Mitigating Cognitive Problems and Fatigue With Brain Stimulation in Long COVID
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 66
- 试验地点
- 1
- 主要终点
- Fatigue
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Fatigue
时间窗: Fatigue will be measured within two weeks before and within two weeks after treatment, and at 3 and 6 months follow-up.
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.
次要结局
- Objective cognitive functioning(Objective cognitive functioning will be measured two weeks before and two weeks after treatment and at 3 and 6 months follow-up after treatment.)
- Arterial Spin Labeling (ASL)(Neuroimaging will be performed within two weeks before and within two weeks after treatment.)
- Magnetic Resonance Spectroscopy (MRS)(Neuroimaging will be performed within two weeks before and within two weeks after treatment.)
- Functional Magnetic Resonance Imaging (fMRI)(Neuroimaging will be performed within two weeks before and within two weeks after treatment.)
- Actigraphy(Continuous period of eight days two weeks before and directly after treatment)
- Short physical performance battery (SPPB)(Physical performance will be measured within two weeks before and within two weeks after treatment and at three and six months after treatment (follow-up).)
- Simple Reaction Time (SRT)(Participants will complete the SRT within two weeks before, within two weeks after treatment and three and six months after treatment (follow-up).)
- Effort-based decision task(The effort-based decision task will be completed within two weeks before and within two weeks after treatment.)
- Neurofilament light (NF-L)(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Brain-Derived Tau (BD-Tau)(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Interleukin-6 (IL-6)(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Eotaxin-1/CCL11(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Checklist Individuele Spankracht (CIS)(Survey will be completed within two weeks before and within two weeks after treatment, and three and six months after treatment (follow-up).)
- Cognitive Failures Questionnaire (CFQ)(Survey will be completed within two weeks before and within two weeks after treatment, and three and six months after treatment (follow-up).)
- Interleukin-1 (IL-1)(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Glial Fibrillary Acidic Protein (GFAP)(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Tumor Necrosis Factor-alpha (TNF-α)(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Illness Perception Questionnaire (IPQ)-short form(Survey will be completed within two weeks before and within two weeks after treatment.)
- Brain-derived neurotrophic factor (BDNF)(Blood samples will be collected within two weeks before and within two weeks after treatment.)
- Bell Chronic Fatigue Syndrome Disability Scale(Survey will be completed within two weeks before treatment, within two weeks after treatment and at three and six months after treatment (follow-up).)
- Patient-Reported Outcomes Measurement Information System (PROMIS)(Survey will be completed within two weeks before treatment, weekly during treatment and within two weeks after treatment.)
- Patient Health Questionnaire 9 (PHQ-9)(Survey will be completed within two weeks before treatment, weekly during treatment, within two weeks after treatment and at three and six months after treatment (follow-up).)
- DePaul Symptom Questionnaire (DSQ)- post-exterional malaise and postural orthostatic tachycardia syndrome related questions(Survey will be completed within two weeks before treatment, within two weeks after treatment and at three and six months after treatment (follow-up).)
- Jacobson Fatigue Catastrophizing Scale (J-FCS)(Survey will be completed within two weeks before treatment and within two weeks after treatment.)
- Cognitive and Behavioral Responses to Symptoms Questionnaire (CBRQ)(Survey will be completed within two weeks before treatment and within two weeks after treatment.)
- Treatment Inventory of Costs in Patients (TIC-P) - Work Absenteeism/Productivity Subscale(Survey will be completed within two weeks before treatment and at three and six months after treatment (follow-up).)
- Multimodal Evaluation of Sensory Sensitivity (MESSY) - multisensory, visual and auditory sensitivity subscales(Survey will be completed within two weeks before treatment, within two weeks after treatment and three and six months after treatment (follow-up).)
- Insomnia Severity Index (ISI)(Survey will be completed within two weeks before treatment, within two weeks after treatment and at three and six months after treatment (follow-up).)
- Self-Efficacy Scale 28 (SES-28)(Survey will be completed within two weeks before treatment and within two weeks after treatment.)
- Credibility Expectancy Questionnaire (CEQ)(Survey will be completed within two weeks before treatment.)
研究者
Sander Verfaillie
Dr.
Amsterdam UMC, location VUmc