Geoff’s Narration
The Gist
Underestimating Long COVID?
The results from the RECOVER’s long-COVID Neuro clinical trial is in – and the news is not good. Then again, it wasn’t expected to be good. RECOVER’s first round of clinical trials hit the long-COVID community with a collective thud.
RECOVER hoped that finding new ways to exercise the brain would help. They didn’t.
RECOVER apparently believed that cognitive problems in long COVID were something that patients could, at least in part, learn to overcome. They had some reason to think these efforts could help. Similar interventions have been shown to work in diseases such as multiple sclerosis and mild traumatic brain injury.
Health Rising’s Quickie Summer Donation Drive is On!They created a nice, hefty effort: 378 patients over 22 sites participated. The study assessed three treatments:
- BrainHQ (Posit Science)—an online program that has been reported to improve cognition in persons with mild cognitive impairment due to neurodegenerative disease5 and multiple sclerosis6;
- PASC-Cognitive Recovery (PASC-CoRE)—a cognitive rehabilitation intervention which has been helpful in mild traumatic brain injury);
- Transcranial direct current stimulation (tDCS), a noninvasive, remotely administered approach to brain stimulation intended to improve cognitive function.
They were compared with a control group that completed online puzzles and games.
THE GIST
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RECOVER hoped that finding new ways to exercise the brain would help. They didn’t.
The results from the RECOVER’s long-COVID Neuro clinical trial are in – and the news is not good. That’s not a huge surprise.
- RECOVER hoped that several cognitive retraining programs, as well as a brain stimulation treatment called tDCS, would be helpful and conducted a large study (n=378) that assessed cognitive functioning after 10 weeks of treatment in multiple ways.
- The news was bleak. None of the treatments moved the bar on cognitive functioning. The one bright spot was that many of the participants felt they were doing better cognitively. That improvement did not show up, though, in the test results.
- The failed trial also demonstrated what a knotty disease long COVID is. Each of the treatments (BrainHQ, the Cognitive Recovery program, and tDCS had managed to at least moderately improve cognition results in diseases such as multiple sclerosis and traumatic brain injury yet they failed in long COVID.
- While the trial failed, it did something important: it cleared the way. Because RECOVER conducts large studies and presumably does so well, this result should close the door on trying to “exercise” the brain into better health and open other doors.
- Past ME/CFS studies suggest that treatments that exercise the brain in new ways probably fail because long COVID and ME/CFS brains don’t have the resources to carry out cognitive tasks. This has shown up in studies that found that physical or mental exercise or being tilted up on a tilt table further impaired ME/CFS patients’ ability to do cognitive tasks.
- They also show that the longer a cognitive task lasts, the more things start to break down. Apparently depleted ME/CFS patients’ brains scramble to keep up by recruiting new brain regions to do the task – an inherently energy-intensive procedure. Plus, the ability to correctly regulate the autonomic nervous system disappears.
- That suggests that an energy problem exists. Numerous factors, including poor blood flow into and through the brain, neuroinflammation, reduced ATP production, and probably others, could account for this.
- RECOVER tried to help using mostly “treatment-lite” solutions. Now that it knows what it’s up against, it needs to dig deeper into these subjects. Hopefully, it will.
Donation Drive Update
We’re keeping a close eye on the massive RECOVER long COVID project.
Thank you to everyone who has contributed to Health Rising, bringing it to nearly 40% of its goal!
Health Rising has been watching the RECOVER Initiative closely. We’ve probably published more about it than other website. (There are one point six six billion ($1.66 billion) reasons why we’re doing that.) Admittedly, the news has not been good. In fact, it’s been downright disappointing.
So why continue to cover it? Because RECOVER presents an immense possibility not only for long COVID but for everyone with a post-infectious disease, and needs to be held accountable. RECOVER’s story has been pretty bleak thus far, but it’s not over. We’ll continue to keep our eye on it. If that supports you, please support us.
