The Big Long COVID Neuroplasticity Trial: Did it Work?

Health Update – two weeks of mostly rest have been helpful 🙂 My concerning symptoms (cold sweats, nausea) are down substantially. Hopefully, a couple more weeks of rest will get me back to baseline.

Note: neuroplasticity is another hot-button issue! Please respond as objectively as possible. Comments like “they’re all frauds” will be removed. Why? For one, it’s not accurate. While many people without academic backgrounds have created neuroplasticity programs, licensed practitioners also use these techniques. The CATS model used in this trial, for instance, has been around for over 50 years and has been studied in animals, laboratory experiments, and humans. 

I was surprised to see the Wyller group’s large clinical trial, “Brief Outpatient Rehabilitation Program for Post–COVID-19 Condition” (n=312) (2025), pop up as I was searching for large, finished long COVID trials.

I was even more surprised that it was one of only three (fluovaxamine, gut microbiome) of 15 trials to show a modestly positive result. Since I wanted to learn more about neuroplasticity, I looked into it. It was fascinating to work through the statistics (ChatGPT helped enormously) to better understand the results.

Health Rising is going to dig into neuroplasticity a bit more. Don’t worry – it’s still going to be almost entirely focused on scientific studies and clinical trials. My commitment, though, is also to bring forth any treatment possibilities, and neuroplasticity now occupies a large space in the ME/CFS/FM and long COVID treatment world – too big a space not to try to objectively tangle with it (Just check out Raelan Agle’s YouTube channel.

Besides, I don’t believe it’s “scientific” to ignore it.  A scientific approach requires that all data points be incorporated. While few neuroplasticity studies have been done (unless you count CBT), neuroplasticity recovery stories on the web abound, and they shouldn’t be willy-nilly pushed under the rug (IMO). So we’re going to do a short series on neuroplasticity.

There seem to be two main camps regarding neuroplasticity interventions. One says it’s all BS, the other says it’s the only way to go. Neither makes sense to me, and my experience explains why.

My Experience

Indeed, my own experience with “neuroplasticity” is mixed. The EST training and assisting I did for the next 7 or 8 years (which I think was crucial) was still easily the most effective thing I’ve done for ME/CFS/FM. I went from lying in bed in pain to engaging in life again very quickly…. It was amazing!

Not all was well, though. I still experienced a great deal of pain; after strenuous exercise, I would often experience severe payback; I generally felt wired and tired and at my limit. I was much improved but not back to myself at all.

Prior to ME/CFS, I was a healthy, athletic young man with a bright future. Post-ME/CFS, when I worked, I worked at the lower-end jobs (fast food, catering, cashiering) that I felt I could handle. As my peers were moving up the job ladder and establishing careers, I was not.

I was always good at school and eventually returned to college, got my BA and MS. After chemical sensitivities kicked in, I was effectively out of the job market altogether. There was a silver lining, though. I started Phoenix Rising in the early 2000’s and then later Health Rising.

I still participate in EST’s predecessor, Landmark Education, and I’ve done 3 neuroplasticity courses, but while I’ve found some helpful practices, the magic has never struck again. Since those early days, I’ve never been able to move the needle significantly on my health with neuroplasticity practices, supplements, diet, or drugs.

I have read quite a few startling neuroplasticity recovery stories, and I know of a highly skilled professional who completely returned to health using these techniques (and some biological adjuncts). I also know people who have tried multiple practices without effect.

So, I’m in the middle. I am not one to dismiss these practices, nor am I one to say they are god’s gift to ME/CFS/FM or long COVID.

This is going to be a fairly short and intermittent series. Over the next couple of months or so, I plan to do a larger blog discussing what kinds of neuroplastic recovery stories, common themes, a neuroplasticity poll, and a few blogs on some of the different practices used.

The Wyller Group’s Big Clinical Trial

The Models Used

Note that the field of neuroplasticity is much too broad to be represented by a single study, but the models used (Cognitive Activation Theory of Stress (CATS), Sustained Arousal) in this study clearly have substantial overlap with practices used by neuroplasticity practitioners.

The Cognitive Activation Theory of Stress (CATS) model goes something like this: an infection triggers symptoms associated with “sickness behavior” (fatigue, flu-like symptoms). This is a normal response, which we should note is entirely driven by the brain. The brain triggers flu-like symptoms to make the ill person lie down, conserve energy, and stop passing the infection to others.

Over time, though, the symptoms should abate as the body clears the infection. When they don’t the CATS model predicts that when the brain expects something to happen; aka – “I’m going to enjoy myself on a walk” but something different happens (I feel fatigue, pain, etc.), it sends out a automatic/unconscious alarm that produces a flight/flight response, affects the hormones and immune system, causes more pain; i.e. the brain produces both the symptoms and biological abnormalities found in these diseases.

