Reprinted with the kind permission of Cort Johnson and Health Rising
(This blog is taken from three sources. A radio interview with Jarred Younger, information on the University of Alabama at Birmingham website and an interview I did with him. Thanks to Jarred for his time.)
Unlike others, Younger was never phased by the lack of attention given fibromyalgia and chronic fatigue syndrome. In fact it was something of a spur to him. He started studying fibromyalgia twelve years ago when little was known about it. He found the field intellectually stimulating because little was known about it and because so many people had it. It was a field, he felt, he could make a difference in.
He’s a new breed of researcher – a researcher who started out and stayed in this field. He placed a big bet – his career – on FM and ME/CFS and that bet appears to be paying off. Hopefully other younger researcher will take note and follow.
His road most recently lead from Stanford where his pioneering studies into the effectiveness of low dose naltrexone and fibromyalgia opened a new treatment option for many to the creation of his own Neuroinflammation, Pain and Fatigue Lab at the University of Alabama at Birmingham. The lab is engaged in wide variety of projects, many of which revolve around the subjects of inflammation and neuroinflammation.
Neuroinflammation and the Microglia
In a recent interview Younger described a remarkable shift that’s occurred in the pain research community. Seven years ago, he said, there was almost nothing on the microglia in the pain conferences. Now they’re loaded with presentations on them.
He demonstrated how microglial activation could contribute to a wide variety of diseases. The microglia are extremely sensitive cells. They’re sensitive to so many factors, in fact – they have dozens of different types of receptors – that they can be triggered in many different ways. Anything that activates the immune system, and that means any stressor – from an infection to psychological stress over time to taking in any number of toxins – could potentially trigger microglial sensitization in the right individual.
They can be triggered in many ways but the microglia can produce so many different chemicals that each trigger or collections of triggers could result in a slightly different response. Those differences could manifest themselves in more fatigue in one person, more pain in another, anxiety in another, etc. The difference between ME/CFS and FM and other disorders could come down to a slight differences in the ratio of the chemicals the microglia are putting out.
First I asked if two of important studies in ME/CFS – The Dubbo studies and the Lipkin/Hornig cytokine studies might be showing the same thing. The Dubbo studies suggested that more severe symptoms and higher pro-inflammatory cytokines early in an infectious process predisposed people to come down with ME/CFS. On the longer time-scale Lipkin and Hornig found higher rates of inflammatory cytokines earlier in the illness and lower rates of cytokines later in the illness. Are both studies, albeit on very different time-scales, highlighting a period of increased inflammation which resets the microglial activity in the brain?
Yes, both sets of results support the hypothesis that a significant immune event or series of events can sensitize the immune system. The shift from high cytokine expression early in the disease course to low cytokine expression in later stages may represent the “chronification” of the inflammatory response. At that point, the inflammation has migrated to the central nervous system where it is harder to detect with normal blood tests. Because of the separation of the brain and body, sensitized microglia could continue to drive fatigue even if the immune system in the body appears to be operating normally.
Acute onset ME/CFS and FM is well known. Many people can remember the day everything changed. A survey Health Rising suggested that that some people can become well and then relapse just as quickly as others became ill. I asked Younger if acute onset or relapse fits into the microglial hypothesis? Can they become enter into a state of chronic activation quickly?
Microglia need only a few minutes to change from their resting state to their activated state. There is some evidence they can move back into their resting state just as quickly. If we inject a human or animal with lipopolysaccharide (LPS, also known as endotoxin), we will see a full activation of microglia very quickly. So, it does seem plausible that an individual could experience symptoms that come and go very suddenly. The symptom severity at any given time may just represent the degree to which the microglia are activated.
Until we find out more about how microglia are triggered, it may be useful for individuals to track any environmental, behavioral, and dietary factors that may have causes their symptoms to get worse or improve. Those quick fluctuations may hold the key for understanding how to manage the disorder for any given individual. We have applied for a grant to work on a new tool that will make that process much easier. It will automatically analyze data that the participant provides and find important cause-effect relationships that may be too complex for us to detect on our own.
