Transcranial Ultrasound Stimulation for Cognitive Function Modulation in Patients With Post COVID-19 Brain Fog

Overview

This study aims to investigate whether a specific brain region mediates the cognitive deficit in long COVID brain fog, and whether targeted modulation of this region can improve cognition. In observational study, the objective was to identify potential intervention targets for patients with long COVID brain fog. A total of 120 patients with long COVID were enrolled. Brain fog (BF) severity was quantified using the Brain Fog Assessment (BFA). Participants completed a continuous random-dot motion (cRDM) task during 128-channel electroencephalography (EEG) and underwent structural MRI and standardized neuropsychological testing. In interventional study, 40 participants with persistent BF symptoms were enrolled for transcranial ultrasound stimulation (TUS). On Day 1, participants completed the BFA and provided demographic data, then performed the baseline cRDM task; 20 minutes later, structural MRI and baseline resting-state MRI were acquired. On Day 2, participants received 60 seconds of TUS (active or sham) according to randomized allocation. Twenty minutes post-stimulation, an 8-minute resting-state MRI scan was obtained, followed immediately by the follow-up cRDM task.

Interventions

• Device sham transcranial ultrasound stimulation
  In the sham group, the transducer power was turned off, pre-recorded pulse repetition sounds were played to control for auditory confounds. The equipment appearance is consistent with the test device. Single stimulation, 60 seconds.
• Device real transcranial ultrasound stimulation
  Ultrasound stimulation was delivered using TPO-203 and H-104MR\_4AA-4CH transducer (Sonic Concepts, Woodinville, WA, USA). In the real stimulation group, theta-burst TUS (Yaakub et al., 2024; Yaakub et al., 2023) was performed with the following parameters: pulse duration = 20 ms; pulse repetition interval = 200 ms; total duration = 80 s. The target free-field spatial peak pulse-average intensity was maintained at 33.85 W/cm². The stimulation target was defined as the overlapping region between

Primary outcome measures

• false alarm rate change [Time frame: Day 1, Day 2]
• accuracy change [Time frame: Day 1, Day 2]

Secondary outcome measures (6)

• false alarm rate [Time frame: Day 1]
• accuracy [Time frame: Day 1]
• cRDM modeling metrics [Time frame: Day 1]
• Neural activation pattern of EEG [Time frame: Day 1]
• Brain structure indicator of MRI [Time frame: Day 1]
• resting-state functional connectivity change in MRI [Time frame: Day 1, Day 2]

Eligibility criteria

Inclusion criteria

• Patients should have a history of COVID-19 infection (positive test results for either polymerase chain reaction or rapid antigen test) and report persistent brain fog (BF) symptoms at least 4 weeks after recovering from acute COVID-19.

Exclusion criteria

• 1\. Presence of any symptoms of cognitive impairment or other neurological symptoms prior to COVID-19 infection;
• 2\. Structural MRI revealing significant intracranial lesions or structural abnormalities;
• 3\. Development of severe neurological complications after COVID-19 infection, including delirium, cerebrovascular diseases, encephalitis, and epilepsy;
• 4\. Other disorders that may cause cognitive impairment, including Dementia, Schizophrenia spectrum disorders, stroke, Alzheimer's disease, and Parkinson's disease.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

China · 2 centers

• Xuanwu Hospital, Capital Medical University — Beijing
• Shandong Daizhuang Hospital — Jining

Identifiers

NCT: NCT07154199 · KS2022105-1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