USA: NIH National Institutes of Health news - latest ME/CFS webinar 14 Jan 2025

Dolphin said:
NIH’s next ME/CFS Webinar will be held on January 14, 2025 from 2:00 – 3:00 pm ET. The webinar will include updates from NIH on ME/CFS-related research activities and a presentation by Vikram Chib, PhD, and Agostina Casamento-Moran, PhD, from Johns Hopkins University. Please register in advance.
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Just reminding people that this webinar is today in about three hours at 2 PM EST or 7 PM GMT. You can still register to join.
 
Potentially interesting finding from the two researchers mentioned above, Agostina Casamento-Moran and Vikram S. Chib from Johns Hopkins University.

They had people with long COVID and controls do some sort of hand grip exertion task. LC felt it was more effort, but they were able to exert the same amount of force as controls. The interesting part is that they measured "neuromuscular coactivation" in the arm while participants squeezed the device. The activation was similar between groups at high forces. In the controls, the less force they exerted, the less activation they had in their muscles. But in long COVID, the activation was more or less constant no matter the force required, suggesting the muscles are overactivated/inefficient at low forces. (p < 0.001)

They have received a grant to do further research which will mainly be focused on seeing how blood brain barrier permeability may be associated with long COVID symptoms, and how permeability changes over the time course of long COVID.

In regards to "effort", one of the tasks they use in the studies is a sort of "gambling" game, where participants can choose to get a reward with a moderate level of effort required, or they can take a risk where they may get the reward with zero effort or with a lot of effort required. They found that people with long COVID chose the risky option more often.

Edit: Fixed typo in name
 
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Some snippets of the rest of the webinar:
  • Walter Koroshetz
    • Summarized findings of Incidence and Prevalence of Post-COVID-19 Myalgic Encephalomyelitis: A Report from the Observational RECOVER-Adult Study, 2024, Vernon
    • Regarding RECOVER: "One other thing that came out of RECOVER [...] Dr David Walt [sp?] looked for evidence of COVID virus proteins in the blood of people with long COVID 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. [...] You can see how there's an enrichment of finding these antigens [...] which goes along with the 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?"
  • Avi Nath
    • On deep phenotyping cohort data: "There are at least two manuscripts that are currently being prepared for submission for publication."
    • Another study being inititiated by National Heart, Lung, and Blood Institute (NHLBI) who received funding from Bench to Bedside Program.
      • Studying some of the patients from the deep phenotyping cohort but focused on muscle and mitochondrial abnormalities.
      • "They have a novel compound that they are going to use in a treatment trial for that. That funding has just become available so the study now has to be written up and started."
    • "With Vicki [Whittemore]'s leadership and Brian Walitt's help, they are helping develop a new criteria for clinical trials, and this will be called the Hinxton Criteria [thread]. It's an international collaboration [...]"
    • For long COVID, there is an ongoing natural history study, as well as a placebo controlled IVIG study in the enrollment stage.
    • Also for LC, there is a viral reservoir study that has been approved.
      • "It's going to look at every body fluid and every organ system that we could possibly biopsy. A lot of imaging along with it as well."
    • "Lastly we're going to do a clinical trial, if we can get funds for it, to use a checkpoint inhibitor in long COVID patients."
      • "In our previous study in ME/CFS, we had shown a very prominent abnormality in those patients were that the immune cells, they get exhausted. What that means is that we have persistent antigen of some sort; your immune cells 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 of other groups and so we are eager to try to reverse that process of the T cells. And if you can, then our hypothesis 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 is quite possible that the viral antigen that is just sitting there doesn't do anything and that will still be an important question to answer."
    • Says that Paul Wang has done some work studying mitochondrial function in ME/CFS and long COVID, and found impairment of mitochondria-related proteins including WASF3. He is going to do a small clinical trial related to this.
  • Joe Breen
      • It is now officially an NIH-supported scientific data repository.
    • At Columbia, Ian Lipkin's lab has a hypothesis that there are innate immune triggers of ME/CFS, and they are doing metabolomics, proteomics, and cytokine assays to study this.
  • Vicky Whittemore
    • After 2017, there was a significant increase in NIH funding for ME/CFS from about $5 million up to 2014 to around $15 million, but it has decreased somewhat since 2022 to around $13 million.
      • Decrease due mainly to two reasons: They've had a flat budget for two years which significantly limits research they can fund for all conditions "as well as the fact that we've funded two, instead of three, research centers."
    • NINDS receiving applications from multiple groups interested in performing clinical trials.
    • Continuing to map funded projects to the priorities outlined in the Research Roadmap last year, "so we can really focus in on the gaps and the opportunities."
    • NIH partnered with CDC to make biospecimens from CDC's MCAM study available to researchers through searchmecfs.org, with the associated clinical data available on mapmecfs.org.
    • Ongoing work on ME/CFS "common data elements" including the aforementioned Hinxton criteria, to "standardize the collection of data across research studies." Received some additional funding by Office of Data Science and Strategy for this.
      • Discussions began at Invest in ME 2024. The working group's co-chairs are Nancy Klimas, Ian Lipkin, Simon Carding, and Jesper Mehlsen, with members from USA, Norway, Canada, UK, Denmark, Sweden, and Austria.
      • Goals include identifying optimal criteria, intervention possibilities, subtyping/phenotyping measures, and outcome measures.
    • Two funding opportunities available to researchers to study neurological effects of infection-associated chronic illnesses. Also they have approval for another ME/CFS specific funding opportunity which they will announce soon.
    • Says that investigators she speaks to are interested in including more elderly patients in studies. NIH is interested in supporting more research on children, but there is currently very little research and very few groups doing this.
      • (Joe Breen comments that Darya Unutmaz has seen immunological changes in people with ME/CFS over age 50, and says that larger samples are needed to study older people in more detail.)
    • Several groups she has been speaking to are planning to use wearables and remote testing in studies which will allow participation by severe and bedbound patients.
  • Agostino Casamento-Moran and Vikram S. Chib
    • Additional information about upcoming study about blood brain barrier permeability in long COVID mentioned a few posts ago.
      • "We'll do task based fMRI [...] so we can measure how the brain activity changes as people are processing different effort values. We'll also have structural imaging that will look at blood brain barrier permeability."
      • Will try to include wearables. "It will be interesting to take the effort-based decision making data that we have in the lab and see if it translates into real world decisions to perform activities."
 