I asked Younger if chemical sensitivity might be caused by microglial activation. “You mentioned diesel particles sensitizing the microglia. Could multiple chemical sensitivity be a microglial sensitization disorder?”
It is possible, and especially likely if the individual experiences fatigue, cognitive disruption, and other symptoms classically attributed to microglia activation. Unfortunately, chemical intolerance is a poorly researched phenomenon. There are probably multiple routes by which inhaled chemicals can make someone feel sick, and not all of them would involve microglia.
The neuroinflammatory hypothesis for FM and ME/CFS makes sense in so many ways but it’s still almost entirely unproven. So far as I know just one study, thus far, has looked for it (and found it) in ME/CFS. I asked Younger what would it take to convincingly demonstrate that neuroinflammation is at the root of chronic fatigue syndrome and fibromyalgia? What kind of evidence would be needed to show that?
There are two things that need to be demonstrated. First, we need to show that a brain imaging technique (like the brain thermometry tool) can reliably detect neuroinflammation. We could do that by seeing if the imaging technique is sensitive to microglia activation caused by the injection of endotoxin.
Once we have a validated brain imaging technique, the second part is to administer individuals with FMS or ME/CFS a drug that we suspect reduces inflammation in the brain. If we see that giving that drug reduces the symptoms AND it reduces the neuroinflammatory signal on the brain imaging scan, then we will likely have adequate support for the idea.
The search for validation has been a long one for both ME/CFS and FM. I asked Younger if he and others can convincingly show states of neuroinflammation are present in ME/CFS and FM patients how would that change things? How would it change things for your program and how would it change things for ME/CFS and FM research efforts?
It would change things considerably. The primary difference would be in the therapies being developed, tested, and used. The scientific and medical communities would focus less on drugs that target the nervous system, and instead start trying existing and new anti-inflammatories. For example, researchers may modify current anti-inflammatories so that they can pass the blood brain barrier and reduce neuroinflammation (most anti-inflammatory medications used today cannot get to the brain).
Health Rising recently published a blog showing the scores of different techniques researchers are using to try and measure neuroinflammation. (see “The Brain Game”) I asked about how he’s going about measuring it. It turned out that he’s using a different methods from all the others detailed in that blog. He expects to have it up and running and using it to study ME/CFS and FM patients soon.
We are currently working on a technique called magnetic resonance spectroscopic thermometry (MRSt). The technique uses a magnetic resonance imaging (MRI) scanner to non-invasively determine brain temperature. It will essentially act like a thermometer for the brain. When our immune system is activated in the body, there is an increase of temperature. We believe the same thing happens in the brain. Once we are finished, this tool may be able to detect when someone is suffering from neuroinflammation. We expect to have the tool ready by the end of this year, and we will likely start recruiting individuals early in 2016.
Effective treatments are, of course, the ultimate goal. Studies suggest that some antibiotics and antivirals as well as LDN and herbal preparations may all have microglial inhibiting properties. But what about new drugs? Are new drugs being specifically developed yet to rein in over-active microglia?
Absolutely. Many groups are working on new microglia modulating compounds. There are dozens being tested right now. Some of those promising agents push the microglia back into their resting state, while other agents push the microglia into an alternative, neuroprotective state (called the M2 state). Any one of those agents may be very successful in treating ME/CFS or FMS.
Unfortunately, the process of developing a new pharmaceutical, testing it for safety and efficacy in animals, and progressing cautiously in humans takes many years. Also, there is no true FMS or ME/CFS animal model. So, there is a big risk that we will miss an important drug only because animals did not respond well to it. For those reasons, it is critical that we test currently-available compounds that can be used in humans much more quickly.
I asked Younger how he was testing possible microglial inhibitors?
