NIH ME/CFS Advocacy Call – January 14, 2025

Transcript

Barbara McMakin:  Good afternoon, everyone. 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.

Following NIH updates and a scientific presentation, we will open up the webinar to your questions. During the Q and A session, if you have a question for our speakers, please select the raise hand button at the bottom of your Zoom screen and we'll call on you to unmute. If you are joining us by phone, please dial star nine to raise or lower your hand, and star six to mute and unmute. You can also submit questions using the Q and A box at the bottom of your screen. Now I would like to hand the call over to Dr. Koroshetz, director of NINDS.

Dr. Walter Koroshetz:  Thank you, Barbara. And thanks everyone for joining us today. There have been several developments at NIH related to ME/CFS since our last webinar in May of 2024, and we look forward to sharing those updates with you today. We have a full agenda.

We're going to hear from Dr. Avi Nath, who's the clinical director and chief of the section of infections of the nervous system at NINDS, who has been studying both ME/CFS and Long COVID in the intramural program here in Bethesda. We will then hear from Dr. Joseph Breen from NIAID, who will let us know about the studies coming out of the ME/CFS Collaborative Research Centers and the Data Management Coordinating Center. And then Dr. Vicky Whittemore from NINDS will provide updates on open funding opportunities for ME/CFS research and other infection-associated chronic conditions. She'll also update us on the ME/CFS Research Roadmap Report, and we're also excited to have two guest speakers with us this afternoon. We'll talk about their work on ME/CFS, and they'll be introduced by Dr. Whittemore.

I've mentioned in the past the importance of understanding Long COVID for ME/CFS. We have now much more evidence that Long COVID, like many forms of ME/CFS, is one of the chronic conditions that occur after infectious diseases, potentially after some other insults too, but clearly with COVID after a virus. At NIH, we've been running what's called the RECOVER study, which has recruited over 15,000 adults and thousands of children to follow them over time and to try to get at what their natural history of their illness will be and to try and understand what is causing this chronic illness after a COVID infection.

What I wanted to talk about today is a paper from Dr. Suzanne Vernon of the Bateman Horne Center and her team who looked at this huge cohort of over 15,000 people infected with SARS-CoV-2 virus and compared them with people who were uninfected. And what they looked at is the number of people who satisfied the IOM criteria for ME/CFS after six months of their initial infection. What they found was that 4.5% of the people in the RECOVER program who came in with symptoms of Long COVID had fit criteria for ME/CFS at six months. And this compared with only 0.9% of people who were uninfected but were also part of the study but met criteria for ME/CFS at six months. The 0.9% is very similar to what's been reported even pre-pandemic, but the 4.5% is clearly a five-fold increase almost in the risk of developing ME/CFS in people who had Long COVID.

In addition, I wanted to also mention that there was a large percentage of people with Long COVID had symptoms that are common to ME/CFS but may not have fit the full criteria. So, of those people who came in with symptoms of Long COVID, 29% of them had post-exertional malaise, 25% of them had orthostatic intolerance, 20% had unrefreshing sleep, 24% had cognitive impairment, and 21% had fatigue. So the overlap between Long COVID and ME/CFS is really quite striking. And as I mentioned, even using the strict IOM criteria, 4.5% of patients with Long COVID in this study met the criteria for ME/CFS.

And if you figure that we don't know exactly, but if say for instance some figures of about 20 million people in the U.S. had Long COVID, that's going to calculate to over 800,000 people in the U.S. coming from Long COVID into ME/CFS. So this pandemic, unfortunately, has really increased the numbers of people with ME/CFS in this country, and hopefully I think, and I think it will occur that this new data is going to really push people to study ME/CFS much harder, bring more people into the field and hopefully we'll hear from some of those today.

So this is just one example of what the RECOVER program has been bringing out. I think a lot more will be coming now that the enrollment is complete. There's still follow-up going on. There are samples that have been collected. There's research going on - on those samples and on the data and we’re looking forward to what comes out of the RECOVER program, not just for understanding Long COVID but for understanding ME/CFS as well. So those are my remarks to open and now I'd like to turn it over to Dr. Avi Nath from the NINDS intramural program. Avi?

Dr. Avindra Nath:  Thanks, Walter. Thanks for that update as well. So let me tell you a few things about what we are doing right now. So we are continuing to study the cohort that we had originally enrolled and there was a lot of data that we collected from there. And so there are at least two manuscripts that are currently being prepared for submission for publication. So I think that work is coming along really nicely.

And then there is another study being initiated by NHLBI and they received some funding from a program called Bench to Bedside. And so that will be studying some of the patients that we enrolled into our cohort, the ME/CFS patients, but from the standpoint of muscle and mitochondrial abnormalities. And so they have a novel compound that they're going to use in a treatment trial for that. That funding has just become available, so the study will now have to be written up and then started.

