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

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An excerpt from a terrific article about a new finding by Jarred Younger, which finding is yet to be formally published.



Researchers have thought for decades that neuroinflammation is probably present in chronic fatigue syndrome (ME/CFS), but it’s only recently that the technology has been able to pick up the lower levels of neuroinflammation believed present in diseases like ME/CFS and fibromyalgia. The Japanese were the first to take a crack at it.

Neuroinflammation has long been thought to play a role in ME/CFS but only recently have the tools to study it become available.

They have long believed that inflammation produces central fatigue (fatigue emanating from the brain), which plays a major role in ME/CFS. In 2013, Watanabe proposed that inflammation in the brain was whacking the “facilitation system” which pops up when we are fatigued to boost signals from the motor cortex to keep our muscles moving. He also hypothesized that an inhibition system was turning up the fatigue in ME/CFS.

A 2016 study rounded the circle when it found evidence of reduced dopaminergic activity from a part of the brain (the basal ganglia) which activates the motor cortex. That fit in just fine with Miller’s results, which suggested that problems with the basal ganglia could be producing both the fatigue and the motor activity problems in ME/CFS.

The big breakthrough came in 2014 when the Japanese startled just about everyone with a PET scan study which found widespread neuroinflammation in the brains of ME/CFS patients. The study was small (n=19) but the findings appeared strong.

The neuroinflammation was widespread but was highest in the areas of the brain (thalamus, amygdala, midbrain, hippocampus) that had shown up in ME/CFS before. Plus, the Japanese were able to link specific regions of inflammation to specific symptoms. Inflammation in the thalamus was associated with cognitive impairment, fatigue and pain; inflammation in the amygdala was associated with cognitive issues; and inflammation of the hippocampus was associated with depression.

Anthony Komaroff called the findings the most exciting in decades. The Japanese began a much larger (n=120) neuroinflammation study. This year they published a large number of papers on ME/CFS in the Japanese Journal, “Shinkei Kenkyu No Shinpo” (Brain and Nerve). One of the papers was specifically on neuroinflammation but the findings have not yet been published in English journals.

Neuroinflammation – The Younger Way
Jarred Younger – who runs the Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham has also long believed that neuroinflammation plays a major role in chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM).

In 2015, he noted what a hot subject neuroinflammation had become. Seven years ago, he said, there was almost nothing on the microglia at the pain conferences. Now they’re loaded with presentations on microglia.

These immune cells are sensitive to so many factors and can be triggered in so many ways that virtually any stressor, from an infection to toxins to psychological stress, can potentially trigger a state of microglial sensitization in the right individual. With their ability to produce dozens of different inflammatory mediators, Younger believes that the difference between ME/CFS and FM could simply come down to small differences in how the microglia are tweaked.

Both diseases could be triggered by high rates of immune activation which, over time, sensitizes the microglia to such an extent that they start pumping out inflammatory factors at the first sign of a stressor.

New Non-Invasive Technique
Younger had just finished up his ME/CFS brain thermometry study. He used a new, less invasive way of assessing the brain called magnetic resonance spectroscopic thermometry (MRSt). The technique, which aims to create a thermometer for the brain, uses a magnetic resonance imaging (MRI) scanner. While Younger was assessing the temperature of the brain, he was also examining its chemical makeup.

My partner asked him how he glommed onto the heat mapping idea? It turned out that Younger had been trying for quite some time to find a non-invasive way to assess neuroinflammation. He needed a technique he could safely use again and again in his longitudinal (Good Day/Bad Day) studies.

None of the present techniques, however, fit the bill; they were all heavily invasive. The PET scan approach uses radiation to image the brain. Another approach using magnetized nano particles is supposed to be safe but it still requires putting little bits of metal into peoples’ brains…

After hitting several dead ends, he hypothesized that because inflammation produces temperature increases, he could try and create a heat map of the brain. Looking through the literature, he realized that thermometry was already being used in the brain to assess stroke and cancer patients. It turns out that the brain’s attempts to repair the damage from stroke and cancer results in huge temperature increases. The stroke and cancer researchers, though, were just focused on small areas of the brain.

Because Younger didn’t know exactly where in the brain to search in ME/CFS, that technique wouldn’t work for him. He had to develop a method that would produce a heat map and a chemical signature of the entire brain, and found a Florida researcher who developed a way to do that.

With this technique, it takes just 20 minutes in the machine to get an entire 3-D heat and chemistry map of an ME/CFS patient’s brain. After The Solve ME/CFS Initiative (SMCI) provided funding, he got to work and ultimately scanned the brains of 15 ME/CFS women and 15 age and sex matched healthy controls.

