Spoonie Radio Ep 15: Jarred Younger, PhD

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In Ep 15, Dr. Younger talks inflammation as it relates to the symptoms of ME/CFS and fibromyalgia. He talks about his research findings, treatment options, testing, and more

Dr. Craig:             Thanks for tuning in for another episode of Spoonie Radio. I am your host Doctor Dr. Craig Craig. My guest today is Doctor Jarred Younger. Doctor Younger received his PhD in experimental psychophysiology in 2003 at the University of Tennessee in Knoxville. He then completed postdoctoral fellowships at Arizona State University and then Stanford University School Of Medicine. In 2014 he joined the faculty of the University of Alabama in Birmingham and established in the neuro-inflammation pain and fatigue laboratory.

Doctor Younger's goal is to end chronic pain and fatigue by focusing on inflammation in the brain. He and his group are working to develop techniques for diagnosing and treating neuro-inflammation pain and fatigue so welcome to the show Doctor Younger.

Jarred:                  Thank you.

Dr. Craig:             So many people in this community are really excited to learn about your work and this is all relatively recent within the past year or two. Long-term patients like myself are really intrigued by some of the research you guys have already uncovered because it seems like you are looking at chronic fatigue syndrome and fibromyalgia in a different way than we have maybe seen before from other research. So how did you land on this type of research and really hone in on the neuro-inflammation specifically when there is so much other research out there looking at different puzzle pieces in ME/CFS?

Jarred:                  So I did a postdoctoral fellowship in Arizona State University and we were looking at rheumatoid arthritis, osteoarthritis and fibromyalgia, that's the three groups they are investigating, all with chronic pain. And they had a pretty good idea of what was happening at RA, they had a pretty good idea of what was happening at OA but they had no idea what's happening with fibromyalgia.

And being a scientist, I went after what was the most mysterious, most complex problem and I also saw these people, it was about 6 million people with fibromyalgia who had really good careers, they were athletes and then they were completely debilitated when they were hit with this disorder, same thing with chronic fatigue syndrome and so it's where I saw the greatest need and it was also the greatest. I could tell that none of the physicians knew what was going on and the researchers didn't either.

As far as neuro-inflammation, everyone was looking at the neurons or everyone was looking at the neuronal system and they were trying to boost serotonin and dopamine, they were trying antidepressants and nothing seemed to work and so what that tells me is that everyone may be on the wrong track.

I noticed that a lot of the symptoms, and this was the key thing for me, what got me started in this particular line of research, is when I looked at the symptoms and whether it's chronic fatigue syndrome or fibromyalgia or related disorders, pain sensitivity, profound fatigue, cognitive disruption, sleep disruption, depressed motivation sometimes, all of those we see that somewhere else and we see that anytime someone gets hit with a severe illness like the flu and they feel sick for a few days and we call that cytokine induced sickness response and we see it in basically every kind of mammal.

And so these symptoms we are looking at in these patients look exactly like what happens when the immune cells in your brain think you have an infection and they produce these chemicals to make you feel sick and so it's really just more of a logic thing than even a science thing. It is like well, maybe that means, in these patients, their immune system has been tricked into thinking there is an infection going on all the time and so it's producing the symptoms of being infected with something, a virus or a bacteria when you actually aren't and it's the dysregulation of the immune system. So that's really how I got started in it and it was just saying: where do we see the symptoms? Where does it come up and is that perhaps a clue in what is going on in these disorders?

Dr. Craig:             Right, and I think a lot of patients can certainly relate to this idea of having their brain inflamed but they just kind of take a step back. Can you explain more what is neuro- inflammation? On a physiological level, what is actually happening to cause the inflammation in the central nervous system?

Jarred:                  Sure, yes, good question. So we start with inflammation in the body, that's what people are more familiar with.