They certainly didn’t stint on cognitive tests. The primary endpoint was something called the “Everyday Cognition Scale 2 (ECog2)”, and PROMIS assessments were used to track cognitive functioning, general health status, fatigue symptoms, depression, anxiety, and sleep-related impairments. Plus, neuropsychological testing (Auditory Verbal Learning Test, the Symbol Digit Modalities Test, the Digit Vigilance Test, the National Institutes of Health Toolbox Flanker Test, lexical and semantic fluency, and the Cogstate Brief Battery) was done. From what I could tell, the tests matched up pretty well with tests that have proven effective in ME/CFS.
Results
Patient participation couldn’t have been better. Better than 90% of the participants completed greater than 80% of the interventions.
Cognitive retraining is not the answer to the brain fog found in long COVID.
Unfortunately, nothing worked…Despite working on them for 10 weeks, not one of the over a dozen tests showed significant improvement. While no improvement on the tests was seen, 74% of the participants reported they believed that participating in the cognitive training did “help” their cognitive functioning (222 [74%]) or improved their overall functioning (74 [58%]).
The subjective benefit is not nothing, and it suggests that some people might want to give these programs a try. The failure to improve cognitive functioning, however, means this avenue is probably closed. Note that with RECOVER, even a failure provides a benefit. RECOVER’s clinical trials are likely large enough and well-designed enough to either open or close the door to future trials.
The authors noted that other attempts to improve cognition have failed. This trial failure suggests that exercising the brain in new ways is not going to markedly improve cognition – and that’s helpful. The worst outcome might have been some sort of middling result in which some but not much improvement was made. Any positive result could have shut down other avenues of inquiry.
*Update! – the Beacon University REACT study which used computer games to improve cognition reportedly had positive results. It should be published soon.
Tough Disease!
The results also demonstrate what a brutally tough disease long COVID is. The expectations were never that high: these treatments generally produce small to moderate effects, but RECOVER surely expected to achieve that.
Long COVID is a tough disease. With four failed clinical trials, RECOVER is learning just how tough it is.
One would have thought that a program (Brain HQ) that improved cognition in multiple sclerosis and pre-Alzheimer’s disease would help in long COVID, but no. (The authors were so jazzed by the results that they asserted the program “can be readily applied to other neurological conditions associated with cognitive dysfunction”.) Similarly, it was thought a cognitive program (PASC-Cognitive Recovery) that helped with mild traumatic brain injury patients would help with long COVID, but no.
(There’s nothing “mild” about mild traumatic brain injury, by the way. It causes symptoms like confusion and difficulty concentrating, memory problems and short-term memory loss, headaches, dizziness/loss of balance, and sensitivity to noise or light.)
If tDCS is able to increase processing speed – a key cognitive problem in ME/CFS – in multiple sclerosis, it should certainly be able to do so in long COVID – but, again, no. The takeaway – long COVID is a surprisingly challenging disease, and researchers will have to dig deeper to understand how to help with cognition.
A Missing Piece and Moving Forward
Note that this study did not include an exertion stressor, which would have revealed additional cognitive issues. Indeed, studies indicate that exertion plays a key role in cognitive functioning in these diseases, and that provides a nice clue.
Dane Cook, in his superb study, “Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“, found that exercise exacerbated symptoms, impaired cognitive performance, and affected brain functioning. Another study found that after being tilted – which reduces blood flows to the brain – people with ME/CFS did worse on cognitive tests.
As the brain fades under stress, more challenging and longer cognitive tests tend to illuminate the cognitive problems in ME/CFS more. Cook, for instance, found that ME/CFS patients did worst on the more challenging PASAT test. As the test proceeded, and as their brains scrambled to keep up, more and more brain regions (parietal cortices, the supramarginal gyrus, cingulate cortex, and the frontal temporal cortices) needed to become activated – an inherently inefficient and energy-consuming endeavor.
A Japanese study found that sympathetic nervous system activity increased during a cognitive test, but once the test ended, the parasympathetic nervous system was unable to restore the brain and body to a resting state. The inability to do that was highly correlated with fatigue. Once again, we see exertion discombobulating things. Everything seems to point to a lack of resources/energy.
Time to dig deeper into the brain!
All this suggests that the long-COVID and ME/CFS brain doesn’t have the resources to carry out normal tasks – something no amount of cognitive training is going to alter substantially. Long-COVID patients inherently understood that – hence the, at best, muted reception they gave these efforts. It’s no surprise they failed.
