Potential linking FM, mast cells, sleep deprivation, food intolerance, exercise intolerance and ME?

[dejurgen]

This idea is very new. But I may have stumbled upon something exciting enough to write it now rather then let it ripe for another year. So take it as an early first attempt to casting a wide net around the things mentioned in the title.

I'll start by referring to two recent blogs Cort made on FM (thanks Cort for making my "job" so much easier ):
LINKA: https://www.healthrising.org/blog/2...iber-neuropathy-fibromyalgia-chronic-fatigue/
"Is the Brain Causing the Small Fiber Neuropathy in Fibromyalgia (and ME/CFS?)"
LINKB: https://www.healthrising.org/blog/2...mall-nerve-fiber-fibromyalgia-increased-pain/
"More is Not Better: Increased Small Nerve Fiber Problems in Fibromyalgia Spell Trouble"

From LINKA:
"How could nerve damage in the body, after all, be explained by central sensitization in the brain?"
"Given the small nerve “burnout” found, the immune system was immediately fingered, but immune studies, including a recent study that looked for an autoimmune cause, have been unrewarding."
"The SFN in FM appears to result in smaller nerves as well as reduced nerve density – an unusual combination."
"Plus, the SFN symptoms in FM are a bit different. The traditional stocking presentation seen in diabetes, where the symptoms first start in the feet and moves upwards, often doesn’t occur in FM."
"Several studies have produced a proximate cause – increased levels of the excitatory neurotransmitter, glutamate, and reduced levels of an inhibitory neurotransmitter, GABA – in the insula. Studies indicate that when Lyrica works, it works by rebalancing those levels."
"They proposed that hyperactivity in the insula is producing such strong pain sensations that the body was effectively burning out the nerves in the periphery in an attempt to stop them."
"Increasing the glutamate levels in the insulas of rats resulted in increased sensitivity to heat and pressure and – a reduction in the nerve fiber density in the rodents’ hind paws."

Recently I learned plenty about the potential role of glutamate in ME and FM thanks to discussing it with expert on the topic Issie.

Hypothesis:

• An excess of glutamate versus a shortage in GABA excites the brain a lot. That is a poor combination to get a good night of sleep. Poor and unrefreshing sleep is common in both ME and FM. Being in pain makes it harder to get a good night of sleep too.
• Sleep deprivation can alter the immune system functioning. I did found some research on it but need to sort that out better. For now I will fall back on both mine, Issie's and Tracey Anne's clear observation that even a single night of good or bad sleep can make a large difference on mast cell degranulation related problems. See https://www.healthrising.org/blog/2019/09/16/alzheimers-chronic-fatigue-fibromyalgia/#comment-922184
• With mast cell related degranulation problems I do mean mast cell degranulation itself or near indistinguishable problems like basophil degranulation or similar problems due to degranulation of eosinophils or neutrophils. I'm still learning if I can distinguish them with myself.
• When eosinophils (another type of immune cells that can "pop" and dump their toxic load) degranulate https://en.wikipedia.org/wiki/Eosinophil then "Following activation by an immune stimulus, eosinophils degranulate to release an array of cytotoxic granule cationic proteins that are capable of inducing tissue damage and dysfunction.[23] These include: major basic protein (MBP)..."
• "Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues.[21] Eosinophil cationic protein and eosinophil-derived neurotoxin are ribonucleases with antiviral activity.[24] Major basic protein induces mast cell and basophil degranulation, and is implicated in peripheral nerve remodelling.[25][26]" => nerve remodeling? Like in gardening by trimming stuff here and planting and growing new stuff there? That sure could trim and change peripheral nerve structures.
• The above "remodels" nerves and causes a major amount of mast cell and basophil degranulation. With the three people mentioned above all having FM, sleep deprivation causes massive "mast cell degranulation like" effects.

=> It is easy to see how excessive neuro-excitating glutamate could hamper sleep a lot. Sleep deprivation has been reported to affect the immune system. The three of us have "strong anecdotal evidence that sleep deprivition causes very potent mast cell like degranulation effects in our bodies.

As our experiences are not pure science, I used a search machine. Few research is done on the subject, but the linked article is published in Nature, together with Science the absolute undisputed world wide top in research https://www.nature.com/articles/srep45528
"the results of the present study sustain the theory that sleep is a fundamental process that is capable of modulating the immune response of mucous membranes, particularly the one generated against the parasite Trichinella spiralis."
"Sleep deprivation... ...which, in turn, affect the intestinal barrier (IB)"

=> Sleep deprivation increases food sensitivities and reactions to food in all three of us badly. At worst sleep deprivation I would gag when drinking a mere glass of water. (Link with food intolerances)

"Particularry studies suggest that REM sleep deprivation involves changes in the modulation of the immune system and may increase the production of pro-inflammatory cytokines and cells15,16, which participate in the innate immune response."
"In addition, using confocal endomicroscopy and scanning electron microscopy, it has been recently reported that REM sleep deprivation induce changes in the gastric mucosa showing the initial phases of the acute inflammatory response18."
"The lamina propria of the duodenum mucosa accomodates numerous migrant and resident cells of the immune system such as eosinophils, neutrophils, mast cells, and macrophages, populating the connective tissue of the villi core, the diffuse lymphatic tissues, and lymphatic nodules. In a healthy person, the eosinophils are located only in the lamina propria, mainly along the villi20,21"
"The establishment of the parasite in the duodenum represents the acute, or entherical, phase characterized by goblet cell hyperplasia, increased mucin and intestinal tirefoil factor expression, and an inflammatory infiltration in the lamina propia26. At this stage, the intestinal inflammatory infiltrate is comprised of lymphocytes, mast cells, and eosinophils recruited to the intestinal Peyer patches and solitary lymphatic nodes27. Mastocytosis in the intestinal mucosa is also a typical feature of infection with T. spiralis27"

=> Now an acute infection with parasite has, among others things, creates an inflammatory reaction in the "lamina propria" where eosinophils reside. And then eosinophils and others are recruted and boooooom, mastocytosis (or massive mast cell degranulation in plain speak) happens in the intestinal mucosa (the gut).

Food sensitivity, immune system activation, initial acute trigger, gut inflammation all in one line. And with https://en.wikipedia.org/wiki/Mastocytosis can come Nausea and vomiting, Bone or muscle pain, Olfactive intolerance (being hyper sensitive to smells if I get it right), Headache, Malabsorption, Ear/nose/throat inflammation, Fatigue, Ocular discomfort... and release of histamine and other pro-inflammatory substances from mast cells among others.

Now https://en.wikipedia.org/wiki/Histamine by itself is "a neurotransmitter for the brain, spinal cord, and uterus.[3][4]"
Just some of the properties of histamine:
On the H1 receptor in the CNS:
"CNS: Sleep-wake cycle (promotes wakefulness), body temperature, nociception, endocrine homeostasis, regulates appetite, involved in cognition"
On the H1 receptor in
"Periphery: Causes bronchoconstriction, bronchial smooth muscle contraction"
=> E.g. poor breathing and oxygen uptake

On the "Histamine-gated chloride channel"
"Brain: Produces fast inhibitory postsynaptic potentials"
https://en.wikipedia.org/wiki/Inhibitory_postsynaptic_potential
"An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential."
=> I don't know if that is good or bad but it sounds a lot like messing with our brain.