So inflammation is just a response to some kind of injury or some kind of infection. It's an alarm system that calls all the immune cells to that area and they fight, they mount kind of the battle against whatever the problem is so if it's a cut they will go to that area and fight off bacteria. You can get inflammation anywhere in your body and it's the healthy thing if it only lasts a short period of time. So if you get a cut you want it to be inflamed because that's part of the immune defense against any kind of invading bacteria or any kind of internal problem.

But when inflammation goes on for a long time it causes severe problems. So for example people are very familiar with osteoarthritis, if your knee gets inflamed for a week for a problem and, that's not a big deal but if you have information in your knee for years, you're not going to be able to use that knee very effectively. So wherever you have chronic inflammation you start to have problems in that area. If you have inflammation in your heart it could lead to heart disease. If you have inflammation in your gums, they are going to bleed so inflammation over a long time is a bad thing.

So just like we can have inflammation in the body, you can have inflammation in your brain and it's the same basic process although the cells are little bit different. So in our body we have T cells and B cells, we have all of these specialized cells. In our brain, we have microglia and they are responsible for everything. So they are like these incredible multipurpose immune cells but the process is pretty similar.

When they think there's a problem, they become activated which means they change their shape and they start to throw out a bunch of chemicals to fight that problem. And as opposed to in your body, if you have inflammation in your knee, your knee hurts when you have inflammation in your brain, it affects who you are because that's what makes us who we are, it's what's going on in our brain so you are not going to feel like pain in your head, it's going to come across as the things we talked about before. You are going to feel really, really tired, you're going to feel like it's hard to get anything done. You may be more sensitive to someone that's pressing on your body because it makes you more sensitive to pain and it really is going to make you just want to be in bed all the time. And so that's different in terms of the symptoms even though the mechanisms is the same so your inflammation is just inflammation that just happens to be occurring in the brain.

Dr. Craig:             Yeah, good explanation. So a lot of viruses then have been implicated in this illness as potential triggers and many of them are like herpes viruses are, in fact nervous tissue. So are these potential triggers that are setting off a vicious cycle of microglia activation that some patients just cannot overcome?

Jarred:                  Absolutely. So there is two scenarios that are possible and we don't know and probably both, some of them some people suffer from one, some suffer from the other. In one scenario, the virus gets in your body and like a lot of herpes viruses, after you fight it off, it stays kind of dormant or it stays in a suppressed estate and they hide next to your spinal cord or may hide in your brain somewhere and then when it gets an opportunities, it might emerge a little bit and then your body mounts a defense and suppresses it.

Tere is a scenario where people could have this chronic viral infection that keeps, maybe every few days, keeps trying to get out and your body fights it off and so you're getting these mini infections all the time. That would create the symptoms of fibromyalgia or chronic fatigue syndrome so that's one scenario is that you have a chronic infection.

The other scenario is that the virus came in and because it was such a bad infection, think of a really horrible mono virus, which we talked about, Epstein-Barr virus and it was such a hit to your immune system that it left the immune system in a sensitized state. And so the virus is gone but the immune system doesn't realize it and it continues to operate as if you have an infection. So those would both lead to the exact same symptoms but we treat them differently and in the first case we would want to give antivirus to try to suppress and get rid of that virus. The second case, we have to find out why is the immune system sensitized and how do we get back to its normal state.

Dr. Craig:             Yeah, that second piece is quite challenging. Do you believe that there is a genetic component here that sets the patient up because of their predisposition to develop this vicious cycle?

Jarred:                  Yeah, probably so. We don't know what exactly that would be but certainly we know enough to know that there is a family history component to this and if you have a family member that has classic autoimmune disorder like rheumatoid arthritis, then you are more likely to have something like fibromyalgia or chronic fatigue syndrome. So this tells us there is probably some genetic component.

We also know that women are more likely to have these disorders. If you look at children, the rate between boys and girls are very similar and they are very low until puberty and then we see the rates in girls start to climb pretty drastically. So there could also be a sex hormone component to it and it may also be a timing thing. So we are starting to get really interested in it could be the time in your life when your immune system is assaulted in this way and it might even be a time in cycles.