Then the other thing is that with Vicky's leadership and with Brian Walitt's help, they're helping develop a new criteria for clinical trials and this will be called the Hingston criteria. So, it's an international collaboration with experts in ME/CFS to have gotten together now a few times and are in the process of developing these criteria.

Then with our Long COVID patients, we've got a natural history study that's ongoing, it's enrolling really well. We have an IVIG clinical trial placebo control study, and that's also enrolling really well. And so that's ongoing. We have a study just to look at viral reservoirs and that's just been approved, so we'll start recruiting for that. It's a very extensive study because it's going to look at every body fluid and every organ system that we could possibly biopsy. And with a lot of imaging and stuff along with it as well.

Then lastly, we're going to do a clinical trial, if we can get funds for it, it's on the use of a checkpoint inhibitor in Long COVID patients. Excuse me. So, I'm very excited about that possibility because in our previous study in ME/CFS, we had shown that a very prominent abnormality in those patients was that the immune cells, they get exhausted. And what that means is that we have persistent antigen of some sort. Your immune cells can no longer, after a while, they try to eliminate it, but after a while what happens is they're unable to do so, and they're still alive but they're exhausted. And we identified a number of other immune abnormalities to explain why that actually happens, and we think there's a very specific immune response in ME/CFS patients that leads to T-cell exhaustion or lack thereof.

And this has been now reproduced by a couple other groups, and so we are eager to try to reverse that process of the T cell. And if you can, then our hypothesis is that they should go and eliminate the reservoir. So the hope is that if that reservoir is the one that's responsible for the symptoms, then the patient should get better. But either way it'll answer the question. It's quite possible that maybe the viral antigen that is sitting there, it is just sitting there doesn't do anything, and that would still be an important question to answer. So I'll stop here and hand it over to Joe Breen from NIAID.

Dr. Joseph Breen:  Thanks, Avi. Hi. My name is Joe Breen. I just want to give a short update on some research progress from the Collaborative Centers that NIAID and NINDS support really to better understand the basic biology of ME/CFS. So I've mentioned on previous versions of this call that there's a center at Cornell led by Dr. Maureen Hanson with a co-investigator Andrew Grimson. And actually, related to what Dr. Nath just talked about, they had a paper just published in December that described 28 ME/CFS patients and 30 sedentary controls and looked at immune cell differences. It's been known for some time that there were as immune dysregulation ME/CFS, but they used very sophisticated single cell RNA techniques and were able to show a number of different differences. One of them was this exhausted T cell type, which was very apparent and statistically different between the groups. And that's important for the reasons that Avi mentioned that it really highlights that there may be a persistent antigen, but we don't know what that is.

And it also with sophisticated techniques now opens up for not only potential drugs using that methodology and that pathway that Dr. Nath mentioned, but also more sophisticated ways to try and understand the antigen that might be responsible in ME/CFS or at least associated with ME/CFS. So that's very exciting. And now this is a number of research groups including Dr. Nath's and now Dr. Hanson as well as a few others have shown this exhausted T cell phenotype. So I think that's validating and that just shows the importance of it. And the Cornell group is continuing to follow up. There's a Cornell Chronicle article that describes this study in lay language that's really nicely written that was published December 3rd. Now if you want to look on the web for that.

The Data Management and Coordinating Center, which is a grant that is funded by NINDS, which really is organizing certainly the data from the NIH-funded collaborative centers for research, had some milestones. One thing they have is a mapMECFS, really a search engine and data organization tool that is utilizing curated ME/CFS data and they now have over 200 users of that database, which has increased 50% in the last year with 94 public data sets. Again, trying to increase the scope of the people that can really analyze that data and increase the community of folks who are looking at this problem similar to what Dr. Koroshetz mentioned earlier.

And the mapMECFS repository is now an officially NIH supported officially scientific data repository that is actually another important validating step. Another thing the Data Coordinating Center is doing has to do with some samples from the CDC, which Vicky is going to talk about in a minute. So I'll leave that to her. And the other research center is at Columbia where they're looking really hard to understand innate immune triggers in ME/CFS patients. And Dr. Ian Lipkin who leads this center talked about this in December at NIH and is continuing to follow up where he has a hypothesis that there are innate immune triggers for a variety of reasons. And he's doing metabolomic, proteomic, and cytokine assays pre- and post-exercise to really understand what those triggers are and how that's contributing to the pathology that's seen with ME/CFS.

And I just want to leave you with the impression that there's an active research in these Collaborative Research Centers in addition to the unsolicited grants that are being supported by NINDS and NIAID that Vicky and I would be happy to talk about separately. And I think I'll stop there and turn it over to Vicky.

Dr. Walter Koroshetz:  Before you go, Joe, I just wanted to mention one other thing that came out of RECOVER that's related to what you mentioned, which is this question of whether or not there's a persistent piece of a virus or infectious particle that is continuously affecting the immune system and leading to this T cell exhaustion.