Histamine also plays a role in the sleep-wake regulation

Histamine itself however does not cross the blood brain barrier, but:
Histamine "attacks and thins" the blood brain barrier https://link.springer.com/chapter/10.1007/978-3-319-40308-3_8
with title "Histaminergic Regulation of Blood–Brain Barrier Activity"

Now how do we "solve" the problem that histamine can't cross a (healthy) BBB? Estrogen!
https://mthfrsupport.com.au/2016/09/histamine-and-mental-health/
"Another interesting explanation is that histamine causes estrogen levels to rise, and this hormone can actually cross the blood-brain barrier.
As you can see in women, estrogen has powerful effects on mood, both positive and negative. You’ve also learned from one of our previous articles that histamine and estrogen is synergistic, meaning they create a vicious cycle wherein one induces the release of the other and vice versa."

=> There are so many links when searching for "histamine estrogen" saying estrogen can cross the BBB and that estrogen can trigger histamine production in the brain and vice versa that it is hard to filter out only the scientific sources.

The first somewhat related scientific link https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537328/:
"Recent findings. Estrogen receptors are found on numerous immunoregulatory cells and estrogen's actions skew immune responses toward allergy."

It sure happens that woman are far more numerous in all this kind of conditions (Issie repeatedly brought the supposed link between ME and estrogen under my attention)

And histamine in the brain affects major centers in the brain, "known" to ME patients and often related to hormone regulation:
https://en.wikipedia.org/wiki/Histamine
"Histaminergic pathways:
Tuberomammillary nucleus (TMN) projections
TMN → Cerebral cortex
TMN → Hippocampus
TMN → Neostriatum
TMN → Nucleus accumbens
TMN → Amygdala
TMN → Hypothalamus"

To me this seems to be a good start for modeling a potential mechanism to transfer accute infection to much as is seen in ME, FM, POTS...
Of coarse it is just a hypothesis and mechanisms may vary between patients.

 

[dejurgen]

Working further from the above on, the link between MCAS-like problems and exercise intolerance seems clear. The above sets the immune system in "hyper" vigilance. Exercise increases immune activation too. An additional activation on top of an already trigger happy immune system is no good thing.

There is also a simple link toward POTS: mast cells do rapidly degranulate in POTS patients when they are standing upright without moving.

From mentioned LINKB in above post:
" Fibromyalgia
Looking at the prevalence of nerve fibers in the lower leg and thigh, four distinct groups of SFN were found in FM:

• 37% had normal small fiber levels
• 17% had reduced lower leg small fiber levels
• 31% had reduced thigh small fiber levels
• 15% had both" reduced lower leg and thigh levels"

When POTS patients (or other orthostatic intolerant patients without fulfilling POTS criteria such as I do) stand upright then legs are most affected by gravity. Or let me rephrase it to: are most affect by an increase in pressure (mast cells seem to be pressure sensitive among others) and fluid retention and blood reflow problems. Now the lower legs and thighs are badly affect according to this study.
=> Does this point to an overlap in FM and POTS via MCAS?

"The authors were also at something of a loss to explain the increased sensitivity to “mechanical stimuli” found in FM"
=> mast cells seem to be pressure sensitive among others (and rather quick acting in my anecdotal experience)

"The Eyes
Small nerve fiber levels were significantly reduced in the eyes of FM patients relative to healthy controls. The small fiber levels in the eyes of people with major depressive disorder and widespread pain were, again, similar to those in the healthy controls."
"The authors also had difficulty explaining the nerve loss and reduced nerve lengths found in the cornea of the eyes, as the eyes are not a place they would expect to find that."

=> When not taking my hay fever spray, my eyes are (oddly, I know) both dry and tearing a lot. Hay fever is a basophil and or mast cell related disorder.
=> When being sleep deprivated my eyes hurt badly and tears are biting, meaning they hurt the "skinny side of my eyes pointing to the nose" and my faces skin when they roll down my face almost as bad as if it were my 3% hydroperoxide undiluted (when I had too much brain fog I misused my contact lens products a few times) lens solution. In short: it stings badly!

=> It seems mast cells and or basophils and or eosinophils (with their "major basic protein") are present in high amounts in the eyes and may be "remodeling" my eyes nerves (yikes!).

"The FM patients with the most widespread small fiber loss (in their lower legs, thighs and eyes) were in significantly more pain that FM patients without small fiber loss."
=> If the above hypothesized immune thing holds, that would make sense as a more massive immune reaction would likely lead to more peripheral nerve "remodeling".

"Also, the questionnaires indicated that this group reported greater impairment and disability, had more severe symptoms overall (Fibromyalgia Impact Quotient), and were more anxious."
=> Such near continuous massive immune response would do so, yes.

"But what about the third or so of FM patients without any evidence of small fiber neuropathy?"
? Various causes and pathways to FM may exist, aka different subgroups?

"The FM group as a whole, after all, demonstrated considerable amounts of abnormal nerve functioning. "
?Maybe that group has as much new nerve growth as old nerve destruction? ?determining nerve age might be an interesting experiment here?

"They seemed to tip their hats towards the body, though, when they reported that the small fiber pathology found in FM could be affecting the small blood vessels and could help explain the problems with muscle perfusion, exercise intolerance, the deep muscle pain sometimes felt, and even the brain fog."
The hypothesis in previous post could explain much of it.

"Dr. Rice found a veritable explosion of small nerves not in the skin but in the hands of FM patients"
"major basic protein" "remodels" the peripheral nerves. It doesn't say cut away or trim. Remodels is like in cutting here and planting there in a gardeners sense. So yes that could happen for some reason under this hypothesis.

There may also be a reasonable link towards a paper discussed in the comment section
https://www.biorxiv.org/content/10.1101/713495v1
"Here we show that sensory hypersensitivity in FMS is caused by autoantibodies that act by sensitizing nociceptive sensory neurons. Administration of IgG from FMS patients increased mouse pain sensitivities to stimulation with mechanical pressure and cold. In contrast, transfer of IgG depleted samples from FMS patients or IgG from healthy control subjects had no effect on pain sensitivity."
=> It is a triggering of the immune system that may or may not be related to the above hypothesis.

 

[Issie]

Autoimmune dysfunction and inflammation! Seems to be at the "core" of the issues. But figuring out how to tweak the "cause" and treat the "symptoms" is still a work in progress.

Dejurgen and I have done extensive research on glutamate and GABA. One affects the sympathetic system, the other parasympathetic system. When either conversion issues happen or there is an abundance of one or the other - much dysfunction happens. Having learned that mast cells and glutamate are closely connected and knowing one of my largest problems is MCAS and my POTS didn't get better until I started treating that - trying to keep the degranulation down and not add to glutamate excess and more sympathetic response is of necessity for me.

