Thread by @UntoNuggan

I have been down a research rabbit hole for the past couple days, and now I'm coming up for air and sharing with Twitter

Today's topic: new research on the glymphatic system, and potential implications for Dysautonomia (and like... honestly every neurological issue)

#NEISvoid

First off, what the heck is the glymphatic system?

Well it's basically how our bodies clean gunk out of the brain

Including the leftover products from making/using energy, as well as immune waste

Clearing waste products out of the brain is Important, because some of them are neurotoxic

Meaning they can damage the brain if they stick around

Glymphatic System Problems (tm) have been documented in a number of neurodegenerative conditions, including Alzheimer's and MS etc

Scientists used to think that the lymphatic system didn't actually reach the brain directly, and this was to protect it from pathogens using the lymphatic system to infect the brain

But this got disproven in 2012 with the discovery that the brain does have a lymphatic system

Not to get too technical, but there aren't lymphatic vessels in the brain itself.

There are Lymphatic Vessels in the tissue that surrounds and protects the brain.

Instead, the body uses glial cells and astrocytes and cerebrospinal fluid inside the brain

The lymphatic system in the brain is called the "glymphatic" system because it's a combo of glial cells and lymphatic system or something

I forget the exact phrasing rn

Initial research into the glymphatic system showed that it's most active during sleep, specifically deep phase Delta Wave sleep

Basically the body sends less blood to the brain to make room for waves of cerebrospinal fluid to pulse through and "wash" the brain

This is where we get to the exciting new research

Which shows that the glymphatic system can also "wash" the brain during wakefulness

And it seems linked to this thing called "neurovascular coupling"

https://twitter.com/8Eevert/status/1641695920038244353?t=A7aZBH7TbMUbH8-x3KFQgA&s=19

The past couple days have basically involved a lot of reading about what the heck neurovascular coupling is

Combined with one million tabs for looking up neurology terms

Yay for hyperfocusing lol

If you want to read up on neurovascular coupling yourself, here's where I got most of my information

ncbi.nlm.nih.gov/pmc/articles/P…

Ok so here's the deal:

Our brains use a lot of energy (20% of our body's glucose supply even)

They don't have room to store that energy

Energy needs change depending on how much work the brain is doing

Our bodies get energy through the vascular system, ie that nice supply of blood and oxygen and glucose and other goodies

"Neurovascular coupling" is just a fancy way of saying "when the brain uses more energy, the body sends more energy to the brain"

(At least, ideally)

What's also pretty cool is that neurovascular coupling is specific to the area of the brain that's active

So if you're doing right brain things, then your body sends more fuel (via blood) to the right side of your brain

To study neurovascular coupling, scientists basically do some scans of the blood flow in your brain while you're doing something that activates your brain

Often this involves looking at images (I think because it's consistent, and easy for you to stay still while they scan you)

Neurovascular coupling is a pretty neat system that works during all kinds of energy demands, including exercise

... unless you have a condition that has borked your neurovascular coupling

Here's a chart of things that we know can mess with neurovascular coupling

Spoilers: autonomic dysfunction is on the list

So that would include all forms of dysautonomia, including POTS

ncbi.nlm.nih.gov/pmc/articles/P…

Here's some background reading on POTS, in case you need a refresher

But uh basically your body can't get enough blood to your brain, and then it activates an emergency switch to force blood there that involves rapid heart rate and generally feeling bad

https://twitter.com/UntoNuggan/status/1179469395854331905?t=u2ETj_066CLvgAAwqGIp6g&s=19

The new research I'm excited about?

They basically had participants do the standard neurovascular coupling tests where they looked at images while scanning their brains

Except the researchers watched what the glymphatic system did in response

As an aside, we know that the lymphatic system in your muscles responds to exercising those muscles

So it would make sense that "exercising your brain" via looking at pictures would also activate your glymphatic system

The question is, does the glymphatic system only do things while you're asleep? Or does it clean up brain gunk during wakefulness too?

And this new research shows that yes, the glymphatic system syncs up with your brain's activity and energy use

What happens when the glymphatic system activates?

Most of the research is about glymphatic activation during sleep, so I don't know if all of this translates to awake glymphatic activation

But. Basically, glymphatic activation involves:

1. Decreased blood flow to the brain (and I assume, increased blood flow to other parts of your body cause it's gotta go somewhere)

2. increased cerebrospinal fluid flow to the brain and out the lymphatic vessels

The assumption with POTS has been that the autonomic nervous system is not working properly

...but what if the autonomic nervous system is working as designed?

What if the reduced blood flow we see in people with POTS is because the glymphatic system is hard at work?

This has actually been demonstrated in studies of severe brain trauma

They describe a bunch of changes in blood flow to the brain in the first 24-48 hours after injury

All the blood flow (hyperemesis) and low blood flow (hypoemesis)

pubmed.ncbi.nlm.nih.gov/25154387/

This study was published before the new research on the glymphatic system, so researchers assumed that the decrease in cerebral blood flow was not supposed to happen

But uhhh healing injuries makes a lot of waste, and the glymphatic system is what deals with waste

Ok so, why would the glymphatic system malfunction?

