Preprint A region-specific brain dysfunction underlies cognitive impairment in long COVID brain fog, 2025, Yang et al

[forestglip]

A region-specific brain dysfunction underlies cognitive impairment in long COVID brain fog

Spoiler: Authors

Yang, Jinhao; Zhou, Shaojiong; Wang, Zhibin; Xu, Jiahua; Chen, Jia; Yin, Zhouqian; Wei, Tao; Geng, Chaofan; Liu, Xiaoduo; Li, Xiang; Zhou, Xiaoyu; Li, Kun; Gu, Ruolei; Dolan, Raymond; Tang, Yi; Liu, Yunzhe

[Line breaks added]

Abstract
Long COVID "brain fog" is a common and debilitating subjective syndrome often associated with persistent cognitive impairment after COVID-19 infection. Here we identify a specific regional brain dysfunction that mediates this cognitive impairment and provide evidence that targeted neuromodulation improves this deficit.

In 120 patients with long COVID brain fog, we found an aberrant perceptual processing pattern. Patients with more severe brain fog committed significantly more false alarms (impulsive responses to non-signals) despite preserved overall accuracy.

Both high-density (128-channel) EEG and structural MRI analyses provided converging evidence of a right inferior insula deficit, characterized by a blunted neural monitoring signal and cortical atrophy.

We confirmed this deficit in a separate 796-participant UK Biobank longitudinal COVID re-imaging cohort, where COVID-19 survivors also showed selective impairment on a perceptual processing task and corresponding longitudinal atrophy of the right inferior insula compared with healthy controls.

Finally, in a proof-of-principle randomized, sham-controlled trial (n = 40), a non-invasive, excitatory theta-burst ultrasound stimulation protocol targeting the right inferior insula rescued the perceptual deficit by reducing false alarms.

These findings provide evidence of a causal role for right inferior insula dysfunction in long COVID-related perceptual impairment and show that modulation of this region can rescue the deficit, establishing it as a novel therapeutic target for long COVID cognitive impairment.

Web | DOI | PDF | arXiv | Preprint

 

[DHagen]

Between this and the GWI paper just posted I would be very interested to hear reactions from those who strongly reject evidence of inflammation and/or brain damage in ME/CFS and LC. To my untrained (and likely damaged) mind, the evidence presented here in favor of serious injury to the brain is more compelling than the suggestion that TUS can ameliorate the symptoms (but presumably not restore the lost brain matter), but then, there is much that I do not understand.

Spoiler: Page 19:

We next tested whether longitudinal brain changes were associated with this cognitive
deficit, focusing on cortical regions highlighted by Study 1. For each participant, we
computed the change in cortical thickness between the pre-COVID and post-COVID
scans. We then performed a GLM analysis to identify brain regions where thinning
predicted the change in TMT-A performance. The right inferior insula, as defined in Study
1, again emerged as the significant predictor in COVID-19 cases: greater cortical thinning
in the right inferior insula was associated with a larger increase in TMT-A completion time
(i.e. greater slowing) (β = –0.21, p = 0.029; Fig. 5c). Thus, COVID-related atrophy of the
right inferior insula specifically tracked the degree of post-COVID perceptual slowing. This
finding aligns with our patient cohort findings, underscoring the functional relevance of
right inferior insula damage: the critical structural change that predicts the hallmark
cognitive impairment of long COVID.

Spoiler: Page 27:

More broadly, dysfunction of the right inferior insula provides a unifying explanation for the
diverse clinical features observed in post-COVID conditions. The insula has emerged as a
consistent site of COVID-related brain changes. Large-scale imaging studies have
repeatedly identified the insula among regions with post-COVID structural atrophy10,11.
The insula is also a key interface for processing the peripheral inflammation thought to
drive long COVID pathology8,9. It maintains dense bidirectional connections with the
autonomic and immune systems, such that insular dysfunction can both result from and
contribute to systemic inflammatory processes47,48. Moreover, as a primary cortical hub for
olfaction and gustation49, insula provides a direct neural substrate for the loss of smell and
taste, which are hallmark symptoms of acute COVID-1950,51. We also note that insula
abnormalities are not unique to COVID-19. Similar “ brain fog ” symptoms in other
conditions, such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), have
been linked to insular hypoactivation and connectivity changes52. These observations
suggest that right inferior insula dysfunction may represent a common neurobiological
mechanism connecting sensory and inflammatory disruption with cognitive impairment.