There may be times when estradiol or progesterone are high and if you get an injury during that time it's going to be more likely to lead to chronic pain. And we don't know that for sure but there is some preliminary evidence to suggest that's the case. So yeah, it's probably a combination of the trigger people get a harbor infection are more likely to develop these disorders; the genetics of that person and also the timing of that.

Dr. Craig:             The timing piece is very interesting. I haven't seen anything about that. And that brings up the issue of hormones. And one of the most exciting things that your group has come out with I think so far is this a small pilot study from last year when you measured inflammatory markers in patients, an extensive look at different cytokines. But there was one particular thing that stuck out and that was the hormone leptin. So could you talk about that? What is leptin and how does that fit in to the neuro- inflammation piece?

Jarred:                  Yeah, so we have known about leptin for a really long time but we didn't realize the extent that it changes our experience. So we used to think of leptin as just an appetite regulatory hormone. So leptin is produced by adipose tissue which we call white fat tissue. So the kind of normal fatty tissue in our body that we think of, those cells produce leptin and some other cells do as well but primarily the fat tissue. So leptin is increased as we get heavier so with a greater obesity your leptin levels will typically get higher and after every time we eat or leptin levels will increase and so one of leptin's main functions is to suppress or appetite. So it's supposed to be a feedback system where if your leptin levels get really high you will slow down your eating and so it regulates how much we eat. If you have no leptin in your body you may eat all the time which would be very dangerous and very destructive. So leptin is very important, it plays a very important role in our balance of hunger versus satiety.

But it has another function that we discovered more recently and that is its inflammatory. So when leptin gets into the brain, it actually sensitizes microglia cells. So that immune system we talked about a little while ago, when they are exposed to leptin, they become more sensitive and so it takes less of a trigger to set them off and then when they do get set off, they do so much more robustly. So leptin itself doesn't activate the immune systems cells but it sensitizes it so it's more likely it will be activated by something else and that's very interesting.

So when you get sick, your leptin levels will increase pretty drastically and that's why people with the flu tend to not eat very much because the appetite is suppressed by the leptin and so this is very interesting. We know that it has the potential to sensitize the microglia and then when we looked in the people with the chronic fatigue syndrome, we have also seen this in fibromyalgia, we see on days with their leptin is high, those are the worst symptom days and they track very well with each other. So if you have low leptin, you are probably going to have low fatigue, high leptin, you're probably going to have high fatigue or pain. So there does seem to be an association there.

We don't know exactly what's happening, we don't know if maybe these individuals have developed a resistance to leptin and so their bodies producing too much of it because these individuals are not necessarily obese, really in our study it had nothing to do with obesity. People who were very small actually can still have very high levels of leptin so something else is going on there.

Dr. Craig:             Yeah, most of the obesity research surrounding leptin is regarding leptin sensitivity, not responding properly to leptin signals. So a lot of patients may be are thinking already – well, how can I reduce my leptin? If this is still a small study are you working on replicating these findings in a larger group?

Jarred:                  Yes, so the good news is those initial results were so strong that the national Institute of health gave us a very large grant to study this in about 200 more women. The original study was 10. So we are going to have a excellent opportunity to make sure that this is a true finding. And again, 10 people is very preliminary. The results were very strong because we saw it in so many people but it is still 10 people so we are conducting the study right now.

I think we have run two cohorts already, we started a few months ago and so we probably have about 20 new people through and we've got to run a lot more the next couple of years. So after we do that we will have a much better idea of whether this is true or not so I would tell people probably not to try to manipulate their leptin levels until we get some more information.

But there are ways to do it. I mean they are not fun though. The caloric restriction exercise, the problem with these things is they have other effects. So exercise will reduce leptin levels but exercise also produces other chemicals that may actually exacerbate fibromyalgia or chronic fatigue syndrome. So there are drugs that may target leptin but those aren't available for widespread use yet so there is not really any great ways yet of truly manipulating leptin levels for therapeutic effect.