In the RECOVER program, Dr. David Walt looked for evidence of COVID virus proteins in the blood of people with Long COVID in RECOVER versus controls. What he found was that 43% of the people with Long COVID had evidence of these viral proteins compared to, I think it was only 21% in people who did not have Long COVID. They probably had COVID, but they didn't have Long COVID.

But you can see how there's an enrichment of finding these antigens in people with Long COVID, which goes along with this idea that there's some persistent stimulation of the virus going on in the Long COVID patients. And one question, say pre-pandemic ME/CFS, could there be some other virus or even a bacteria that is still causing persistent antigen presentation to the immune system? So a lot of the pieces of evidence are kind of coming together, as Joe and Avi mentioned.

Dr. Joseph Breen:  Thanks, Walter.

Dr. Walter Koroshetz:  Thank you for that. And let me hand it to Vicky.

Dr. Joseph Breen:  I should have mentioned that the exhausted T cell phenotype is seen also in Long COVID patients. I didn't mention that. And we know, that's immunologic evidence that there's a persistent, at least viral antigen there. And it's interesting that we have an immune signature that looks like a persistent signal in ME/CFS. We just don't know what's driving that, whether it would be bacterial, presumably an infection because there's such a strong connection with post-infection disorder. But that's really an active area in both Long COVID and ME/CFS. And I'll stop there. Go ahead, Vicky.

Dr. Vicky Whittemore:  So thank you. I'm just going to share some slides here briefly. So if you look at the NIH funding for ME/CFS research, you can see that there was a significant increase in the amount of funding between around 2014 and then up through 2021. And since then, there's been, again, been a decrease. And that's due in large part to a couple of things.

First, the challenges we have with a flat budget, which we've had for two years now, which has really significantly impacted the number of projects and research we can fund across the board, not just for ME/CFS, as well as the fact that we funded two instead of three research centers. But we're really still continuing to really encourage grant applications to come in and working with investigators. And the encouraging sign is that at NINDS, we are talking to or have seen applications come in from multiple groups interested in putting forward clinical trials in ME/CFS. So there really are new investigators coming into the field, especially those who are interested in moving forward with clinical trials.

So just some research activities. So as many of you may know, we presented the ME/CFS Research Roadmap to the NINDS Advisory Council in May. And since then we have been looking and working to map the funded projects to the research priorities that were outlined in the ME/CFS Research Roadmap so that we can really focus in on the gaps and the opportunities to really support research across the board so that more on that, hopefully by our next telebriefing we'll have some more to report about that whole mapping effort.

As Joe had mentioned, we've been partnering, NIH has been partnering with the CDC to make biospecimens from the CDC-funded multi-site ME study or they called MCAM available to investigators. And investigators now can access and request access to biospecimens through searchMECFS, which is a tool that's developed by the Data Management Coordinating Center and the correlated clinical information from that study. And that data is available on mapMECFS and the link, those websites are listed there.

As was mentioned by Avi, we have an international ME/CFS Clinical Trial Working Group, and I'll talk more about that on the next slide. And we have ongoing work to work on ME/CFS common data elements and criteria. As again Dr. Nath mentioned, we're working on Hingston criteria that came from discussions at the Invest in ME conference in the U.K. last year, as well as we were able to obtain additional funding from the Office of Data Science and Strategy to continue work on the ME/CFS common data elements that will standardize the collection of data across research studies.

In terms of funding opportunities, there are two opportunities open at this point in time, both put forward by my colleague Will Daley at NINDS. The first towards a better understanding of the neurological effects of infection-related chronic illnesses, which is, and these are, so the first is an R21 and also an R01. So those opportunities are currently open to investigators for grant submission. And we also have approval from the NINDS Advisory Council to move forward with a specific funding announcement for ME/CFS research and that will be coming soon.

And just to end, just to tell you about the ME/CFS Clinical Trial Working Group, this is a partnership between NIH Invest in ME in the U.K. and the European ME Research Group. And as I said, initial discussions about this took place last year at their conference in the U.K. and it was decided to move forward with this working group. And the co-chairs, we have co-chairs from the U.S., Dr. Nancy Klimas and Dr. Ian Lipkin, and from Europe, Simon Carding in the U.K. and Jesper Mehlsen in Denmark. And working group members are clinicians and researchers from U.S., Norway, Canada, U.K., Denmark, Sweden, and Austria.

And the goals of this group are to discuss and reach consensus on ME/CFS criteria to be used in clinical trials, to identify and prioritize interventions for ME/CFS clinical trials, to determine the appropriate phenotyping or subtyping of study participants for ME/CFS clinical trials. So we're enrolling in the individuals with ME into the right clinical trial for them. And lastly, to identify clinical trial outcome measures that will be rigorous and that will help us to lead to FDA approval of treatments for ME/CFS once the clinical trials are completed.

