The building is dark – the doors are locked – everything has been shut down. It’s early 2020 and the coronavirus pandemic has struck. A figure walks down the street, pauses – briefly peers into the entrance – and moves on. He turns left at the end of the building, pauses at a locked door, digs into his pocket, takes out a key, and enters the building.
He’s the only one in the massive building. It’s Jarred Younger – finding a way to get at his data in his Neuroinflammation, Pain, and Fatigue Laboratory.
Brain on Fire? The Big NIH-Funded Brain Scan Study
An earlier pilot study of Younger’s revolutionary new thermography technique to assess neuroinflammation using a kind of heat mapping technique had been successful. Now Younger was in the third year of a major five-year NIH grant to determine – yes or no – whether the thermography technique was effective. Along the way, he would assess neuroinflammation in 90 ME/CFS women and 30 healthy controls. The study had all the hallmarks of a big NIH grant – it was huge, complex, and novel. It had three parts:
- Measure neuroinflammation across the brain using 4,000 assessments of gray and white matter, and cerebrospinal fluid.
- Use a good day / bad day approach in 20 women to see if the neuroinflammatory markers picked up in the brain scan were linked to symptom severity.
- Assess the efficacy of the new thermography approach using a PET scan that picked up activated microglia.
It was another example of an ME/CFS researcher pushing the medical research field further. The study could potentially validate how much and where neuroinflammation was present in ME/CFS – thus validating the disease itself and throwing it into the class of major neurological disorders.
So here he was in year 3 of the study. I asked him how it was going. He said 50 ME/CFS and 30 healthy controls had gone through the study – enough to start the interim analyses.
I remarked how exciting (terrifying?) it must be to work on something for years and have it all come down to a single statistic. Younger said that was his favorite part, though. As a scientist, that’s where the juice lies for him. It was all about the discovery. Did the technique reveal the truth?
A positive result could change the course of brain imaging. Right now, researchers use radioligands that attach to receptors on active microglia to assess neuroinflammation. The approach is controversial because the ligands can attach or dock to other receptors as well. Younger suspected that Watanabe’s 2014 ME/CFS study was correct – neuroinflammation is present in the brains of people with ME/CFS, but the ligand he had available to him (PK11195) – was messy – it could dock to a bunch of stuff.
The next-generation ligands had problems as well, and now third-generation ligands are being developed (but are not available for human research yet). We still lack access to radioligands that can distinguish between activated microglia and astrocytes. That’s an important distinction as activated microglial cells could be kicking off long-term inflammation in the astrocytes.
Determining how to treat what’s going on will require knowing where the neuroinflammation, if it’s present, is coming from. Younger is working with a group that invented one of these new markers and was hoping to test it this year with some ME/CFS and FM patients.
Because Younger’s new thermography technique is considerably cheaper and side-effect free, it had the potential to revolutionize how brain scans were done. Not only would the technique be available to more people, but it could be used to assess the effectiveness of treatments on the brain.
Younger is clearly on the cutting edge of neuroscience – in fact, that’s where he said he likes to be. I asked him about the thermography technique – are other groups picking it up? He said seizure and schizophrenia groups were picking up it at UAB (the University of Alabama at Birmingham). So far, it was working really well.
“Going Nuclear?” The Brain Invasion Study
Talk about a fascinating and potentially far-reaching study. Health Rising reported on the ME Research UK funding leukocyte infiltration study back in 2018.
Only now is the study about to actually start testing patients. The study is so novel that it took years to get through the regulatory hurdles posed by it. Younger obviously thrives on developing cutting-edge technologies, but it makes it more difficult at times as well.
Everything is new. First, you take out the white blood cells (leukocytes), then you separate them, put a radiotracer inside them, put them back in, and this is the tricky part – have them act as if nothing happened and have them go on about their business as usual.