Think of the high sympathetic nervous system response those if us have with HyperPOTS and high norepinephrine levels have. They actually check us for an adrenal tumor called a phechromatoma. It gives such a high "fight or flight" response and that comes multiple times a day. But, when having a MCAS response, it can give the same feelings with a feeling of panic and hypervigilance. Not to mention flushing, hot flashes, naseau, and possible anaphylactic response. (My face goes numb on one side as a warning of what is about to come.) Also can be triggered by exercise, getting over hot, strong emotion etc.

When I first figured out the possible connections to glutamate with POTS and MCAS was a long day of research where I chewed two very large containers of gum with Aspartame in it. It gave me much energy and the writing flowed. But the end results was a severe mast cell reaction that hit my heart. I took massive amounts of antihistamines before going to the hospital. When I got there, it appeared I was having a heart attack. EKG and high blood pressure and tachycardia and of course severe POTS. They gave me nitroglycerin and it helped. Then gave me another dose and it helped more. Then put a patch on me and put me into Intensive care over night to monitor. They ran labs to watch for muscle damage that would indicate heart attack. Thankfully, there was none. I did not have a heart attack. But it was mast cell. The illness is named Kounis Syndrome. I knew the gum had caused it and found that Aspartame causes glutamate to increase. That's why I felt so strongly as to this connection and felt it held a key to the sympathetic response in these two illness.

With further research I found connections to endometriosis and MCAS. Of which I also had. But I also had a hysterectomy at a very young age due to this and a ruptured appendix. Long story, but 8 abdominal surgeries trying to have kids and do clean ups - end results was a complete hysterectomy at age 36. But I was estrogen dominant, and the first thing they try with endometriosis is to lower estrogen and stop cycles. How did estrogen play into this? I felt it did. I also felt that since my dad had prostate cancer and daughters of men are more susceptible to cancer - that maybe I had avoided it. But why was I still estrogen dominant? Later, all tries of hormone replacement was a complete failure. Progesterone caused me mast cell issues. Appears glutamate at play again. And mast cells a big part here. I kept having hot flashes and thinking I was in the change, but the hot flashes were mast cell induced. I still get them when I have mast cell degranulation and I'm past the change. (Just a note to the younger women. When you have a complete hysterectomy, your body has a programmed time to be past the change and for hot flashes to stop. I was told I would have hot flashes and things that go along with the change until I was past that time clock. That was all true. I did find herbals to help and we finally did a compounded estriol cream that helped. Estriol is actually known to decrease breast cancer.)

I was in a study with 23&me because of a gene that I unfortunately inherited that is also connected to mast cells and basophils. Since my DX of MCAS was from Mayo - the doc on staff put me in the study. The sad thing is the study was for a type of cancer called MPN that is in the bone marrow. ***I do not show any signs of having this.***** But my dad did and he died from bone cancer. All his labs indicated MPN. Whether or not it was his prostate cancer metastasized or MPN, we won't know. But MCAS is connected to this. I only mention this as others may find connections here. And since estrogens, glutamate, mast cell, basophils all at play here........it may be important piece to the puzzle.

Dejurgen uncovering that basophils may also cause response like/as mast cells......actually gives me a different thing to look into. And knowing that at times my mast cell medicine does not work, may be an answer as to why.

And as to sleep, ugh......I've been in a bad crash and sleep has been horrible. It has affected me severely and caused massive digestive issues and mast cell response to near everything. Not that I'm complaining, but I've lost 12 lbs in a few weeks due to this. And lack of sleep, we feel, has been a big key to more mast cell issues and hypervigilance due to mast cell and possibly high glutamate (over sympathetic response).

Then let's talk about the brain and cognitive function. Glutamate is excitatory and too much can be neurotoxic. We found plenty of studies indicating this. But, happy to say......I feel like I'm getting my brain function back. (A few months ago, I wouldn't had been able to write this as I was in a bad crash.) Part of it is the tweaking I'm doing with mast cell. But also improving blood flow with herbs to help with blood flow and reperfusion issues that can come along with POTS. Also thinning my blood due to having coagulation issues. (Another problem with some POTS people.)

We also uncovered that H1 and H2 work peripherally and H3 in the brain. The H3 also has the highest connection to GABA and potentially glutamate. So I'm trialing some herbs and RX to tweak the H3 receptor and to lower glutamate. So far, I'm encouraged. And Dejurgen is trying something else (leave it to him to talk about that if he desires).

We know this is still in a hypothesis mode, but we both feel we are onto something here. I'm excited that Dejurgen has helped me with my long time hypothesis. It seems to hold even more weight now. We have found already documented studies pointing to connections. His brain works much better than mine and he can piece it together better and explain.

Thanks Dejurgen. Keep up the search......we have more to learn. We have to find the "purple bandaid"!

 

[Issie]

And then there is FM and the pain. Sooooo much pain. That being one of my worst symptoms and I have progressing neuropathy. Finding this as a connection makes much sense. When I have a mast cell "attack" I walk with straight legs and flat feet and don't want to curl my fingers and everything hurts. Mast cell "attack" with FM symptoms. Connections???????

 

[dejurgen]

And Dejurgen is trying something else (leave it to him to talk about that if he desires).

I am much more reluctant in trying new things then Issie and so my pace for trying and evaluating changes is a lot lower. I had some bad experiences with things backfiring on me. Don't expect anything soon on how I try to deal with it as I wish to look at a few dozens of angles first.

Part of it is the tweaking I'm doing with mast cell. But also improving blood flow with herbs to help with blood flow and reperfusion issues that can come along with POTS. Also thinning my blood due to having coagulation issues.

Note from me: I am a strong believer in going low and slow and one thing at a time when trying out new things. Not doing so can cause a very nasty backlash. Some people can deal with such backlashes and remain on their feet when they hit such unpleasant surprises, but I am not one of them.

 

[Issie]

Because of having been at this for so many years and knowing I may paradox with things..... I'm much more adventurous in my experiments. There is only one way for me to find out what my response will be. I can research it and find out properties and what it is supposed to do, but that doesn't mean it will work that way for me. (In fact, what works for dejurgen doesn't work for me at all. And he hasn't tried what I'm doing.) So despite us both tweaking glutamate channels, we are having to use different approaches.

That also tells me that "one pill" approach for the masses will not work for all.