So with that, I will turn it over now to our guest speakers from Johns Hopkins. So it's my pleasure to introduce Vikram Chib who is an associate professor of biomedical engineering and a research scientist at Kennedy Krieger Institute where he leads a lab to understand how the brain integrates information about rewards to motivate performance. And he has recently received funding from NINDS for an R01 grant entitled Neural Mechanisms of Fatigue in Post-Acute Sequelae of SARS-CoV-2. Joining him is Agostina Casamento-Moran, who is currently a postdoctoral fellow in Dr. Chib's lab. She currently has a MOSAIC K99/R00 grant entitled Neurobiological Mechanisms of Fatigue in Health and after COVID-19, and it's my pleasure to congratulate her and announce that she's just accepted a position at the University of Florida in the Department of Applied Physiology and Kinesiology. So with that, I will turn it over to you, Agostina. Thank you.

Dr. Vikram Chib:  Okay. Hi, everyone. I'm going to start the presentation by sort of giving you an overview of the framework that we use to understand fatigue in the lab, and then Agos is going to present some data that she's collected in COVID, beginning to look at what's happening in the nervous system in people with Long COVID. And then we'll wrap back around and tell you about the recent grant that we were awarded and what we plan to do in the future. So our research begins with our multidisciplinary team. So we use a lot of different modalities, computational modeling of behavior as well as neuroimaging. So we have in our group engineers that use math to model behavior and brain activity, physicists who create MRI sequences to study different aspects of the brain and how those are influenced by COVID, and clinicians who help us understand the challenges the patients are facing and the questions that we should focus on trying to understand.

In our lab what we try and do is understand the different factors that influence fatigue and decisions to exert effort in a general framework in healthy individuals and individuals that are suffering from different diseases. And so to do this, we employ well-controlled behavioral experiments and those often involve subjects interacting with electromechanical systems like robots or force sensors like Agos is going to present today. We'll often have people do those tasks while they're in an MRI scanner. So we can look at the brain activity that is associated with that behavior such as exerting effort and the feelings of fatigue that come with exerting that effort and how the brain encodes those different ideas. We'll then use that data both the behavioral data and the MRI data to generate mathematical models of behavioral and neural activity. And the reason we use math is because it gives us a very objective way to study this very subjective concept of effort and fatigue.

And so that can then hopefully give us a better idea of the neural mechanisms that are involved in fatigue and effort, and then develop diagnoses and treatment to better understand how people process effort in the brain and how fatigue is represented in the brain, and what sort of might go wrong in some of these conditions where fatigue is a big problem.

And so to give an idea of an example where we experience effort and fatigue, we can think of this case of sitting at our computer working on a project, maybe typing all day and deciding to ourselves we're going to reward ourselves with a nice cup of coffee. So we've spent the whole day working on our projects on our computer, we've put in all of that cognitive effort and we might decide to reward ourselves by getting kind of a mediocre cup of coffee walking down the hallway and getting a mediocre cup of coffee or putting in more effort and getting a really nice cup of coffee.

And here you have a balance between the effort that you need to exert whether you want to walk that short distance for the mediocre cup of coffee or take a further bout of exertion further bout of effort to get that really nice cup of coffee. And this is a fun example where we're having to balance effort and reward. But you can also think when you're in a clinical state, when you're feeling fatigue from Long COVID, having to make this decision brings on even more difficult choice. You are in a very fatigued state and making this really long walk down the hallway could be very difficult.

So you might actually think to yourself, "I'm going to pace myself and I might not put as much cognitive effort in so I can keep some effort in reserve to get that really nice cup of coffee." And so these are trade-offs that you have to make that weigh your fatigue state whether you have Long COVID or not and sort of motivate your decision to engage with your environment. And so Agos is going to give you some data now in Long COVID patients where she looked at this idea of fatigue and effort and how it's processed in the nervous system.

Dr. Agostina Casamento-Moran:  Yeah. So basically, we recruited 34 participants with Long COVID and 34 healthy age sex and fitness matched controls. Our cohort was primarily women and all participants with Long COVID reported that their perceived physical and cognitive status was lower than the pre-COVID estimates.

Now to understand fatigue in Long COVID, we use four different behavioral tasks. The first one is looking at feelings of tiredness by having participants move a cursor in a continuous line to rate how tired they feel at that particular moment in time. We also looked at motor performance, and just like Vik mentioned for this, we used force sensors where we basically asked participants to squeeze this force sensor to hit targets on the screen. So if the participant, the exerted force is accurate, this term like bar will be filled green, otherwise it will be red, basically like a video game. And we particularly chose this task because its isolated and submaximal nature allows us to look at fatigue and effort while minimizing the detrimental effects on participants' health, like minimizing for example, post-exertional malaise.

So after participants exert these different forces, we're also interested in understanding how effortful these forces feel to them. And again, we present them with a rating scale where they're going to move a cursor and tell us how effortful those forces were where zero means no effort at all and 100 means maximal effort. And lastly, we have this very cool paradigm in the lab that basically allows us to look at effort-based decision-making, kind of like the example that Vik was just saying about the coffee, where now we ask participants to make a choice between exerting a certain amount for sure or taking a gamble where they have a 50/50 chance of exerting a higher amount or no effort at all.