The question at hand is whether white blood cells are making their way through the blood-brain barrier into the brains of ME/CFS patients. The brain has its own unique immune cells called microglial cells. White blood cells – chiefly T and B-cells from the body – on the other hand, are only pulled into the brain as a last resort. These are amongst the most powerful cells in the immune system but once they’re in the brain, they don’t know friend from foe. Like bulls in a china shop, they go on a rampage.
Avindra Nath – who has also wondered whether these cells have gotten into the brains of ME/CFS and long-COVID patients, has said they’re like unwanted guests who never leave.
Younger been working for years for this moment. He now knows that the technique works – he can show the labeled white blood cells moving across the body and into the brain, and monitor them for almost a week (a new record) as they move across the body. Mostly they go to the muscles, where they hang out. He knows they’re safely cooped up in the brain’s blood vessels in healthy people’s brains. The next step is monitoring them in the brains of people with ME/CFS, multiple sclerosis, and other diseases.
Finding them in ME/CFS patients’ brains would be significant indeed – what Younger called a “severe pathological inflammation”. It would mean that the brain has either gone nuclear and has brought in dirty weapons to resolve something serious or that an important communication pathway has been upended and the brain is calling in strikes on itself for no good reason. It’s also possible that the blood-brain barrier has been seriously damaged in some way.
If Younger does find immune cell penetration he’ll do a gadolinium scan to see if the blood-brain barrier has become leaky. There are no treatments for immune cells in the brain but groups are working on that and if this technique pans out they’ll have a way to monitor it.
Noting that a leaky gut is present, and a leaky blood-brain barrier may be present, I asked if the same thing could be causing leaks in these different areas. Younger said it was possible that a similar process was occurring.
The Fibromyalgia Psilocybin Trial
Younger mentioned as an aside that the Epilepsy Division Director, Jerzy Szaflarski MD, Ph.D. is finding that cannabis works really well with epilepsy. (The UAB has one of the most advanced epilepsy research centers in the country and Alabama actually passed a law allowing cannabis to be used in the treatment of pediatric epilepsy.)
The last time I talked to Younger, he shied away from cannabis research because it was just too hard and time-consuming given all the roadblocks at the federal level, but he said, “Everything is getting easier”, and that they were a few months away from doing a psilocybin trial in fibromyalgia (!). He’d heard from enough people that it helped that he was going to give it a go. The approvals were all in – it was going to happen.
It’s going to be a small, proof-of-concept, pilot trial – just 10 people. Noting that some anecdotal evidence suggests that a full dose of psilocybin might be able to cure FM pain for several months, the study was going to involve a full dose, not a microdose. A brain scan the day before and after the drug is going to be part of the study and is going make up a Ph.D. student dissertation.
Clinical psychologists will meet with the participants before the trial for a couple of weeks. Someone will be in a room made up to feel calming and comfortable in the hospital the entire time. (I asked if Jimi Hendrix posters were going to be part of the décor but no). Each session (trip?) will last about six hours. The main goal on the psychologists’ part is to keep the participants calm and anxiety free.
Younger said he’d been thinking about this trial for quite a while. This arena has finally been loosening up as researchers show positive benefits. DMA, ecstasy, and LSD are all becoming available for testing. Younger celebrated the fact that if you have good scientists and good protocols, these agents are becoming available to be tested in medical trials.
Psilocybin and LSD are 5HT2A agonists (activators) that turn on that specific receptor and the serotonergic system. Exactly what it’s doing is not clear yet. Genetic evidence suggests, though, that abnormalities in this pathway exist in FM. Michigan and Daniel Clauw are starting one and there’s another one as well.
The Patient-Led Research Fund – ME/CFS and Long-COVID LDN Grant and the Next LDN? (Dextro-naltrexone)
This is going to be a decentralized trial. Interestingly, the money provided was in crypto and UAB didn’t know yet how to manage that. Younger, again, was pulling them in a new direction – albeit one he hadn’t anticipated.