Spoiler: Notes 8-11

8. Needham, E.J., et al. Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses. Brain 145, 4097-4107 (2022).
9. Michael, B.D., et al. Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses.
Nature Communications 14(2023).
10. Douaud, G., et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 604, 697-707 (2022).
11. Wood, G.K., et al. Posthospitalization COVID-19 cognitive deficits at 1 year are global and associated with elevated brain injury markers and gray matter volume reduction. Nature Medicine (2024)

Spoiler: Notes 47-52

47. Harrison, N.A., et al. Neural Origins of Human Sickness in Interoceptive Responses to Inflammation. Biological Psychiatry 66, 415-422 (2009).
48. Koren, T., et al. Insular cortex neurons encode and retrieve specific immune responses. Cell 184, 5902-5915.e5917 (2021).
49. Avery, J.A., et al. Taste Quality Representation in the Human Brain.
Journal of Neuroscience 40, 1042-1052 (2020).
50. Bilinska, K. & Butowt, R. Anosmia in COVID-19: A Bumpy Road to Establishing a Cellular Mechanism. Acs Chemical Neuroscience 11, 2152-2155 (2020).
51. Mao, L., et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. Jama Neurology 77, 683-690 (2020).
52. Lee, J.-S., Sato, W. & Son, C.-G. Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis. Autoimmunity Reviews 23(2024)

 

[Hutan]

Chinese study

Experiment 1
120 patients with persistent post-covid brain fog
Brain fog severity was self-reported




Accuracy (correctly identifying a signal - green) didn't vary with severity of brain fog.

False alarm rate (rate of responses outside of the signal window - red) increased slightly with brain fog severity (p value 0.031). But, this was after adjustments in the data for sex, age and education.

 

[Utsikt]

Between this and the GWI paper just posted I would be very interested to hear reactions from those who strongly reject evidence of inflammation and/or brain damage in ME/CFS and LC. To my untrained (and likely damaged) mind, the evidence presented here in favor of serious injury to the brain is more compelling than the suggestion that TUS can ameliorate the symptoms (but presumably not restore the lost brain matter), but then, there is much that I do not understand.

Can you define damage or «serious injury to the brain»?

The evidence against whatever is wrong with pwME/CFS’s brains being structural and permanent is that disability can vary over time and in the people that recover it’s completely gone.

 

[forestglip]

I think one thing I would have liked to see is a negative control for the transcranial stimulation portion, where they stimulated other areas to confirm that it is indeed stimulation of specifically the right inferior insula that leads to a reduced false alarm rate.

 

[Eleanor]

Baseline and post-stimulation box plots for the real and sham TUS (20 people each) don't look like they've found anything especially gamechanging.

 

[duncan]

To my untrained (and likely damaged) mind, the evidence presented here in favor of serious injury to the brain is more compelling than the suggestion that TUS can ameliorate the symptoms (but presumably not restore the lost brain matter), but then, there is much that I do not understand.

White matter lesions (perhaps due to hypoperfusion/hypoxia?) come to mind. And these have been known to resolve in some cases which could explain the uncommon incidences of recovery.

ETA: I think things like this can boil down to can you have brain damage without apparent structural damage, and I believe you can.

 

[alex3619]

Can you define damage or «serious injury to the brain»?

The evidence against whatever is wrong with pwME/CFS’s brains being structural and permanent is that disability can vary over time and in the people that recover it’s completely gone.

I am currently in favor, and have been on and off for heading toward 30 years, that in ME (not specifally LC) its more a dynamic dysfunction, caused by signaling whether neurological or biochemical. I suspect that something similar applies to LC but with Covid there could easily be surprises.

 

[Creekside]

To my untrained (and likely damaged) mind, the evidence presented here in favor of serious injury to the brain is more compelling

My experiences with my ME symptoms--including brainfog--abruptly vanishing compels me to believe that there is no injury, but rather a set of biochemicals maintaining the ME state, which can be rapidly reversed.

 

[duncan]

My experiences with my ME symptoms--including brainfog--abruptly vanishing compels me to believe that there is no injury, but rather a set of biochemicals maintaining the ME state, which can be rapidly reversed.

I would suggest that something like this or aberrant signaling would qualify as damage. It implies a change in a patient's normal brain make-up/functioning characterized by negative consequences.

An additional question might be what is causing it.

 

[Mij]

Hypoperfusion can resolve in pwME but their condition continues to worsen.

 

[Utsikt]

I would suggest that something like this or aberrant signaling would qualify as damage. It implies a change in a patient's normal brain make-up/functioning characterized by negative consequences.

If someone tells you you’ve got brain damage, I think most people would take that to mean that there is a physical injury that probably isn’t reversible. Like a stroke or blunt force trauma injury. Or MS, Parkinson, Alzherimer, etc.

So I think it’s misleading to say that there is brain damage in ME/CFS.