Dr. Craig:             Caloric restriction and periodic fasting is something that I do actually quite frequently to manage my symptoms. But I wonder if you have seen maybe some patients that you have worked with, to do this, does it actually even make any change in the leptin with the caloric restriction as expected or does it perpetually elevate it no matter the food intake?

Jarred:                  I think it would be impacted by those things because when we look at people, even when we are not trying to change leptin levels, we see their leptin levels are varying drastically within persons. So clearly some things can go up and down. I think if they did do fasting or just reduce the caloric intake, it doesn't necessarily have to be fasting, that probably would impact the leptin levels. So I always recommend that if someone is going to drastically change their diet, that they are being supervised by a medical professional. But it is something that people could try and you would know very quickly if it's going to impact your symptoms are not.

But it is possible there is a mechanism if you reduce your caloric intake, your leptin levels would go down. So if you're leptin levels were driving your symptoms, that could help.

Dr. Craig:             Okay. Now getting back to the microglia piece, you mentioned that we don't really have many options as far as maybe leptin modulation yet and we don't have enough information yet to think about that. But microglia inhibition is that more well known? Are there more treatment options available there that could potentially be helpful?

Jarred:                  Yes, this whole line of research is pretty new. So we're talking about going back maybe six years and that's not very long in science because things move pretty slowly. So the line of research is still in its infancy and so there aren't a lot of agents for human use that target the microglia.

Now there are many labs that are producing agents but they are being used in animals right now, that's the classic process is they go through a lot of animal research before we try it on humans and our lab doesn't do animal stuff but we certainly follow that science. So there is a lot of things that are coming along that are being designed specifically for that purpose.

I can't really guess how long it would take before it starts being used in humans, probably another 3 to 5 years before we start seeing this in clinical trials. In the meantime there are chemicals that were used for other purposes and they were subsequently discovered to also reduce microglia sensitivity. And so low dose naltrexone is the one our lab works with the most so we can talk about that one. But dextromethorphan, which is something you can find in cough syrup at the low dosages, that also suppresses microglia, there is a drug called AV411 and minocycline, so there's probably five that are being used currently in science that people can actually try right now and those all reduce microglia excitability.

And there is probably another 5 to 10 agents that we probably could use in people right now but we haven't seen any trials that have done that. So there are a few things that we could try and certainly one of the goals of our lab is we want to do some really quick trials making 10, 20 people try all of these agents to see which one looks promising and then we will get additional funding to do a larger more proper clinical trial.

Dr. Craig:             Right. I don't know if any CFS physicians out there are that open to trying some of these experimental medications but the information is there.

Jarred:                  Yeah, and we now have multiple publications about especially Lotus naltrexone, so certainly any physician has access to that information if you read what's the chances of success they could see what the side effects are which are pretty minimal in our experience. And any physician can prescribe these things, it's just they are looking out for their patience and they want to be safe and so they would like to see huge clinical trials with hundreds or thousands of people so they are confident that they are giving something that has been very thoroughly screened and vetted and so I understand that small pilot trials don't necessarily change physicians prescribing habits.

There is a company I think that's going to produce a commercial version of naltrexone at the very low dose, I can't remember what it's going to be called but I do think that's coming along and once there is an FDA approved product for this, more physicians will be prescribing it. So I think you will see more of it.

I hear from rheumatologists all the time that are trying this and I think we will be hearing more about it in the next few years.

Dr. Craig:             Great, a lot of listeners of the show are also very interested in supplements and natural products. So are there any strong lines with different types of natural products affecting neural inflammation?

Jarred:                  Yeah, there are some really good clues almost all from animal literature so we would have to guess what the impact on humans would be but my angle is inflammation and so we are going to be targeting specifically agents to have the ability to cross into the brain and reduce again microglia excitability.