So looking at this task, we first looked at feelings of tiredness and we found that individuals with Long COVID depicted with this black bar, reported stronger feelings of tiredness compared to healthy controls, which are the gray bar. Interestingly, we then looked at the exert component of that exertion task that I described, and we find actually similar motor performance between the groups. So on the Y-axis you have basically exerted force as a function of the target force that we asked them to exert, and you have Long COVID in black, healthy controls in gray. And you can see that individuals with Long COVID were very accurate, as accurate as healthy controls and were able to generate the same forces than healthy controls. But when you're generating these forces, you're basically activating your muscles to generate that force. So we then were curious to understand how are individuals with Long COVID using their muscles when they're generating these forces.

And we actually found higher neuromuscular co-activation in Long COVID. So on the Y-axis you have muscular co-activation as a function of how much force they were exerting. And you can see that healthy controls which are depicted in gray use lower muscle co-activation in lower forces, but then they increase the amount of co-activation when they are exerting higher forces. However, Long COVID depicted in black here, you see that they don't modulate the amount of muscle activity that they use and they're always using high levels of muscle activities irrespective of how much force they are exerting. So these results suggest that Long COVID has inefficient neuromuscular activity well to generate the same forces than healthy controls.

And so we then looked at how effortful these forces felt for individuals with Long COVID and we actually also find also higher effort assessment in Long COVID. So here you have effort assessment on the Y-axis as a function of exerted force, Long COVID in black, healthy controls in gray. And now you can see that individuals with Long COVID feel that the same forces are more effortful than the healthy controls.

So a brief summary here, we find that individuals with Long COVID can generate the forces but they use more muscle activity and find these forces more effortful. So next we wanted to understand the relationship between these neuromuscular performance and effort assessment. And we actually find that the exerted force mediate the relationship between EMG co-activation and effort assessment. But what's important here is that this relationship is actually impaired in Long COVID, suggesting indeed that this inefficient neuromuscular activation results in heightened assessment of effort in this population.

So lastly, looking at the effort-based decision-making using the choice paradigm, we also find riskier effort-based decision-making in Long COVID and this is depicted with a lower subjective effort cost for Long COVID compared to healthy controls. These results surprised us because our hypothesis was that maybe individuals with Long COVID, because they have these stronger feelings of fatigue, they would actually be less risky than controls. We're still trying to understand this data, but we have two working hypotheses.

The first one has to do with the zero component here on the gamble that we present. Is it possible that individuals with Long COVID are trying to pace themselves and by choosing to gamble they are increasing the likelihood that they will have to exert any effort at all? That's one hypothesis. The other hypothesis is that individuals with Long COVID are really willing to exert these higher efforts despite their detrimental effects that it can have on their health if they don't pace themselves. We're still working to understand all of this data.

So in summary, we're finding inefficient neuromuscular activity in Long COVID that results in higher perceived effort from exerting this task and potentially also riskier effort-based decision-making.

Dr. Vikram Chib:  Yeah. So now I thought I'd just sort of give you an overview of what we're planning to do in the future with the new grant that we received. So just to give you an overview of the aims, the first aim of the grant, I should say this grant will use a lot of the same paradigms that Agos has described. And in addition, we'll be taking measures of blood-brain barrier permeability with structural MRI, and that'll allow us to look at how different neurochemicals transfer into the brain and might lead to neuroinflammation. That could be a cause of Long COVID.

So the first aim will be to use the paradigms that Agos mentioned and look at relationships between blood-brain barrier permeability and neural and behavioral representations of effort in individuals with Long COVID. And aim two, we'll also take blood-brain barrier permeability measures and introduce a behavioral paradigm in which we give repeated physical exertion to people, how people do repeated physical exertion to bring on a little bout of fatigue and see how those bouts of fatigue which are going to be sort of submaximal exertions to get small bouts of fatigue to see how that is influenced by blood-brain barrier permeability. And then the last aim is to look at how permeability changes, blood-brain barrier permeability changes through the course of recovery and through the course of time and how these behavioral and neural measures change over the course of time as people recover from Long COVID.

And so to give you an idea of how this works is we understand that fatigue for individual patients is very different, right? There can be different factors that contribute to fatigue in different people, and they might all experience fatigue, but in a multi-dimensional way it manifests in very different ways. And so our idea is to basically take batteries of cognitive and physical measures to get at these individual differences. So that'll include neuroimaging to get at functional brain activity, structural imaging to get at blood-brain barrier permeability, also the effort-based decision-making tasks and this effort assessment that Agos has shown you before.

