Trial By Error: Can “Cognitive Rehabilitation” for Long Covid “Reverse” Brain Fog?

By David Tuller, DrPH

Cognitive dysfunction, also known as “brain fog,” is among the most disabling aspects of Long Covid—and investigators have struggled to figure out what causes it and how to treat it. Last fall, a study from the National Institutes of Health’s RECOVER initiative, which focuses on Long Covid, found no benefits in cognitive symptoms from three specific interventions. The conclusion: ”The trial failed to demonstrate differential benefits from online cognitive training, a structured cognitive rehabilitation program, or transcranial direct current stimulation in participants with cognitive long COVID.” 

In contrast, a recent article in JAMA Network Open—“Cognitive Rehabilitation and Functional Outcomes in Long COVID-Related Cognitive Impairment: A Randomized Clinical Trial”—offered some better news. The investigators, from University College London, reported that a cognitive rehabilitation program “led to significant and sustained improvements in goal attainment in people with long COVID–related cognitive impairment.”

The trial did not argue that the cognitive problems associated with Long Covid were psychosomatic or psychological in nature, nor that they were “functional.” To the contrary, the trial protocol outlined the physiological processes believed to be implicated in generating the symptoms, noting that  “recent work has confirmed the ability of SARS-CoV-2 to invade the brain from the periphery, with entry via the olfactory neural-mucosa interface.”

The new trial was relatively small, with 78 participants compared to 328 in the RECOVER study. Nevertheless, given the lack of progress in identifying proven treatments, the findings were widely reported and led to some amped-up news coverage. “Long Covid treatment breakthrough as scientists find simple ways to reverse ‘brain fog,’” declared The Mirror. Time, The Independent, and other outlets also highlighted the study as a sign of hope for patients.

But did the study really find a way to “reverse” brain fog? 

The trial was unblinded, as trials of psychological and behavioral interventions usually are. So participants clearly knew whether they were receiving the intervention or not, and the primary outcome was “participant-reported.” This trial design—unblinded and reliant on subjective outcomes—is a recipe for an unknown amount of bias. Modestly positive results could be expected even in the absence of a treatment effect.

Before participants were randomized, they all completed an online tool called the Bangor Goal Setting Interview (BGSI), which was also the primary outcome. Through the BGSI, they selected three personal goals and assessed how effectively they were able to attain them. A given example of a goal was: “I will write a report for 30 minutes without breaks, twice a week.” The BGSI goal-attainment scale runs from one to ten, with higher scores representing greater goal attainment. A difference of two points on the scale is considered “clinically meaningful,” noted the study.

Of the 78 participants, 38 received the intervention, a form of cognitive rehabilitation similar to that received by patients with stroke or traumatic brain injury. The intervention featured ten individual weekly one-hour sessions, in which participants focused on “applying evidence-based strategies” to their three “individually selected, personally meaningful functional goals.” Three sessions were devoted to each goal, with a final wrap-up session at the end.

The other 40 participants received “treatment as usual” (TAU), which varied among individuals. The comparison arm did not receive an active control condition designed to match the therapeutic time and attention associated with the intervention. Some trials use an active control arm to try to minimize some kinds of bias.

As secondary outcomes, the trial included a large number of additional cognitive and quality-of-life measures.

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“Pacing” was the intervention’s most popular strategy

Participants’ separate BGSI scores for each of their three goals were averaged. At baseline, both groups had average BGSI scores of 2.9, on the lower end of the scale. At three months, the BGSI scores for both groups had increased, but the score for the intervention group had increased more. The TAU group score was 4.97 and the intervention group score was 7.84; the adjusted difference between the two arms was 2.88.

Given that those receiving cognitive rehabilitation were guided in how to maximize attainment of their three goals, it is not surprising that they would report greater goal-attainment success—especially right after the intervention, when the impact of the training would likely be strongest. Of course, the impact of any bias inherent in the trial design would also likely be strongest at that time point.

By six months, the difference in BSGI scores between the two groups had fallen to 1.72 points—less than the two-point threshold considered to be a clinically significant difference. Much of that narrowing involved improvement in the BGSI in the TAU arm during the three-month period, to 5.74. However, there was also some decline in the score of the intervention group, to 7.46, presumably as some of the effect of the training wore off.

So did the intervention, when compared to TAU, confer long-term, clinically meaningful benefits, per the BGSI, the primary outcome? Not according to these results. The investigators reported that benefits in the intervention arm were “sustained.” That’s true, given the results at six months. But the investigators failed to mention that the difference in scores between the arms at six months did not meet their clinically meaningful threshold of two points. The TAU group appeared to be catching up. On top of that, most of the secondary outcomes—including fatigue, postexertional malaise (PEM), anxiety, depression and sleep disturbance—showed no statistically significant differences between the groups.

That doesn’t mean that the benefits weren’t real for those who reported them. In another analysis, 84% of those in the intervention group improved by at least 2 points on the BGSI compared to 53% of the TAU group. However, as in the primary analysis, the difference had decreased by six months, with 71% and 58% of the intervention and TAU groups, respectively, reporting  an improvement of at least 2 points from baseline. (These analyses were exploratory and so were not subjected to the same rigorous statistical calculations as the primary outcome.)

Which aspects of the intervention were reported to be most useful? In that regard, Figure 2, which depicts “cognitive rehabilitation strategies used during intervention sessions,” is revealing. Of the 11 itemized strategies, participants were most likely—by far—to pursue “pacing.” In short, the most popular strategy paralleled the standard patient-promoted advice geared toward preventing PEM: Don’t overdo it!

The second most popular strategy was “chunking”—dividing larger tasks or activities into smaller, more manageable bits. This approach is also popular among patients. Indeed, pacing itself often involves a great deal of chunking—deciding which actions must be taken now and which can be taken later. A much smaller number of participants reported using some of the other strategies in the cognitive rehabilitation intervention—“visualization,” “building routines,” “behavioral registry,” and so on.

In the end, the most useful strategies proved to be those that long-time patients have long practiced. That raises an interesting possibility. Perhaps the continued improvement in the TAU group between three and six months occurred because some of the participants learned how to “pace” and “chunk” better through their own experiences–as tends to happen over time as patients get better at coping with their limitations.

Apart from the headline in The Mirror, much of the reporting has been more circumspect. An article in The Independent, for example, offered an account of a 62-year-old man in Brighton, England, who said the program “helped him ‘work within new limits.’”  

In the Mirror article itself, Emma Hamilton, 57, a study participant from Surrey, was quoted as saying that the intervention taught her strategies like “how to break tasks down into smaller pieces and stop getting so overwhelmed.” She added: “I can now accept that long Covid has changed my life because now I can manage it better, therefore I’m living better.”

These accounts of improvement are heartening, but they do not support claims that brain fog has been “reversed.” Nor do they indicate that the intervention is an actual treatment for the underlying disorder—that is, for whatever is causing the brain fog in the first place. Rather, the cognitive rehabilitation program seems to have offered some participants some practical work-arounds, although how much of a role bias played in boosting the reported findings remains unknown.

Moreover, if the difference on the primary outcome between the two groups is no longer clinically meaningful at six months, what would the one-year results show? Would any of the apparent benefits from the intervention remain? Hard to know.

Bottom line: Might be somewhat helpful for some. Not a treatment. No apparent “reversal” of anything.

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