Webinar - ME/CFS Involves Brain Inflammation: Results from a Ramsay Pilot Study - Jarred Younger

Really good webinar. Quickly from memory before I forget it all:

More information about the brain scanning studies that looked at lactate and other chemicals and brain temperature, and found distinct differences between people with ME, compared with people with rheumatoid arthritis and healthy controls.

Their paper on this has been accepted for publication and should come out in the next couple of months.

They are also researching low dose naltraxone and another low dose drug I've forgotten, and some 'botanicals' including curcumin. I think he said he'd just started analysing the botanicals data and found some definite improvements in symptoms between two of them and healthy controls but he doesn't know which ones yet as the unblinding hasn't been done yet.

He also talked briefly about other possible avenues of treatment being cooling the brain by cooling the neck to cool the blood supply to the brain as is done in acute cases of brain injury like American footballers who get concussed, but that at the moment needs specialist equipment and would need a proper clinical trial.

And vagal nerve stimulation using external equipment is another one he'd like to look at.

His hypothesis is that ME/CFS symptoms can be explained by the inflammation in the microglial cells in the brain in areas which affect the sickness response like you get in the flu, which can explain most of the symptoms of ME.

I love listening to Jarred Younger - he is such a good speaker and explains things really clearly.

There were lots of good questions at the end.

I haven't covered everything!
 
I have not looked at the webinar but am trying to catch up with the earlier discussion.

One point worries me. Inflammation is associated with a rise in temperature of the organ involved if that organ is normally at below core temperature. In other words hands and feet get hot with inflammation but I am not at all sure that a liver or a brain would get hot. The 'heat' of inflammation is due to more blood at core temperature flooding in to tissues that are normally colder. If a tissue is normally at core temperature - as brain is - then the increased blood flow of inflammation would not be expected to raise the temperature. It might even help cool the tissue down a bit.

Temperature might also rise because of cellular activity but brain cells are about the most metabolically active in the body anyway. I suspect microglia have very low energy requirements in comparison.

In other words, although it would be fascinating if brain was at a different temperature in ME I rather doubt it would indicate inflammation.
 
What they found was some quite small areas in the brain had a temperature about 1 degree higher than the rest of the brain. And it coincided with the areas with the peak in chemicals that suggested microglial inflammation. It was definitely not the whole brain overheating.

He also explained that the brain is very metabolically active and would heat up if it didn't have blood circulating from the body to cool it down.
 
Moderator note: Post moved from another thread

Just watched the SMCI webinar with Dr. Jarred Younger, presenting the results of his Ramsay fund (from SMCI) study on neuroinflammation. Thus far, his hypothesis that ME involves brain inflammation has been verified.

The study has been through peer review, and will be published in about a month or so in the journal Brain Imaging and Behaviour.

This is of course a small study to start with: 15 with ME; 15 controls. Significant signs of neuroinflammation in pwME, and not in controls. The specific stats will be released by the journal.

Jarred is applying for more funding, collaborating with researchers new to this field, keeping track of neuroinflammation research in other fields, such as Alzheimer's, Autism, and epilepsy.

He said three other previous studies have found neuroinflammation in pwME, however, their ability to research chemicals that cause the inflammation was more limited.

He is also looking at herbs reported to reduce inflammation. This is double blind, and still in process.

The brain imaging he is using is an MRI with an extension to examine chemicals that cause inflammation. Two of these found to be significant in this study are lactate and choline.

As regards an ad for ME; another wild and crazy idea: there was an ad about "your brain on drugs", that showed fried eggs in a frying pan. How about a photo of a brain scan showing neuroinflammation in ME: "your brain with ME", the "ME brain", the "ME brain on fire"...

Jarred Younger is an excellent presenter. SMCI said the number of registrants for this webinar far exceeded any previous ones.
 
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A couple more points about Jarred's webinar: he said clinician/researchers are already coming to him with requests on how to do this more complex MRI testing.

He hopes that with more data, this technique will be able to distinguish between various brain injuries/diseases. He showed an image of a concussed brain which looks different than ME brains.

His study did not find elevated levels of N-acetylaspartate which I understand can cause brain damage like that seen in MS.
 
