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.

Background Long COVID, also known as Post-COVID Condition (PCC) or Post-Acute Sequelae of COVID-19 (PASC), is characterized by persistent symptoms following SARS-CoV-2 infection without an alternative explanation. Fatigue and cognitive dysfunction are among the most common and disabling complaints, with substantial effects on daily functioning, work participation, and quality of life. Converging evidence from neuroimaging and fluid biomarkers points to altered cerebral perfusion, disrupted functional connectivity, and neuroinflammatory processes in at least a subset of people with PASC.

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that can modulate cortical excitability and large-scale networks, with downstream effects on cerebral blood flow, connectivity and inflammatory signaling. Small, uncontrolled studies in PASC and related fatigue conditions suggest potential benefits of rTMS for fatigue and cognition, but placebo-controlled evidence in PASC is lacking and prior studies have used relatively few sessions. The present trial addresses this gap by testing a functional magnetic resonance (fMRI)-guided rTMS protocol in a randomized, double-blind design, while characterizing neurobiological mechanisms of change.

Objectives The primary objective is to determine whether high-frequency (10 Hz) rTMS reduces fatigue severity in adults with PASC compared with sham stimulation. Secondary objectives are to evaluate effects on physical and cognitive functioning, patient-reported outcome measures (e.g., mood, sleep, and quality of life), to quantify rTMS-related changes in neuroimaging and blood-based biomarkers reflecting neuronal integrity, cerebral perfusion, and (neuro)inflammation, and to examine whether these biomarkers can predict symptom improvement.

Design and procedures This is a single-center, randomized, double-blind, sham-controlled clinical trial. Sixty-six adults with PASC characterized by severe fatigue and cognitive complaints will be enrolled through the Post-COVID Network Netherlands. After baseline assessments, participants are randomized 1:1 to active rTMS or sham rTMS using block randomization implemented in Castor EDC with allocation concealment; participants and outcome assessors are blinded.

Treatment is delivered four times per week for six consecutive weeks (24 sessions). A minimum effective dose of 16 sessions applies when burden needs to be reduced. Outcome assessments are conducted within two weeks before the treatment at baseline (T0), within two weeks after the intervention period (T1), and at follow-up three months (T2) and six months (T3) after treatment to evaluate long-term effects. During the six-week intervention period a brief subset of patient-reported measures is collected weekly to monitor symptom trajectories and adverse effects.

Neuroimaging and blood sampling are obtained at T0 and T1. The MRI protocol (3T Siemens VIDA) includes structural, perfusion (ASL), resting-state and task-based fMRI (Tower of London), spectroscopy (MRS), and conventional FLAIR/SWI. Blood-derived biomarkers (e.g., NfL, GFAP, brain-derived tau, IL-6/IL-1/TNF-α, CCL11, BDNF) are assayed from EDTA plasma with standardized handling and storage prior to batch analysis. Actigraphy is assessed over 8 days prior to treatment and 8 days following treatment, and heart-rate variability is assessed during 4 nights and 4 times directly after waking for 5 minutes 2 weeks before treatment and directly after treatment.

Interventions Active treatment consists of high-frequency (10 Hz) rTMS delivered to the left dorsolateral prefrontal cortex at 110% resting motor threshold, with intensity adjusted for scalp-to-cortex distance. The stimulation target is individualized using task-based fMRI activation from a Tower of London planning task and neuronavigation (Localite). Sham sessions are performed with a placebo coil, that mimics sound and sensation, and at 60% motor threshold, so that it delivers no effective magnetic field. Participants and researchers involved in clinical assessments, data collection, and analysis remain blinded to allocation; technicians are trained to avoid any disclosure that could compromise masking. To enhance feasibility for participants with fatigue and sensory sensitivity, the treatment environment is kept low-stimulus with reduced lighting and noise, scheduling is flexible with a weekly buffer option, and the minimum 16-session option supports completion.

Endpoints and analysis The primary endpoint is change in fatigue from baseline to post-treatment, analyzed as the between-group difference in pre- to post-treatment change under the intention-to-treat principle. Secondary endpoints span cognitive functioning, mood, sleep, quality of life, and physical performance, together with multimodal neuroimaging and blood-based biomarkers that analyse neuronal integrity, cerebral blood flow, functional connectivity, and inflammation. Statistical analyses use linear mixed-effects models with appropriate covariates and multiplicity is handled via Bonferroni for secondary endpoints and FDR for neuroimaging and exploratory analyses.

Safety and ethics Safety is monitored throughout treatment and follow-up via standardized AE questionnaires and weekly tolerability questions. Known contraindications to rTMS/MRI are applied at screening, and procedures for managing common side effects and rare events are in place. The study is conducted per the Declaration of Helsinki and national regulations, with approval by the METc Amsterdam UMC. Participants provide written informed consent, travel costs are reimbursed, and a small participation compensation is provided.

Recruitment and setting Recruitment is coordinated through the Post Covid Network Netherlands patient portal, enabling efficient identification of potentially eligible individuals who consented to be approached for research. The trial is conducted at Amsterdam UMC.

Conclusion If the intervention proves effective, this study will provide the first placebo-controlled evidence for high-frequency rTMS to reduce fatigue in long COVID, with neuroimaging and blood biomarkers to shed light on underlying disease and treatment mechanisms. Even if no between-group difference is observed, the trial will yield valuable information on PASC and underlying mechanisms.

Inclusion Criteria:

• 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 Criteria:

• 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.

Participants and the investigators conducting neuropsychological assessment and doing data analysis will remain blinded to treatment allocation. Due to the nature of the intervention, rTMS technicians cannot be blinded. However, they will be asked not to reveal allocation to participants and other researchers.