 

[dejurgen]

I had over a year ago good experiences with eating a piece of papaya before every protein rich meal and "religiously" continue to do so. I now may understand better as to why it helps me:

original post with plenty of fishing of me as to why it would work; first and last comment will explain for most people: https://www.healthrising.org/forums...-improvement-in-health.5980/page-2#post-35533

repeat of last comment:

I may get closer to some answers. Recently I learned to recognize the symptoms of MCAS (mast cell activation going hand in hand with histamine release) and in hindsight I seem to have that for many years.
​

https://www.ncbi.nlm.nih.gov/pubmed/6400589​

"Papain reduces gastric acid secretion induced by histamine and other secretagogues in anesthetized rats."​

​

I'm not an anesthetized rat but that may explain part of the benefit I have from using it. I had gastric acid reflux for years and learned late this spring that it costed me more health then I anticipated. After gastric acid reflux I often had to cough for about a minute. I mistakenly attributed that to having the common cold as it went hand in hand with a stuffed and runny nose and sneezing. But as that turned out to be due to newly developed hay fever, I had to search for a cause of the coughing. It appeared that that was due to the "grainy debris drenched in stomach acid flowing back into my lungs, causing them to inflame and my body trying to cough the garbage out.​

​

It also explains why dipping a bit of papain on acne-like rash even once a day helps with rash. People with MCAS can become more sensitive to many types of rash. Please stay clear of sensitive body parts like eyes as it still is a powerful digestive enzyme!!!​

​

Helping with digestion may be just a bonus.​

​

NOTE: Papaya will not be good nor safe for all people with MCAS, some people are for example allergic to it!

I got the idea from https://rawlsmd.com/health-articles/how-to-cope-with-mast-cell-activation-syndrome:

"People with MCAS may also benefit from herbs that assist the body with reducing elevated histamine levels. Natural antihistamines like quercetin, bromelain, and stinging nettle can be helpful."

With bromelain comparable to papain but having IMO more chances to interfere with commercial drugs.

Stinging nettle is also a puzzling one as it releases histamine in its sting! But (flogging with) stinging nettle is already used since ancient Roman times in order to combat rheumatism.

 

[Issie]

Another thing I've done for rash and itching associated with MCAS is gotten a bottle of NasalCrom. (This is a diluted solution of GastroCrom. And is a mast cell stabilizer.) Putting a whole bottle in some fragrance free cream and mixing, makes for a soothing cream that calms down a histamine reaction and seems to stop my itching.

 

[Issie]

I mentioned in a blog that I am in my off cycle of Tramadol and Bentyl. These have been my best medicines for HyperPOTS. There could be more than one reason, Tramadol has mild calcium channel blockading properties and help to vasodilate. Tramadol works on all the neurotransmitters including NMDA/ glutamate receptors. Having been off these for 3 weeks (with no withdrawal, such a low dose to only affect autonomic nervous system and only take an edge off pain), I've had no withdrawal at all. However, I do have severe FMS - with pain being one of my worst symptoms. My doc told me to get PEM with lutolin. She said it is helping chronic pain and MCAS. This is the brand that was recommended.

Check this out at Amazon.com
Mirica® - Pea (Palmitoylethanolamide) and Luteolin - Natural Pain Relief - Made with OptiPEA® from The Netherlands - Anti-Inflammatory Supplement - 60 ct https://www.amazon.com/dp/B07365MZLY/ref=cm_sw_r_other_apa_i_W.OIDbH3BPEQB

I find that my pain isn't any worse being off the Tramadol/Bentyl and my POTS is staying at a dull roar. With tweaking these glutamate receptors and this enzyme - I seem to be doing pretty well. Still needs tweaking as to dosage. So far, not feeling need to go back on them.

I'm also doing some other things for cognitive function. I feel I'm getting my brain back. Since one of the things is a keeper for me, I will tell what I'm using. This isn't all. But this one seems to make a difference.

Brain Supplement. Memory Support. Clari-T by LifeSeasons
https://lifeseasons.com/clari-t-brain-health-support-supplement

It can be gotten cheaper but since this is the company's website there is more information about it.

I will come back later when I figure out if other things are necessary.

 

[Issie]

A bit of a caution.....go slow in starting to increase blood flow as there is a thing called reperfusion that can cause damage. These herbs have things to assist with this. But when there is a change of more oxygen and blood there could be an adjustment period. It may feel a bit too stimulating to start with.

 

[dejurgen]

In my search to better understand the role of excess glutamate and calcium channels I took another look at https://en.wikipedia.org/wiki/Neurotransmitter and https://en.wikipedia.org/wiki/Chemical_synapse#Structure.

These are difficult topics and I am still searching my way into them myself. However beneath I made an attempt to simplify and summarize the topic. I think the summary is still largely correct. If anyone notices clear errors, mistakes or shortcomings please reply and help me further. Based on the summary below I'll try and link it to ME.

Summary
Glutamate is (also) a messenger molecule. When you think, you release some of it (in the space between synapses in figure https://en.wikipedia.org/wiki/File:Neuron_synapse.png). And part of that will be lost in the space between cells (escaping to the left and right side of the gap between the two synapses). When you look at figure https://en.wikipedia.org/wiki/File:Neuron_synapse.png, you'll see the connecting synapses are broad and close together so loss of messenger molecules will be small but higher then zero. And when the concentration of glutamate in the space between brain cells rises too high, it can cause too much excitation of the brain (as high levels of glutamate in the space between brain cells is known to be very excitatotry). That is a bad thing that can get toxic when it gets extreme. Chances for it to become toxic are very real when either oxygen or glucose in (parts of) the brain becomes too low.

Now consider this space between the cells to be something where the excess glutamate has to be continuously mopped up, a bit like the Dutch continuously have to pump water out of their fields as most of them are below sea and river level. In the past they used those cute traditional wind mills for that. The more wind, the better they could pump the water out of it. A month of too few wind would mean their crops being swamped by water. A windmill without wind is like a mitochondria without either energy or oxygen. And a windmill with raged sails would be a bit like poor genetics slowing the mitochondria down a lot.

So comparing people with poor genes or mitochondria to the Dutch windmills and fields: they have low capacity to pump the water out of the fields so their fields are more swamped with water. They can't pump well enough to keep them in perfect condition. Or, speaking about their mitochondria and excess glutamate in (between cells of) their brain, their mitochondria (and maybe poor ion channels) do a poor job of pumping enough glutamate out of it to keep it to desired levels.

So either if they have too few wind (partial ischemia or lack of glucose) or ragged sails (poor mitochondrial genes) the effect is similar and stacks: poor water draining from the fields (glutamate draining from the space between cells in their brain).

I hope this analogy is a lot more clear then those two wikipedia links and helps to understand this difficult topic.
End of summary

Now there are a few things that can be done. But going the chemical route may be a bit too tricky. So I prefer a "classic" route:

* the more you think, the more glutamate is released into this space between the cells.
* the more you think, the less fuel and oxygen is available for these "pumps" removing glutamate.
* the more you think, the more ROS your cells generate.
* the more ROS your cells generate, the more energy (that you lack) is needed to clean up that ROS by producing anti-oxidants
* energy used for cleaning up ROS can't be used for thinking or mopping up excess glutamate (glutamate transporters require ATP too)
* much of above consumes so much energy that you risk getting your brain into partial ischemia, leading to glutamate dumps, toxicity and inflammation
* cleaning up that inflammation costs energy...
* and so we get many parts for a vicious circle that we'd better break.