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forestglip said:
They had people with long COVID and controls do some sort of hand grip exertion task. LC felt it was more effort, but they were able to exert the same amount of force as controls. The interesting part is that they measured "neuromuscular coactivation" in the arm while participants squeezed the device. The activation was similar between groups at high forces. In the controls, the less force they exerted, the less activation they had in their muscles. But in long COVID, the activation was more or less constant no matter the force required, suggesting the muscles are overactivated/inefficient at low forces. (p < 0.001)
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i.e. the LC patients' interoception was accurate, which will be annoying for those at the NIH who want LC to be an 'interoceptive disorder'.
 
Jaime Seltzer's very long thread on Bluesky is interesting. I haven't read it all yet, but whizzed through to the end where I read this:

‪It's ME(Jaime)‬ ‪@exceedhergrasp1.bsky.social‬
Worth saying my impressions at the end: There is still a STRONG push for behavioral studies from high w/in NIH. Eye-rolling from a scientific stance; gut-roiling from an ethical one. And no, it doesn't matter how their language shifts, it's quite clear.

I hope Jaime will write it up in a format we can all read.
 
Trish said:
There is still a STRONG push for behavioral studies from high w/in NIH.
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I'm thinking she's just talking about the two guest researchers (they are a team that presented together). No one else seemed to talk about behavioral stuff (apart from Vicky introducing them). But it was odd how much time they gave those two. Out of the full hour, it was about 15 minutes for the presentation, plus about 7 minutes of them answering questions from viewers.

Felt strange that they gave so much time to one specific research group, and no other non-NIH leadership speakers. Wondering if they just needed to fill time? A favor from someone at NIH to these researchers? Apart from the neuromuscular activation I mentioned, their presentation wasn't particularly interesting. It was also odd how many times they said the word "effort". I think they're very focused on that "gambling game" task I mentioned earlier, which they also refer to as "effort-based decision making". Sounds similar to "effort expenditure for rewards task" (EEfRT). Wasn't there an element of chance in EEfRT as well?

To re-summarize what they say about the task: Individuals could get a reward with definite moderate effort, or choose an option where chance determines if they will have to do zero effort or high effort to get the reward. I don't think they go into what the effort is. I think the reward is money. They say there was "riskier effort-based decision making in long COVID". The graph shows long COVID has lower "subjective energy cost" but I'm not sure what exactly that means. They say the result surprised them, and now their two working hypotheses are that either people with long COVID really want that zero effort option, or that they are "really willing to exert this higher effort despite the detrimental effects that it can have on their health." They say it "seems to go beyond demographics and could be really hinting at some sort of neurobiological mechanism of choice. 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."

That same "effort-based decision making" task, and maybe other "effort"-related tasks, will be a part of the future study they have planned. I think at least one aspect will be seeing how it relates to BBB permeability.

When they were asked why they think BBB permeability might change over time, they just said it's a "hypothesis" but didn't give any evidence. Chib said, "I think it's hypothesized that blood brain barrier permeability is a big factor in neuroinflammation, and so our working hypothesis is that that might change, and if it changes in a favorable way, it could lead to good outcomes."