The fact that cognitive retraining/brain stimulation programs that have helped in other diseases failed to do so in long COVID is, if anything, a wake-up call for an initiative that needs one.
With its failed Paxlovid and Neuro trials, the RECOVER Initiative and the long COVID field are hopefully done with ‘the easy stuff,’ which Michael Peluso believed the field had to do if only to get past it. The good news is that RECOVER has numerous options (blood flows into and through the brain, energy production, and neuroinflammation) to explore.
Now that the preliminaries are done, let’s hope that’s the next step.
Donation Drive Update
We’re keeping a close eye on the massive RECOVER long COVID project.
Thank you to everyone who has contributed to Health Rising, bringing it to nearly 40% of its goal!
Health Rising has been watching the RECOVER Initiative closely. We’ve probably published more about it than other website. (There are one point six six billion ($1.66 billion) reasons why we’re doing that.) Admittedly, the news has not been good. In fact, it’s been downright disappointing.
So why continue to cover it? Because RECOVER presents an immense possibility not only for long COVID but for everyone with a post-infectious disease, and needs to be held accountable. RECOVER’s story has been pretty bleak thus far, but it’s not over. We’ll continue to keep our eye on it. If that supports you, please support us.
Good, now we can 100% leave this whole cognitive training behind us and focus on biological grounded research on the disease instead!
I’m trying to understand the science behind various neuroplasticity programs for ME (DNRS, Primal Trust, ANS rewire etc.). Am I correct in my assumption that this trial was more about cognitive exercises and training (brain-ups) and less about rewiring the limbic/ANS system with a variety of “neuroplasticity” techniques? I’d love to have help in clarifying the differences in approaches. I guess I hold out some hope for neuroplasticity, properly employed, as a supportive treatment if not a cure and don’t want this trial to nix that! (Unless they did use the same techniques and then I’ll move on.) Thank you!
That’s my understanding. Apples and oranges. Neuroplasticity, in my experience, seeks to tone down danger signals coming from the subconscious. I don’t know what these programs do but I don’t believe they do that.
I don’t want to sound pessimistic but that won’t be happening. The neuropsychiatric “crowd” behind CBT & GET have so much money and influence and they are doing everything they can to make hoax studies, influence the treatments given to people with LC and CFS/ME and dismiss every study that finds biological causes behind these illnesses.
But we can always hope they will soon be a thing of the past.
What are CBT and GET?
Cognitive Behavioral Therapy and Graded Exercise Therapy. Well, these aren’t exactly the same as brain retraining but in the same field and mostly promoted by the same persons / organizations.
CBT and GET as treatments for ME/CFS are outdated and are no longer seen as effective.
Yes they are but they are still pushed in many countries (including mine) as the only available treatments.
Unfortunately, that residue remains. There are helpful aspects to CBT – stopping catastrophizing and using pacing, for instance, can help in many diseases, but when it was promoted as a cure, and then when it sucked up millions of precious clinical trial dollars, that was way too far.
Cort, yes I agree, CBT can be helpful as a supportive therapy when it is combined with “real” treatments like LDN, Mestinon and others. But like you said, when it is used as a curative treatment and (I also add) when combined with GET, it fails. I have seen many patients ending up worse with these treatments and they can end up being worse for the rest of their lives and the treatment givers are never held responsible. It is always the patients who are being mocked that they don’t want to get better.
In my country, a new “functional disorder” clinic just opened a few years ago that solely uses CBT+GET and patients are even forced to go to these clinics. It is like a nightmare.
Im am sorry to hear that. Thankfully, there are these day also some psychologists and psychiatrists who clearly take the side of ME/CFS patients. Just today, in Germany ME/CFS experts were heard in a meeting pertaining to the National Research Decade for Postinfectious Disease, where 500 Mio EUR over 10 yrs will be distributed to postinfectious disease research, and Bettina Grande, the German psychologist specialised on ME/CFS, gave a strong written statement against GET and clearly said that the role of psychotherapy in ME/CFS is to support and protect, not to activate or psychologise.
In Germany, I feel that probably neurologists are lagging behind the most in terms of understanding that in ME/CFS the assumed psychosomatic connection of “what helps the psyche will help the body too” is truly broken due to exertion intolerance.