It proposes that the brain has gotten locked into a threat response even when the original cue (the infection) is no longer present.

While your symptoms are real, they’re the result of a maladaptive alarm response rather than ongoing tissue damage, and that your brain can be retrained to stop the automatic alarm response. This idea appears to pervade neuroplasticity practices.

The practitioners would ask the participants things like:

• What situations do you view as threatening?
• What do you expect will happen?
• How do you interpret the symptoms that resulted?
• What did you do in response to those symptoms?
• whether your responses reinforced a sense of danger or lack of control

For instance, if someone said, “When I feel this sensation, I automatically expect deterioration, and so I alter my behavior to avoid that,”  the participant would be encouraged to consciously construct a different prediction like “This sensation may not signal damage, and I may be able to perform this activity safely” and test it.

Notice that a key aspect of brain retraining – that an ongoing alarm response is present – fits quite nicely with some biological findings and hypotheses in ME/CFS/FM and long COVID.

The wired-but-tired symptoms, the increased pain sensitivity, the danger-response hypothesis, Jarred Younger’s touchy microglia, and findings indicating that the immune system and metabolic exhaustion are present could result from an ongoing alarm response.

The Sustained Arousal Model – Wyller’s sustained arousal model applies the CATS model specifically to diseases like ME/CFS and long COVID. It proposes that an infection may initiate a real biological stress response, but that a self-reinforcing process keeps it going after the infection has been resolved, which is, pretty much CBT 101.

The Key is Feeling Safe

One of the main goals –  to have a person feel safe – is a key tenet in neuroplasticity. In neuroplasticity videos, the idea of cultivating a sense of safety shows up again and again. The idea is that the safer you feel, the less the damaging alarm response kicks in. As the alarm response shuts off more and more, you can safely engage in more and more activities.

It doesn’t seem unreasonable to me that the brain – faced with this perplexing situation – would react with alarm. My understanding is that when the brain encounters a situation, it immediately maps onto it what happened in a similar situation from the past.

If I keep going for walks and feel terrible when I do, at some point the brain will raise the alarm and produce thoughts, feelings, and symptoms in an attempt to stop me from doing it.

The big question, of course, is how significant a role these automatic processes play in these diseases. The practitioners propose that “maladaptive expectations” and the sustained arousal they produce are the major perpetuating causes of long COVID or ME/CFS.

Others, of course, disagree.

The Study Results

The behavioral intervention was delivered 2-8 times, with 2-6 weeks between sessions. About 10% of people never started the program or dropped out, but the variability in the number of sessions attended was largely baked into the study. The median number of behavioral sessions was 4.

The authors did not assess whether people with more behavioral sessions did better than those with fewer.

The authors were happy with the results of the study and concluded that the

“The findings of this trial suggest that brief outpatient rehabilitation based on a cognitive and behavioral approach is effective and safe for patients with PCC.”

In the first write-up of the trial, almost 1/5th of the participants would have been classified as “recovered” (aka the PACE trial) when they entered the trial. (How did the authors miss this?). They did, though, redo the analysis.

The Key Test – the SF-36 Physical Functioning Score

The primary goal of the study was to improve the physical functioning score on the SF-36. The physical functioning score does not measure strength, exercise capacity, steps, or similar measures. It asks how much a person believes their health limits their ability to perform ordinary physical activities.

This assessment made sense because the model’s main thrust was to help long COVID patients believe they could do more physically without harm.

The average physical function score of the participants at baseline was 63/100. This indicated that they were not severely ill, and could take care of themselves and engage in some ordinary activities, but were substantially limited when it came to longer walks, walking up stairs, carrying heavy items, bending, moderate activity, or strenuous activity.

After the Intervention

Can You Believe? Physical Functioning Score Shows Some Improvement in Some People

Both the behavioral intervention and the usual care group improved their physical functioning score. Approximately 67% of the intervention and 46% of controls improved their physical functioning score by at least 10 points.

The behavioral intervention group improved by about 9.2 points more than the usual care group. The 9.2 increase did not meet the authors’ criteria for clinical significance (10-point increase).

The study has been criticized for not meeting that endpoint, but it almost met it. Whether it’s 9.2 or 10, the study came close.

A nine-point shift could indicate a number of things.  Some people may have gone from feeling they were “limited a lot” to “limited a little” when climbing stairs, or walking longer distances, or some people may have gone from feeling “limited a little” to “not being limited” on routine activities.

