NIH ME/CFS Advocacy Call, October 22, 2021

Ms. Barbara McMakin: Good afternoon my name is Barbara McMakin and I'm from the NINDS Office of Neuroscience Communications and Engagement. On behalf of the NIH, I would like to welcome you to this afternoon's call and to thank you for your interest in participating in this discussion with us today.

Today's call is being recorded. If you have any objections, please disconnect at this time. Dr. Walter Koroshetz, director of NINDS, will introduce the speakers, each of whom will make some remarks after which we will answer your questions. If you have a question for our speakers, we invite you to submit it through the Q and A box at the bottom of the Zoom screen. We will try to make our remarks brief so we can answer as many questions as possible in the time we have available to us this afternoon. Now, Dr. Koroshetz.

Dr. Walter Koroshetz: Good afternoon and welcome to the second ME/CFS telebriefing of 2021. Since our last call, there have been several developments at NIH related to ME/CFS and we look forward to updating you on what we have been doing. Unfortunately, we are still dealing with the pandemic and many of the clinical studies are still not quite up to speed, but certainly doing better than they were a couple of months ago.

As you know, there's considerable evidence that people will be suffering from ME/CFS after they've passed through the acute infection stage. There's a great deal of science that's being launched to try and solve that problem best we can, given the emergency situation that has occurred across the country. We'll talk a little bit later as we think that this work has real potential for uncovering some of the biological drivers underlying ME/CFS, in general terms.

As you may know, a number of years ago, NIH along with many different institutes developed a consortium for ME/CFS collaborative centers and a data management center. They're coming into their fifth year and all the NIH grants are pretty much five year grants. The councils at NINDS, with input from the other institutes, have approved reissuing the funding announcement to support the ME/CFS Collaborative Centers. This would be support for an additional five years, and we expect that these funding announcements be released in the next few months. Dr. Breen will talk to you a little bit later about a very interesting meeting that the consortium members held recently.

During the call today, you'll hear from Dr. Nath, who will provide updates on the intramural ME/CFS study. As you know, Dr. Nath is the Clinical Director of the NINDS Intramural Program. Dr. Joe Breen from NIAID will let us know what has been happening in the consortium and about the recent annual meeting. Then, Dr. Vicky Whittemore will discuss activities of the Trans-NIH ME/CFS Working Group and a very interesting recent workshop that was held with the Sleep Research Society on the biology of fatigue.

In addition, we're really excited we have a guest speaker this afternoon, Dr. Rakib Rayhan from Georgetown University, who will be giving a brief presentation. We have made major efforts to try to attract young scientists into the ME/CFS field, and he's the first to receive what we call the F30 training grant award that NIH has. He received this award to investigate the neural underpinnings of chronic fatigue. I'm real excited to have new young investigators join the fold. As always, we are eager to hear from you, so we will keep our own remarks very brief and then we'll be turning to the questions that occur in the Q and A box. With that, let me turn it over to Dr. Avi Nath.

Dr. Avi Nath: Thank you, Dr. Koroshetz. I'm going to give you a brief update on what's been happening with the intramural program. As you know, when the COVID pandemic hit, we moved into data analysis mode. And so at that time, we had 17 ME/CFS patients that had been fully adjudicated and 21 healthy controls. So we formed several working groups: we had a clinical description working group, an immunology working group, and a physiology working group.

Because it's a trans-NIH effort, there are lots of people within each of these working groups. They have spent numerous amounts of time collecting and analyzing all the data, and then going back and doing additional experiments as necessary to confirm some findings. Most of that data has now been fully analyzed, there are few remaining things that still need to be done. Now, we have formed a manuscript writing group that consists of the leaders of each of these working groups and a couple additional people.

We are now starting to put together the figures and the rest of it, so we hope that we will be able to produce a substantial manuscript with the findings that we have in a short period of time. The major observations that we have found a number of physiological abnormalities in the testing that we've done, as well as immunological abnormalities. The challenge is to really synthesize it into a single story, which seems to be a bit of a challenge. But I think that's the challenge within the field and it will point in the direction for what additional studies need to be done in other cohorts, and may even point to potential therapeutic targets that would lead to a subsequent study.

In the meantime, since a lot of the long COVID patients now have symptoms that are overlapped with ME/CFS, and may very well be the entirely the same disease, we have established a huge cohort of those patients, another 400 patients we've screened. We have several protocols now both for phenotyping as well as for intervention. We're going to be bringing those patients now to the Clinical Center for further study, so this will continue with a slightly different population, but the questions are still the same.