Our technique for testing microglia inhibitors is fairly basic. We read the scientific literature to create a prioritized list of compounds to try. The compounds with the most convincing basic science support (typically in cell cultures or in animals) will be placed at the top of our list. Then, we give those compounds to individuals with ME/CFS or FMS in a closely-monitored clinical trial. We are going to be testing several such compounds this year. Participating in a clinical trial is sometimes the only way to try new medications before they are available to the public (usually a few years in advance). But they are also typically more risky because we haven’t collected as much safety data. We do our best to pick only those compounds that seem to be safe.
Low Dose Naltrexone (LDN)
The LDN/Younger story is an example of a newer breed of researcher being willing to step beyond the normal options. Younger initiated the first and to this day the only LDN studies in fibromyalgia. Those studies have made a world of difference of to the many FM patients who’ve benefited from the drug.
Younger believes LDN is probably calming down the microglia that release chemicals that make you feel horrible. HE noted that small unpublished studies suggest that no less 65% of FM patients respond well to LDN. Originally, it was thought best to take it before bedtime but he found that it works as good when taken in the morning as at night. It does not have to be in your body to be helpful. Even when someone stops taking it it takes them about a month to get back to baseline.
An Australian post doc working in Younger’s lab found that LDN reduces inflammatory factors in the blood. If so it’s doing so in a way that has not been seen before. The next step is to do brain scans before and after LDN administration.
Showing LDN can reduce brain inflammation would be a huge step forward for it. We saw recently that researchers are scrambling to develop ways to assess levels of inflammation in the brain. Once they do that the next step will be to try and reduce it. If LDN turns out to be effective at suppressing neuroinflammation it may finally start getting the study it deserves.
Opioids and the Microglia
Most doctors use opioids to treat chronic pain. While they’ve effective for some they can also come with some serious and sometimes paradoxical side-effects – one of which is increased pain sensitization. I asked him about one of those:
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In an interview you noted that opioids sensitize the microglia. Does the ability of opioids to put the microglia on a hair trigger explain the seemingly paradoxical and troubling pattern of long term opioids resulting in hyperalgesia – increased sensitivity to pain?
Exactly. While the exact mechanisms are being worked out, some great work by Linda Watkins, Mark Hutchinson, and colleagues have shown that opioid administration can drive hyperalgesia via activation of microglia. Those findings open up the exciting possibility that we can block the microglia activation and therefore prevent the negative aspects of opioid use, while still receiving the beneficial effects of opioids. That system has not yet been developed successfully for humans, but groups are working on it.
Do you know in what percentage of long term opioid pain drug users become more sensitive to pain over time?
We don’t really know. The only way to know if someone develops hyperalgesia is to track them over time. It likely develops slowly over time, and may not even been noticed by the patient. Someone who seems to be hypersensitive to pain is likely to be told that their original pain condition is just getting worse, or the pain is “generalizing.”
Very few physicians have access to the pain testing equipment needed to track the development of hyperalgesia. I have not seen a single study trying to identify the percentage of pain patients who will develop opioid induced hyperalgesia. And while we know it happens, we don’t know if it is a severe problem or just a minor nuisance.
Individuals taking opioids should note if they start to develop pain all over their body, especially if they have been taking higher and higher dosages of painkillers. Some good news, though, is that we have found simply reducing the opioid dosage can reverse hyperalgesia in many patients.
Younger proposed one scenario – and it’s only one – which could explain the post-exertional experienced by some people. The increased blood pressure that occurs during walking or exercise is known to release endorphins. Ordinarily those endorphins should make you feel better, but if the microglia are sensitized to endorphins; i.e. if they get activated by them – those endorphins could trigger the opposite – feelings of fatigue and pain that last for several days.
That’s just one possibility. It may not be happening at all. The point is that the microglia are such central actors in the brain they could be tweaking it in ways we’re hardly aware of now.
