Efficacy of Transcranial Direct Current Stimulation for Severe Primary Dysmenorrhea

Study Overview
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Brief Summary
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Primary Dysmenorrhea (PDM), defined as menstrual pain without discernable organic causes, is inexorably common in adolescent women, about 40-90% of women may suffer from it, and 20% of them can be severe in the context of being refractory to medication, daily function impairment, and having pain of severe degree. Novel therapeutic method is in need for pain alleviation for this particular phenotype. We have previously reported that PDM females may engage motor-cortex based descending pain modulation system in our resting-state functional Magnetic Resonance Imaging (rs-fMRI) and thermal pain-activation fMRI studies. Based on the reported analgesic efficacy of transcranial Direct Current Stimulation (tDCS) on the motor cortex for various experimental painful conditions and clinical pain disorders, we reason that tDCS can be effective for the severe and medication-refractory PDM patients. This study aim to investigate the analgesic efficacy of tDCS in severe PDMs and to elucidate the dynamic brain neuroplasticity in the context of functional connectivity (FC) of pain matrix after tDCS intervention. We will recruit 30 severe PDMs and randomly allocate them to either real or sham group in a triple-blind manner. rs-fMRI for functional connectivity analysis will be performed before and after the tDCS intervention. The imaging data will be correlated with behavioral and psychological measurements. This is the first study in the literature investigating the tDCS efficacy for severe PDM. The result can promise a new possibility for clinical application.

Official Title
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Efficacy of Transcranial Direct Current Stimulation for Severe Refractory Primary Dysmenorrhea: Translational and Genetic Neuroimaging Studies

Conditions
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Primary Dysmenorrhea

Intervention / Treatment
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* Device: Active tDCS
* Device: Sham tDCS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 20-35 years old PDM patients Right-handedness A regular menstrual cycle: 27-32 days Cramping pain during the menstrual period in the last 6 months , VAS ≧ 7 Abstinence for daily activities due to PDM Need analgesic or Physical therapy despite of no prominent effect Exclusion Criteria: History of head injury Pathological pituitary gland disease Organic pelvic disease, psychiatric disorder Pregnancy, childbirth A metal or pacemaker implant. Take hormone agents within 6 months

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: active, sham
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active tDCS<br>The anode sponge electrode will be placed on the scalp over the left primary motor cortex (M1) and the cathode sponge electrode will be positioned over the right supraorbital cortex (SO). Active stimulation consists of 2 mA current applied continuously for 20 minutes. | Device: Active tDCS<br>* The anode and cathode sponge electrode (51 cm2) will be placed over C3 and FP2 (10-20 system) respectively. 2 mA current will be applied continuously for 20 minutes.<br>|
| Sham Comparator: Sham tDCS<br>The anode sponge electrode will be placed on the scalp over the left primary motor cortex (M1) and the cathode sponge electrode will be positioned over the right supraorbital cortex (SO). The 2 mA current will be applied for 30 seconds at the beginning of the session. | Device: Sham tDCS<br>* The anode and cathode sponge electrode (51 cm2) will be placed over C3 and FP2 (10-20 system) respectively. 2 mA current will be applied for 30 seconds at the beginning.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scale (VAS) | pain scale; from 0 to 10; score 0: no pain, score 10: unbearable pain | change from baseline (1st menstrual phase, before tDCS) at one month (2nd menstrual phase, with tDCS), change from baseline (1st menstrual phase, before tDCS) at two months (3rd menstrual phase) | 
| Functional connectivity of rs-fMRI Imaging | Resting-state functional magnetic resonance imaging (rs-fMRI) is a well established method of functional magnetic resonance imaging (fMRI) that is used to evaluate regional interactions in the brain that occur in a resting (task-negative) state, when a subject is not performing an explicit task. Functional connectivity is the connectivity between brain regions that share functional properties, it can be defined as the correlation between spatially remote neurophysiological events, expressed as the neural networks of brain. | change from baseline (before tDCS, before 2nd menstrual phase) at one week (after tDCS completion), change from baseline (before tDCS, before 2nd menstrual phase) at four weeks (before the 3rd menstrual phase) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative sensory testing (QST) | To assess the threshold of thermal sensation (cold, cold-pain, heat, heat-pain; from 0 to 50 centigrade temperature), according to the established protocol of an ascending limit approach for heat pain and a descending limit approach for cold pain. | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase) | 
| Spielberger State-Trait Anxiety Inventory (STAI) | To assess anxious symptoms; from 20 to 80; score 20: not anxious, score 80: extremely anxious | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase) | 
| Beck Anxiety Inventory (BAI) | To assess anxious symptoms; from 0 to 63; score 0: not anxious, score 63: extremely anxious | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase) | 
| Beck Depression Inventory (BDI) | To assess depressive symptoms; from 0 to 63; score 0: not depressed, score 63: extremely depressed | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase) | 
| Pain Catastrophizing Scale (PCS) | To assess pain-maladaptive psychological status; from 0 to 52; score 0: not pain Catastrophizing , score 52: extremely pain Catastrophizing | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase) | 
| Long-form McGill Pain Questionnaire (MPQ) | To assess pain status; from 0 to 78; score 0: not painful, score 78: extremely painful | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase) | 
| Short-Form Health Survey (SF-36) | To assess quality of life; he SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. From 0 to 100; score 0: equivalent to maximum disability, score 100: no disability. | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at five weeks (after the 3rd menstrual phase) | 
| Blood Hormones Measurement | To assess testosterone, progesterone, estrogen | change from baseline (before tDCS) at one week (after tDCS completion), change from baseline (before tDCS) at four weeks (before the 3rd menstrual phase) | 
| Genotyping | To genotype the single nucleotide polymorphism genotyping (i.e., BDNF Val66Met polymorphism (rs6265), COMT Val158Met polymorphism (rs4680), OPRM1 (rs1799971), 5HTR2A (rs6313), SLC6A4 (rs25531)) from blood specimen | baseline | 
| Efficacy of tDCS blinding | To assure blinding efficacy; Patients do self-assessment about whether they receive real tDCS or sham tDCS. Assessment questionnaire:1 or 0. 1: real tDCS; 0: sham tDCS. | At 1 months after tDCS intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dysmenorrhea, Neuromodulation, Transcranial direct current stimulation, Neuroimaging, Neuroplasticity