There's another study that Dr. Walitt is now the PI of, and that is on the Gulf War syndrome in collaboration with the VA system. And that has been funded just within the last few days. So there will be another cohort of patients coming in. But the questions are still the same and I think the benefits will be for the greater community of ME/CFS from all these studies put together. I'll stop here. Thank you.

Dr. Walter Koroshetz: Thank you Avi. And now we'll turn to Dr. Joe Breen to talk to us about the consortium and the recent consortium meeting.

Dr. Joseph Breen: Thank you Dr. Koroshetz. My name is Joe Breen, I'm the National Institute of Allergy and Infectious Diseases representative on the NIH working group. I work very closely with Dr. Koroshetz and others on the call here. I'm going to just briefly tell you a little bit about the annual meeting for the Collaborative Research Centers that Dr. Koroshetz mentioned, and are entering into their final year of support.

It was held just about a week ago and representatives from the all the centers, as well as our close Canadian collaborators, participated. And community advisory committee involvement was also notable. I'll say a little bit more about that in a second. So I think there was a lot of convergence on data presented. A lot of the data is pre-publication, but I think it will be published quite soon.

The feeling from the meeting was that there was a lot of convergence on some findings, namely metabolomics and some microbiome biomarker type or differences that were seen in ME/CFS patients versus controls. This was exciting because some of the very similar changes were seen in different experimental settings and with different methodologies, in fact. So one of the goals of the centers was, at the outset, to try and validate findings across centers and that is something that we're starting to see achieved, even given the issues with recruiting patients etcetera with the pandemic. Most of the centers are able to now recruit again, but there was an obvious lag, unfortunately. There was some really nice enthusiasm, some strong correlations and associations that were noted.

So, I mentioned that there was input at the meeting from the community advisory committee and their input will be publicly available quite soon. That will be in the form of feedback from the meeting itself, as well as suggestions about feasibility of further studies and priorities based on their input. So that was welcome.

The Data Management Coordinating Center presented some ideas about how to further integrate and improve some very valuable products that they've generated, called mapME/CFS for data sharing, and as well as searchME/CFS, a way to access samples that could be accessible for discovery and also cross-validation. We're looking forward to formal input from the community advisory committee.

From the results, I mentioned the metabolomics and microbiota, but there was also some convergence around age and gender differences, which were important in terms of the patient population to look for markers. So it would be really exciting if this was to be validated and again, since multiple groups are seeing some of these common changes tending to be in energy metabolism. Some really classic energy metabolism pathways that in fact are well studied, and if they turn out to be more than associative here, there may be ways to disrupt those pathways.

From my perspective, I think there were some really positive outcomes and nice productivity that will be represented. This is represented in some publications and I think we'll see more. I'll stop there and I'm happy to answer any questions when we get to that part. Back to you Dr. Koroshetz.

Dr. Walter Koroshetz: Thanks Joe. Now let me turn to Dr. Whittemore to talk to us about the Trans-NIH Working Group for ME/CFS and the recent workshop on the neurobiology of fatigue.

Dr. Vicky Whittemore: Thank you Dr. Koroshetz. The Trans-NIH ME/CFS Working Group has been focused quite a lot on reissuing the RFAs for the Centers and for the Data Management Coordinating Center, as well as thinking about strategic planning and how to move that process forward on both the NIH side and on the extramural side.

Investigators and clinicians became very swamped with all of the Long COVID work. Many of us on the NIH side were pulled into working on working groups for the RECOVER Initiative, and when we discussed starting this strategic planning process with investigators and clinicians, many of them said we simply don't have time.

But we have plans in place to begin to move that forward, and we actually have started to have conversations with the FDA and CDC around clinical end points for clinical trials, as well as conversations with both U.S. and European clinicians to really think about harmonizing clinical trial endpoints so that we can really move that area of research forward toward clinical trials. I think some of our initial conversations are going to really lead to pointing out the need for some very specific targeted research to validate and to understand how to utilize some of the tools that we have out there in better ways as we move forward in clinical studies and clinical trials.

Just to touch quickly on the fatigue workshop, this was a workshop, as Dr. Koroshetz said, that was organized together with a working group from NIH made up of individuals who are also on the Trans-NIH working group and part of the Blueprint Neuroscience Research Program at NIH. Together, we partnered with individuals from the Sleep Research Society.