=> See where I am going? Pacing mental activities, emotions and physical activities (that are costly to the brain too!) leads slowly and bit by bit to lower vulnerability towards these problems, helping either slow or halt a decline or start a slow and ongoing recovery. That may be part of why pacing helps reducing brain related ME/FM symptoms.

 

[dejurgen]

I wrote the previous as several people mentioned the connection between being a highly sensitive person, being a type A personality, being stressed, anxious or having OCD or not being a person having taken enough rest when needed before having this disease in https://www.healthrising.org/blog/2...esponse-to-exercise-and-treatments-in-me-cfs/.

All of the above personality traits do make people more vulnerable to end up in the mentioned vicious circle at the bottom of the previous comment.

Let me take the example of athletes having lived on a low carbs and protein diet and studying for 8 hours a day plus training being more vulnerable to over training syndrome (see Cort's recent blog https://www.healthrising.org/blog/2...yndrome-chronic-fatigue-two-similar-diseases/).

• Studying for 8 hours a day certainly is a demanding mental task. It requires a lot of thinking. As said in previous comment that releases and increases glutamate in the space between brain cells and it is an energy costing activity that will increase ROS production in the brain.
• After 8 hours of studying, the glutamate levels in the space between brain cells will be clearly increased and during all those hours glutamate will have diffused from the brain regions used for learning, focus and memory towards other parts of the brain including the motor functions.
• Eight hours of brain work will have cost quite an amount of energy for the thinking itself plus for cleaning up part of the excess intercellular glutamate and the increased production in ROS.
• As these athletes live on a low caloric diet and train after studying, their glycogen and protein reserves likely aren't huge at the start of the day. Eight hours of study will further reduce both their glycogen and protein reserves (protein is a back-up source of energy able to produce glucose but also able to produce ATP in other ways in the brain). Fat reserves (that are likely not large with athletes either) outside the brain are of few use to fuel the brain as plain fatty acids have a really hard time crossing the blood-brain barrier.
• When athletes do not rest sufficiently after studying for eight hours, they deny their brain the rest needed to clean up this excess glutamate and oxidative stress.
• When they do some training that evening without having taken enough rest, they start training with already quite a large amount of extracellular glutamate and ROS needed to be cleaned up. Extra ROS inhibits their brain mitochondria to some extend, reducing energy production speed in their brain.
• Now suppose our athlete trains by running for miles. Movement is costing a surprising amount of energy to the brain. Remember that robots that move like humans are very very hard to develop, and that is in part because movement is so complex and computational demanding.
• Now their brain needs to work hard again, but has poor conditions (excess glutamate and ROS) to start with. Protein reserves in the brain are decreased, reducing energy supply to the brain.
• The extra physical training now brings in a competition for glucose and protein between the muscles and the brain. But both glycogen deposits and protein reserves were already low to start with. Also oxygen supply has to be divided between both the brain and the muscles demanding a high supply of it.
• Both organs will be strained by a too low supply of energy and oxygen. That will lead to oxidative stress less (quickly) being cleaned up in both allowing cells in both muscles and brain to "receive" more damage due to oxidative stress. That will require inflammation the following days as inflammation is (when all goes well) supposed to be the healing mechanism to repair such damage.
• The brain will have excessive levels of intercellular glutamate on top of it.
• Soon after the workout (when it happens after the studying) the athlete will get to bed for sleeping, but will have plenty of exciting intercellular glutamate in their brain. That will make for poor sleep and with it poor recovery.
• And so we get a vicious circle.

When thinking of many people with ME being highly sensitive:

• Let us suppose that increased exiting intercellular glutamate levels are part of ME.
• These increased levels make neurons fire more rapidly when an additional brain signal comes in. That is the definition of excitatory: easier and faster firing neurons.
• So with lower signal inputs the neurons of people with ME fire faster. That means they react faster to sensory inputs, they think faster, they are less likely to ignore small signals. In fact they become more sensitive "thanks to" these increased levels of intercellular glutamate and less inhibition of rapid neuron firing.
• For people with gradual onset ME, this can be a very tricky and seducing thing at first. It's like your brain is on steroids. Colors look brighter, smells are stronger, thoughts are quicker and produce more powerful effects then ever. It's like a new world opening. It sure was for me when (in hindsight) my disease started. For three years I lived fuller then ever. I felt on top of the world. But the cost was huge: I didn't timely noticed I was depleting all my reserves at a fast pace!
• So are highly sensitive people more prone to ME: likely they are. But ME (or the hidden health conditions preceding it) itself makes people more sensitive too!

Note that this model also aligns well with the observation that ME people's brain look to "be firing all over the brain" when doing simple activities, compared to more regional and focused uplighting of brain regions in healthy people's scans.

Let us take a look at sensory overload too.

• ME/FM patients having too much excitatory chemicals in the brain all day around, their neurons are firing much more rapidly and more often. They often fire when neurons in healthy brains would inhibit the same signals.
• Once a sensory input gets brain neurons firing, other parts of the brain are triggered by passing this sensory information. For example, a tiny movement that healthy people's brain would block at the sensory level now gets passed to for example these parts of the brain that try and determine if this movement signals any danger. The brain quickly tries to analyze the image for being an animal, a fast moving object, a flame... All this extra analyzing (that would not be done in a calm healthy brain) does cost extra energy that we lack and it does produce extra intercellular glutamate (and ROS). Here we have the vicious circle again. As this "danger analyzing region" also "bathes" in excitatory chemicals, this regions is encouraged to do things rapidly too. And doing things rapidly increases the load on the brain a lot further, making the problem even worse.

For the many many patients with brain fog, what I wrote with "It's like your brain is on steroids. Colors look brighter, smells are stronger, thoughts are quicker and produce more powerful effects then ever. It's like a new world opening." is so much not what is happening. Rather then be able to think faster, clearer and better it all becomes slow and very fogged. These ideas do not conflict with this model of overload by excitatory chemicals however:

When there is so much excessive glutamate in the intercellular space and ROS and inflammation is so excessive, near all of the energy the brain has available has to go to continuously cleaning up this highly toxic dump. The brain has near no energy available to do any actual thinking or do any decent sensory processing. Then things like faltering vision (tunnel vision, literally seeing so much grey fog...) are "normal" given these conditions. The little thoughts we have become incoherent and inefficient as the little energy that is left to fire neurons lets them fire in disorganized manner as these neurons are still bathed in these excitatory chemicals.

The main difference IMO between these early years of living to the fullest and the following years of deep total body wide crippling disease is the lack of ability to overcome the problems by "conjuring up" all of the bodies (energy) reserves.

 

[Issie]

I definitely have a deep thinking brain. When I do research and comment too much on a blog, it will put me into a Hyper state and over drive. This could/has at times thrown me into a crash. Learning to moderate and pace and recognizing limits is a hard thing to do. As this "surge" does feel quite good at the moment but the day after is a crash that we may not associate with over exertion from our brain "thinking" and the chemicals that releases. If we tend to be in a sympathetic nervous system mode too long then we possibly have upped the glutamate to alarming levels. Glutamate does help brain function, memory and processing. But for too long, the excitotoxin effect becomes apparent. Then as dejurgen said, we may have too much ROS and other issues happen body wide.