I had to ask about dextro-naltrexone – a potentially more powerful form of LDN. Younger, with his Stanford studies, had basically birthed the LDN fibromyalgia movement. And I hadn’t heard of dextro-naltrexone until I heard of it from him. It’s never been used on a human before but keeps all the good parts of LDN and gets rid of the problematic parts that can cause side effects. That could mean being able to take higher doses and having much better effects.
Younger had hunted down a source, and applied for NIH funding, but was rejected. He needed about $1.2 million to get the dextro-naltrexone study going. Younger said it was on the top of his list and noted how frustrating it was that it hadn’t been tested. Talk about an opportunity, though, to potentially make a difference for a lot of people with a better and more effective form of LDN. Against that possibility, the $1.2 million seemed small, indeed. (Any donors out there?)
The Botanicals Study Wins Out
Younger has basically been beating the bushes in an attempt to flush out things that can help right now with neuroinflammation. In a randomized, crossover, quadruple masked trial, he tested 9 botanicals (Boswellia serrata, Curcumin, Epimedium, Fisetin, luteolin, nettle, pycnogenol, Reishi mushroom, resveratroil) over a variety of doses in Gulf War Illness.
- Jarred Younger – runs the Neuroinflammation, Pain, and Fatigue Laboratory at the University of Alabama at Birmingham. Its goal is to “end chronic pain and fatigue for millions of people across the world”.
- I met with him at his office. He’s in the midst of a major NIH-funded grant to measure neuroinflammation across the brain in people with ME/CFS, to determine if markers of neuroinflammation are associated with symptoms in ME/CFS, and to determine if his new thermography approach to assessing neuroinflammation works.
- Because Younger’s new thermography technique is considerably cheaper and side-effect free, it has the potential to revolutionize how brain scans were done.
- Seventy participants have been through the study and Younger will soon begin an interim analysis to determine if neuroinflammation was found.
- Younger has also developed a technique to assess if white blood cells (WBCs) from the body have entered the brain. Because the brain already contains its specialized immune cells, and WBCs don’t know friend from foe, they’re only called into the brain under the direst circumstances.
- It’s taken years to develop this new technology and get it past regulatory hurdles, but Younger will soon start testing people with ME/CFS to see if their brains have “gone nuclear” and brought in dirty weapons, so to speak, to combat something in the brain.
- If Younger finds WBCs in ME/CFS patients’ brains, he’ll begin assessing the blood-brain barrier to see if it’s developed leaks that could also explain a WBC invasion.
- Reporting that it’s become considerably easier recently to test these kinds of drugs, Younger will shortly begin a small full-dose psilocybin study to see if the drug relieves pain in fibromyalgia. He’s also beginning a low-dose naltrexone (LDN) study in long COVID and ME/CFS shortly. He has yet to get funding to study LDN’s probably more effective cousin – dextronaltrexone.
- Younger’s Gulf War Illness botanicals study found that these were helpful: curcumin, stinging nettle, and resveratrol.
- Younger’s findings suggest that the immune system is kicking in too late in fibromyalgia, and that when it does kick in, it does so with a vengeance – producing symptoms. In this scenario, people with FM and ME/CFS never get a terrible cold but are always getting whipsawed back and forth by the immune system.
- Younger’s been great at developing new technologies and getting funding but has his own supply-chain issue to deal with – post-docs. The Ph.D.’s that researchers use to write up their studies virtually disappeared for Younger and his colleagues during the pandemic. The result – about 20 papers are in the queue, waiting to be written up.
- Seven years after Younger created his Neuroinflammation, Pain and Fatigue Lab at the University of Birmingham, everything is telling him his initial hypothesis – that neuroinflammation is playing a major role in ME/CFS, fibromyalgia, and now long COVID – is correct.
Three Microglial Inhibitors That Worked
- Curcumin – Pure Encapsulations: low dose – 500 mg; high dose – 1,000 mg; – reduced pain and fatigue; note – it adds some load to the liver.
- Stinging Nettle – Nature’s Way: low dose – 400 mg; high dose – 800 mg. (Might stop a virus from replicating.)