There is actually quite a few old Chinese medicines, there is herbal Indian medications that can do that so I can give you a few of those. We're actually going to be testing nine of these in the next few months. We are starting with Gulf War illness which is very much like fibromyalgia and chronic fatigue syndrome but we are going to expand it to other diseases as well. But at the top of the list in terms of looking over the literature, my best guess is curcumin. So curcumin is from turmeric root. And turmeric root is a very powerful anti-inflammatory agent and curcumin is the active ingredient in turmeric root so you can buy curcumin by itself at really high potency.

No it has to be combined with black pepper in order for your body to absorb it and it doesn't stay in your body very long. I think that's why it hasn't been a blockbuster agent because we need to find a way to keep it in your system so you don't have to take it every few hours but curcumin is a good one.

Really in terms of things you can take I think the key is really the anti-inflammatory stuff. So I think its worth people trying that would be a Mediterranean diet. So a lot of omega-3 oils, reducing a lot of the Omega-6 oils, getting a lot of colorful vegetables, putting sugar at really, really low levels like low, hopefully even below 15 g a day, so super low sugar is very, very inflammatory. Decreasing the carbs which can act like sugar, if there is a simple carbs. And then getting a lot of the spices like ginger, cinnamon, peppers that have anti-inflammatory properties, those are probably the best bets.

Dr. Craig:             Yeah, all good tips. So your current projects now, you are in the Alabama area and if any listeners are from that area, is there ways that they can get involved in some of your projects? Maybe act as subjects or help with group controls? How can listeners get involved with some of these projects?

Jarred:                  Yeah, absolutely. I mean it's the most important part of the research. Everything we do has human participants and so the most important part of these studies is actually getting people who are willing to give their time and will participate in the studies and so we are always very grateful for people who are willing to be in the studies. And you are right, patients with these disorders and we need healthy individuals to act as controls in all of our studies so we can really find out what the normal system looks like so we can know what the dysregulated system looks like.

We do have a Facebook page for the lab. I think if you are on Facebook you can type in neuro-inflammation pain and fatigue in the search box you would get us and that has a link to our online screener. So we typically have people doing online screening things first and then we can call them and do further screening to see if they are eligible for our studies.

They can also sign up for our newsletter and I guess it's okay to put out an email address. It's a generic one so youngerlab@uab.edu and they can sign up to our webpage there for our newsletter. We also have a webpage. If they do, younger neuro-inflammation pain and fatigue, it will come up and they can sign up for the newsletter there and that will give them the links where they can do the screening and get involved in the research.

Dr. Craig:             Great, and all of those links will also be available in the show notes when this episode is transcribed on the blog.

Are there any other projects that you can talk about that maybe we have missed so far?

Jarred:                  We do a lot of things. So very busy lab and the thing is, we don't use a particular technique. We will use whatever it takes to get at this.

Remember that we've got this hypothesis that there is inflammation in the brain. The problem is that you can't get to the brain in living humans. I mean you've got the skull, you can't put in needles and draw stuff out so it's very complex to go down this line of research so we have to be very creative and we have to use a lot of different techniques.

So we talked about the immune stuff, we talk about some drug studies we do. We also do a lot of neuroimaging because that's probably the best way of seeing what's going on in the brain without actually taking someone's skull off and getting to the brain. And so we are working on some new, I think interesting techniques to try to detect. Right now we have no way of knowing when someone has neuro- inflammation. There is no test for it anywhere in the medical world. So we are trying to develop that.

One thing we are working on is called magnetic resonance spectroscopy thermometry and what that is is just, if anyone has had an MRI scan, it's like that, it is the same scanner but if we change the code a little bit so it actually gets this brain temperature. So just like if you want to know if you have an infection, put a thermometer somewhere, now we have a way of doing that in the brain. And so we think if someone has inflammation that's locked in the brain, their brain temperatures tend to be higher than the rest of their body and so we are going to see if that discrepancy between brain and body may be a objective test for brain inflammation.