And the goal of the workshop was to bring researchers together to talk about how fatigue is described and studied across different diseases, not just chronic fatigue syndrome. We touched on MS, on autoimmune disease, on cancer, and on other types of diseases, and thought about the potential underlying mechanisms of fatigue, how is it being studied both in clinical populations, as well as in animal models. Then, the last session focused on the neurobiology of fatigue and what we understand about how we perceive fatigue, how cerebral spinal fluid flow and sleep cycles relate to fatigue and cognitive dysfunction. With emphasis from the Sleep Research Society, the focus was on the role of sleep and unrefreshing sleep in fostering chronic fatigue within many different syndromes. We actually had several individuals who are ME/CFS investigators who participated in the workshop.

The next steps are that we're working very quickly to put out a report in summary from the workshop and internally talking about next steps to really foster cross-disciplinary, multi-disciplinary research on fatigue that I think will really help us much more broadly across diseases to understand the underlying mechanisms, and how can we target those mechanisms and develop treatments that will really help to alleviate and hopefully eliminate fatigue in its chronic stages, especially. With that, I will stop and turn it back to Dr. Koroshetz.

Dr. Walter Koroshetz: Thank you very much Vicky, and let's see. The biology of fatigue workshop video cast is now available for people to see. Not sure how. Maybe someone can put the link in the Q and A so others can see it.

Dr. Vicky Whittemore: It's on the Blueprint website and we'll put that link in the in the Q and A (see

Dr. Walter Koroshetz: Great, well thanks very much and I think Dr. Rayhan was in clinic if I remember right. I'm not sure if he was able to join yet. Barbara, do you know?

Ms. Barbara McMakin: No, he's not here yet.

Dr. Walter Koroshetz: Okay, before we go to the questions, I did receive a couple in advance. There were a number of questions about the RECOVER Initiative and the interplay with ME/CFS.

So I think the main points are that there is significant symptom overlap between what people are suffering from in what's called Long COVID and what people are suffering from in ME/CFS. In the beginning, the only real difference was that the duration wasn't qualifying for ME/CFS, but that has passed.

Now, I think a large proportion of people who are suffering from Long COVID, and now out to six months, have fatigue, they have cognitive trouble, they have autonomic trouble like postural orthostatic tachycardia, they have unrefreshing sleep, and some of them have post-exertional malaise. They are going to qualify for what we call ME/CFS.

I think that's an important thing to understand, and with regard to that, as I've said in other instances, this terrible pandemic does actually present a unique opportunity to understand these symptoms and those overlapping with ME/CFS in a way in which we could never do before.

And that is because in the case of ME/CFS, many folks dated their symptoms to a particular event which sounded like an infectious illness, a viral illness, but we didn't know what the virus was. People came in months, years afterwards and although we've tried, you know it's been very difficult to try to understand these biological underpinnings. But with COVID, we have thousands, tens of thousands of people coming out. We know what the virus is, and we know exactly when they got infected. We have the ability to actually study people as they recover from the virus to understand why some recover quickly and others have persistent symptoms. That's something we could never do before in our ME/CFS research.

Now, people have asked why don't you do the same thing for ME/CFS people that you've done for, or that you're doing for, the RECOVER people? The fact is that you can't because you don't have that opportunity to see people who are acutely infected. The comparison of those who are getting better quickly versus those who are not getting better quickly, I mean, it's really only in the case of COVID can you do that.

Similarly, if you look at people who have persistent symptoms six months or a year afterwards, the control group is people who had COVID six or seven months ago, matched. So that control group is not possible with ME/CFS because those folks usually have had a disease for many years. It's comparing apples and oranges.

What I do think is going to happen, and this is where I'm very hopeful, is that we will have some findings coming out of the RECOVER Initiative looking at the recovery from COVID and as soon as those are nailed down, then we can look to see if they generalize to an ME/CFS group that was not affected by COVID. I think that is the most beneficial way of looking at this to try and milk everything that comes out of post-COVID to see if it applies to ME/CFS.

I hope that this helps a little bit in clearing up these issues. The RECOVER program is, by Congress, one hundred percent devoted to COVID. So we can't use that money for other purposes.

With regard to knowing who in the RECOVER cohort has symptoms of ME/CFS, I think that we, Vicky, Joe, and a big team, have worked with the people setting up common data elements. So, fatigue, cognition, postural orthostatic tachycardia, unrefreshing sleep, and post-exertional malaise are going to be our elements that will be collected for every individual, actually every individual, who comes into that cohort. In the cohort, we're looking for 15,000 people and a control group, those who are infected, those who have persistent symptoms six months later, and those who are six months out and have no symptoms.