At some point the pathways producing fibromyalgia and ME/CFS will be clear and treatments will be developed to fix them. Until then, Younger believes the key to treating ME/CFS and FM probably revolves around reducing inflammation. Inflammation, in particular, central nervous system inflammation, is something that we as a society have not been taking seriously enough.
The term inflammation is probably going to broaden significantly over the next five years as researchers find it in new places and and find new ways of measuring it. Dr. Montoya recently noted that the typical measures of inflammation used – SED and CRP tests – don’t pick all kinds of inflammation. The most common anti-inflammatory, aspirin has no effect on neuro-inflammation. More fine-tuned ways of testing for and battling inflammation are emerging. Ultimately the crush the immune system ethos of the steroid era will disappear.
Younger believes low amounts of inflammation should be battled rigorously lest they trigger a kind of system reset that results in ME/CFS and fibromyalgia. People with osteoarthritis, for instance, have an increased risk of getting FM. Why? Steady pulses of inflammatory/pain signals increase the possibility of some switch getting flipped that causes a widespread pain sensitization.
Younger’s earlier study suggested leptin may be a big player in the inflammatory milieu in ME/CFS. He noted during the interview that women have three times the leptin levels that men do. We still don’t know enough about leptin yet to conclude it’s the key – further studies need to validate the findings- but if leptin is a player then cutting down stress eating., losing body fat, exercising at a very steady and light rate and eating low glycemic and staying away from high carbohydrate diets could help a bit.
Depression is another disease that probably has a central nervous system inflammationn component. Younger believes depression may not be so much low levels of brain chemicals like serotonin or dopamine as it is brain inflammation. The reason it’s taken so long to gloam onto that is because it’s been so hard to measure brain inflammation. That is changing.
The Lymphatic Brain Network
Health Rising recently a published a blog on lymphatic network recently discovered in the brain that may provide a new window on whats happening in many neuroimmune disorders. I asked Younger how researchers will go about using it to study disease? Is it accessible? What kinds of studies should we expect to see and can we expect to see any from you?
It won’t be easy to study because it is still on the inside of the skull, and therefore inaccessible to direct investigation in living humans. Some researchers will use animals to see if inflammatory agents can somehow make their way to the brain via the lymph system.
I think the most exciting aspect of the lymph system is that it could be a way to monitor the brain without actually having to get to the brain. The lymph that drains from the brain down through the neck is carrying everything it picked up from the brain, including inflammatory agents.
If we can sample the lymph in the neck, we could see what is going on inside the brain. But it will be much more easily said than done. The researchers who found the brain lymph system suggested that those vessels run very deep in the neck. They are likely behind both muscles and lots of nerves, so it may be too dangerous to try to reach them with a needle. We will see what is possible.
I asked Younger about a small study he’s doing on alcohol, fibromyalgia, and the immune system. Alcohol intolerance has been one of the very distinctive but wholly unexplained aspects of ME/CFS/FM for me since the disease began. To me this study also exemplifies what a creative researcher with his/her own lab can do. It also indicates that Younger is well plugged in with the ME/CFS/FM communities as this issue is rarely mentioned. I asked him to say more about the study.
I thought to study alcohol intolerance because the majority of ME/CFS or FMS participants in my studies were reporting that they almost never drink because they don’t like how they feel afterwards. Alcohol intolerance is almost never studied medically for one simple reason – people who suffer from it just need to avoid alcohol. Also, many people don’t like to drink alcohol because they lack the enzyme to metabolize it properly – allowing toxins to build up and make them feel ill.
Obviously, I think alcohol intolerance (in people who have the proper enzymes) may help us understand the pathophysiological mechanisms of ME/CFS and FMS. Recent research shows that drinking alcohol does set small-scale inflammatory processes in motion. If individuals with ME/CFS or FMS have sensitized microglia, that small-scale inflammation may turn into large exacerbations of symptoms.
