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

TL;DR

This study identifies right inferior insula dysfunction as a key factor in long COVID brain fog and demonstrates that targeted neuromodulation can improve perceptual deficits, offering a new therapeutic approach.

Contribution

It reveals a specific brain region involved in long COVID cognitive impairment and shows that non-invasive stimulation can restore function, a novel finding in this context.

Findings

Right inferior insula shows atrophy and neural deficits in long COVID patients.

Targeted ultrasound stimulation reduces perceptual false alarms.

Longitudinal data confirms insula impairment in COVID survivors.

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.