We also have an autopsy program which will look at people who have died and have had Long COVID. They probably did not die from Long COVID, they probably died from other causes, but it'll give us an opportunity which we've never really been able to do in ME/CFS to look deeply into the tissues of the body for signs of immunologic or viral pathology. So again, that's something that could potentially shortcut to an answer.

Also, I think that we have, right from the beginning, had investigators who were sophisticated in ME/CFS and part of the groups that formed the RECOVER Initiative. There are hundreds of investigators in this project, really hundreds. I suspect that there are people there who know about ME/CFS. Also, I'm very hopeful that of those hundreds of people in RECOVER that because of the similarities, they will actually become ME/CFS researchers in the future as well.

I just wanted to kind of address those issues with regard to the RECOVER Initiative straight off. Now, I see Dr. Rayhan has been able to join. Is that right? Rakib, are you good?

Dr. Rakib Rayhan: Yeah, I'm working at the hospital right now and the entire hospital's Wi-Fi is down, so they're trying to figure it out.

Dr. Walter Koroshetz: Okay, well I think people would really love to hear about your project and then also, how did you get into it in the first place and how can we put people into this area of science? So, what could you offer folks?

Dr. Rakib Rayhan: I can just start. Because of all the technical difficulties I think Ms. Barbara has my slides. If she is on, she can hopefully put them up. I just have a couple slides here and there. Okay, very good.

Briefly about me. My name is Rakib Rayhan. I am an MD/PhD, and I completed my MD/PhD at Howard University College of Medicine in Washington, DC and completed very recently. Now, currently I'm a first year resident in the Department of Neurology at Georgetown University Hospital. So it's my first year and right now I'm doing a rotation in the VA. Unfortunately, everything in the VA, their wi-fi is not working, so at this point I thought let's go to my car.

A little bit more about me. When it came to studying and going into fatigue research, I actually started a long time ago. In 2010 or 2011, I was a research assistant in Dr. James Baraniuk's laboratory in Georgetown University Medical Center and really fell in love with research. I fell in love with neuroimaging and trying to really understand the underpinnings of fatigue, something that we see often in a clinical setting pretty much in any chronic illness, but it's pretty much ignored. So since then it's been my research track.

So, today I had this wonderful opportunity from Dr. Whittemore to be able to present the work that I've done. This is specifically geared towards the grant that I got during my pre-doctoral stage of studying fatigue and using neuroimaging to study fatigue. This was an F30 grant, so the title of my thesis work was "Investigating the Neural Underpinnings of Chronic Fatigue" and as you can see, it’s a multi-modal approach. You can go to the next slide.

That's a brief overview of what we just went over. About the F30 grant. The initial application was in 2017 and the proposal was really taking advantage of something that we saw in another fatiguing population called Gulf War Illness where we were able to use exercise and fMRI to see what the brain does before and after some sort of exertional exhaustion, something that kind of models exertional exhaustion. From the findings in the Gulf War illness study, we proposed a similar type of study in ME/CFS. And the rationale was because of the similarities in the symptomatology, we were expecting to see similar findings as far as brain tests go. So, next slide.

The rationale again is, as we've talked about, fatigue is very subjective, part of pretty much any chronic illness, but despite its significance, we really just don't know much about it, as we all know. There's really no strong consensus as far as a mechanism or an underlying etiology that really leads to the chronicity of fatigue and so we were hoping that by taking this kind of exercise modality we could maybe standardize a way of studying fatigue, taking away or maybe leaning less on 0 to 10 rating scales and more so on something that we can quantify. So, next slide.

One of the big things that I proposed in this this grant or this proposal was taking advantage of the cardinal complaint as we all know: post-exertional malaise. It was really intriguing to me as a symptom, particularly because of the fact of how long it is and how debilitating the symptomatology is for our patients. By looking at it in a standardized way, saying hey you know what, let's look at the brain and how it activates before exercise and look at how the brain activates afterwards, then maybe we can identify why patients have this prolonged malaise in ME/CFS after exertion.

And it really did present that wonderful opportunity because we were able to standardize things. Oftentimes, when I see patients with ME/CFS, many have described the duration of their symptoms as being variable: some may say for ten years, some maybe three or four years, or twenty years. So by using this type of modality we were able to say okay, we have this very discreet amount of time and we can now look at everyone in a more homogenous way and maybe get some sort of great data out of it. So, next slide.