The kynurenine pathway is upregulated in many central nervous system disorders and there’s some evidence that it’s upregulated in fibromyalgia as well. Do you plan at any point to look for evidence of kynurenine pathway upregulation in FM or ME/CFS?
It is an interesting hypothesis that would tie together a number of different disorders that share some features. I will keep my eye on any new work in that area, but we don’t have any plans to investigate it specifically any time soon. We have to stay focused on our primary line of research in order to quickly either turn it into a productive treatment, or rule it out and move on to the next idea.
Younger’s Neuroinflammation, Pain and Fatigue Lab and the Future
to successfully completing a human research
study is recruiting the participants.”
Younger worked at Stanford until the University of Alabama at Birmingham sought to become a leader in ME/CFS and FM in the South and reeled him in. Younger said he’s been given a lot of resources and has been able to grow his lab very quickly. He said he’s gotten a better response at UAB at Birmingham than in Stanford.
I am not surprised. Younger may have to face fewer headwinds at UAB than Montoya does at Stanford. UAB with Younger, like Nova Southeastern University with Dr. Klimas, appears committed to making its mark in the field. The Stanford program, on the other hand, was jump started by outside donors. Montoya appears to be getting excellent support from his colleagues now but can’t yet work full-time on ME/CFS. Klimas and Younger are working full-time in labs dedicated to these diseases.
Ron Davis has been proposing that advances in ME/CFS are going to open up understanding of other diseases. Do you feel that’s true for ME/CFS and fibromyalgia and, if so, how?
I believe that many disorders are at least partially driven by brain inflammation, so I definitely agree with Dr. Davis. Any treatment found to be effective for ME/CFS or FMS should be immediately tried in the other disorder. The same goes for: Gulf War Illness, irritable bowel syndrome, major depressive disorder, cognitive problems after traumatic brain injury, fatigue from rheumatoid arthritis, fatigue due to cancer treatments, and dozens of other conditions. I also believe neuroinflammation drives many symptoms of normal aging, such as increased fatigue and decrease cognitive functioning. An effective and safe anti-neuroinflammation agent may become something that almost anyone could take, similar to how aspirin is used by so many people to help control peripheral inflammation.
I asked him how the fibromyalgia and chronic fatigue syndrome communities could support him in his work?
Thank you for asking. Without a doubt, the biggest obstacle to successfully completing a human research study is recruiting the participants. Every study we conduct requires people, both ill and healthy, to dedicate their time to the project. No new diagnostic techniques and no new treatments can be developed without those individuals. We are especially grateful for those participants when the disease itself makes coming to the laboratory so difficult.
We have had a great response from the community since moving to Alabama, and have a good list of individuals who are interested in participating. But as the laboratory grows, the studies will grow as well, and we will need more and more people to volunteer. So, the best support people can give is to participate in studies if they can. We completely understand that sometimes people are just too sick to help in that way. The next best thing they can do is get the word out to as many people as they can whenever we have a new study or research finding.
As our group becomes more nationally and internationally recognized, it allows us to attract more participants, more donors, and more resources. I think it is very likely we could leverage that reputation in the future to develop a large, interdisciplinary research center specifically for these disorders, and start studies that operate across the United States to reach as many people as possible. We are on track to make those things happen, so I am very excited to be in the position I am in.
- Sign up to get updates from the lab here.
- Help the lab decide what videos to use in an upcoming study.
Here are some of the studies the lab is engaged in now:
- Discovering the source of chronic pain and fatigue – to produce diagnostic tests for ME/CFS and FM
- Daily immune monitoring in men with Gulf War Illness
- Using botanical anti-inflammatories to treat Gulf War Illness
- Developing better methods for detecting inflammation in the brain
- Exploring the effects of opioid painkillers on the brain
- Examining Low-dose naltrexone and other microglia modulators for pain
- Assessing alcohol intolerance in ME/CFS
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.