Brain Stimulation in Long COVID
Mitigating Cognitive Problems and Fatigue With Brain Stimulation in Long COVID
Amsterdam UMC, location VUmc
66 participants
Nov 17, 2025
INTERVENTIONAL
Conditions
Summary
Cognitive problems and severe fatigue are two frequently occurring symptoms in long COVID, also known as Post-Covid Condition or Post-Acute Sequelae of COVID-19 (PASC), and their causes are currently unknown. Previous studies have shown reduced blood flow and increased inflammation in the brains of people with PASC. These brain processes are related to fatigue and cognitive problems. In other conditions, these disrupted brain processes have been treated safely and successfully with non-invasive brain stimulation. This may offer an effective treatment for people with PASC. The main goal of this clinical trial is to see whether non-invasive brain stimulation called repetitive transcranial magnetic stimulation (rTMS) can reduce fatigue in adults with PASC who also have trouble concentrating. rTMS uses short magnetic pulses on the scalp to gently stimulate a small brain area. In this study, 66 adults with PASC will be included, recruited through the Post-COVID Network Netherlands. Participants will be randomly assigned to receive either active rTMS or sham (placebo) rTMS. Sham rTMS feels and looks similar to the active treatment, but it does not generate effective magnetic pulses. The brain area that will be targeted is personalized using a brain scan (MRI) during a planning task. All participants will receive 24 rTMS sessions over six weeks (four per week). Fatigue will be measured within two weeks before and two weeks after treatment to determine whether active rTMS works better than sham. We will also look at cognition, brain connectivity and blood flow, signs of (neuro)inflammation, daily activity using an activity watch, and questionnaires about quality of life, mood, and sleep. Follow-up on cognition and questionnaires will take place 3 and 6 months after the end of the treatment.
Eligibility
Inclusion Criteria7
- Meet the World Health Organization (WHO) definition of long COVID.
- Aged 18 years or older.
- Severe fatigue, defined as a score ≥35 on the Checklist Individual Strength (CIS) fatigue subscale.
- Significant cognitive complaints, defined as a score ≥18 on the CIS concentration subscale.
- Commitment to actively undergo rTMS
- Ability to attend the study site regularly for treatment sessions.
- Capacity to provide written informed consent.
Exclusion Criteria14
- Prior rTMS treatment or current intensive/experimental treatment for long COVID.
- History of epilepsy or first-degree family history of epilepsy.
- Recent initiation or dosage change of psychotropic medication (less than six weeks for psychotropic medication including antidepressants and antipsychotic drugs, less than two weeks for benzodiazepines). Medication doses must remain stable during the study.
- Other active concurrent pharmacological treatments for post-covid symptoms
- Contraindications to MRI scanning (e.g., non-removable metallic implants, severe claustrophobia).
- Presence of a cochlear implant.
- Neurological disorders such as multiple sclerosis or other neurodegenerative conditions.
- Pregnancy.
- Known brain lesions or ischaemic scars influencing seizure threshold.
- Severe uncontrolled migraines.
- Severe cardiovascular disease
- Raised intracranial pressure.
- High alcohol consumption (males/females: 21/14 units per week) or use of epileptogenic drugs.
- Severe sleep deprivation at the time of treatment.
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Interventions
The active intervention will consist of high-frequency (10 Hz) TMS delivered to the left dorsolateral prefrontal cortex (DLPFC), at 110% of the individual's resting motor threshold, adjusted for the individual cortex-skull distance, with 3,000 pulses per session with a total duration of 30 minutes (60 trains of 5 seconds, 25-second inter-train intervals). Sham-stimulation will be administered at 60% motor threshold at the same location (left DLPFC) using a placebo coil, which is identical to the stimulation coil in appearance, but with a built-in metal plate that blocks most of the active stimulation while maintaining mechanical scalp sensation. The stimulation target will be individualized using functional MRI data acquired during a Tower of London planning task allowing neuronavigation to the site of task-related activation. Each participant will receive four sessions per week for six weeks, totaling 24 sessions.
Sham-stimulation will be administered at 60% motor threshold at the left DLPFC using a placebo coil, which is identical to the stimulation coil in appearance, but with a built-in metal plate that blocks most of the active stimulation while maintaining mechanical scalp sensation. 3,000 pulses per session will be applied with a total duration of 30 minutes (60 trains of 5 seconds, 25-second inter-train intervals). The stimulation target will be individualized using functional MRI data acquired during a Tower of London planning task, allowing neuronavigation to the site of task-related activation. Each participant will receive four sessions per week for six weeks, totaling 24 sessions.
Locations(1)
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NCT07278206