A region-specific brain dysfunction underlies cognitive impairment in long COVID brain fog
Jinhao Yang, Shaojiong Zhou, Zhibin Wang, Jiahua Xu, Jia Chen, Zhouqian Yin, Tao Wei, Chaofan Geng, Xiaoduo Liu, Xiang Li, Xiaoyu Zhou, Kun Li, Ruolei Gu, Raymond Dolan, Yi Tang, Yunzhe Liu
arXiv 2025 · 10.48550/arxiv.2511.14188
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.
Abstract via datacite.
Exposures
Exposure 1: Theta-burst TUS of right inferior insula
Target: insular cortex — “right inferior insula (inferior circular sulcus, Destrieux atlas)”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · H-104MR_4AA-4CH transducer with NeuroFUS TPO-203 ✓
| Waveform | theta burst | |
|---|---|---|
| Fundamental frequency (kHz) | not reported | ⚑ |
| Pulse duration (ms) | 20 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | 10pulse duration × PRF gives 10% | ✓✓✓ |
| Sonication duration (s) | 80 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | 33.8 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | 7.37 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported |
Theta-burst TUS consisted of 20 ms pulses within a 200 ms pulse-repetition interval (5 Hz PRF, 10% duty cycle), for a total of 400 cycles (80 s), delivered once to the right inferior insula under MRI/Brainsight neuronavigation guidance. The sham group underwent an identical procedure with no ultrasound output but matched auditory/procedural cues (transducer operational sound via bone-conduction headphones plus a pre-recorded TPO sound).
Flags from extraction
exposures[0].fundamental_frequency_khz— Transducer model (H-104MR_4AA-4CH, Sonic Concepts) is stated but the operating fundamental frequency is never given in the text.n_subjects— n_subjects reflects only the 20 participants who received real ultrasound (TUS group); the sham group (n=20) received no ultrasound output.