And if that's the case, that would be very, very helpful because you could do that really quick scan and it is 20 minutes. Say okay, this person has neuro- inflammation, we need to give them anti-inflammatories that can target the brain.

Dr. Craig:             Fascinating. Is that an invasive type of technique, 20 minutes, just wearing it like a skullcap? How does that work?

Jarred:                  No, it's not invasive at all. It basically uses big magnets so you don't feel a thing. There is nothing injected. You have to go to a special room, you have to take off all of your metal and it pulls you into the scanner so you are kind of going into a tube for about 20 minutes but that's about it, you just lay there quietly for 20 minutes and you hear some funny noises as it takes pictures and you get out. So it's pretty simple, pretty low impact for the patients.

Dr. Craig:             Very cool. I would love to know the temperature of my brain on days when I am having a relapse. It certainly feels on fire.

Jarred:                  That's going to be one of our first studies, is to take individuals who have fluctuations and then scan them on good days and bad days and that would be excellent support for the hypothesis if we see the brain temperatures elevated on the bad days, that would be a groundbreaking paper. It may be more important than just for pain and fatigue. I mean that may have implications for depression. We think in a lot of cases the depression is also caused for brain inflammation.

                                A lot of the neurodegenerative disorders, I am thinking Alzheimer's and Parkinson's and even just normal aging so as people get older, they become more easily fatigued, they become more sensitive to pain, their motivation decreases and it is possible that those things are being caused by low level information in the brain so we may be able to prevent some of all of the bad stuff we think is inevitable with aging that may not be inevitable at all. We may be able to treat it.

Dr. Craig:             That's really exciting, is trying on all of those pieces together. And that is one thing that is very interesting about your research that I think is unique, is you measure patients on their good days and their bad days and you take these blood measurements every single day consecutively which you don't really see in a lot of other papers. This makes for very strong research.

Jarred:                  No one else does it. There is a good reason they don't. I mean you can imagine, it's just the practical issues of trying to have someone come in every single day, same time of day each day to do a blood drawing, it is asking a lot. We compensate people pretty well because we realize it's disrupting your life quite a bit but it's really not that bad. You would think it would be really tough to be stuck 25 days in a row but when you use these really, really tiny needles, we're talking about 23 gauge needles and you have really skilled nurses, you can get through, I think I have showed pictures of this before in presentations, you can get through the whole 25 days without any bruising if everything goes right. In fact, most people don't bruise over the whole period so it's actually not bad. They are very small needles.

And you are right that the information it gives us, it's tremendous. It is far beyond what you get by just drawing one sample from hundreds of people. This is a totally new dimension to information and it is revealing things that cannot get any other way so we are really excited about this approach and what we are working on now is ways to make it easier.

So there's actually some startup companies that are developing ways to do this at home through little kits. I'm not going to mention companies by name, I can't remember the names but there is multiple companies that are looking at ways to do a little finger prick that you can barely feel and it will actually run the test for you at home and then log it to your smart phone and so when you finally going to be talking to those companies and trying to find ways for people to do this themselves and that way they don't have to come into the lab. But in the meantime we are still getting great data from this and I am glad that the NIH like the idea and the Department of Defense did as well so we are getting a lot of funding to pursue that type of research and I think it is going to yield some really good results.

Dr. Craig:             Yeah, I think it will. This is fantastic news, fantastic information. We are about out of time but I want to thank you so much for really looking at this illness kind of outside the box and am looking forward to all of these projects coming out. I wish you the best of luck in that.

Jarred:                  Thank you, I am happy to be doing this, it's really fun and hopefully I will come up with the cure sometime soon, that's definitely what we are working on.

Dr. Craig:             That's great. Thanks so much and thanks again for tuning in for another episode of Spoonie Radio. If you like the show, head on over to iTunes, give it a review, give it a rating and don't forget to subscribe so you never miss an episode. This is Spoonie Radio signing off.

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