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This trial aims at understanding the mechanisms of optimized transcranial direct current stimulation (tDCS) (16 tDCS sessions combined with exercise)] on pain control. Optimized tDCS can lead to stronger engagement of the endogenous pain regulatory system that will ultimately lead to increased pain relief in patients with fibromyalgia (FM). Therefore, the investigators designed a 2x2 factorial mechanistic trial [tDCS (active and sham) and aerobic exercise (AE) (active and control)] to evaluate the effects of 4 weeks of tDCS coupled with exercise on the endogenous pain regulatory system assessed by conditioned pain modulation (CPM) and central sensitization as assessed by temporal slow pain summation (TSPS), and compared to either intervention alone and to no intervention.
Recent evidence has suggested that FM pain can be related to deficits in pain endogenous regulatory control and that novel non-pharmacological interventions, such as tDCS can modulate this system and, consequently, reduce pain intensity. Widespread pain in FM is thought to represent enhanced pain sensitivity that is maintained by central mechanisms. This suggests changes in the descending pain control mechanisms and a possible relationship with the central sensitization phenomenon. Recent evidence has suggested that pain inhibitory pathways are affected in FM; thus, further understanding these pathways' role can significantly change how the treatment of this condition. In this study the investigators will test the effects of two interventions -tDCS and aerobic exercise - on the modulation of the endogenous inhibitory pain system in fibromyalgia.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Active tDCS and Active Exercise | Experimental | Active tDCS for 20 min Active exercise (60-70% max HR) for 30 min |
|
| Sham tDCS and Active Exercise | Active Comparator | Sham tDCS for 20 min Active exercise (60-70% max HR) for 30 min |
|
| Active tDCS and Sham Exercise | Active Comparator | Active tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min |
|
| Sham TDCS and Sham Exercise | Sham Comparator | Sham tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Active tDCS | Device | Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. |
| Measure | Description | Time Frame |
|---|---|---|
| Conditioning Pain Modulation (CPM) | Pain intensity was measured using the Numeric Pain Scale (NPS; 0 = no pain, 10 = worst pain). Higher scores indicate worse pain. A "pain-6 temperature" was first identified (temperature that elicits NPS = 6). Test stimulus: Pain-6 temperature applied for 30s; participants rated pain at 10, 20, and 30s. The test-stimulus score is the average of the three NPS ratings. Conditioned stimulus: After 5 minutes, the left hand was immersed in 10-12°C water for 30s while the same pain-6 temperature was applied again. Pain was rated the same way, and the conditioned-stimulus score is the average of the three NPS ratings. CPM calculation = (test-stimulus average) - (conditioned-stimulus average). Positive values = better endogenous pain inhibition; negative values = worse. | 6 weeks |
| Temporal Slow Pain Summation (TSPS) | Participants first determined the temperature that elicited Numeric Pain Scale (NPS) = 6 ("pain-6"). Using this temperature, a train of 15 heat pulses (0.4 Hz) was delivered to the right forearm with a TSA-II thermode. Pain was rated using the NPS after the 1st and 15th heat stimulus. TSPS calculation: TSPS = NPS rating after the 15th stimulus - NPS rating after the 1st stimulus. Higher TSPS values represent greater temporal pain summation (worse outcome). | 6 weeks |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Felipe Fregni, MD PhD MPH | Spaulding Rehabilitation Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Spaulding Rehabilitation Hospital for Continuing Care | Cambridge | Massachusetts | 02138 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38652585 | Derived | Pacheco-Barrios K, Teixeira PEP, Martinez-Magallanes D, Neto MS, Pichardo EA, Camargo L, Lima D, Cardenas-Rojas A, Fregni F. Brain compensatory mechanisms in depression and memory complaints in fibromyalgia: the role of theta oscillatory activity. Pain Med. 2024 Aug 1;25(8):514-522. doi: 10.1093/pm/pnae030. | |
| 31672712 | Derived |
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Upon completion of the trial and after publication of the primary manuscript, we plan to publish the de-identified dataset following the guidelines of our institution (Spaulding Rehabilitation Hospital/Partners Healthcare and Harvard Medical School).