There is also connections to dopamine and glutamate (which has a reward feeling associated with it). We have information coming on this at a later time. Compiling information. I'm leaving the technical to dejurgen.

 

[dejurgen]

I definitely have a deep thinking brain. When I do research and comment too much on a blog, it will put me into a Hyper state and over drive. This could/has at times thrown me into a crash. Learning to moderate and pace and recognizing limits is a hard thing to do.

That's quite well worded how I do feel now. I know I'm overexerting yet "have" to finish writing a few comments. I know I would better try and rest. The problem is however that, when my head is so much buzzing with ideas, that things are on a runaway path. It's VERY hard to stop it. The thing I do now is writing these ideas down knowing it will put me deep into over exhaustion domain. I do so because when I've written what is in my head then and only then I will be able to let it come to rest again, experience. I know it's a poor coping strategy but it's this or a night of very poor sleep and an even bigger crash.

The "good" news: I recognize the symptoms of MCAS clearly know I learned to recognize them with the help of Issie: tearing pain in the muscles, acid reflux while I haven't eaten for a while, flushing (mostly warm head but also body, first time I recognize it since Issie told me to look out for it) and I'm on the borderline between my head buzzing with ideas and it becoming clouded and confused. So now I'll "have" to push adrenaline to push out my writings (in order to be able to come to rest again). As said: poor coping strategy. But it experimentally and anecdotally links brain exhaustion, pain "sinking to mainly my legs", brain fog, MCAS, glutamate, hands feeling cramped and stiff...
Oddly enough I don't get dry or tearing eyes or a stuffed nose (yet). But that may be more related to basophil degranulation then to mast cell degranulation.

So, too much exhaustion can cause too much glutamate in the intercellular space. That entices a lot to do even more (it excitatory) and, at least in the first phase of it when still having a small energy reserve, indeed feels good and feels as "being better and more able to do something" or like a small improvement in health. After a period of being able to do less and "having to catch up for the lost time" with urgent things to be done, it's easy to fall for it and elicit a new crash.

But that is only part of it. At the end of it, glutamate and ROS pile up in the brain and mast cells all around the body start to degranulate. That brings the body in a precarious situation or a real emergency situation (ROS being uncountered and overrunning the cells massively is a very dangerous situation that can devastate entire organs in less then an hour). The best hormone to deal with real emergencies is... ...adrenaline so the body tries to push adrenaline levels up a lot. That increases both breathing (blood oxygenation) and blood sugar including converting proteins in a rapid pace to glucose and other fuel, ripping through their stocks.

Adrenaline is also a hormone that allows a frail weak person to lift a car in order to save a child without questioning oneself if that is either possible or sane to try and do. It makes one blind to common sense that it can't be done. It is also a hormone pushing people to get into action. So it "helps" ME patients to push even further through their limits, feel good and be unable to notice that they are close to their worst rather then at their best in many days. At least it does so for a few more minutes by cutting very deep into the already poor reserves we have.

On top of that there is also the possibility that the brain rewards us when pushing so much trough our limits, because being able to do more and feel good about it is good and must be rewarded, isn't it? But if that is only because our brain is overloaded with glutamate in the intercellular space and with excessive (nor-)adrenaline levels, then it triggers us to do time and again the same: over exhaust, don't see it, do even more, crash deep, create more damage, get better, over exhaust...

We so easily get stuck in this cycle of crash, pump, crash, pump and we know it yet can avoid it so poor. Maybe that concerted "chemical assault" is why.

 

[dejurgen]

Linking of glutamate excitotoxicity to calcium channels:


As Issie kept asking what the relation between glutamate and calcium channels was, as she felt strongly about there being a link, I kept looking into it more then once but until now in vein.

Then I think I've got it:
When looking at the second picture https://en.wikipedia.org/wiki/Chemical_synapse#/media/File:SynapseSchematic_lines.svg on https://en.wikipedia.org/wiki/Chemical_synapse#Structure, one sees the "sender" (of chemical signals between neurons) called "Axon terminal" on top of the picture and the "receiver" (of chemical signals between neurons) called "Dendrite" on the bottom of the picture.

According to https://en.wikipedia.org/wiki/Chemical_synapse#Structure, signalling happens by 9 steps described in
"Signaling in chemical synapses
Overview"

Step 2 is: "...channels to open that are permeable to calcium ions."
Translated: that is opening calcium channels

Step 3 is: "Calcium ions flow through the presynaptic membrane, rapidly increasing the calcium concentration in the interior."
Translated: Calcium ion concentration is a huge lot higher outside the cells then inside. When opening the "gates" calcium flows inward in the "sender" or "Axon terminal" and the concentration of calcium ions in it increases rapidly.

Step 4 is: "The high calcium concentration activates a set of calcium-sensitive proteins attached to vesicles that contain a neurotransmitter chemical."
Step 5 is "These proteins change shape, causing the membranes of some "docked" vesicles to fuse with the membrane of the presynaptic cell, thereby opening the vesicles and dumping their neurotransmitter contents into the synaptic cleft, the narrow space between the membranes of the pre- and postsynaptic cells."
Translation of combined steps 4 and 5: if calcium ion concentration in the sender is high enough, a sizeable packet of "neurotransmitter chemicals" (in this case glutamate) is dumped in the horizontal space between "sender" (Axon terminal) and "receiver" (dendrite).

Step 6 is: "The neurotransmitter diffuses within the cleft. Some of it escapes, but some of it binds to chemical receptor molecules located on the membrane of the postsynaptic cell."
Translated: Some of the transmitters (glutamate) is used (the one that binds to receptors) but some of it escapes (to the intercellular space), increasing the amount of glutamate in the intercellular space. And it is that one that is very very excitatory and even toxic when levels are to high.


=> By partly blocking calcium channels with chemicals, step 2 goes slower. In other words, the transmission of signals from neuron to neuron does no longer go at a rabid fast pace like it does in ME patients. It slows down. Like in "relax and take it easy man". And when step 2 slows down, all the following steps slow done. So (partial) calcium channel blockers can bring back both the speed of thinking and the "easiness" by which pain sensations trigger neurons to process it.

The slower thinking part, as long as it is modest, does decrease energy consumption and glutamate release and concentrations in the intercellular space and increases coherence of brain signals aka brain clarity. The decrease in ease and speed by which pain signals trigger a neuron to act decreases pain sensitivity (and hence works as a pain drug). That may be why some pain killers or anesthetics also have some energy / exhaustion / brain clarity influence on ME.

!!!Strong warning!!!
Calcium blockers ALSO block transport from the intercellular space to the "Axon terminals" and the Astrocytes.

Translated: calcium blockers also reduce the clean up speed of intercellular glutamate in the brain! The excess gets mopped up quite a bit slower. So when you overdo it when using those you may be in for a nasty surprise like a really long and bad crash!

They are a dangerous double edged sword. And they interfere with plenty more vital functions!