This is just the brief overview of what we call, or I love when we call it, the sandwich protocol. Patients were stuck into an MRI before any exercise, then we put them on a bike to exercise them. And then after the two bicycle exercise stress tests, we took another scan of their brain and we compared what the brain looked like before and after. We did that with controls and obviously Gulf War illness. Then for the specific F30 the grant that I was working on, we did it with ME/CFS patients. Quite a large number actually, for an fMRI study. Next slide.

So just briefly, this is what we saw in our GWI. In our initial study, before exercise we had the controls, and we had these two subgroups of GWI that I really won't go into. Then after exercise what we saw was that the two GWI subgroups, of another fatiguing illness, had this increased amount of activity within this region that we know as the default mode network, which is really intriguing. It's really exciting to see that nothing like this has ever been reported before. We thought maybe something like this could be seen in ME/CFS. Next slide.

So, what is the default mode network? It is actually, to me at least, I would consider it to be the core, if not the linchpin network, within the brain. It interacts with pretty much every other network within the brain, it modulates every other network within the brain. And in fact, even slight disruptions within this network has been seen across many myriads of diseases, whether you can say depression, schizophrenia, Alzheimer's, Parkinson's. Any sort of debilitating cognitive illness that you can think of often has some sort of disruption within the default mode network. Next slide.

So, here what we did was looking at the methods, the number of controls and ME/CFS patients that we had, we were able to recruit a pretty large number. I believe for the entire set we had about 57, close to 60 people which is actually pretty big for an MRI study. And we were able to have pretty equal groups, as far as ages go, they were pretty equal for that. What we saw again, fortunately, was that after exercise, ME/CFS patients did have discrete changes within their brain patterns. Go to the next slide.

So this is the brief methods. The methods that we used here are that we looked at the functional activity within the brains and we broke them down into nodes, and these nodes are parcellations of the networks that we have within the brain. Then once we parcellate it out, we used machine learning, hierarchical clustering to be able to make identifications of these networks.

What we saw was that if you look all the way to the left, the purple, I'm not sure if you can see it. That area right there is the default mode network of the sub nodes, as we say, which includes the medial prefrontal cortex, the precuneus, and parts of the parietal as well. Go to the next slide.

So, what we saw was in our ME/CFS patients, before exercise again, there was really no significant difference within the activation patterns in our controls versus our ME/CFS patients. However, after exercise, what we saw was there was a significant increase in activity within the medial prefrontal cortex. So that was something that we were excited about because not only did it give us reproducibility as far as our exercise protocol goes, but it also showed us that the default mode network indeed does play a role within these fatiguing illnesses. Next slide.

The other important thing was we were able to also see that the activation within these discrete regions correlated with the severity of the symptoms, particularly after exercise. Prior to exercise, the symptoms did not correlate with the activity. But after exercise, when we looked at the activation patterns and we correlated to the symptoms, we saw that there was actually a significant correlation. That was something that was also very exciting for us because it shows that you're going to have to stress the system before you're able to really see some sort of actual pathophysiology within ME/CFS. Next slide.

So really what it comes down to is, I've been condensing almost three or four years of research in about 10 minutes, but what we saw was that the medial prefrontal cortex itself has a very important role not only within the default mode network, but when it comes to the subjective appraisal and awareness of fatigue. In fact, the medial prefrontal cortex is one of the first regions to start to activate when someone is doing a fatiguing task. They've shown in multiple studies that if you do a fatiguing task of some sort, the medial prefrontal cortex is one of the first regions to start to activate. In fact, if you have disease within that region, let's say from a TBI, patients tend to have more levels of fatigue than patients who have TBI in other regions of the brain.

The implications of all the research that I was able to do was: one, we were able to reproduce a model, something that was standardized, we didn't have to rely on ratings anymore; and two, we were able to show that MRI, a non-invasive method, really has some utility here. And finally, one of the big things is maybe hopefully attempting to find potential pharmacological targets here. So next slide.

The summary of all the work that we did was, we identified a model, we were able to study and detect fatigue objectively without ratings of any sort, and we were able to really see that modeling post-exertional malaise in two separate groups using this modality was robust enough to be able to really find great fMRI findings. So, the evidence itself, one of the takeaway points that we can say here is that the inability to stop the default mode network from activating could possibly be a potential biomarker for fatigue. It could be that the region or the network is just not appropriately controlled, maybe in ME/CFS or other fatiguing illnesses.

All of this work that I just went over is going to be published soon. The final manuscript for all of this is in the late stages of review. You can go on to the next slide.

