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.
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;
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).
Crossover
Active tDCS
DevicetDCS is performed using a monophasic current device. Pairs of silicon sponge sur-face electrodes (35 cm2) are soaked in saline and positioned as follows: the anode is placed over the region of the dorsolateral prefrontal cortex (DLPFC) per the international 10/20 system at point F3 (left DLPFC), and the cathode is placed on the contralateral supraorbital area (FP2 site). For active tDCS, the current is ramped up for 30 seconds until the center electrode reaches a target intensity of 2 mA, then remains for 29 minutes before dropping for another 30s.
Aerobic exercise
BehavioralParticipants will perform a moderate aerobic exercise (AE, known as aerobic power index), using a cycle er-gometer. The exercise intensity is moderate and individually tailored based on each participant's estimated maximum heart rate (HRmax), calculated using the validated formula: HRmax = 211 - (0.64 × age).
Sham tDCS
DevicetDCS is performed using a monophasic current device. Pairs of silicon sponge sur-face electrodes (35 cm2) are soaked in saline and positioned as follows: the anode is placed over the region of the dorsolateral prefrontal cortex (DLPFC) per the international 10/20 system at point F3 (left DLPFC), and the cathode is placed on the contralateral supraorbital area (FP2 site). In the sham condition, current is ramped up to 2.0 mA for 30 seconds and then ramped down to 0 mA, with the total session duration matched to the active condition. This procedure was used to mimic the tingling sensa-tions typically experienced at the beginning of stimulation. Participants received identical instructions, session timing, and room setup across conditions.
Pain intensity
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
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
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
Pain intensity is measured using a 0-10 Numeric Rating Scale (NRS), where 0 indicates "no pain" and 10 indicates "the worst pain imaginable".
Fatigue
Brugmann Fatigue Scale (BFS). Fatigue is assessed with the BFS, an 8-item self-report questionnaire (4 mental and 4 physical items; each scored 0-3). Subscale scores range 0-12 (mental; physical), and the total score ranges 0-24; higher scores indicate greater fatigue/rest propensity.
Fibromyalgia symptom impact
Revised Fibromyalgia Impact Questionnaire (FIQR). The FIQR evaluates the overall impact of fibromyalgia on functioning, symptoms, and quality of life. The total score ranges 0-100 (higher = greater disease burden), comprising function (0-30), overall impact (0-20), and symptoms (0-50) after standard weighting; each item is rated 0-10.
Central sensitization symptoms
The Central Sensitization Inventory (CSI) is administered to assess symptoms related to central sensitization, such as sensitivity to touch, light, or sound, sleep disturbances, and concentration difficulties. Scores range from 0 to 100, with higher scores reflecting greater symptom severity. Each item is rated 0-4.
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