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.
