Daily Sessions of rTMS to the Left DLPFC Modulate the Pain Thresholds and CPM

Study Overview
=================
Brief Summary
-----------------
The main purpose of the study is to assess whether repeated sessions of repetitive trancranial magnetic stimulation (rTMS) applied on left dorsolateral prefrontal cortex main boost the pain thresholds.

Detailed Description
-----------------
Pain is the largest health-related burden on society and, despite many decades of pain research, there are still few effective treatments. Since pain experience is a construct of the central nervous system (CNS), chronic pain has been recently thought to be a CNS disorder. Repetitive transcranial magnetic stimulation (rTMS) is a safe, non-invasive technique for cerebral cortex stimulation and the clinical applications of which have expanded considerably in recent years. Recent studies have been shown that 'classical' rTMS to different cortical areas temporary reduce chronic and acute pain, suggesting that rTMS may ´have some clinical application in future management of chronic pain. However, new rTMS paradigms involving theta burst stimulation (TBS) have recently been described with the major clinical advantage to be much shorter than 'classical' rTMS. The investigators hypothesize that cTBS would yield analgesic effects similar to or, possibly, even stronger than those produced by 'classical' rTMS. The investigators will carry out a sham-controlled, randomized, double-blind, crossover study in healthy volunteers, to compare the analgesic effects of two rTMS protocols over dorsolateral prefrontal cortex: classical high-frequency rTMS (10 Hz), and TBS. As rTMS-induced analgesia may be dependent on changes in pain modulatory systems, the investigators will analyze the effects of the stimulation on conditioned pain modulation (CPM). More specifically, the investigators will compare the effects of multiple sessions of rTMS on the inhibition of a test experimental stimulus induced by heterotopic noxious stimuli, to assess possible changes in diffuse noxious inhibitory controls.

Official Title
-----------------
Can Daily Sessions of rTMS to the Left DLPFC Boost Diffuse Noxious Inhibitory Control and Pain Thresholds in Healthy Subjects

Conditions
-----------------
Pain Relief

Intervention / Treatment
-----------------
* Device: repetitive transcranial magnetic stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy volunteers Exclusion Criteria: Major medical conditions

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: cTBS group<br>Transcranial magnetic stimulation (TMS) is used to stimulate small regions of the brain. During a TMS procedure, a magnetic field generator, or coil, is placed near the head of the person receiving the treatment. TBS refers to a rTMS protocol where pulses are applied in bursts of three, delivered at a frequency of 50 Hz and an inter-burst interval of 200 ms (5 Hz). | Device: repetitive transcranial magnetic stimulation<br>* Repetitive transcranial Magnetic Stimulation (rTMS) can be used to temporary modify the brain activity.<br>|
| Active Comparator: High frequenct rTMS group<br>High frequency refers to a rTMS protocol where pulses are applied in at 10Hz frequency | Device: repetitive transcranial magnetic stimulation<br>* Repetitive transcranial Magnetic Stimulation (rTMS) can be used to temporary modify the brain activity.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pressure pain thresholds (PPT) | Pressure will be applied at a rate of 30 kPa/s perpendicularly to the surface of the skin using a handheld algometer (1-cm2 probe; Somedic, Hörby, Sweden). Three readings at the pressure pain threshold (PPT) will be made at 1-minute intervals, at four sites; i) right elbow, ii) left elbow, iii) right leg and iv) left leg. The data will be reported in kPa. | The study comprises two interventions of four experimental sessions on consecutive days (Day-1 to Day-4). Changes from Day-1 at Day-4 will be investigated. | 
| Cold pain thresholds, heat pain thresholds and supra-thresholds painful stimuli | The temperature of the thermode is slowly decreased or increased to the maximum tolerable levels. The participant will click a button as soon as the tolerable level has been reached, which will bring the temperature back to baseline 32 degrees Celsius. Thresholds are determined by raising or dropping the temperature slowly from baseline skin temperature until the participant reports feeling of pain. The experimenter will then determine the temperature that is consistently rated as moderately painful by applying a temperature above the threshold level and asking the participant to rate the pain from 0 (no pain) to 10 (most intense pain imaginable). | The study comprises two interventions of four experimental sessions on consecutive days (Day-1 to Day-4). Changes from Day-1 at Day-4 will be investigated. | 
| Condition pain modulation (supra-thresholds painful stimuli ): visual analogue scale (VAS: 0-100mm) | First, the volunteers will immerse the left hand in a bucket with water and ice at 4° C for around 45-60 seconds to reach a VAS pain of 60-70/100mm. Immediately after, supra-thresholds painful stimuli over the right leg will be repeated in a randomized order. The supra-thresholds painful stimuli will be reported in a VAS scale (from 0 to 10). | The study comprises two interventions of four experimental sessions on consecutive days (Day-1 to Day-4). Changes from Day-1 at Day-4 will be investigated. | 
| Condition pain modulation (pressure pain thresholds): visual analogue scale (VAS: 0-100mm) | First, the volunteers will immerse the left hand in a bucket with water and ice at 4° C for around 45-60 seconds to reach a VAS pain of 60-70/100mm. Immediately after, pressure pain thresholds over the right leg will be repeated. The pressure pain thresholds will be reported in kPa. | The study comprises two interventions of four experimental sessions on consecutive days (Day-1 to Day-4). Changes from Day-1 at Day-4 will be investigated. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
repetitive transcranial magnetic stimulation, dorsolateral prefrontal cortex, pain thresholds