Unravelling the Epigenetic Mechanisms of Exercise-induced Pain in Chronic Widespread Pain: DNA Methylation Regulation of the Brain-derived Neurotrophic Factor Expression and Its Modulation by Transcranial Direct Current Stimulation
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Blood BDNF levels
研究概览
简要总结
Many people with chronic widespread pain (CWP) feel more pain and fatigue after exercise. This makes it hard to stay active. Unfortunately, the investigators do not fully understand why this happens and how to prevent it.
The primary goal of this study is to explore the underlying genetic and epigenetic mechanisms of BDNF gene in response to exercise, and investigate if transcranial direct current stimulation (tDCS) during exercise works to improve worsening symptoms response to exercise in people with CWP.
The investigators designed a randomized crossover study and will enroll 60 patients with CWP and 60 healthy controls. Participants will undergo 2 interventions in random order: 1) exercise + active tDCS, and 2) exercise + sham tDCS. Participants will visit the hospital twice with at least one week in between the visits.
详细描述
Many people with chronic widespread pain (CWP), such as those with fibromyalgia, experience increased pain in response to exercise, which discourages continued physical activity. Although abnormal gene expression via epigenetic mechanisms has been implicated in CWP, the underlying mechanisms by which exercise exacerbates symptoms remain unclear. DNA methylation is one way that environmental factors like exercise can alter gene expression, and brain-derived neurotrophic factor (BDNF) plays a central role in both neuroplasticity and pain processing. The investigators hypothesize that aberrant expression of the BDNF gene contributes to post-exercise symptom flares in CWP.
Transcranial direct current stimulation (tDCS) has been shown to modulate neuroplasticity and influence gene expression, making it a promising approach to normalize BDNF regulation during exercise.
In this randomized crossover trial, 60 CWP patients and 60 healthy controls will each undergo two sessions: (1) exercise with active tDCS and (2) exercise with sham tDCS. Each participant will visit the hospital twice, with at least one week between sessions. During each session, participants will receive one bout of submaximal aerobic exercise (20 min), along with a single session of active or sham tDCS (30 min) simultaneously. The order of interventions will be well-balanced and randomly allocated to each participant. We will measure pain intensity, serum BDNF protein levels, and BDNF gene methylation before and after each session. To capture longer-term effects, participants will also complete online symptom assessments at 8 hours, 24 hours, 48 hours, and 7 days post-exercise.
The primary objective of this study is to determine how active versus sham tDCS during exercise influences BDNF expression, DNA methylation patterns, and pain intensity in CWP patients.
The secondary objectives are to 1) compare these tDCS-induced changes between CWP patients and healthy controls; and 2) identify factors that influence tDCS/exercise-induced changes, including baseline BDNF levels, DNA methylation patterns, genetic polymorphisms and Lifestyle variables (e.g., physical activity).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants in the patient group must meet all of the following criteria:
- •Diagnosis of chronic widespread pain (CWP) or fibromyalgia;
- •Age between 18 and 70 years old;
- •Body mass index (BMI) ≤ 35;
- •Widespread Pain Index (WPI) assessment: the WPI questionnaire (0-19 points) will be used to record the number and distribution of painful body sites. Participants will be classified as having CWP if pain is reported on both sides of the body, above and below the waist, and in the axial skeleton, with pain symptoms lasting ≥ 3 months;
- •Stable medication use for at least 1 month prior to study entry.
- •Healthy control group
- •Participants in the healthy control group must meet all of the following criteria:
- •Age between 18 and 70 years old;
- •Body mass index (BMI) ≤ 35;
- •No chronic conditions, such as chronic pain and diabetes.
排除标准
- •For both patients and healthy controls, participants will be excluded if they meet any of the following:
- •Current pregnancy or pregnancy within the past 12 months;
- •Contraindications for non-invasive brain stimulation (NIBS), in line with published safety guidelines;
- •History of neurological disorders, including epilepsy (personal or family history), traumatic brain injury, stroke, dementia, or Parkinson's disease;
- •Major medical conditions, including cancer, endocrine or metabolic disorders, urine, genital and cardiovascu-lar diseases (e.g., myocardial infarction, heart failure, arrhythmia, uncontrolled hypertension).
- •Substance abuse.
- •Presence of psychiatric disorders other than depression or anxiety.
研究组 & 干预措施
Exercise + active tDCS + patients
Patient participants will receive one bout of submaximal aerobic exercise, along with a single session of active tDCS simultaneously.
干预措施: Active tDCS (Device)
Exercise + active tDCS + patients
Patient participants will receive one bout of submaximal aerobic exercise, along with a single session of active tDCS simultaneously.