Issie has some success with them but even then she knows that only a little can help in some specified circumstances and that even remotely normal doses can fire back big way.

Also, I have IMO even for ME patients really good senses. But my senses are no way near good enough to get any reliable nor safe results with such powerful chemicals. Issie's senses are truly exceptional. So don't try this at home!

So why do I write about it? In order to hope to shed more light on the topic, gather more patient's experiences, *maybe* attract attention from doctors or researchers for them to develop safer and checked methods and trying to gather ideas on how to use this knowledge in a far more safe and reliable manner. It's not because walking on a cable between two skyscrapers is possible that it should be done.

 

[dejurgen]

Last one for the day:
Why do some things work well for one patient and fire back badly for another one?

In this part I'll only deal with things relating to glutamate (like, among others, NMDA receptors) receptors here.

Let us look back at figure https://en.wikipedia.org/wiki/File:Neuron_synapse.png.

Suppose we have modest but a bit too high levels of intercellular glutamate and modest but a bit too high activation of glutamate receptors on the lower part or "dendrite" (see also https://en.wikipedia.org/wiki/Chemical_synapse#Structure for naming).

Then I believe (as I don't know for sure) that many receptors on the "receiver" or "dendrite" are empty. So when a signal to the upper part (the Axon terminal, see previous comment) is applied it triggers a cascade of effects and it then releases a "sizeable package" of glutamate in the synaptic cleft (the wide but narrow space in between Axon terminal and dendrite).

When most receptors on the receiver / dendrite are empty, it is easy for the freshly dumped glutamate to bind to the receptors of the dendrites. Doing so "activates" the dendrite and triggers a fast and strong response.

We can try and dampen this fast and strong response with chemical like GABA and others. Those are chemicals that also bind to these receptors on the dendrites but have a calming effect slowing down the speed by which the receiver / dendrite passes and processes signals. That slows down the speed of thinking, makes one more relaxed and reduces the pain threshold (thus acting like a pain killer). For ME/FM patients this sounds very nice.

BUT there is also another part to it:
When plenty of receptors in receiver / dendrite are occupied (by "calming" chemicals), it is more difficult for a package of fresh dumped glutamate to bind to a free receptor as there are less of them. That sounds non to bad as we have the calming effect of chemicals like GABE anyways, don't we? But if that fresh dumped glutamate doesn't bind that easily to free receptors, chances are real that more of it will drift away into the intercellular space and hence increase the concentration of glutamate there. That is bad.

Once it is there, over time it will diffuse to other parts of the brain influencing those too. But that isn't the worst part yet. "Calming" chemicals like GABA also attach to the receptors of astrocytes. That are the cells that clean up excess glutamate from the intercellular space. And GABA binding on astrocytes also causes a "relax man feeling" with those cells. So they will be very "relaxed" about cleaning up the excess glutamate from the intercellular space.

So (and here I am probably deviating quite a bit from standard medicine, but our diseases don't seem to bother with that too much neither don't they?) there is the chance that either the calming effect of GABA on the dendrites (as said on top of this comment) dominates OR that the increase in intercellular glutamate and the reduction in astrocytes cleaning it up dominates (as said after the "BUT" part).

Much of the effect of these "calming" chemicals hence may depend on things like how bad is the excess of intercellular glutamate, how many receptors are there per dendrite (genetic and epigenetic changes can increase or decrease that number), how well can astrocytes clear up glutamate (likely depends on qualtiy of both glutamate transporters, energy transporters like glucose transporters, mitochondria quality and ROS,...). So quite a bit of parameters likely will influence if the net outcome of upping these "calming" chemicals will either calm you or make you more anxious and prone to crashing IMO.

Note: for those thinking of supplementing GABA: it can't pass a healthy brain-blood barrier so supplementing it this way to directly calm the brain doesn't work that well, but it can have other good effects.

 

[Issie]

Wow, dejurgen.....if you don't crash after this marathon of a post, in one day ..... I will be very surprised. (And people, English is not his first language. I think he does Amazing!!!)

I'll add some observations to his thoughts. He spoke of calcium channels and my use of mild calcium channel blockers. These are not calcium channel blocking medicine, but have these properties included in them. The one I still use on occasion, and only when necessary, is a mast cell stabilizer that has calcium channel blocking properties. It is GastroCrom. It actually calms me down when there is a mast cell attack in progress. The surges, hot flashes, anxiety feelings, pallor, dizziness and with me numb face and tachycardia and it stimulating a POTs episode can be tamed down with a couple of concentrated vials of GastroCrom and children's liquid Allegra an H1 histamine blocker. And trying to calm down the sympathetic feelings of being out of control with calming breaths (as it's possible to hyperventilate when this occurs). It affects ones moods and thinking. GastroCrom was initially created to treat asthma. So it helps vasodilate and increases blood flow. Since I have, at times, pretty bad Mast Cell Activation Syndrome (MCAS) - I'm one to have everything close and also epi pens around the house for just in case. (Thankfully not had to use them.) I have of recent started using an H3 medicine called Singular. Appears this also can help asthma and allergic response and tends to affect more in the brain and GABA and potentially glutamate. Whereas an H1 (Allegra) is more peripheral histamines. But I do find this H1 beneficial and it doesn't cause me sleepiness or brain fog. I have of recent stopped the H2, as Zantac has actually had some recalls. Also found that H1 And H3 are being used to treat cognitive illnesses. So should help with brain fog issues. I am trying to slowly get away from any of these as I'd rather try more pacing and possibly some alternative things that I'm not ready to talk about just yet. (I've actually had some days of being able to not need any of these things and then will over push or get an exposure and have to use them again. I do find if I use too much or too often the GastroCrom, it makes my heart hurt and I will get a bit of a heart flip feeling. So I only use small amounts and only when necessary. Until I started treating mast cell issues, my POTS didn't get better and was barely tolerable.

The other mild calcium channel blocker (property type) medicine is Tramadol. (I talked about this above.) It has this as a mild affect and also works on all the neurotransmitters including NMDA (glutamate) receptor. This had been my very best POTS medicine to calm down the much overactive sympathetic response. I can use a very small amount and it would calm the tachycardia and the "I'm in a locked room with a lion" feeling. I cycle on and off this and go back on even lower amounts when I go back on it. I have been off this medication for a month, I don't have any withdrawal when I do this, as I stay so low on it. With some of the new things I'm trialing.....haven't felt the need to go back on it. (But it will stay on reserve as it has been very beneficial to me.)

With me, GABA and anything trying to increase GABA seems to paradox (do the opposite). Instead of it calming me down, it hypes me up and causes what seems to be a glutamate (sympathetic) response. GABA is supposed to increase parasympathetic and be calming. Dejurgen has explained why this may be happening with some. If we build too much glutamate and it doesn't get "mopped up" (his words) then there is excitotoxin happening and possible damage to cells with not only ROS but a possible mast cell response causing degranulation and a dump of all sorts of inflammatory things released. This then could go on to affect the immune system.

