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.

Study Overview

• Status: Recruiting
• Conditions: Chronic Widespread Pain; Fibromyalgia (FM)
• Intervention / Treatment: Device: Active tDCS; Behavioral: Aerobic exercise; Device: Sham tDCS

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 120
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Pain in Motion research group; Phone Number: +32 497783956; Email: huanyu.xiong@vub.be

Study Locations

• Belgium
  • Jette, Belgium, 1090
    • Recruiting
    • VUB
    • Contact: Pain in Motion research group, PhD; Phone Number: +32 0497783956; Email: Jo.Nijs@vub.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Exercise + active tDCS + patients; Patient participants will receive one bout of submaximal aerobic exercise, along with a single session of active tDCS simultaneously.	Device: Active tDCS; tDCS 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.; Behavioral: Aerobic exercise; Participants 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 Comparator: Exercise + sham tDCS + patients; Patient participants will receive one bout of submaximal aerobic exercise, along with a single session of sham tDCS simultaneously.	Behavioral: Aerobic exercise; Participants 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).; Device: Sham tDCS; tDCS 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.
Active Comparator: 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.	Device: Active tDCS; tDCS 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.; Behavioral: Aerobic exercise; Participants 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 Comparator: 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.	Behavioral: Aerobic exercise; Participants 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).; Device: Sham tDCS; tDCS 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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".	Participants rate their pain at baseline, and 30 minutes after the intervention.
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.	Blood samples are collected at baseline and 20 minutes after exercise-tDCS session.
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.	Blood samples are collected at baseline and 20 minutes after exercise-tDCS session.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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".	Participants rate their pain at immediately, 8 hours, 24 hours, 48 hours, and 7 days after the intervention.
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.	Participants rate their fatigue at baseline, and 24 hours, 48 hours, 7 days after the intervention.
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.	Participants rate their FIQR at baseline, and 7 days after intervention.
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.	Participants rate their CSI at baseline.
Pain catastrophizing	The Pain Catastrophizing Scale (PCS) is used to measure catastrophic thoughts and feelings related to pain, in-cluding rumination, magnification, and helplessness. Each item is rated 0-4. Total scores range from 0 to 52, with higher values indicating stronger pain catastrophizing tendencies.	Participants rate their PCS at baseline, and 30 minutes after the intervention.
Anxiety and depression	HADS consists of two subscales: HADS-A, designed to detect anxious states, and HADS-D, designed to detect de-pressive states. Each subscale consists of 7 items with a 4-point ordinal response format. Scores range from 0 to 21 in each subscale, with higher scores indicating higher levels of anxious or depressive state. Participants an-swer each item thinking of how they felt and/or behaved during the past week.	Participants rate their HAD at baseline.

Collaborators and Investigators

• Sponsor: Vrije Universiteit Brussel

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2026
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): June 30, 2028

Study Registration Dates

• First Submitted: October 1, 2025
• First Submitted That Met QC Criteria: October 1, 2025
• First Posted (Actual): October 8, 2025

Study Record Updates

• Last Update Posted (Actual): April 20, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: pain; exercise; BDNF; DNA methylation
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Rheumatic Diseases; Pathological Conditions, Signs and Symptoms; Behavior; Signs and Symptoms; Pain; Fibromyalgia; Chronic Pain; Motor Activity; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Exercise
• Other Study ID Numbers: EC-2025-255

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No