- Resveratrol – Pure Encapsulations: low dose – 200 mg; high dose – 600 mg). WebMD reports resveratrol may be able to open the blood vessels, reduce clotting, decrease pain and help maintain proper blood sugar levels.
Pycnogenol was a possibility – it did well in the tests – but did not show a dose-response effect.
Why the Type of Pathogen Doesn’t Matter in ME/CFS (or … Why the findings in Long COVID will probably apply to ME/CFS)
Younger thinks of long COVID as a type of ME/CFS – the only thing that’s really different about it is that we know which pathogen triggered it. If Younger is right about chronic microglial activation producing the neuroinflammation (e.g. sickness behavior) that’s driving ME/CFS, the specific pathogen that triggered the microglial activation doesn’t matter. What matters is that the microglial cells (the immune cells of the brain) have become chronically activated.
The microglial cells (the immune cells of the brain) are dotted with toll-like receptors that respond to different pathogens (viruses, bacteria, mold) that turn the microglial cells on. The microglial cells have off switches – in fact, as they go into fight mode, those switches get amplified – but Younger has evidence indicating that the off switches are not working in fibromyalgia.
Younger temporarily ramped up the microglial response in FM with a bacterial toxin. As the body dealt with the toxin, a microglial inhibition response involving fractalkine should have turned the microglia off once the threat had passed. In FM, though, the microglial inhibition response (fractalkine) never kicked in, leaving the microglia activated and producing the pain hypersensitivity and flu-like symptoms associated with FM.
Younger stated that the data suggests some immune suppression in FM is giving the pathogen an extra in. The immune system does eventually kick in, but instead of dealing judiciously with the pathogen, it overreacts – causing symptoms. This happens again and again and again. You never develop a huge infection, but you’re always getting whipsawed by the immune system – and that’s potentially causing the symptoms in ME/CFS and similar diseases. That paper is under review right now.
The Great Survey
Health Rising will have more on this later, but Younger and his Neuroinflammation, Pain, and Fatigue Laboratory have rolled out a new chronic disease survey – and it’s doozy. It’s the most comprehensive illness survey I’ve ever taken (and I’ve taken many).
It needs to be comprehensive because Younger’s group will be applying artificial intelligence and machine-learning techniques to it to better understand ME/CFS, fibromyalgia, and similar disorders. (Thankfully, it has a save and continue capability.) They’re aiming for 5,000 completed surveys.
A Dearth of Post-Docs!
Younger’s obviously done well at UAB. (Too bad for you, Stanford). He’s developed two new technologies and has been an ace at getting grants – but he has a problem. He’s sitting on a ton of data! He said he has over 20 papers waiting to be written, but one man can only do so much.
Younger’s limiting factor right now is a dearth of post-doctoral students (Ph.D.) that researchers use to write up their findings.
His big NIH-funded Daily Immune Monitoring Study, for instance, and its tens of thousands of data points are done and are waiting to be analyzed and written up. Valuable data on leptin and fractalkine – two immune factors not often discussed in these diseases but which could make a difference – are sitting there – not making much of a difference right now.
Something happened during the coronavirus pandemic that isn’t clear. Either the post-docs went to industry, or out of academia, but they are mostly gone – and not just for him but for his peers as well. Instead of rolling in post-docs, he’s having trouble finding them right now.
One of Health Rising’s first pieces on Younger called him “The Neuroinflammation Man”. Younger’s been at his Neuroinflammation, Pain, and Fatigue UAB Laboratory now for 7 years. I asked him how he feels about neuroinflammation now after all this time. Was he as confident in his hypothesis as before? He was. So far, everything he’s seen supports his hypothesis that neuroinflammation is a big player in ME/CFS and fibromyalgia.
BIG (Little) Drive Update
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Jarred Younger is another researcher Health Rising makes every attempt to keep up with. This time that included taking a wide detour during a cross-country trip to Cape Cod to visit him. If these kinds of interviews spark your creative juices and leave you more hopeful for the future please support us.