Indeed, in Germany after finally receiving a long covid diagnosis, the LC clinic didn’t treat patients. I was sent to the painclinic to be treated for yhe disabling neuropathies. I filled in a mindboggling 1.5 hr questionnaire and added my medical record. They invited me for an 8 hr!! screening. Exercise, multiple talks and test day. Completely out of check with reality. I had to decline and got offered a 30 min talk w some doctor. This person decided, based on my form I filled in, that it was all psychosomatic. In spite of the added written proof from a psychologist that denies a ‘functional disorder’ . So they denied me paintreatment and i stead offered me a lenghty cbt programs with exercise to which i should show up 3 x a week.
I got such a nervous breakdown after this i ended up in severe pain for weeks. When I recovered I complained to the board and ‘patientenrat’, but after weeks of back and forth, they unanimously stood behind the psychologist. If I had the energy I’d go on tv or take them to court. The country must know what is happening to us patients.
I would have killed myself without my partner to believe in me. The reality of living with this amount of pain, gaslighting, losing our lives our identities..
It’s outrageous how we are treated
I am so sorry you had to go through this. I totally understand wanting to do something about it and not having the energy. But maybe there are small things you can do if you haven’t done so already, like at dropping an Email with your above summary to the three big patient organisations (DGMECFS, Fatigatio, LongCovid Deutschland) so they can take your experience away with them into their political work. I think it’s also possible to lodge a complaint with Ärztekammer, but don’t know how energy intense a process this is.
If you can say so, which pain clinic was that, and how did the Long Covid clinic that diagnosed you react – I don’t assume doctors like it if colleagues overturn their diagnoses?
If useful, here’s a statement for you on false positive outcomes of depression/anxiety questionnaires in case of ME/CFS and LongCovid https://x.com/GrandeBettina/status/1525448143357239299?cxt=HHwWhoCzwaLAvasqAAAA .
Argh, one wishes all psychologists were informed enough to understand that, and that it is well known that stress can trigger ME/CFS-Schübe which does not mean ME/CFS or LC are psychosomatic.
I’m glad that you have your partner’s support and hope that there are still people in your corner.
If you are around Saarbrücken, let me know and I can ask a friend for you about the pain clinic that she’s getting her medications from.
Best wishes!!
My understanding of CBT and GET, as promoted by a few specific groups decades ago, was that they were *curative* of ME – obviously incorrect, not to mention terribly damaging to ME patients.
This incorrect promotion tainted the original intentions of CBT and GET – therapies intended for anyone, not just ME patients of course.
I once heard Dr. Peter Rowe, a well respected dysautonomia specialist, at a conference give as an analogy of an example of CBT that could be helpful to even him (*not* an ME patient) might be to stop watching hockey games late into the night so he wouldn’t be exhausted the next day — just being cognitively aware of his behaviour. (A paraphrasing, based on my memory.)
And as for GET, most anyone would approach any exercise in an incremental manner (graded), ME patients (if they were able) and non-ME patients alike.
I looked it up a couple of years ago – Funding for CBT/GET had been dropping precipitously in ME/CFS for several years. I think funders realized it was not providing answers.
As a patient with all the diagnosis you are studying I’m interested in finding out how to be involved in these tests, as I would love for them to be able to study all the damage that my body has suffered due to COVID and all the issues like fibromyalgia, hpp, brain fog just a few issues that have shown up that I never had before Covid attacked my system.
Thank you for all you’re doing.
—Caregiver to adult child with Long COVID (March ‘20) 😢😢
Cort, I do follow your articles as I am a soon to be a 6 year Long Covid, long hauler and and ME-CFS sufferer and regularly concur with your writing. I also co-founded a peer support group for long Covid and ME-CFS patients. I have been actively involved as a lay person in the UK BEACON -ReaCT Study into brain fog and cognition, run by The University of Exeter. Being one of 12 lay people selected to help in the design of the BEACON games app and as a member of the study cohort, playing the games. This was a large study cohort, more than double the RECOVER Study. The results do not match those reported in the RECOVER Study. The results showed a marked improvement in the cognitive function of those with brain fog and cognitive dysfunction in the cohort playing the games over the trial period compared to those playing in the control cohort. The paper is currently in production and is expected to be released very soon. My point is to anyone reading this, there is conclusive evidence that brain training games can have an impact on brain fog and cognitive dysfunction, so there is hope.