Trish said:
He also explained that the brain is very metabolically active and would heat up if it didn't have blood circulating from the body to cool it down.
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That is what is puzzling, because by definition inflammation is associated with increased blood flow, so that should cool the brain down, rather then heating it up.

I am pretty sure the metabolism of microglia will be quite slow in comparison to neurons, which use huge amounts of energy for electrical signalling. So an increase in local brain temperature would be better explained by an increase in nerve cell activity rather than inflammation.
 
Jonathan Edwards said:
That is what is puzzling, because by definition inflammation is associated with increased blood flow, so that should cool the brain down, rather then heating it up.

I am pretty sure the metabolism of microglia will be quite slow in comparison to neurons, which use huge amounts of energy for electrical signalling. So an increase in local brain temperature would be better explained by an increase in nerve cell activity rather than inflammation.
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Best you watch it when the video is made available. I may be mis-remembering the details.
 
Jarred is an excellent speaker.

I think people could relate to the brain images, and see this as important, and why ME has multiple symptoms, which is why I think ads about this area of research and findings could be effective, and why I included my summary of the webinar in this thread. I've missed stuff too, so thank you for your notes!

More research of course needs to be done - larger subject numbers etc., but pointing out the link to the new study, with photos would, I think be somewhat effective, if not for the public, then for those in medicine.
 
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Jonathan Edwards said:
That is what is puzzling, because by definition inflammation is associated with increased blood flow, so that should cool the brain down, rather then heating it up.

I am pretty sure the metabolism of microglia will be quite slow in comparison to neurons, which use huge amounts of energy for electrical signalling. So an increase in local brain temperature would be better explained by an increase in nerve cell activity rather than inflammation.
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Does the increased nerve cell activity cause the excitotoxicity Cheney talks about....my symptoms calm with Klonopin and I can be more functional for a short time...it's like the old me comes back. Also, I wonder if increased nerve cell activity causes the wired feeling at night, the racing brain? Im not convinced by Jarred Youngers hypothesis, I think there's more going on, that's my tuppence worth as a patient. Plus he is looking at mild to moderate patients, not the severe. So maybe alot more going wrong in severe spectrum
 
Jonathan Edwards said:
I have not looked at the webinar but am trying to catch up with the earlier discussion.

One point worries me. Inflammation is associated with a rise in temperature of the organ involved if that organ is normally at below core temperature. In other words hands and feet get hot with inflammation but I am not at all sure that a liver or a brain would get hot. The 'heat' of inflammation is due to more blood at core temperature flooding in to tissues that are normally colder. If a tissue is normally at core temperature - as brain is - then the increased blood flow of inflammation would not be expected to raise the temperature. It might even help cool the tissue down a bit.

Temperature might also rise because of cellular activity but brain cells are about the most metabolically active in the body anyway. I suspect microglia have very low energy requirements in comparison.

In other words, although it would be fascinating if brain was at a different temperature in ME I rather doubt it would indicate inflammation.
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I was curious about brain temperature so I did a google search and this paper seemed interesting.
Brain temperature and its fundamental properties: a review for clinical neuroscientists 2014, Huan Wang et al.

A few quotes:
Extensive animal and human data have conclusively established that core brain temperature is generally higher than body temperature, but correlates well with body temperature...