The paper reported that about one third of the behavioral intervention group improved their physical functioning scores to the age- and sex-adjusted normal range. However, because 10% of that group was already in the normal range before the intervention started, removing them from the analysis indicates, if I have it right, that 1/4 of the behavioral participants improved to the normal range of the physical functioning score on the SF-36.

A post-trial analysis found that for every 5 people treated with the behavioral intervention, one more person improved by more than 10 points compared with standard care alone. In other words, the behavioral intervention significantly increased the physical functioning score in about 1/5 of patients trying it.

The Cohen’s D statistic (.42) indicated a great deal of variability existed. While the group overall improved, many people in the intervention group ended up with worse PEM scores than in the usual care group, and some people in the intervention group either stayed the same or got worse. It suggests that the treatment produced a modest effect.

Not So Vital

Things were not so promising regarding vitality and fatigue. The vitality part of the SF-36 asks about feeling energetic, full of life, or worn out or tired.

At baseline both groups had very low energy (vitality), and experienced high fatigue and severe interferences with their ability to do work.

While the behavioral intervention group improved its vitality score from 22 to 37.6, the standard care group also increased its score from 22 to 29.9; i.e., the behavioral intervention group improved by 7.8.

This is considered a small to modest increase. It might cause a person to feel energetic “a little of the time” rather than “none of the time”; or they might feel tired “most of the time” rather than “all of the time.”

Overall, the behaviorally treated group still had very low vitality.

Cohen’s D (.31) indicated that some participants improved noticeably, many improved only a little, and some probably didn’t improve at all.

Contrast that to a Cohen’s D statistic of .5, which is considered a “clear, clinically meaningful average benefit, or a .8 finding, which indicates that most of the treated patients improved substantially, or a 1.0 finding, which indicates a dramatic treatment effect.

Still Quite Fatigued

Similarly, while the behavioral intervention did decrease the fatigue score from 25 to 17.6, the usual care group also decreased its fatigue score by almost as much (25-21.2). In other words, as a group, while they did improve a little, they were still quite fatigued.

Cohen’s D (.33) again indicated a small-to-modest treatment effect. It appears that some of the participants improved noticeably, many improved only a little, and some probably didn’t improve at all.

Post Exertional Malaise (PEM)

The PEM score for both groups -the behavioral and the usual care group – declined significantly (66-39; 65-52).  The behavioral group improved their PEM by about 12 points more than the usual care group. This was considered a “small to perhaps moderate effect”.

Cohen’s D (.42) was slightly higher but still within the “modest” range. Many of the treated participants still had worse PEM than many controls, and the PEM in some of the controls improved substantially. Similarly, some of the participants who received the behavioral treatment did not improve or got worse.

The Dilemma

We end with a bit of a dilemma. By the end of the study, a significant subset of participants in the behavioral group believed they could do more physically and socially. While their sense of vitality and fatigue increased a little, they’d started from a very low level, and their vitality remained low, and they were still quite fatigued.

Their belief that they could do more physically did not translate into substantially reduced fatigue or increased vitality.

Hidden in that group was probably a small subset of patients whose PEM, fatigue, and vitality improved noticeably.

In the end, we don’t know a crucial fact: were some people in the study exerting themselves more and experiencing substantially fewer symptoms? Assessing step counts or time spent upright could have shown that. Further biological data, such as autonomic nervous system, immune system, and exertion tests, would have told us whether the protocol had significantly altered their biology. These tests are rarely done in treatment trials, but they are beginning to be incorporated into them.

Summary

In the end, I don’t see what the fuss is about. The study findings were very much in line with past CBT studies; i.e., they were quite modest, and honestly they are what I would have expected from any study that attempted to tamp down the stress response. I’m convinced that the UK and Dutch governments stopped funding CBT/GET studies because, in the end, they just did not pan out – the results were too modest.

The idea, though, that the brain is inputting negative thoughts, feelings and emotions that are not helpful makes sense in any chronic illness. It does not contradict the idea that biological factors may also keep people with long COVID, ME/CFS, etc. in check. Both can be and probably are happening at the same time.

This is just one slice of the field of neuroplasticity. People who embrace neuroplasticity can take some cheer from the fact that a small subset of patients did appear to improve noticeably. The Wyller group wants to isolate that subset and I hope they can.

Because these practices often are fairly cheap and some come with money-back guarantees, if you’re interested in this area, they may be worth a try – you might be in that group!

People focused on biological explanations of these diseases can take cheer from the fact that the results from the behaviorally treated group as a whole were quite modest; i.e., nothing in this study says that CATS is a pathway to recovery for most people with long COVID.

Coming up shortly: a long COVID study finds a way to assess energy production in the brain, and Jarred Younger talks

 

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