So really now comes the future direction: so often the question is well, what does this all mean? You did all this work for maybe a couple of years; can you tell us what your next steps are? One, prior to undertaking any of this type of research, we knew that the brain had some sort of involvement or role within the chronicity of fatigue. But after this study, we were able to parcellate and identify discrete regions, which is really important. The brain has multiple regions, hundreds of regions in fact, that have distinct functional components to it. To be able to now say that we have three or four regions that are within the default mode network that are associated with fatigue, it now gives us a way to pinpoint or figure out a better way to obtain the next research steps.

So at least for me, from a research perspective, the next steps would be to do something called pharmacological neuroimaging. Can we look at before and after? Can we find targets for these regions?

There have been studies that have shown that several serotonin receptors, opioid receptors, even glutamate receptors, are significantly associated with these regions versus other regions. Those could be potential targets in the future. So, just thinking about that, it's really exciting just because nowadays ideally you would want pharmacological therapy to start in the murine models, but because of the fact that we have known targets, we have known medications that can go to these targets. It gives us an opportunity to really push the translational foot forward here.

That's the hope for the next steps as far as research goes with what we're doing. The last slide is just a thank you or a bit of bibliography. That is about five years of research in about, you know, five to ten minutes. I'm more than happy to take any questions.

Dr. Walter Koroshetz: Well, thanks so much. Very interesting, very interesting data. So if I could just simplify it. The main finding was increased activity after exercise in prefrontal cortex. So, do you have any thoughts on where the drivers are? Is there a decrease in inhibition of prefrontal cortex that's coming from somewhere, or is there an increase in excitatory input into prefrontal cortex? What's upstream?

Dr. Rakib Rayhan: I think it could be one or the other. I think that's why the pharmacological targets and having next step research that takes advantage of that will maybe allow us to better answer that question.

If we know that it's either an inhibitory or excitatory issue, at least from what I've seen, when it comes to the most cutting edge research on receptors within the brain, I think this would be more so a loss of inhibition versus a gain in excitatory activity. I think that's where I'm leaning, but I definitely would need to research that before we can make that as a solid claim.

Dr. Walter Koroshetz: Yeah, interesting. There are some studies in the motor cortex with fatigue that suggest that the motor cortex is actually inhibited at the time of fatigue. You can get a strong motor output by transcranial stimulation in the fatigue state, but not in the non-fatigue state. So, but again, you know prefrontal cortex is so different than M1.

Yeah, it's really interesting to try to piece these together. Certainly prefrontal cortex has a lot to do with the reward system. I'm sure there's a lot of inputs from limbic cortex, amygdala.

Dr. Rakib Rayhan: Right, I think one of the things is, at least from the data we've seen, is that the most significant activation patterns were more so in the lower parts; the ventral medial, much more closer to the limbic system. And so, you could at least, from all the data that I have seen, if there is an increase of activation or neuronal activity within those lower regions, they would cross-talk to the more higher level regions and then kind of shut them off.

So I'm thinking that could possibly be one of the reasons why CFS or ME/CFS may have such a broad symptomatology in the sense of brain fog and word loss or memory loss, and things of that nature. I think it could be some sort of one start point that affects all parts of the higher level parts of the brain. So, it's lots to still dig into for sure.

Dr. Walter Koroshetz: That's right, yeah. Oh I could talk to you all day about this, very interesting. I really appreciate it, appreciate you coming on.

Dr. Vicky Whittemore: Do you have time to answer a couple questions, or do you need to get back to the hospital?

Dr. Rakib Rayhan: No, no I told them. I told my other resident to just take care of the patients for now. Yeah, questions, I'm more than happy to answer.

Dr. Vicky Whittemore: So there was a question, if you could just repeat the protocol, the exercise protocol that you used in your study?

Dr. Rakib Rayhan: Sure, so the protocol itself. One, patients would come in and prior to doing any exercise we would get this baseline fMRI scan. Within the scanner, patients would get something called a resting state scan where they would just kind of sit there not doing anything, and then they would do a task as well in the scanner. It's called a working memory task. And within this, within these functional realms, we would also get structural scans as well, so we would get white matter data, gray matter data.

Then after all of that pre-exercise, the brain scan is done, they would then get on a bike. So this wasn't a treadmill, it was what we would call a sub-maximal exercise stress test. Dr. Baraniuk I think is somewhere on the call. But pretty much the gist of that exercise cycling test is that patients would reach their heart rate up to 70 percent and then get to 85 percent. And then we would stop. We wouldn't attempt to try to push the patient to true exhaustion just because we did have a second exercise coming up the next day. So it was enough to induce fatigue, but it wasn't enough to cause, I would say, just outright, completely, anything like they wouldn't be able to do the test the next day or go into the scanner the next day. I think those are the important parts of it.