Well one stellar possibility is: neuroinflammation

We're still learning a lot about neuroinflammation because, again, scientists thought the brain had special protection from infections

Because they thought it was "immunologically privileged" by not being hooked up to the lymphatic network

So they thought infections in the brain were rare, and inflammation typically follows infection

Most research on neuroinflammation has focused on infections that can cross the blood brain barrier (like chicken pox, syphilis, SARS/covid, and cryptococcus)

But more recent research has shown that neuroinflammation can also happen due to Immune System Shenanigans, like autoimmune conditions or mast cell disorders

And we're still trying to learn more about that

"A plausible general scenario in the setting of neuroinflammation is that glymphatic impairment aggravates inflammation by suppressing cytokine clearance from the brain"

pubmed.ncbi.nlm.nih.gov/34299111/

I'm still working my way through the article above, but the basic hypothesis is that there's Too Much Inflammation for the Glymphatic System to Cope With

So there's a backlog of Inflammatory mediators (like cytokines) and neurotoxic stuff, which causes...More Inflammation

It's sort of like if you're really sick or busy or whatever, so you don't get to routine household maintenance like cleaning the shower

And then your shower goes from "a little pink stuff" to "disaster zone"

And then that snowballs into more problems like "how will I shower"

How does the autonomic nervous system come in?

Well now I'm in "beyond what has currently been studied"

But say, hypothetically, the body suppresses blood flow to the brain to increase glymphatic system cleaning time

The let's say you do something, like think a lot or exercise or whatever

That uses more energy than your brain currently has

We definitely know that if your brain isn't getting enough nutrients to support itself, it slams the autonomic nervous system to send blood stat

Fun fact: Activating the autonomic nervous system emergency red button also activates the immune system

(And I think also causes oxidative stress, and a bunch of waste products from that)

Creating more "mess" for the poor glymphatic system

mastattack.org/2017/06/mastat…

There's a bunch more potential side effects of frequent autonomic system activation

For example, emergency mode affects digestion and how fast food moves through your digestive system

Contributing to gastroparesis, SIBO, and potentially other types of gut dysbiosis

I don't want to get on a whole tangent, but there's a whole "gut brain microbiome" communication system

That relies on *checks notes* the autonomic nervous system and the immune system

Pro-inflammatory signals from the gut can affect the brain, and vice versa

I haven't read enough about microclots to map out all the exact ways they can contribute to neuroinflammation (and vice versa) and impaired glymphatic system drainage

But I can think of one million possibilities

So it's early days, lots more research is needed

But I'm very excited by all of the new research questions raises by all the stuff we're learning about the glymphatic system

And how it relates to what we're learning about neuroinflammation

For instance, I've had some bouts of idiopathic intracranial hypertension

Which is basically "your body makes too much cerebrospinal fluid for some unknown reason, and then there's too much pressure inside your skull and it squashes important stuff"

liminalnest.wordpress.com/2023/03/19/idi…

There's been a couple studies saying "hmm seems like neuroinflammation and IIH might be related, but we don't know how exactly"

But uhhh if that extra cerebrospinal fluid is being made because the glymphatic system is working on overdrive??

That would maybe explain a lot 👀

Anyway, thanks to @8Eevert for sharing the research that sent me down this rabbit hole!

You always post such interesting studies, and you had a similar train of thought when looking at the research too

ETA: just remembered neuroinflammatory mediators also include chemokines, which basically go "hey can we get some white blood cells over here!"

The glymphatic system relies on reduces blood flow to make room for waves of CSF, and uhh perhaps excess chemokines could disrupt that

In the replies, @jreidchapman asked about whether lymphatic drainage techniques could be used to help support the glymphatic system

With the caveat that a lot of this is just my opinion/educated guesses, you can check the replies for some of my ideas

https://twitter.com/jreidchapman/status/1643193187773693955?t=hfwlkCLLm0TkUdAh2iuGNw&s=19

If you enjoy reading about neuroinflammation and post-viral illness, you might also like this thread about the microbiome and neuroinflammation

The gut-brain-microbiome connection is super exciting!

https://twitter.com/UntoNuggan/status/1635283556133113856?t=hfwlkCLLm0TkUdAh2iuGNw&s=19

As mentioned above, the brain relies on getting a constant supply of energy to function

One finding in ME, Long Covid, and honestly most neurodegenerative illnesses is hypometabolism in the brain

https://twitter.com/drclairetaylor/status/1588288494618939393?t=_A-vl1MFEte_gUpmSI4UdQ&s=19

As mentioned above, reduced cerebral blood flow allows the glymphatic system to help clear waste and inflammatory mediators like cytokines

I'm very curious if the hypometabolism we see on scans (above) is basically areas of neuroinflammation and increased glymphatic activity

The primary source of energy for the brain is glucose, and one thing we're seeing in a lot of people with post viral illnesses is weird endocrine/glucose/cortisol/metabolic problems

It's possible these are essentially a side effect of neuroinflammation/glymphatic activation

And of course, endocrine issues like hypoglycemia or adrenal/cortisol issues

(As well as digestive issues due to pancreatic weirdness)

Can also contribute to neuroinflammation. Like "not enough glucose for the brain, activate emergency mode"

https://twitter.com/UntoNuggan/status/1631746868114849799?s=20

Also because there seem to be multiple ways that inflammation throughout your body can contribute to neuroinflammation

We're still trying to learn more about this, because again, scientists thought this was Not A Thing due to thinking the brain didn't have a lymphatic system