We'll use some computational modeling of neuroimaging and behavior to then generate objective parameters that describe these different physiological and behavioral ideas to then basically get at individualized ideas of what fatigue might mean for different people. And so in the context of our grant, that level one cognitive and physiological battery, it will include effort, behavior, both decision making and assessment, brain activity in the form of fMRI, blood-brain barrier permeability in the form of structural imaging, and also blood markers. So we'll take blood draws to look at different neurochemicals that might be influencing feelings of fatigue and changes in brain and behavior. And so that concludes our presentation and we'd be happy to take any questions.

Barbara McMakin:  Okay. Great. Thank you for that presentation. We will now transition to the question answer session of the webinar. As a reminder, if you have a question for our speakers, please select the raise hand button at the bottom of your Zoom screen and we will call on you to unmute. If you're joining us by phone, please dial star nine to raise or lower your hand, and star six to mute and unmute. You can also submit questions using the Q and A box. We'll try to answer as many questions as possible, but we may not be able to get to all of them today. We want to hear from as many people as possible, so we request that everyone ask only one question. As a reminder, this call is open to the public and is being recorded. Please exercise discretion in sharing personal information including personal medical information.

So we've received quite a few questions to the Q and A box already, and I will start with some questions for our guest speakers. What are the illness durations of this major cohort and do you separate age groups?

Dr. Agostina Casamento-Moran:  Yeah. So actually, the illness duration was quite variable. We started with the original definition of Long COVID, which was four weeks, but we also have people that have up to six months of Long COVID. We tried separating it by age, but we didn't find any effect of age. So the results are quite homogeneous across all age groups despite the wide range of ages.

Barbara McMakin:  Okay. Great. Thank you. How did you come across with the idea that the blood-brain barrier permeability might change over time?

Dr. Vikram Chib:  So we know that blood-brain barrier or I think it's hypothesized that blood-brain barrier permeability is a big factor in neuroinflammation. And so our working hypothesis was that that might change and if it changes in a favorable way, it could lead to good outcomes. So right now that's a hypothesis and in Long COVID and we're going to go about trying to test that.

Barbara McMakin:  Thank you. For the hypotheses about effort results, did you ask the participants who mostly chose the gamble, why they made that choice? Also, what was the reward for doing these tasks? Was it enough to motivate someone with fatigue and really sick to complete the task?

Dr. Agostina Casamento-Moran:  Yeah. So the reward, I'll start with the second one. The reward was constant for everybody because we just compensated people for their time of coming into the lab. So we in a way do this task trying to control for reward so that we can isolate effort costs. And this is getting in the weeds a little bit, but we just try want to look at the effort in controlling for reward. And yes, everybody finished their studies, and I would say that everybody was quite motivated to participate and finish and be compliant with the experiment.

As for whether we asked them if they chose, honestly most people had preferences for their choices, but nobody really, how can I say it, had a reason why they chose it. They just were saying that's what they preferred to do. But the good thing about this task is that it's really tapping into preferences without obvious strategies. You're just making choices on how you feel, not necessarily what you want to do. Vik, I don't know if you have anything to say?

Dr. Vikram Chib:  Yeah. So there are two ways. So in that task there was a risky decision where you're deciding if you want to flip a coin for a large amount of effort or no effort at all. And then there's a sure amount of effort, a small amount of effort that you could exert. So there are two ways that you could think about or conceptualize avoiding exerting effort. One is to take the risky option in which hopefully zero comes up and you don't have to exert anything, or you could think of an avoidance of effort by taking the small sure option as well. So there are different ways to think about avoiding exerting effort, and it's just interesting to us that individuals with Long COVID chose to take the risky option.

Barbara McMakin:  Great. Thank you. Are the healthy control subjects verified throughout the study? For instance, are they confirmed to not tested positive for COVID during the study or post-recruitment?

Dr. Agostina Casamento-Moran:  We tried to have people that never had COVID, but it became impossible. So most people really were COVID recovered. We did have a few people that said that they have never contracted COVID, but I would argue that 85% of our healthy controls had had COVID but were not [inaudible]. And as Vik mentioned, we work in tight collaboration with our clinical collaborators, Dr. Asola and Dr. Malone. So everybody that came even either came from their clinics or from the community, we were ensured that they were not experiencing Long COVID symptoms.

Barbara McMakin:  Great. Thank you. We do have a couple of attendees with their hands raised, so let's switch over to them. Danielle Gillen, you can go ahead and unmute.

Danielle Gillen:  Hi. Can you hear me?

Barbara McMakin:  Yes, go ahead.

Dr. Vikram Chib:  Yes.

Danielle Gillen:  So I am somebody, I used to be a pediatric bone marrow transplant nurse. For me, I got COVID in, so we're not supposed to talk about our ourself, but for patients that have multiple reservoirs in their body, like the brain, the lung and the esophagus, how do they become eligible to register for these reservoir studies?

Dr. Avindra Nath:  I can take that. So the reservoir study hasn't started yet, but it's about to start. But you can just send me an email and we'll put your name on the list and contact you as soon as the study gets started or we can actually start some pre-screening questionnaires and stuff to make sure that you fall into the criteria anyways.