But it was the protocol itself, the bicycle exercise protocol, at least from what we've seen from the data, was sufficient enough to induce post-exertional malaise. The objective findings that we did see on the MRI.

Dr. Vicky Whittemore: So, yeah thank you. There are lots of comments in the Q and A thanking you for the work that you've done and that it's amazing. So, thank you.

Dr. Rakib Rayhan: Thanks.

Dr. Vicky Whittemore: Sort of following on to that question, you know there's huge controversy in the field about the use of graded exercise in chronic fatigue syndrome. And there's a question about whether this brain imaging is actually a demonstration of the impact of exercise, or if it can actually show you the impact of exercise on fatigue and on individuals with ME/CFS?

Dr. Rakib Rayhan: Yeah, I mean that was the goal, to be able to have controls and ME/CFS patients do a standardized exercise protocol. I think it's not the exercise that we were focusing on; it was more so of having patients go into an induced fatigue state or be part of something that causes exertion where the body's systems are feeling stressed. I think there could be several things that we could have used, but I think this was the best way to approach a standardized way of inducing exertion within a large population.

And the graded exercise controversies, I know it's back and forth, but I think at least for us within this protocol the attempt was to induce a fatigue state acutely and that's what we were trying to really achieve. So, yeah.

Dr. Vicky Whittemore: There's several questions that sort of get at how does a viral infection, neuroinflammation, potentially lead to, down the road, showing these kinds of results in the brain using this kind of imaging?

What's the connection of someone who is now post-infection having these kinds of results? Can you make those connections or not?

Dr. Rakib Rayhan: Unfortunately, I don't think you could just because there are so many insults that could occur to the brain and to the brain's milieu, as we would say, throughout their initial viral infection to when they finally were diagnosed with ME/CFS. It'd be very hard to say specifically. It would be very difficult to say.

But obviously there are associations with post-viral illnesses. Obviously with COVID now and even in prior and before COVID, we've had that association in ME/CFS, but as far as the mechanisms go it just would be very hard to say at this point.

Dr. Vicky Whittemore: Okay, there's lots of questions. Actually, I see a job offer here for you in the Q and A, too. I see a job offer; they're asking if you'd like to work at the Bateman Horne Center.

Dr. Walter Koroshetz: Got to finish his residency first.

Dr. Rakib Rayhan: I know.

Dr. Vicky Whittemore: Yeah so, there's a question that just came in about if you could talk about patient selection methods and diagnostic inclusion criteria you used to select the individuals with ME/CFS who participated?

Dr. Rakib Rayhan: Sure, so the patients just had to meet the criteria for ME/CFS. We really didn't, our exclusion criteria were really focused on making sure that they didn't have congestive heart failure or things that would exclude them from being a part of an exercise study.

Another exclusion we had was no metal implants or things that would, claustrophobia. But we really didn't have too many, I would say, exclusions that would muck up the patient population. If you had ME/CFS, you met that criteria if there wasn't like I said, heart failure or some sort of cardiac issues or inability to actually participate within the study. We had a pretty solid number from a wide group, I would say, of patients with ME/CFS that didn't fit any specific cluster. So our exclusion criteria wasn't large.

Dr. Vicky Whittemore: Okay, and one last question for you before we move on to get to some other questions here. Did you evaluate heart and lung issues of the participants while participants were on the bike? For example, your VO2 max to see whether they were going into an anaerobic state?

Dr. Rakib Rayhan: Yeah, we did, we did. That's all in the manuscripts, as my mentor Dr. Baraniuk would say. We did before exercise. We also did serial measurements of orthostatics throughout the entire exercise protocol. So there were several components of that.

As far as the lung goes, the only time was during the exercise, we did look at pulmonary capacity, VO2 capacity. But we didn't do, let's say, what do you call that, the blow tests. We didn't do those. We did just the orthostatics as far as heart rate and blood pressure goes, but that's about it. We didn't do anything like that.

Dr. Vicky Whittemore: Okay, well once again thank you so much for joining us today and for the research you've done, and we hope you come back to ME/CFS research when you finish your training.

Dr. Rakib Rayhan: I will, I will.

Dr. Vicky Whittemore: Excellent, thanks.