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116 subjects were enrolled and randomized
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| ID | Title | Description |
|---|---|---|
| FG000 | Active tDCS and Active Exercise | Active tDCS for 20 min Active exercise (60-70% max HR) for 30 min Active tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. Active Exercise: Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes |
| FG001 | Sham tDCS and Active Exercise | Sham tDCS for 20 min Active exercise (60-70% max HR) for 30 min Active Exercise: Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. |
| FG002 | Active tDCS and Sham Exercise | Active tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Active tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. |
| FG003 | Sham TDCS and Sham Exercise | Sham tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Baseline participants for randomized subjects
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| ID | Title | Description |
|---|---|---|
| BG000 | Active tDCS and Active Exercise | Active tDCS for 20 min Active exercise (60-70% max HR) for 30 min Active tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. Active Exercise: Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Conditioning Pain Modulation (CPM) | Pain intensity was measured using the Numeric Pain Scale (NPS; 0 = no pain, 10 = worst pain). Higher scores indicate worse pain. A "pain-6 temperature" was first identified (temperature that elicits NPS = 6). Test stimulus: Pain-6 temperature applied for 30s; participants rated pain at 10, 20, and 30s. The test-stimulus score is the average of the three NPS ratings. Conditioned stimulus: After 5 minutes, the left hand was immersed in 10-12°C water for 30s while the same pain-6 temperature was applied again. Pain was rated the same way, and the conditioned-stimulus score is the average of the three NPS ratings. CPM calculation = (test-stimulus average) - (conditioned-stimulus average). Positive values = better endogenous pain inhibition; negative values = worse. | Posted | Mean | 95% Confidence Interval | Unit on a scale (NPS 0-10) | 6 weeks |
|
4.5 months
Adverse effects were collected with a questionnaire for adverse effects
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active tDCS and Active Exercise | Active tDCS for 20 min Active exercise (60-70% max HR) for 30 min Active tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. Active Exercise: Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Allergic reaction | Skin and subcutaneous tissue disorders | Systematic Assessment | The clinicians who treated her reported that the allergic reaction was associated with a poisonous plant around her neighborhood. This adverse event was considered serious as she was admitted for investigation. This event was unrelated. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mild Tingling | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Felipe Fregni | Spaulding Rehabilitation Hospital | 6179526154 | fregni.felipe@mgh.harvard.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Mar 13, 2023 | Nov 11, 2025 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D005356 | Fibromyalgia |
| ID | Term |
|---|---|
| D009135 | Muscular Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
| D009468 | Neuromuscular Diseases |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| D052580 | Muscle Stretching Exercises |
| D015444 | Exercise |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
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|
|
| Active Exercise | Procedure | Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes |
|
|
| Sham tDCS | Device | Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. |
|
|
| Sham Exercise | Procedure | Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. |
|
|
| Castelo-Branco L, Uygur Kucukseymen E, Duarte D, El-Hagrassy MM, Bonin Pinto C, Gunduz ME, Cardenas-Rojas A, Pacheco-Barrios K, Yang Y, Gonzalez-Mego P, Estudillo-Guerra A, Candido-Santos L, Mesia-Toledo I, Rafferty H, Caumo W, Fregni F. Optimised transcranial direct current stimulation (tDCS) for fibromyalgia-targeting the endogenous pain control system: a randomised, double-blind, factorial clinical trial protocol. BMJ Open. 2019 Oct 30;9(10):e032710. doi: 10.1136/bmjopen-2019-032710. |
| BG001 | Sham tDCS and Active Exercise | Sham tDCS for 20 min Active exercise (60-70% max HR) for 30 min Active Exercise: Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. |
| BG002 | Active tDCS and Sham Exercise | Active tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Active tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. |
| BG003 | Sham TDCS and Sham Exercise | Sham tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG001 | Sham tDCS and Active Exercise | Sham tDCS for 20 min Active exercise (60-70% max HR) for 30 min Active Exercise: Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. |
| OG002 | Active tDCS and Sham Exercise | Active tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Active tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. |
| OG003 | Sham TDCS and Sham Exercise | Sham tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. |
|
|
| Primary | Temporal Slow Pain Summation (TSPS) | Participants first determined the temperature that elicited Numeric Pain Scale (NPS) = 6 ("pain-6"). Using this temperature, a train of 15 heat pulses (0.4 Hz) was delivered to the right forearm with a TSA-II thermode. Pain was rated using the NPS after the 1st and 15th heat stimulus. TSPS calculation: TSPS = NPS rating after the 15th stimulus - NPS rating after the 1st stimulus. Higher TSPS values represent greater temporal pain summation (worse outcome). | Posted | Mean | 95% Confidence Interval | Unit on a scale (NPS 0-10) | 6 weeks |
|
|
|
| 0 |
| 28 |
| 0 |
| 28 |
| 23 |
| 28 |
| EG001 | Sham tDCS and Active Exercise | Sham tDCS for 20 min Active exercise (60-70% max HR) for 30 min Active Exercise: Participants will walk briskly in a treadmill (as to keep at 60-70% maximum heart rate) for 30 minutes Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. | 0 | 28 | 0 | 28 | 21 | 28 |
| EG002 | Active tDCS and Sham Exercise | Active tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Active tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. 20 minutes of tDCS will be applied. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. | 0 | 30 | 0 | 30 | 18 | 30 |
| EG003 | Sham TDCS and Sham Exercise | Sham tDCS for 20 min Sham exercise (within 10% baseline HR) for 30 min Sham tDCS: Active tDCS: A 1x1 Low-intensity DC Stimulator will be used to deliver direct current through rubber electrodes in saline soaked sponges. The anode will be placed over the left primary motor cortex (M1) while the cathode will be placed over the contralateral supra-orbital area. Only 30 seconds of current will be applied for the sham condition. Sham Exercise: Participants will walk in a treadmill (as to keep at 10% within their baseline heart rate) for 30 minutes. | 0 | 30 | 1 | 30 | 28 | 30 |
|
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| D009422 |
| Nervous System Diseases |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |
| D005081 | Exercise Therapy |
| D012046 | Rehabilitation |
| D000359 | Aftercare |
| D003266 | Continuity of Patient Care |
| D005791 | Patient Care |
| D026741 | Physical Therapy Modalities |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |