Cognitive impairment and associated neurobehavioral dysfunction in post-COVID syndrome, 2025, Schmidt et al

[forestglip]

Cognitive impairment and associated neurobehavioral dysfunction in post-COVID syndrome

Laura Marie Schmidt, Carsten Klingner, Insa Petersen, Annika Volkmer, Minne Schreiber, Alexander Schmidt, Philipp Reuken, Bianca Besteher, Christian Geis, Markus Ullsperger, Kathrin Finke, Eva Maria Martin, Sven Rupprecht, Stefan Brodoehl, Franziska Wagner

[Line breaks added]

Highlights
· Post-COVID patients show significantly slower reaction times on cognitive tasks.
· Slower reaction times in post-COVID patients are associated with brain hypoarousal.
· Increased reward influence over time: The effect of rewarding cues on task performance increases significantly over time for post-COVID patients.
· fMRI scans reveal delayed activation in the left frontal gyrus and increased task-positive network activity during cognitive tasks.

Abstract
There is a high prevalence of neuropsychiatric sequelae in post-COVID syndrome, most commonly chronic fatigue, the mechanisms of which remain poorly understood. As altered function of the reward system has been suggested as a causal factor, we aimed to distinguish whether reward processing or task-unspecific cognitive operations are impaired in post-COVID syndrome.

Our cohort study included 24 patients diagnosed with post-COVID syndrome and 24 demographically matched healthy controls. Questionnaire assessment of neuropsychiatric symptoms and socio-demographic variables, the Monetary Incentive Delay Task during an fMRI scan, and pupillary measurements were performed.

In addition to clinical neuropsychiatric symptoms, participants in the post-COVID group demonstrated significantly slower task performance compared to healthy controls, although the function of behavioral reward circuits appeared unimpaired. However, the influence of rewarding cues on post-COVID patients increased significantly over time during task performance, correlating with temporally delayed activation of the left frontal gyrus and increased activity in task-unspecific brain regions in post-COVID patients. Furthermore, slower reaction times on the task were associated with a lower pupil diameter and a higher pupillary unrest index.

This study proposes that post-COVID syndrome is a process that may not affect reward processing, but leads to neural hypoarousal and temporally altered brain activity in frontal and task-unspecific brain regions.

Link (Psychiatry Research) [Paywall]

 

[Utsikt]

Fatigue coincides with anhedonia in a variety of medical conditions (Billones et al., 2020). Both symptoms are thought to result from impaired reward processing (Der-Avakian and Markou, 2012; Miller et al., 2014). This dysfunction has been described in chronic fatigue syndrome and other neurological disorders (Pardini et al., 2013). Recent evidence points to chronic neuroinflammation as a key mechanism behind the structural and functional impairments that lead to deficient reward processing, clinically manifested as fatigue or anhedonia (Heitmann et al., 2022). This background implies that a similar dysfunction within the reward system may underlie chronic fatigue in PCS.

Fatigue as a result of faulty reward processing? Sounds a lot the «effort preference». And of course they found that reward processing wasn’t impacted. Which means that they have to discard the hypothesis.

 

[Eleanor]

So they expected to find PCS patients were less reward-motivated (because of our "anhedonia" causing us to imagine that we're fatigued, innit)

We hypothesize slower task performance and reduced reward sensitivity in PCS patients compared to healthy controls, expecting a general performance decline with prolonged task engagement[...]

but they actually found the opposite?

One of the two main findings was that the effects of rewarding cues increased with increasing number of trials for PC, but not for healthy controls (HC).

 

[Utsikt]

@Eleanor I’m not sure I agree with their hypothesis. Because why would your performance decline over time because you’re less motivated by rewards? Wouldn’t it make more sense to see a general lower performance overall?

Unless they believe that people automatically stop putting in effort over time, and they need rewards to keep going? But at that point, it can be questioned if the rewards are high enough?

From the study:

To this end we used a modified version of the Monetary Incentive Delay Task (MID-T) (Knutson et al., 2000), during fMRI scanning.

This is from the user manual of the MID-T, and the example uses very low rewards.

Participants are asked to respond to a brief target shape that follows 2 different cues: one an incentive cue (e.g. an orange shape) and the other a nonincentive cue (e.g. a blue shape). Responses to nonincentive targets (aka targets following nonincentive cues) never have an impact on money gained or money lost; nevertheless participants receive verbal feedback whether they were fast enough or not. Responses to incentive targets have different consequences depending on three different reward conditions:

Control vs. Reward vs. Punishment.

In the Reward condition, participants who respond fast enough to a target that follows an incentive cue get a monetary reward (e.g. $1). If they are not fast enough, no money is won.

In the Punishment condition, participants who respond fast enough to a target that follows an incentive cue do not lose any money (e.g. $1). If they fail to respond in time, they lose money (e.g. $1).

In the control condition, there is no difference between incentive and nonincentive targets. Participants can neither win any money, nor can they lose any.

I also wonder if it was only the effect of the rewarding cues that increased, or if they observed the same effect with the other cues as well. Because that might indicate an overall learning effect - that people with brainfog need some time to get going.

After all, the PC performed worse in general.

 

[rvallee]

Fatigue as a result of faulty reward processing? Sounds a lot the «effort preference». And of course they found that reward processing wasn’t impacted. Which means that they have to discard the hypothesis.

Oh. Yes. Hypothesis totes discarded. For they are scientists, and scientists totes discard their debunked hypotheses.

Although, it's not as if this is a valid way of testing this. Not that we can see the details, but it's not possible to differentiate fatigue from lack of motivation, and they can simply be a matter of perspective. Just like paralysis can be framed as giving up on the motivation to walk, if one has the motivation to frame it this way.

Best they can do is ask. Usually in the hands of psychs it would involve very odd questions that are interpreted even more oddly. And they can simply discard results if they disagree with them.

Basically the simple choice of looking yet again for this ridiculous gotcha says everything about the intent of this study. They're just doing a very expensive version of trying to catch someone who is paralyzed by continuously looking away and back very quickly in a "HAHA! Gotcha moving! Oh, nevermind." "HAHA! Gotcha moving! Oh, nevermind." "HAHA! Gotcha moving! Oh, nevermind." "HAHA! Gotcha moving! Oh, nevermind."

 

[rvallee]

This is from the user manual of the MID-T, and the example uses very low rewards.

I wonder what it says that this is basically identical to the EEfRT junk, but they don't mention it, and it's not in the references. Maybe they're unaware, but this is the same test with the same intent and conditions that make it invalid.

Also very insulting and infantilizing. As if a dollar is something that should motivate an adult suffering from chronic illness, like we're clapping seals begging for a fish. I hate how they look down on us so smugly while pushing out the most mediocre effort humans can put together.

 

[Utsikt]

I wonder what it says that this is basically identical to the EEfRT junk, but they don't mention it, and it's not in the references. Maybe they're unaware, but this is the same test with the same intent and conditions that make it invalid.

Also very insulting and infantilizing. As if a dollar is something that should motivate an adult suffering from chronic illness, like we're clapping seals begging for a fish. I hate how they look down on us so smugly while pushing out the most mediocre effort humans can put together.

Yeah, it’s the same issue all over again, especially the refusal to consider alternative explanations and interpretations of the tests.

 

[Eleanor]

I also wonder if it was only the effect of the rewarding cues that increased, or if they observed the same effect with the other cues as well. Because that might indicate an overall learning effect - that people with brainfog need some time to get going.

Good point.

The whole thing is probably pretty tenuous anyway given the infant nature of the art of trying to interpret psychological states from fMRI, and perhaps especially so in the context of other people's findings on cerebral blood flow.

 

[Turtle]

Maybe they caught cognitive PEM on fMRI camera without knowing?

 

[SNT Gatchaman]

In the present study, we report that task-unspecific mechanisms are rather impaired than reward processing in post-COVID fatigue. PostCOVID patients (PC) having chronic fatigue respond significantly slower to a reward-based reaction time task while displaying preserved reward system function. One of the two main findings was that the effects of rewarding cues increased with increasing number of trials for PC, but not for healthy controls (HC). Pupil measurements were determined to predict reaction time data. As our second main result, we found that these behavioral findings were associated with time-dynamic functional magnetic resonance imaging (fMRI)-specific altered activity in the left dorsolateral superior frontal gyrus (SFG) for PC.

The PC group demonstrated significantly slower overall reaction times

impaired motor speed may contribute to poorer task performance in PC, but this cannot be inferred from the data in this study because we did not explicitly examine motor speed or motor cortex excitability.

both groups, control and post-COVID, demonstrated faster reaction times with higher predicted rewards without statistically significant group differences. Faster reaction times to higher rewards are generally considered to be an intact function of the reward circuitry.

These discrepancies are particularly striking given the significant sleep disturbances reported in post-COVID conditions, which would typically suggest a diminished reward response.

Given the high likelihood of severe impairments in other cognitive domains, preserved reward system function may compensate for deficits such as impaired working memory

Furthermore, we observed increasing reward effects with increasing number of trials in the PC group, while the effects remained stable in the HC group

Summarizing the foregoing aspects, the poorer task performance of the PC as compared to the HC is attributable to cognitive impairments such as selective attention and working memory, while the function of the reward system remains unaffected. Functional impairments that occur may to be compensated by an intact function of the reward system as well as by increased neuronal activity in task-unspecific brain regions. These compensatory mechanisms are thought to be activated with some temporal delay, resulting in improved task performance and increased reward sensitivity as time on task progresses.

In our study, we observed a decrease in reaction times for both groups with an increasing number of trials. This observation contradicts the well-documented time-on-task effect, which suggests that task performance typically deteriorates with prolonged engagement, often accompanied by reduced brain activity. This decline is commonly attributed to mental fatigue

it remains contradictory that PC with more rapid fatigability do not show effects of mental fatigue during the task. However, reaction times in the PC group are not only dependent on task duration, but especially on the size of the reward offered.

considerable variability in reaction times within the PC group leads to a reconsideration of the generalized slowing of reaction times.

The decrease in both behavioral and functional deviations with increasing time on task suggests the presence of compensatory neural activity that is activated with a temporal delay. However, the lack of decreasing task performance with increasing task duration raises the question of whether chronically fatigued PC meet the criteria for chronic fatigue syndrome.

 

[MSEsperanza]

Link (Psychiatry Research) [Paywall]

Just would like to make people aware that this is an Elsevier journal so you can request patient access:

Elsevier journals -- Access for healthcare and patients

Patient access
Patients and caregivers can make requests for individual papers related to medicine and healthcare at no cost. These papers can be requested by e-mailing patientaccess@elsevier.com. We aim to provide the requested articles within 24 hours. Please include the article title and author(s), date published, and/or the URL if available. This will ensure that our team can locate the requested content as quickly as possible. In addition, patients and caregivers who participate in the publication of an article and have a preference or need to publish that article open access, but lack the funds for the Article Publishing Charge, can make a request for a waiver of the APC by emailing oapolicy@elsevier.com . Please include the article title; author(s); and the journal title you have submitted the article to.

https://www.elsevier.com/open-science/science-and-society/access-for-healthcare-and-patients

(Maybe we could add the link to the opening posts of threads on research articles published by Elsevier?)

 

[rvallee]

Yeah, it’s the same issue all over again, especially the refusal to consider alternative explanations and interpretations of the tests.

The most disturbing thing about the EEfRT episode was when the creators of the test, who explicitly said it should not be used in a similar context, found nothing wrong with that, most likely because they don't believe in ME/CFS, or at best just don't understand how it meets their criteria for not being valid in this case. It just sealed the deal for just how much this is not a problem with individuals but with systems that are simply not functioning correctly. How as long as the systems are malfunctioning, most individuals will simply fail because it's the only acceptable way of doing things.

It just reminds me exactly of the worst politics out there, where some people will completely flip their approval of one thing or another, usually because their chosen leader has changed their tune, even to the point of rejecting things they have claimed as deep core personal values for most of their lives. It's the exact same problem.

 

[jnmaciuch]

Yeah, it’s the same issue all over again, especially the refusal to consider alternative explanations and interpretations of the tests.

I think it’s just an extremely pervasive problem in psychological testing. I once did a a very similar “test” for ADHD where letters flashed on the screen and you had to press a key on the right ones.

The idea was that people with ADHD would get bored a lot faster and their reaction time/accuracy would be a lot worse.

They told me I couldn’t have ADHD because my reaction time in the later part of the test was even better than average. Which was because the test had the exact same mechanism as a mini-game l had been playing a lot recently in a popular video game.

Funnily enough, the fact that I would spend hours and hours on games and completely lose track of time, to the point of forgetting to eat or drink, was a piece of evidence of ADHD hyperfixation for the competent psychiatrist who eventually diagnosed me.

 

[Utsikt]

I think it’s just an extremely pervasive problem in psychological testing. I once did a a very similar “test” for ADHD where letters flashed on the screen and you had to press a key on the right ones.

The idea was that people with ADHD would get bored a lot faster and their reaction time/accuracy would be a lot worse.

They told me I couldn’t have ADHD because my reaction time in the later part of the test was even better than average. Which was because the test had the exact same mechanism as a mini-game l had been playing a lot recently in a popular video game.

Funnily enough, the fact that I would spend hours and hours on games and completely lose track of time, to the point of forgetting to eat or drink, was a piece of evidence of ADHD hyperfixation for the competent psychiatrist who eventually diagnosed me.

I’m glad you eventually found a competent psychiatrist!

I had a similar experience with my neuropsychiatric evaluation after I got ME/CFS from covid. I did a load of tests, and many of them were very similar to things I like doing anyways. I don’t think those make me any smarter, just good at solving and optimising silly games.