Because perfusing blood clears the metabolic heat produced in the brain, the thermal gradient is from the brain (heat source with higher temperatures) to the blood (heat sink with lower temperatures). At rest, cerebral heat balance is established with a jugular-venous-to-arterial temperature difference (v-aDtemp) of approximately 0.3°C (Yablonskiy et al., 2000; Nybo et al., 2002b).
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Human data overview
On average, deep brain temperature is less than 1°C higher than body temperature in humans, unless cerebral injury is severe enough to significantly disrupt the brain-body temperature regulation (Soukup et al., 2002). Theoretically, the maximal brain temperature elevation over blood temperature, under physiological conditions, would be approximately 0.9°C for a typical hematocrit level of 40% (Yablonskiy et al., 2000), and both the magnitude and direction of the difference can be temperature dependent (Nybo et al., 2002b; Smith et al., 2011). The temperature gap may become more accentuated at higher body temperatures and diminish or even reverse in its relationship at lower body temperatures.
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Cerebral circulation and the thermal environment of the brain
The net chemical reaction of oxygen and glucose generates most of the energy required for cerebral metabolic activities. While some of this energy (33%) is immediately released as heat, the rest is used to produce ATP molecules to fuel a complex chain of chemical reactions (Siesjö, 1978). Given that no mechanical work is performed in this process, the final ATP hydrolysis releases the energy back to the biological system as heat (Siesjö, 1978). On average, 0.66 J is released every minute per gram of brain tissue (Yablonskiy et al., 2000). If not promptly removed, this heat generation and accumulation will lead to a continuous increase in local brain temperature. In humans and other large animals, the principal heat removal mechanism is through the cerebral circulation.
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In awake or anesthetized large animals, the physiological direction of thermal energy flow is from the brain (heat source) to the blood (heat sink). Cooling or warming of the perfusing blood results in prompt thermal exchange with various brain sites. In regards to speed and amount of heat transfer, it is most effective in the cerebral cortex adjacent to a cortical arteriole (Hayward and Baker, 1968b). With no significant change in metabolic heat production, vasodilatation enhances cerebral heat clearance, while vasoconstriction impedes brain cooling
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I'm not sure how much this improves my understanding. I guess if some regions of the brain are hotter than others they are more metabolically active and/or the circulation there is reduced so they are not being cooled fast enough, or both.
 
Trish said:
I was curious about brain temperature so I did a google search and this paper seemed interesting.
Brain temperature and its fundamental properties: a review for clinical neuroscientists 2014, Huan Wang et al.

A few quotes:








I'm not sure how much this improves my understanding. I guess if some regions of the brain are hotter than others they are more metabolically active and/or the circulation there is reduced so they are not being cooled fast enough, or both.
Click to expand...
Disclaimer: I had to skim through the video so I could have misunderstood.

In the video, Younger specifically talks about the heat mapping with areas of increased lactate and choline. He seems to have identified increased chemicals in the brain first, and then correlated this with the hot spots so that the MRS can be used non-invasively to measure chemical increases.

When he mentions neuroinflammation, I don't think he uses it in the same way other people use the term 'inflammation'. I.e., while inflammation seems to increase blood flow to an area, this appears to be the opposite.

What he means is overactive cells (microglia, mostly) producing too much choline or lactate because of a speeded up process of cell replacement, and increased aerobic metabolism in the brain (respectively).

He thinks that cells are dying too quickly, and therefore being replaced too quickly, which increases the choline, while aerobic metabolic processes are also speeded up, so that an excess of lactate is accumulating.

It's this 'brain on fire' idea again. Notably, he doesn't think there's neuronal death.
 
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adambeyoncelowe said:
What he means is overactive cells (microglia, mostly) producing too much choline or lactate because of a speeded up process of cell replacement, and increased aerobic metabolism in the brain (respectively).

He thinks that cells are dying too quickly, and therefore being replaced too quickly, which increases the choline, while aerobic metabolic processes are also speeded up, so that an excess of lactate is accumulating.
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I think that is indeed what he thinks but I think it would help the scientific process in general to say that rather than talk of 'neuroinflammation'. The query I have is why increased cell activity and lactate production should be attributed to microglia rather than neurons, which have a much higher metabolic rate normally. And I am not clear what cells dying and being replaced would have to do with it.

I didn't think aerobic processes generated lactate. I thought they generated CO2 and water through the Krebs cycle.
 
This is all way over my head and I still haven't watched the video but

Jonathan Edwards said:
it would be fascinating if brain was at a different temperature in ME
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so it would be great to make progress on getting to the bottom of the mechanism, with questions like these:

Jonathan Edwards said:
The query I have is why increased cell activity and lactate production should be attributed to microglia rather than neurons, which have a much higher metabolic rate normally. And I am not clear what cells dying and being replaced would have to do with it.
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Can we contact Jarred Younger? Can we invite him to a post-publication discussion of his work here on S4ME? (Not sure if we still have the capacity for that, @Andy?)

It bothers me that researchers may be silo'ed off from each other in such a way that a full discussion of their findings from all angles doesn't always seem to happen at an early enough stage. If this brain-heating is a genuinely exciting observation (and it seems like one to my inexpert eyes) then it would be great to get it thrashed out in a big discussion.
 
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