Thanks Grant – I will add a note to the blog that we may see better results soon. 🙂
Thank you Cort
Would that by chance be a variety of games where you have to learn a diverse set of new (in game) skills?
Elder people that regularly learn different new skills that they hadn’t before have been shown to have cognitive improvements that even show up on imaging. For example learning to play piano for a few months, then learn to play darts or to start painting…
No, it was a set of prescribed cognitive games, which became progressively harder as the trial progressed. There was a marked increase in the patients results from the start of the trial to the end, thereby suggesting that regular playing helped improve their cognitive function, which was a symptom of brain fog. The algorithms set in the study also looked at age-related decline so as not to distort the results. Prof. Anne Corbett of Exeter University should publishntge full paper shortly.
Studies show that ME/CFS brains are inefficient. Maybe if the right kind of computer games increased their efficiency….????
I am sorry, but what you write here, that the participants with time got better at the same game with higher difficulty level, coulndnt it be just getting used to the game and practice practice practice? I recognised that myself when I tried BrainHQ. Even with ME/CFS on the moderate/severe housbound level, I can get better at a cognitive task when I repeat it alot. it gets easier, uses up less energy etc. But when I try another new task, I start at the beginning again.
Marco, I think you hit the nail on the head!
Dr Paul St Amand is the inventer of the guifenesin protocol for fibromyalgia. He wrote a book “What your doctor may not tell you about fibromyalgia”. In the book he argues that the disease is caused by energy deficiency resulting from insufficient ATP production. He proposes to rename fibromyalgia to energopenia.
Yes…ive known about dr Paul st Amanda….ive tried the protocol…it did nothing for me.which solidifies that I had a true infection…which led to fused vertabrea and many other complications
All the many decades of trying to get help fell on deaf ears.
MAJOR GASLIGHTING IS ALL I GOT
PURE 😈 EVIL
Follow that money train $$$$$$$$$$$
They made lots of money from govt paid visits 🇨🇦. Great that’s its free Healthcare but as you see its very one sided.once they get you in the system they pass you around and around to all their buddies so they can all profit. You may get a diognosis in 10 or so years…many don’t get a diognosis that have me/cfs or fibromyalgia. The pain and suffering continues.
You can see how high the placebo effect is in this type of study. I wonder how many participants have long COVID who are vaccinated and who are not. And how many vaccinations they have had, etc…
Cort, I wonder how these trials correct for other treatments the patients are having in parallel? I’ve seen many trials that don’t do this, and probably the treatments actually need to be done in a sequential manner. E.g., cognitive training might be helpful (as a rehabilitation strategy) once someone has onboarded the right medication to help mitochondrial efficiency or neurotransmitter balance.
I’m missing these trials thinking about not only *if* it helps but also *when* it helps. Have you heard or seen anyone trying to address this?
I didn’t see anything about that. It’s a nice idea, though 🙂
Hi Cort,
I always love reading your synopsis of studies. As a note, there are some clinically proven ways to improved cognitive performance in both ME/CFS and Long COVID.
The clinical trial published at https://pmc.ncbi.nlm.nih.gov/articles/PMC12540111/ documents that oxaloacetate significantly increases cognitive efficiency in ME/CFS patients and that the cognition improvements were tied to overall fatigue in the oxaloacetate group (p < 0.0001) but was random in the control group. Oxaloacetate has been shown to significantly improve neurocognitive elasticity and reduce overproduction of brain glutamate in animal trials.
The clinical trial published at https://pubmed.ncbi.nlm.nih.gov/40757370/ documents that oxaloacetate significantly increases cognitive efficiency in Long COVID patients, and with strong correlations between symptom response and cognitive gains.
Further discussion of this improvement in cognitive function in both ME/CFS and Long COVID was presented at the IACFS/ME meeting this fall. A video presentation of this talk is available at https://youtu.be/4fEMOwPxuqo
In full disclosure, I work for the company providing oxaloacetate, but the co-authors of these studies were all third-party experts in ME/CFS and Long COVID that have no financial affiliation……
That certainly fits in with the idea that problems with energy production play a key role.
