The Added Value of Transcranial Direct Current Stimulation (tDCS) During Exercise for People With Chronic Widespread Pain

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

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.

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).

By elucidating the epigenetic regulation of BDNF in exercise-induced pain and evaluating tDCS as a modulatory intervention, this study seeks to identify biomarkers of symptom exacerbation and develop non-pharmacological strategies that enable CWP patients to remain active without worsening their pain.

Inclusion Criteria:

Patients

Participants in the patient group must meet all of the following criteria:

1. Diagnosis of chronic widespread pain (CWP) or fibromyalgia;
2. Age between 18 and 70 years old;
3. Body mass index (BMI) ≤ 35;
4. 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;
5. 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:

1. Age between 18 and 70 years old;
2. Body mass index (BMI) ≤ 35;
3. No chronic conditions, such as chronic pain and diabetes.

Exclusion Criteria:

For both patients and healthy controls, participants will be excluded if they meet any of the following:

1. Current pregnancy or pregnancy within the past 12 months;
2. Contraindications for non-invasive brain stimulation (NIBS), in line with published safety guidelines;
3. History of neurological disorders, including epilepsy (personal or family history), traumatic brain injury, stroke, dementia, or Parkinson's disease;
4. Major medical conditions, including cancer, endocrine or metabolic disorders, urine, genital and cardiovascu-lar diseases (e.g., myocardial infarction, heart failure, arrhythmia, uncontrolled hypertension).
5. Substance abuse.
6. Presence of psychiatric disorders other than depression or anxiety.