Widespread Neuroinflammation Found in ME/CFS Patients’ Brains
“The markers were truly elevated” Jarred Younger

It turned out that Younger’s brain-wide search technique was right on. Looking at single areas of the brain in ME/CFS patients would have produced misleading data. It turned out there was no single area or even a group of areas in the brain that were abnormal in ME/CFS: most of the brain was.

Younger found lactate – a product of anaerobic metabolism – widely distributed across the brains of people with ME/CFS. He opened a chart showing an amazing array of lactate-engorged brain regions. He picked out a few: the insula, hippocampus, thalamus, and putamen, which had particularly high levels. They were virtually the same regions the Japanese had found in their 2015 study. The fact that the temperature increases overlapped with the lactate increases provided further confidence that Younger had identified some key areas.

Check out the rest at Cort's blog:
https://www.healthrising.org/blog/2...mation-found-chronic-fatigue-syndrome-me-cfs/
 
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alex3619

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

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

perrier

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

Now if it is inflammation then research into antiinflammatories that cross into the brain, as Cort comments on, is one way to go.
Thanks for your lucid posts. I'm not trying to put you on the spot but do you recall what some of the hypotheses are regarding what may be driving this? And how would this fit in with the metabolic trap?
 
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Think I remember reading melatonin has anti inflammatory properties to the nervous system and apparently it crosses the blood brain barrier - at least I know the liposomal kind does.

Also Japanese Knotweed and Alinia cross the blood brain barrier but I don't know if they have anti inflammatory properties.
 
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alex3619

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Thanks for your lucid posts. I'm not trying to put you on the spot but do you recall what some of the hypotheses are regarding what may be driving this? And how would this fit in with the metabolic trap?
They are variations on a theme that I am aware of. Microglial sensitisation for example. Or epigenetic changes. Or metabolic and immune cross talk, which fits with the metabolomics. Even some claiming the real problem is in the vagus nerve, or spine. The first big question is whether or not this is a brain problem, or the brain is damaged secondary to something else.
 

Research 1st

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Thanks for posting this, it's good to have some evidence we're experiencing brain inflammation as that's how it feels for us, albeit fluctuating in severity of course.

I told a neurologist about Jarred Younger's work on brain temperature and they dismissed it, saying if Lumbar Puncture was normal and MRI is normal, this is proof inflammation is not present.

It's so frustrating that neurologists don't want to accept new ideas, and new technologist when it comes to our specific illness.
 

Research 1st

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They are variations on a theme that I am aware of. Microglial sensitisation for example. Or epigenetic changes. Or metabolic and immune cross talk, which fits with the metabolomics. Even some claiming the real problem is in the vagus nerve, or spine. The first big question is whether or not this is a brain problem, or the brain is damaged secondary to something else.
RE: Latest inflammation finding pertaining to ME CFS states of mild/moderate becoming severe/extreme ME CFS.

It always intrigued me, why the 'sporty or very active people', tend to end up bedridden or housebound, and patients who are given proper advice, or aren't in denial, or simply aren't sporty or always wanting to be productive tend to not end up like this as much.

Could it now be, possible to theorise, those who back off in the early state of the disease (for whatever reason) they aren't overwhelming their bodies by as much inflammation/oxidative stress? And it's now making more sense this inflammation may do something fundamentally wrong to the brain, by chronically bathing it in higher levels of inflammation, and it's this inflammation in the body that forces patients from mild/moderate to severe/extreme forms of ME?

As ME CFS patients (as in Cancer) have elevated Cell Free DNA, and DNA should not be cell free, is it possible this cell free DNA contains 'something' that worsens the condition and spreads it around the body, allowing 'it' to propagate past the BBB of the brain and directly affect brain tissue? I say this as Lyme urine (and co-pathogen) DNA tests tend to be measured post exercise, because the assay designers know the DNA gets damaged by oxidative stress, and the Borrelia in the DNA is then hopefully detected in the urine (e.g.in sero-negative Lyme patients). I'm not suggesting we all have Borrelia, just using it as an example of how pathogens DNA can be associated to moving around via DNA damage, showing hidden infection.

Too many doctors, don't believe that post pushing beyond your limits, or post infectious relapse (both involve inflammation) can be for years or longer. They feel the patient is exaggerating that by ignoring our bodies to the point of collapse (GET) or just pushing way beyond our limits voluntarily (denial, sporty people, hopelessness etc) this really can cause a permanent switch to turn on to keep us much more sick that we were before.