I'm not going to be able to do a marathon post. So will be coming back to add more later.

Hope this is helping to maybe draw light to another possible hypothesis and connection to our illness. Adding a piece to our puzzles. As the picture becomes clearer, we may have better direction for improving. Still searching for the elusive "purple bandaid". I want the WHYS. We don't want to just treat symptoms. Those symptoms may be the lessor evil and not the core issues. And could be the body trying to compensate, trying to right itself.

 

[Merida]

Well, I do love marathons. Hope you two have enough strength to read this. Many of us ( and researchers) have been standing in the middle of a vast forest looking at each individual tree. I am again stepping back to look at the forest.
Recent happening : My brother has been couch ridden for months - pain, eye problems/ pain behind eyes, severe fatigue, and more - just like us. I spoke to him 2 weeks ago, and he commented - I don’t know what I have, but it’s what you have. I told him about the genetic structural issues that probably run in family, but asked him if he’d been checked for Lyme. ( he is in Penna.) No, he says he has never had a tick bite or rash.

Finally he sees a new neurologist - I said “good luck.” But this new doc did the complete Lyme panel, not just the ( inaccurate ) screening. POSITIVE. He is now hospitalized with IV antibiotics - Lyme neuroborreliosis - which is capable of causing every symptom we have and more. But of course, Borrelia is only 1 of 5 or 6 possible infections from ticks.

Then last week I read Jennifer Brea’s blogs at Medium.com. ( she ‘starred’ in Unrest ) Long story, but she got diagnosed with craniocervical instability and tethered spinal cord, had surgeries and most of her symptoms are gone - which included POTS, MCAS, extreme sensitivities, severe fatigue, etc etc. interestingly, her symptoms started with a viral infection.

I have structural issues ( Chiari 0, probable tethered cord ) but am also ( CDC positive for Lyme - 5 specific IgG bands. Tick bite was 9 years ago - one bite in Virginia. I had a small, but apparently rash. My infectious disease doc ( 9 years ago) did the standard ( CDC protocol) for Lyme and it was negative. Ha. Then, 7 years later I saw a naturopath who insisted on the whole western blot panel. Positive. Back to my infectious disease, he did PCR for Borrelia. Negative. But now CDC appreciates that Borrelia burrows into connective tissue and is not found in the blood after 2-3 months.

So 2 weeks ago infectious disease doc redid Lyme through Quest. They just did the screening which was negative!!!!!!!!!! Then they did not do the more detailed Western blot IgG !!!!! What ??? !

I relate this so that you can appreciate how hard to diagnose, how important, how widespread Lyme and coinfections are - how they can produce every symptom we have - including multiple sensitivities, pain, dysautonomia, etc. And some are commenting how EBV seems to get reactivated by Lyme Borrelia. Geez.

To complicate things, it seems as if organisms take advantage of certain structural issues that affect CSF drainage and pressures, and/or blood flow to the brain. Appreciate that dysfunction ( or infection ? ) of the cranial nerves can cause all of this body mayhem.

Anyway, this is where I am, 2019, 21 years of craziness. Hugs everyone. Let us keep up the good fight.

 

[Issie]

@Merida , Lyme was a part of my picture as was CIRS. Also having EDS, there is the structural component. I think we have many pieces to our puzzles and not just one thing to manage. I have friends who had surgery for Chirai and that did not go well. In fact one friend passed away after having this surgery. Not all have good result . But for those that do, it changes their life.

I have what they are calling Post Lyme Syndrome. Where the body thinks it is still present. We are doing some things that would address Babesia and some antivirals. I'm seeing improvement. It's a long process. Since I didn't get treated until years later, after the tick bite, the results didn't go as well.

Hope you and your brother find treatment that is helpful. Alot are finding the Cowden protocol to be giving good results.

 

[Issie]

I have been doing several things for cognitive function and to help blood flow and prevent reperfusion issues that is connected with POTS and possibly ME/CFS and MCAS. All these things also can connect to our hypothesis of issues with glutamate.

As mentioned in another blog/comment, I have been doing some self experiment. Having mentioned that there may be issues with dopamine as a connection, I have been using Velvet Bean as an aid to increase dopamine. I found that I had to make one capsule into 3 doses. So this is a low amount. This along with Clari T (and a few other things) seems to be of benefit with cognitive function, brain fog, blood flow and even energy.

The Velvet Bean I'm using and trust is.
https://supremenutritionproducts.com/MucunaSupreme/

Here's a link to connections with dopamine and glutamate.
https://www.nature.com/articles/cddis2012194
"Glutamate excitotoxicity is responsible for neuronal death in acute neurological disorders including stroke, trauma and neurodegenerative disease. Loss of calcium homeostasis is a key mediator of glutamate-induced cell death. The neurotransmitter dopamine (DA) is known to modulate calcium signalling, and here we show that it can do so in response to physiological concentrations of glutamate. Furthermore, DA is able to protect neurons from glutamate-induced cell death at pathological concentrations of glutamate. .............. Our data indicate that the modulation of glutamate excitotoxicity by DA is receptor-mediated. We postulate that DA has a major physiological function as a safety catch to restrict the glutamate-induced calcium signal, and thereby prevent glutamate-induced cell death in the brain."

Note that dopamine tampers down glutamate damage. Also regulates calcium in cells. (Connection to calcium channel.)

******One thing needs to be determined******* whether or not there is too low dopamine or too high when trying to tweak this. The goal is to balance dopamine to moderate the functions. Too little or too much can both have undesirable consequences. If I increase this too high, it reduces the benefit, as does lowering it to low.

Dejurgen and I are both different in how we are approaching things. The way he is tweaking glutamate, does not work for me. One must be really tuned in to their body and how its functioning to tamper with adjusting neurotransmitters. It could make someone much worse. But for me, a small amount of adding only 1/3 of a capsule of this seems to help balance me. A full capsule makes me worse. I use this in combination with other things. By itself, I don't feel, my results would be as good. (This is not a complete answer, just one piece to very complex issues.) Velvet bean has been used to help people with Parkinson disease as it is like l-dopa.

Here is some info on two things that are in Clari T.

https://lifeseasons.com/clari-t-brain-health-support-supplement

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804326/
"A consistent number of botanicals, including Ginkgo biloba L., clinically improve cognitive impairment by ameliorating microvascular function in the brain whereas Bacopa monnieri (L.) Pennell has provided indications as a memory enhancer and protective agent in epilepsy"

These two things, that are present in Clari T, are being used to increase blood flow and help with reperfusion. Some are using for cognitive issues.

Ginko had several references to help with reperfusion, since I'm talking of cognitive function I'll post link on stroke and the brain being affected, but there was also reference of reperfusion to the spinal cord, heart, bladder and eye.

https://www.ahajournals.org/doi/full/10.1161/strokeaha.108.523480

Bacopa is known to increase cognitive function and can help up GABA. Good article here on many of its benefits. It is also being trialed in research for ME/CFS. It helps inflammation.

https://selfhacked.com/blog/bacopa-monnieri-4/