When asked what markers they'll be testing in the blood, Chib said "I can't remember, I think we said like interleukin-6. I don't remember which ones exactly they were. [...] Our primary hypotheses are about the effort based choice and blood brain barrier." That does not inspire confidence.

Edit: typo
 
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Eleanor said:
i.e. the LC patients' interoception was accurate, which will be annoying for those at the NIH who want LC to be an 'interoceptive disorder'.
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I'm sure they'll find a way to make it fit according to their prior conclusions.

It's funny that AI research is so focused on the problem of overfitting, of massaging your parameters to get the answer you expect, when it's basically the primary objective in many areas of medical research. Completely backwards.
 
forestglip said:
They say the result surprised them, and now their two working hypotheses are that either people with long COVID really want that zero effort option, or that they are "really willing to exert this higher effort despite the detrimental effects that it can have on their health." They say it "seems to go beyond demographics and could be really hinting at some sort of neurobiological mechanism of choice. 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."
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Whatever explanation they come up with is likely to be based more on their preconceived ideas about pwME/LC rather than evidence, I suspect. It reminds me of BPS people who say we are both too scared to be active, and booming and busting. They don't see the contradiction, just their need to blame patients.
 
forestglip said:
They say there was "riskier effort-based decision making in long COVID". The graph shows long COVID has lower "subjective energy cost" but I'm not sure what exactly that means. They say the result surprised them, and now their two working hypotheses are that either people with long COVID really want that zero effort option, or that they are "really willing to exert this higher effort despite the detrimental effects that it can have on their health."
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Or perhaps it suggests that people who are ill may have particular pressures influencing their choices in lab-based tasks that have no relevance to their real-world activities, compared to how healthy people might approach the same task under the experimenter's eye.

(edited to add: I would be willing to bet that actually there was a spread of behaviour across groups, but that this has been mushed down into "LC do one thing, HC do the other" because soundbites sell.)
 
Eleanor said:
(edited to add: I would be willing to bet that actually there was a spread of behaviour across groups, but that this has been mushed down into "LC do one thing, HC do the other" because soundbites sell.)
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I'm not sure if it's acceptable to NIH or the researchers to share a screenshot of the graph, so I'll refrain, though they said they will eventually post the recording on their events page.

But for what it's worth, it does look like a shift down in "subjective energy cost (ρ)" (where apparently a lower score on this metric translates to "riskier"). Controls are spread pretty evenly between about 0.4 and 3.5, while long COVID spread is narrower between about 0.3 and 2.7. No high outliers in the LC group. And it says p<0.01.

Whether this is actually meaningful or useful is another question. I don't know what the reason for focusing on this metric is. This is such a simple, low stakes task that I don't even know if this "riskiness" can be translated to anything relevant in the real world.

If they are trying to show that some "riskier choice" phenotype contributes to causing long COVID, it seems much more likely people with long COVID radically change their behavior or way of thinking after they suddenly get very disabled, after which they do have to think more about energy cost. They'll need to show that healthy people with this "riskier" phenotype are more likely to develop long COVID.

If they think it might be an effect of long COVID and they want to use it as an objective outcome measure, my question is what's the point? It's such an abstract measure that it's going to be hard to figure out whether it's caused by long COVID directly or by some confounder like people with long COVID drank more caffeine that morning. Use step count, or time spent lying down, or work status. We've already got these and they directly measure exactly what many people with long COVID say their condition is affecting.

Edit: I also think they might try to see if they can use neuroimaging to zero in on the part of the brain that is associated with this "riskiness" to see if this could help produce diagnostics or treatments. I think this is really a shot in the dark and the chance of it producing anything useful is slim.

Edit 2: And I'm not saying these particular researchers shouldn't follow up. They did find a difference, and it'd be interesting to see if they can figure out more. My concern is why a huge chunk of the NIH webinar was devoted to this random finding.
 
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forestglip said:
But for what it's worth, it does look like a shift down in "subjective energy cost (ρ)" (where apparently a lower score on this metric translates to "riskier"). Controls are spread pretty evenly between about 0.4 and 3.5, while long COVID spread is narrower between about 0.3 and 2.7.
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So there's a big overlap, with the lower bound only 0.1 of a point apart and the upper bound 0.8 of a point apart, and most participants in both groups falling in the shared area. But it's being sold as a group difference that allows researchers to hypothesize about the behavioural preferences of LC patients as a whole.
 
I feel quite livid that money is being spent on this let's-all-pretend-we're-doing-science!! stuff while in the real world real people are having their lives ruined by a disease that has absolutely and precisely nothing to do with one's willingness to press or not press a damn button.
 
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