 

[duncan]

If someone tells you you’ve got brain damage, I think most people would take that to mean that there is a physical injury that probably isn’t reversible. Like a stroke or blunt force trauma injury. Or MS, Parkinson, Alzherimer, etc.

So I think it’s misleading to say that there is brain damage in ME/CFS.

But most people wouldn't be thinking of signaling or biochemical or viral persistence or immune abnormality issues. Wouldn't any of these constitute "damage"? Damage is just harm of some sort; it can be reversible or not.

 

[DHagen]

Can you define damage or «serious injury to the brain»?

The evidence against whatever is wrong with pwME/CFS’s brains being structural and permanent is that disability can vary over time and in the people that recover it’s completely gone.

With regard to this paper, I would say "atrophy of the right inferior insula" would seem to qualify as potentially serious injury/damage.

With regard to recovery, do we actually have documentation on these? Can we really say that disability is "completely gone"? Outside of random people on the internet claiming that this is the case, I am not aware that there is any certainty that this happens for anyone and the "evidence" that it can occur does not appear to be stronger than any of the other anecdotal claims that get dismissed essentially out of hand here - not because they are necessarily wrong, but because we do not and cannot really know how much credence to give them. If this is not the case, I would be genuinely grateful for additional information!

If someone tells you you’ve got brain damage, I think most people would take that to mean that there is a physical injury that probably isn’t reversible. Like a stroke or blunt force trauma injury. Or MS, Parkinson, Alzherimer, etc.

So I think it’s misleading to say that there is brain damage in ME/CFS.

I would think that "most people" would accept atrophy as damage, but perhaps there is a technical definition of which I am ignorant. As for reversible, that seems to me a separate question and one that needs to be dealt with separately if/when we can document real recovery.

The recovery documented in this paper does not seem very compelling (as @Eleanor indicates above), but to me, the documentation of atrophy does seem significant, though I remain happy to be dissuaded!

 

[DHagen]

Hypoperfusion can resolve in pwME but their condition continues to worsen.

Interesting - May I ask if there a particular study of which you are thinking?

 

[Utsikt]

But most people wouldn't be thinking of signaling or biochemical or viral persistence or immune abnormality issues. Wouldn't any of these constitute "damage"? Damage is just harm of some sort; it can be reversible or not.

When talking about damage in a medical context, I’m pretty sure most people would take that to mean more than just something being not right. And for that reason, I think we should avoid using it and stick to either describing the symptoms or talk about specific mechanisms that might cause the symptoms.

With regard to this paper, I would say "atrophy of the right inferior insula" would seem to qualify as potentially serious injury/damage.

Atrophy is normal with aging and they have only established correlation between one test score and changes in one region in the brain for covid cases. It’s unclear to me if they checked for the same correlation in the uninfected cases in the UKB longitudinal study. They only report differences in changes in test scores between the groups, and in some of them the LC group did better (with p-values >0.05).

With regard to recovery, do we actually have documentation on these? Can we really say that disability is "completely gone"? Outside of random people on the internet claiming that this is the case, I am not aware that there is any certainty that this happens for anyone and the "evidence" that it does does not appear to be stronger than any of the other anecdotal claims that get dismissed essentially out of hand here - not because they are necessarily wrong, but because we do not and cannot really know how much credence to give them. If this is not the case, I would be genuinely grateful for additional information!

There is no reliable data on it for ME/CFS. But from anecdotes from people that have either recovered or experiences significant improvements, their cognitive functioning also improved massively (and some recovered claim completely).

It could in theory be the case that the people that recover are the ones without any permanent damage, so it’s a case of survivorship bias, but considering that most don’t recover and we haven’t seen any reliable evidence of damage, I don’t think we should assume there is any yet.

And wrt LC (or post-covid ME/CFS) vs non-covid ME/CFS, they might not be comparable because we know covid can in theory mess with most parts of the body. So any post-covid damage might be covid-specific and not have anything to do with ME/CFS per se.

I would think that "most people" would accept atrophy as damage, but perhaps there is a technical definition of which I am ignorant. As for reversible, that seems to me a separate question and one that needs to be dealt with separately if/when we can document real recovery.

Excessive atrophy is brain damage, I agree with that.

The recovery documented in this paper does not seem very compelling (as @Eleanor indicates above), but to me, the documentation of atrophy does seem significant, though I remain happy to be dissuaded!

I agree that the graphs don’t look very impressive.

 

[Mij]

Interesting - May I ask if there a particular study of which you are thinking?

It's not from a study, it's based on a close friends experience. He had hypoperfusion on his first SPECT and PET scan which got him disability benefits, after retesting years later it came back normal, but his brain felt more toxic/poisoned. He had ME/CFS for 18yrs.