Brain Stimulation in Long COVID
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18+
SponsorAmsterdam UMC, location VUmc
About this trial
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 criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
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
Trial design
Design model
Parallel
Treatments tested in this trial
Repetitive Transcranial Magnetic Stimulation
DeviceThe 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 device
DeviceSham-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.
Treatment groups
66 Participants
are divided into 2 treatment groupsGroup A: Active rTMSExperimental treatment 1 intervention
Group B: Sham rTMSSham comparator 1 intervention
Trial outcomes
Primary outcomes
1
Fatigue
Fatigue as measured by the 8-item fatigue subscale of the Checklist Individual Strength (CIS). The subscale is scored on a 7-point Likert scale, adding up to a total score between 8 and 56. A score of 35 or higher indicates the presence of severe fatigue.
Time frame
Fatigue will be measured within two weeks before and within two weeks after treatment, and at 3 and 6 months follow-up.Secondary outcomes
1
Objective cognitive functioning
Objective cognitive functioning will be measured using a composite score that combines the T-scores from multiple cognitive tests: (1) Stroop Test (information processing and interference sensitivity), (2) Trail Making Test A/B (various domains of executive function), (3) D2 Test (selective and sustained attention, concentration, and processing speed), and (4) 15-Word Test (memory). These scores will be combined into a composite score by taking the mean of the individual T-scores, which are corrected for age, sex, and education and will provide a comprehensive assessment of objective cognitive functioning. The final composite score will not include any individual test units but will provide an overall score reflecting performance across multiple cognitive domains.
Time frame
Objective cognitive functioning will be measured two weeks before and two weeks after treatment and at 3 and 6 months follow-up after treatment.2
Arterial Spin Labeling (ASL)
We will measure blood-brain barrier integrity and perfusion using ASL.
Time frame
Neuroimaging will be performed within two weeks before and within two weeks after treatment.3
Magnetic Resonance Spectroscopy (MRS)
Neuroinflammation and neuronal injury will be measured using MRS (metabolites for inflammation include choline, creatine and myo-inositol, and for neuronal injury N-acetyl-aspartate, glutamate and lactate).
Time frame
Neuroimaging will be performed within two weeks before and within two weeks after treatment.4
Functional Magnetic Resonance Imaging (fMRI)
Participants will undergo a 10-minute resting-state scan, during which they are instructed to relax and remain awake while looking at a visual fixation cross for the entirety of the scan. After the resting-state scan, participants will complete the Tower of London task to measure task-based activity.
Time frame
Neuroimaging will be performed within two weeks before and within two weeks after treatment.Other outcomes
1
Heart rate variability (HRV)
Participation in HRV measurements is voluntary, and data will be collected only from participants who consent to this component. The Polar H10 will be worn during sleep and for 5 minutes immediately upon waking each day to capture nocturnal and early-morning HRV metrics. HRV will provide indices of autonomic nervous system function.
Time frame
Four nights and four mornings two weeks before and directly after treatmentSponsors and contacts
Click on the lead sponsor to view all of their trials.
Amsterdam UMC, location VUmc
Lead sponsor
ZonMw: The Netherlands Organisation for Health Research and Development
Collaborator
Post Covid Netwerk Nederland
Collaborator
Source ClinicalTrials.gov