Dr. Rakib Rayhan: Thank you so much.

Dr. Vicky Whittemore: So, we're going to move to a couple of other questions. There was a question about if the ME/CFS Collaborative Centers can receive funding through the RECOVER Initiative? I'll just answer that quickly.

The initial call for proposals was open for any institutions and investigators to submit applications. And those sites, my understanding is, have not yet, but are soon to be announced. And there will hopefully be additional initiatives coming down the pike because the first phase is to collect the biospecimens and clinical data from individuals with COVID, acute COVID and long COVID, and then make those biospecimens and data available to investigators. So there will be further initiatives coming along down the road.

I think the next question I'd like to direct to Dr. Koroshetz. Back to your discussion about the appropriation of the funding and that it was for Long COVID, and really the question of do you think that these protocols on the sites will really be set up to identify individuals with ME/CFS in those cohorts, even though the funding is really directed to Long COVID? So, what do you think about that question?

Dr. Walter Koroshetz: Yeah, as I was mentioning, we and you were very helpful in getting the critical components of the symptoms of ME/CFS patients into the common data elements for the RECOVER Initiative. So RECOVER is going to look at all aspects post-COVID, you know, has the pancreas been damaged, is the shortness of breath due to pulmonary fibrosis? In addition to issues that we're real sensitive to: what causes the fatigue, post-exertional malaise, sleep disorder, POTS?

And so those data will be captured and patients I suspect will fall into groups. What we know about Long COVID now is that there's a list of up to 70 symptoms that people experience and there are clusters of symptoms. So we're looking at this from first principles, and trying to put together the biological drivers for these clusters. There may be more than one, there may be more than one thing going on. But I don't think there's going to be a problem identifying the group that actually fits the criteria that we know of as ME/CFS.

Again, I said we're hopeful that this is an opportunity that you're not going to get again to understand what causes this. Then the question is can whatever we find generalize to the ME/CFS population that was not infected with COVID? So if everything is COVID specific, this may not help so much, but I would guess that given the fact that many different post-infectious symptoms that become persistent are so similar, that there's going to be an overlap between the people who have Long COVID with ME/CFS criteria and people who have ME/CFS criteria before COVID.

Then in terms of clinical trials, I think once again, you have this homogeneous population in COVID patients that we're hoping once we find something that we can actually try and test an intervention. And again, those interventions, if they work, would certainly be high on the list to try in people with ME/CFS unrelated to COVID.

Then, thirdly, as said in the chat many times, we are interested in funding more research on ME/CFS and that has been really tough because we don't have, we need a thousand Rakib’s and he's actually our first one to get an F30. But there might be a thousand people, investigators, in RECOVER, and they're going to be working with patients that have symptoms that are very similar to symptoms that ME/CFS patients have. I think that's another opportunity to draw from investigators who are in this short time frame on COVID or over the long run to get them really interested in studying ME/CFS in the generic space.

So, I think there's a lot of opportunities for us in ME/CFS to draw things out of RECOVER. And again, it's an amazing, ambitious project with tens of thousands of patients, hundreds or maybe a thousand investigators. What I'd like to say about NYU is that it's not at NYU, that's just a Coordinating Center, it's all over the country. So, I think we've got to be hopeful, and this is a time to really press down on Long COVID symptoms.

Dr. Vicky Whittemore: Thank you and I'll just add that although the number of grant applications coming in, we're encouraged because we're being contacted by investigators from outside the ME/CFS research area who are interested in doing research on ME/CFS. I've had several calls recently with new investigators who are interested in moving into this area.

There's a question about the discrepancy, for example, between funding for MS, multiple sclerosis, and ME/CFS. I think one of the differences there is that the MS Society has been around for many, many years and has pumped millions of research dollars into seed grants. And those investigators then were able to get grants from NIH. We're beginning to see that with several investigators who had seed grants from the Solve ME/CFS Initiative who are now able to translate preliminary findings into grants that are now being supported by NIH.

We have many more questions I wish we could get to, but we're at the end of the time. I'll turn it back to Barbara.

Ms. Barbara McMakin: Great, thank you so much everyone. A recording and transcript of the call will be posted on the NIH ME/CFS website soon and also I'd like to remind everyone about our listserv for updates from NIH. To be added to the listserv please visit the NIH ME/CFS website at and click on join our listserv at the bottom of the left sidebar.

Thank you again for today's call and have a great afternoon.

Dr. Walter Koroshetz: Thanks, everyone.

This page last reviewed on December 8, 2021