While reading “the gist” of this study and still while writing this I’m laughing 🤣so hard that I can hardly type…of course it could also be my cognitive disability since I have CFS/ME. I’m actually both laughing & crying because this is the mental version of all of the studies & admonitions to “exercise” to overcome CFS/ME since the beginning! I still to this day, hear this from both family & friends. No one can seem to give this up. I’ll be shocked if this is the end of “Exercise” as a “Cure.” 🙄
The problem is energy, or, rather, lack thereof. Our brains use 20% of the body’s energy. When I’m crashed and can barely sit up, and if I talk to someone on the phone (it’s always on the phone, cannot see anyone in person while crashed), I think I sound a little drunk, I have trouble formulating thoughts, my voice slurs a little, I lose my train of thought, etc. etc. My brain is very tired then and just wants to rest. Which does not happen when not in PEM. As someone else said, this is the equivalent of trying to exercise our way to health. If we could do that, we would all be cured, and would have been cured a long time ago. Why was this study even done? Just because exercise helps people with other illnesses? Do we have to keep proving over and over and over that exercise makes us worse? it would seem so. ME/CFS involves a pathological response to exertion, as apparently Long Covid does also. This is the crux and no amount of exercise, mental or otherwise, can overcome this.
Cort, as you said:
All this suggests that the long-COVID and ME/CFS brain doesn’t have the resources to carry out normal tasks – something no amount of cognitive training is going to alter substantially.
This should have been obvious from the get-go. It’s what we’ve been saying for the last 40 years. (27 for me)
I think the same is true for brain fog issues in fibromyalgia and though I don’t know which of these may have been studied to the same extent there, have probably also failed. And once again it’s frustrating that the research isn’t drawing on what’s known from ME/CFS and FM similarities and instead reinventing the wheel.
This is good because it tips the scales strongly towards the idea that cognitive dysfunction in long COVID and ME/CFS isn’t a training problem but a physiological one likely involving energy, blood flow, or autonomic dysfunction -or some combination- rather than lack of practice.
Another really good study out:
https://link.springer.com/article/10.1186/s12967-025-07507-x
I might have to admit that the evidence is mounting for significant immune dysregulation perpetuating ME/CFS,rather than just initiating it.
Really interesting findings in this study that ‘mild/moderate’ ME/CFS patients showed more evidence of viral involvement than ‘severe’ ME/CFS.
My neuropsych administered my cognitive test in two parts.
I found myself having to push myself on the first part, and about two hours in I looked up from my paper–which had shapes I was supposed to arrange–and the test administrator looked at me and, shocked at how I looked, instantly said, “You need to go home.” I don’t know how bad I looked, but I know in the moment I suddenly didn’t know where I was or what I was doing. The ensuing crash lasted three weeks.
A couple of weeks later I did Part 2. It lasted about the same amount of time. This time, I had no confusion at any point and no subsequent crash.
I’m sure others in this forum have similar stories. The point is I was capable of doing heavy lifting, even though I have an illness that can be catastrophic when doing…heavy lifting. It would be great to be able to figure out what was going on in my brain so as to avoid one and court the other.
My case is severe enough so that I would never consider pushing myself to the limit doing a physical task, but I was willing to do it with the cognitive test. It seems there is an opportunity her for researchers to measure physiological responses in p/w/ serious illness who have put themselves in an exhausted state of total breakdown, a work-around to things like the 2-day CPET and the like.
The fact that 74% of patients believed the intervention was helping proves how bad we need control groups.
I tried to sign up for a Recover study in Arizona, but was rejected because I only had an antibody test for Long Covid in 2024 (months after I was ill), not what they were looking for. What is wrong with these researchers? When I was ill, I was by myself, wiped out, and could not drive anywhere for testing. I’ve suffered terribly from fatigue and can barely leave my house. Also, it sounds as if they were using exercise pacing and cognitive training to deal with Long Covid. Also, I can’t drive for two hours for study treatment. I guess I dodged a bullet with those folks.
At this point, it probably wasn’t worth the energy. It’s getting better though 🙂