Barbara McMakin:  Great. Thank you. And then the next person with their hand raised, apologies if I mispronounce their name. It's Noemi JS. You can go ahead and unmute.

Noemie JS:  Thank you so much. Sorry, I also wrote the question in the question boxes. Regarding, I've been told a lot, I'm in Montreal and there's also a Long COVID department there. I've been told we had mitochondria dysfunction. And my question was, regarding mitochondria and intestinal symptoms, what is the role of these in the depleting fatigue? Is this because of a reservoir or is this something else? Thank you so much. And thank you so much for the whole meeting.

Dr. Avindra Nath:  I can start and then if anybody else wants to pitch in, feel free to do so. So yes, you're right. There's a fair bit of study and a fair bit of work being done to understand mitochondrial function in the context of ME/CFS and in Long COVID. And so here within the NIH intramural program and Dr. Paul Hwang, he has done a fair bit of work on it and he is now going to do a small clinical trial to see if they can make a difference. And he's shown that if you look at the muscle itself, there is impairment of mitochondrial-related proteins and one that he studies is called WASF3.

And there are others studying mitochondrial function in the context of this. So the favor of work being done. Why that happens is not entirely clear. There are multiple possible reasons. If you have chronic inflammation, it can actually affect mitochondrial function. There are a lot of things that get deranged. The mitochondria can only handle so much. What we do not think is that there's inherent mitochondrial dysfunction in these patients to begin with. We think it's an acquired dysfunction through a series of cascade of events that leads to that.

Barbara McMakin:  Great. Thank you, Dr. Nath. We have a couple more questions for our guest speakers. What type of neural imaging will be used?

Dr. Vikram Chib:  So we'll do task-based fMRI. So during the tasks that Agos mentioned, we will put people in the MRI scanner and have them do those tasks so we can measure functional brain activity. So how brain activity changes as people are processing different effort values. We'll also have structural imaging that we'll look at blood-brain barrier permeability. So they'll look at how permeable the blood-brain barrier is. So that's more structural. So we'll be using structural and functional measures.

Barbara McMakin:  Great. Thank you. And what kinds of markers will be measured in the blood?

Dr. Vikram Chib:  A variety. I can't remember. I think we said interleukin six. I don't remember exactly which ones they were. The whole idea is to get a battery of - our primary hypotheses are about the effort-based choice and blood-brain barrier - but the idea is to get sort of a battery of things from the blood. But off the top of my head, I can't remember. I apologize.

Barbara McMakin:  Right. We have a RECOVER-related question that came in. It was mentioned that there are 15,000 people participating in this study that was published yesterday. Can you speak to the inclusion plan or efforts to represent a diversity of people with ME? I don't know if Dr. Koroshetz or Dr. Breen, if you want to take that one?

Dr. Joseph Breen:  Well, I can start. So in fact, part of the strength of that study was that it was in coordination with the Bateman Horne Center, which sees both ME/CFS patients and they were able to utilize that expertise to analyze their RECOVER center data that they were associated with. So I think it's trying to get at the crux of the question of how folks with an acute COVID infection then evolve into more serious Long COVID and then eventually, unfortunately meet the criteria for ME/CFS. And that's what that paper's about. And the whole reason that was possible is because RECOVER recruited people with expertise like Dr. Vernon, Dr. Bateman and others so that we could identify that as we unfortunately expected some of that to evolve over the observational cohort during time. So I hope that is answering the question. If not, I'm happy to speak further or I don't know. Actually, Dr. Koroshetz had to drop, so I'll stop there.

Barbara McMakin:  Okay. Great. Thank you. Dr. Nath, this might be a question for you. A person is wondering if there's any ME/CFS research looking at dorsal root ganglia inflammation?

Dr. Avindra Nath: Not that I know of.

Barbara McMakin:  At this point in time, we have many seniors over 65 and young people under 18 that suffer from ME/CFS and have for years and decades. How can we get them included in studies and clinical trials? Dr. Whittemore, I don't know if you want to take that one.

Dr. Vicky Whittemore:  Sure. Yeah. I think that at least the clinical trial groups that I've been talking to in terms of looking at more elderly individuals, they clearly are interested in including those individuals in those studies and obviously then segregating the results by age group. So that's something that people are beginning to do much more frequently.

In terms of pediatric clinical trials, that's still a very huge area of need. And I know from participating in webinars from RECOVER-TLC, which Dr. Breen is very much a part of is that there's significant push and interest in really moving toward clinical trials and better understanding of Long COVID in individuals under the age of 18. And it's the same with ME/CFS. There is just very little research and very few groups who are actually looking at children with ME/CFS unfortunately. But it's certainly something that we're very much interested in supporting. It was one of the research priorities that came out of the Research Roadmap.