干预措施: Aerobic exercise (Behavioral)
Exercise + sham tDCS + patients
Patient participants will receive one bout of submaximal aerobic exercise, along with a single session of sham tDCS simultaneously.
干预措施: Sham tDCS (Device)
Exercise + sham tDCS + patients
Patient participants will receive one bout of submaximal aerobic exercise, along with a single session of sham tDCS simultaneously.
干预措施: Aerobic exercise (Behavioral)
Exercise + active tDCS + healthy controls
healthy volunteer participants will receive one bout of submaximal aerobic exercise, along with a single session of active tDCS simultaneously.
干预措施: Active tDCS (Device)
Exercise + active tDCS + healthy controls
healthy volunteer participants will receive one bout of submaximal aerobic exercise, along with a single session of active tDCS simultaneously.
干预措施: Aerobic exercise (Behavioral)
Exercise + sham tDCS + healthy controls
healthy volunteer participants will receive one bout of submaximal aerobic exercise, along with a single session of sham tDCS simultaneously.
干预措施: Aerobic exercise (Behavioral)
Exercise + sham tDCS + healthy controls
healthy volunteer participants will receive one bout of submaximal aerobic exercise, along with a single session of sham tDCS simultaneously.
干预措施: Sham tDCS (Device)
结局指标
主要结局
Blood BDNF levels
时间窗: Blood samples are collected at baseline and 20 minutes after exercise-tDCS session.
Venous blood samples are collected before and after each exercise-tDCS session. Samples are centrifuged, aliquoted, and stored at -80 °C until analysis. Blood levels of brain-derived neurotrophic factor (BDNF) are quantified using a commercially available enzyme-linked immunosorbent assay (ELISA), following the manufacturer's instructions.
BDNF DNA methylation
时间窗: Blood samples are collected at baseline and 20 minutes after exercise-tDCS session.
Genomic DNA is extracted from whole blood collected at baseline and after the intervention. DNA methylation of the BDNF gene is assessed using bisulfite conversion followed by quantitative analysis of methylation levels at CpG sites within promoter regions previously associated with pain regulation. Methylation levels are expressed as the percentage of methylated cytosines at each CpG site. Changes in DNA methylation are calculated as the difference between post-intervention and baseline values.
Pain intensity
时间窗: Participants rate their pain at baseline, and 30 minutes after the intervention.
Pain intensity is measured using a 0-10 Numeric Rating Scale (NRS), where 0 indicates "no pain" and 10 indicates "the worst pain imaginable".
Blood BDNF levels
时间窗: Blood samples are collected at baseline and 20 minutes after exercise-tDCS session.
Venous blood samples are collected before and after each exercise-tDCS session. Samples are centrifuged, aliquoted, and stored at -80 °C until analysis. Blood levels of brain-derived neurotrophic factor (BDNF) are quantified using a commercially available enzyme-linked immunosorbent assay (ELISA), following the manufacturer's instructions.
BDNF DNA methylation
时间窗: Blood samples are collected at baseline and 20 minutes after exercise-tDCS session.
Genomic DNA is extracted from whole blood collected at baseline and after the intervention. DNA methylation of the BDNF gene is assessed using bisulfite conversion followed by quantitative analysis of methylation levels at CpG sites within promoter regions previously associated with pain regulation. Methylation levels are expressed as the percentage of methylated cytosines at each CpG site. Changes in DNA methylation are calculated as the difference between post-intervention and baseline values.
次要结局
- Pain intensity(Participants rate their pain at immediately, 8 hours, 24 hours, 48 hours, and 7 days after the intervention.)
- Fatigue(Participants rate their fatigue at baseline, and 24 hours, 48 hours, 7 days after the intervention.)
- Fibromyalgia symptom impact(Participants rate their FIQR at baseline, and 7 days after intervention.)
- Central sensitization symptoms(Participants rate their CSI at baseline.)
- Pain catastrophizing(Participants rate their PCS at baseline, and 30 minutes after the intervention.)
- Anxiety and depression(Participants rate their HAD at baseline.)
- Pain intensity(Participants rate their pain at immediately, 8 hours, 24 hours, 48 hours, and 7 days after the intervention.)
- Fatigue(Participants rate their fatigue at baseline, and 24 hours, 48 hours, 7 days after the intervention.)
- Fibromyalgia symptom impact(Participants rate their FIQR at baseline, and 7 days after intervention.)
- Central sensitization symptoms(Participants rate their CSI at baseline.)
- Pain catastrophizing(Participants rate their PCS at baseline, and 30 minutes after the intervention.)
- Anxiety and depression(Participants rate their HAD at baseline.)
研究者
Jo Nijs
Principal Investigator
Vrije Universiteit Brussel