If we could prove this, the psychiatric theory of fear avoidance, and resulting 'symptoms are only caused by deconditioning' theory and GET is perfectly safe in ME CFS would be finally proven wrong, that over activity really does lead to permanent relapse in some.
 

heapsreal

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Now if it is inflammation then research into antiinflammatories that cross into the brain
Do we know of an anti-inflammatories that cross the bbb?
Im guessing prednisone and similar corticosteroids as they are used in many neuro inflammatory conditions like MS etc. But its a band aid at best until they find whats causing the inflammation. Interesting they mentioned autopsies and further research in that direction.
 

heapsreal

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Before Youngers research on the 'Hot Head' thing going on in cfsers, i think there was a post that was quite long where many of us were talking about brain fog and if it worsened it felt like our brain was on fire or going through a bad run of insomnia and our brain would feel on fire. Interesting to see the research showing this.

Now how do we get ice to cross the bbb . Maybe the ice bucket challenge will be an actual treatment??
 

percyval577

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Intersting might also be that
Shan, Finegan et al 2018 Brain function charateristics of chronic fatique syndrom: A task fMRI study mention a lot (even older) findings from neuroimmagin, but they say:
"These CFS structural neuroimmaging results are somewhat inconsistent."

Somewhat inconsistent results are also produced from other regions in the body (cf RA Underhill 2015: "...an infectious disease ...")

I ask myself if that could mean anything. Some exaggerated reactions to different circumstances maybe.


However, they do not mention the PET study from Japan. They do also not mention Younger, whoms approach I find very decent.
.
 

alex3619

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However, they do not mention the PET study from Japan. They do also not mention Younger, whoms approach I find very decent.
This is the first time this technology has been used in ME, and its very recent technology. I am particularly encouraged that its noninvasive, so presumably can be safely used again and again.
 

percyval577

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But very expansive, if I am remembering right.

Maybe even this is the reason that the results havn´t been confirmed yet?
 
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@Murph great find, thanks heaps for posting! Can't wait to read more (so i understand it better hah) and share it with other PwME and allies.

ps. the first link doesn't quite work, might need to fix it
thanks, fixed link.

Does anyone else find benefit from paracetamol against brain fog? I take it very often and it makes things notably better, I sometimes even take it as a preventative if I need to do exercise.

This paper seems to show that paracetamol stops inflammation by stopping microglia from making prostaglandins, which are heavily implicated in inflammation because they are big producers of vasodilation.

When theory lines up with your observation it can help you stick to a regime and I am going to keep taking paracetamol now I have seen all this.
 
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perrier

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thanks, fixed link.

Does anyone else find benefit from paracetamol against brain fog? I take it very often and it makes things notably better, I sometimes even take it as a preventative if I need to do exercise.

This paper seems to show that paracetamol stops inflammation by stopping microglia from making prostaglandins, which are heavily implicated in inflammation because they are big producers of vasodilation.

When theory lines up with your observation it can help you stick to a regime and I am going to keep taking paracetamol now I have seen all this.
Paracetamol in North America is the product Tylenol.
 

pamojja

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Do we know of an anti-inflammatories that cross the bbb?
Don't know how accurate this list it, found it somewhere made by someone else:
Code:
Some Antioxidants Which Cross the Blood-Brain Barrier:
——————————————————————————————————————————————————————————————————
Astaxanthin 12 mg · · · · · Half life: 52 hours · Crosses BBB: Yes, easily
Vitamin C 1000 mg · · · · · Half life: 30 mins· · Crosses BBB: Oxidized form does
Vitamin E 400 mg· · · · · · Half life: 2 days · · Crosses BBB: Yes, to a degree
Grape seed extract 500 mg · Half life: 3 days · · Crosses BBB: Yes
Q10 200 mg· · · · · · · · · Half life: 1.4 days · Crosses BBB: Yes
Fisetin 100 mg· · · · · · · Half life: 3 hours· · Crosses BBB: Yes
Rutin 500 mg· · · · · · · · Half life: ?? days· · Crosses BBB: Possibly
Lutein 10 mg· · · · · · · · Half life: 15 days· · Crosses BBB: Yes
Zeaxanthin 4 mg · · · · · · Half life: 12 days· · Crosses BBB: Yes
N-acetyl-carnitine 500 mg · Half life: 4 hours· · Crosses BBB: Yes, easily
Alpha lipoic acid 200 mg· · Half life: 30 mins· · Crosses BBB: Yes, easily
Lycopene 25 mg· · · · · · · Half life: 3 days · · Crosses BBB: Yes
N-acetyl-cysteine 400 mg· · Half life: 2 hours· · Crosses BBB: Yes