Dr. Joseph Breen:  Yeah. Actually, I can make a comment there. So interestingly in the previous iteration of the Collaborative Research Centers, Derya Unutmaz did some immunological analysis and saw a relationship between change in ME/CFS in people over 50. So I think we need more sample size to get a larger percentage of the population that is in the older age so that we could look at those trends in more detail. Right now, for ME/CFS, we don't have enough. Hopefully with things like the RECOVER observational cohorts and samples available, we'll be able to do that. And unfortunately, there's going to be ME/CFS as we know from the numbers. There'll be ME/CFS patients in there also. But I think it's an area that we are very interested because the science is leading us that way, but we just have to increase the number of folks looking to look at both the pediatrics that Vicky talked about and the older folks as this person questioned. Over.

Barbara McMakin:  Great. Thank you. Carly Goldberg, you have your hand raised. If you want to go ahead and unmute please and ask your question.

Carly Goldberg:  Yes. Hi. This question is for Dr. Chib and Dr. Moran. I'm wondering if there is going to be a qualitative piece to your research to understand why measured, why people who are motivated to push themselves or gamble more or those who decided to be more reserved? And I think you were questioning the results of some of that data, and I'm wondering if there's going to be a look at the social barriers and lack of access to inform these efforts and why people might choose what these conditions to push themselves gamble or reserve or not. Thank you.

Dr. Agostina Casamento-Moran:  So we collected all that data actually. We have social determinants, some social demographics, and we definitely, the more we look at the data and the more not only we understand our data, but also, we learn from other investigators. We're starting to see what other metrics and qualitative metrics we should include as the future grants kick in. So it's definitely something that we're thinking about and thinking through and keeping these ideas in mind. Yeah, absolutely.

Dr. Vikram Chib:  I will say that we do try and so your wealth and things can have an impact on how you decide to make these risky decisions. And so we do try and account for that, as Agos said, by collecting those measures. I will say what we found in healthy participants is actually the opposite of what we find through a number of studies, the opposite of what we find in the Long COVID participants. So healthy participants seem to try to avoid exerting effort by taking that sure option, whereas the patients with Long COVID seem to want to take that risky option. So it seems to go beyond demographics and could be really hinting at some sort of neurobiological mechanism of choice. I don't know what that is, we don't know what that is yet, but it'll be interesting in the future to see why there's such a difference in that decision making.

Barbara McMakin:  Great. Thank you. Are you planning to use any wearable devices in your research?

Dr. Agostina Casamento-Moran:  Yes, absolutely. We know more and more, especially once we start thinking about capturing post-exertional malaise, which in this particular study we minimize, but also we know that this could be a potential way to look at post-exertional malaise and capture, not only with wearable devices, but also ecological momentary assessments of these efforts. So yes, that's definitely future work that hopefully we'll be executing.

Dr. Vikram Chib:  It will be interesting to sort of take the effort-based decision-making data that we have in the lab and see if it translates into real-world decisions to perform activity.

Barbara McMakin:  Great. Thank you. I have a question for Dr. Whittemore. Are there any opportunities for trainee grants or researching funds that will not require large efforts like R21 or R01 available for young researchers?

Dr. Vicky Whittemore:  NIH has several grant mechanisms starting with grants for undergraduates, for graduate students, for post-doctoral fellows, for clinical fellows. Those are all what we call our F and K awards. So training and career development grants. The R21 is a two-year grant that allows individuals to come in and do somewhat exploratory or initial research to, really the goal is to develop preliminary data to then be able to come in with a larger R01 or larger grant to NIH. And those are open at, all of those grant mechanisms are open at all times. And then there are other grant mechanisms somewhat dependent on each of the NIH institutes. And so I think that if you want to follow up with me, I'm happy to have additional conversations about what grant mechanisms and the research which institute your research might fit into.

Barbara McMakin:  Great. Thank you. And then one more question for our guest speakers. Do you have any plans to incorporate severe possibly bedridden patients into any of your research?

Dr. Agostina Casamento-Moran:  The short answer is yes, with the wearables, but no, how do we take these measurements, MRI bringing them into, and how much, the balance between understanding, harm is something that we try to keep in mind a lot. So yes, by extending the research with wearable devices, we will try to reach those populations. But also trying to keep in mind how much harm we do if we want to ask those participants to come into the lab is something that we're continuously talking with our clinical collaborators.

Dr. Vicky Whittemore:  If I can just add a quick comment. Several of the groups that I've been talking to about doing clinical trials are planning to use wearables and testing that could be done from home remotely, which would be able to incorporate individuals who are bed bound and more severely impaired by the disease.

Barbara McMakin:  Great. Thank you. So we are at time. A recording and transcript of the webinar will be posted to the NIH ME/CFS website soon. In closing today's webinar, I'd like to remind you about our listserv for updates from NIH. To be added to the listserv, please visit the NIH ME/CFS website and click on join our listserv. Thank you for an informative and thoughtful discussion and have a great afternoon. Thank you.