimmed (it's long and complex) the link andyguitar posted, and that does show a possible explanation. I hadn't read about NG2 glia before and it seems like they (normally) maintain the other glial cells in quiescent mode, and if the NG2 cells malfunction, the brain becomes chronically neuroinflamed. That's certainly something I'd like to see research into for ME.

 

[lenora]

I skimmed (it's long and complex) the link andyguitar posted, and that does show a possible explanation. I hadn't read about NG2 glia before and it seems like they (normally) maintain the other glial cells in quiescent mode, and if the NG2 cells malfunction, the brain becomes chronically neuroinflamed. That's certainly something I'd like to see research into for ME.

Hmm.....that's rather reminscent of my problems. First off, I have chronic inflammation in the spinal cord itself (lined with glial cells), the brain that caused the encephalitis, so it's possible that it's all ongoing inflammation affecting the sleeping center of the brain. I don't know what could be done about it....if there is an answer. Somehow I've always managed to be just ahead of finding out a solution to a particular problem. This has been going on for years and years. Anyway, tonight I'm going ahead and trying some Dalmane....we'll see how many hrs. that gets me. Thanks, Wishful, and all you other helpful folks. Yours, Lenora.

 

[andyguitar]

I skimmed (it's long and complex) the link andyguitar posted, and that does show a possible explanation

From what i know about this very complex subject (not much) it looks like a possibility. But so do lots of other things!

 

[lenora]

Again, I do have chronic neuroinflammation....the Autoimmune Encephalitis (discovered in January of this year), about the same time the severe sleep problems started, but I either felt there wasn't too much of a deviation, or had enough on my plate at that time. I was one sick person. Of course that was then followed up by another hospitalization in April when I suddenly couldn't breathe....didn't think too much of the earliest signs because I have pretty severe allergies anyway and just figured it was something there. That then led me to more heart surgery, so while I felt I was handling everything's just fine, perhaps it wasn't, and it will take a long time to get my spurs back. And then to think that I'll have more surgery coming up is well, ...... just a bit much! Thanks for digging around...@.Wishful,@ ljimbo423,@ Pyrrhus,@ andyguitar@Mary and any other person who may come along with any ideas.

@Mary....I find that a 1/3rd of Benadryl works OK to send me off to sleep and then still acts as an antihistamine in the a.m. for my allergies. We now have ragweed blowing in from across the plains. I've had an entire 2 wks. off this entire year....they've already started again big time. Again, immune deficiency. I also take another l/3rd if I awaken during the night. Anything I use seems to quit working after 2 nights max., but I'll have Rod pick some Unisom up on his next shopping foray out. Thanks for the tip. I think I just have a lot of things working against me at the moment and you kind folks have more or less confirmed it. Wolfcub, I'm glad to see that you're feeling well enough to be Moderator again. I'm heading off....to a book, at least. Thanks!! Yours, Lenora.

 

[Wishful]

so it's possible that it's all ongoing inflammation affecting the sleeping center of the brain.

Did you notice any change in sleep quality or length during any period when you were on immunosuppressants or immunomodulators? That is, ones that cross the BBB, since I know that cyclosporin doesn't. Has anything that affects your immune system worsened your insomnia?

 

[lenora]

Hello @ Wishful.....I'm trying to think about this, and I have to say that being unconscious for two days lets them use many IV drugs that I still don't have records of. I hate to be so non-helpful, but that's the best answer I can give you.

I took 2 Dalmane and did manage to get some sleep last night. I'm still exhausted and I know this will take a long time to recover from. Still, I have to do my part....and I'm trying very hard to do just that.

Wishful, I thank you for the effort you're putting into this. If I could give you the answers I need, I most certainly would. Yours, Lenora.

 

[Wishful]

I just don't understand how the glia cells could get stuck in an inflammatory feedback cycle without some kind of autoimmune activation or some other kind of chronic stimulation.

As I understand it (it seems quite complex) autoimmune activation involved the trigger mechanism of immune cells: antibodies mistake native molecules for invaders. However, that's just the trigger mechanism; the rest of the immune system is also very complex, so I can easily imagine problems past the trigger getting stuck. Firearms can develop problems where it keeps firing even after the trigger is released, and that's a far simpler system.

Also, I'm not sure of how complete the autoantibody detection system is. If you send a blood sample to a lab, will they detect all autoimmune disorders, or just the common ones? If you had an autoantibody to a molecule only produced in the hypothalamus, would the lab find that? I'm just not sure that an autoimmune disorder can be 100% ruled out for ME at this point.

 

[andyguitar]

If you had an autoantibody to a molecule only produced in the hypothalamus, would the lab find that?

I dont think there are any molecules exclusive to the hypothalumus.

I'm just not sure that an autoimmune disorder can be 100% ruled out for ME at this point.

Indeed not, but it does'nt mean the disorder has it's origin in the brain.

 

[Wishful]

I dont think there are any molecules exclusive to the hypothalumus.

It was just an example, but I'm not sure that there aren't any molecules specific to small portions of the brain. Something differentiates them from other cells, so maybe they express a gene that isn't expressed anywhere else. There's still so much we don't know about the body, especially the brain.

Indeed not, but it does'nt mean the disorder has it's origin in the brain.

No, but from what I've read so far about ME and biology, I'd rate the probability of ME being a neurological disorder much higher than for a muscle-mitochondria disorder or a gut microbiome disorder. I don't rule out a hidden abnormal viral infection in the brain (or nerves), but I'm fairly convinced that it's not a body infection.

Sadly, no one has offered to let me determine where ME funding goes. Darnit!