Mechanism of Analgesic Effect on Prolonged Continuous Theta Burst Stimulation
Condition: Chronic Pain; rTMS
MeSH terms: Chronic Pain
Study type: Interventional

Summary: 
      It has been shown that prolonged continuous theta burst stimulation (pcTBS) , a relatively
      new repetitive transcranial magnetic simulation (rTMS) protocol, of the primary motor cortex
      (M1) or dorsolateral prefrontal cortex (DLPFC) decreases pain in healthy volunteers, in
      various experimental models. In addition, rTMS of M1 has also been shown to have analgesic
      effects in various chronic pain conditions, including neuropathic pain.The mechanisms
      underlying rTMS-induced analgesia remain unclear. Functional neuroimaging studies have shown
      that rTMS of M1 and DLPFC induces changes in the activity of cortical and subcortical
      structures involved in pain processing and modulation. Endogenous opioids and e
      N-methyl-D-aspartate (NMDA) receptor are known to play a major role in these processes. The
      investigator hypothesized that the endogenous opioids systems (EOS) and NMDA receptor might
      be involved in the analgesic action of pcTBS. In the first part,the investigator compares the
      analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex (DLPFC) stimulation
      before and after naloxone or placebo treatment, the intensity of pain induced by capsaicin
      were used to evaluate the analgesic effects of pcTBS. If naloxone does not reverse the
      analgesic effect of pcTBS,The volunteers will be invited to participant the second part of
      the study, which the investigator compares the analgesic effects of motor cortex (M1) or
      dorsolateral prefrontal cortex (DLPFC) stimulation before and after Ketamine treatment.
    

Detailed description: 
      This study comprised 3 parallel arms corresponding to 3 types of stimulation: active
      stimulation of M1, active stimulation of DLPFC-pcTBS, and sham stimulation (of M1 or DLPFC).
      Volunteers were randomly assigned to the 3 arms. In the first part, these volunteers
      participated in 2 experimental sessions 1 weeks apart, in which we compared the effects of
      naloxone and placebo (saline), administered according to a randomized, double-blind crossover
      design, on pcTBS-induced analgesia. Each experimental session started with the determination
      of baseline pain intensity and cortical excitability as well as plasma opioid peptide
      concentrations. Ten minutes before pcTBS (of M1, DLPFC, or sham), the volunteer received an
      intravenous bolus followed by a continuous infusion of either placebo (ie, saline) or
      naloxone, which was continued throughout the rTMS session (2 minutes). The participant was
      then allowed to rest for 60 minutes. Posttreatment pain intensity, cortical excitability and
      plasma opioid peptide concentrations will be determined by the same procedure used at
      baseline.In the second part, ketamine will be delivered the same as the first part.
    

Intervention name(s): Naloxone; Saline; Ketamine Hydrochloride; pcTBS of M1; pcTBS of DLPFC; SHAM stimulation
Intervention type(s): Drug; Drug; Drug; Device; Device; Device
Intervention description(s): The volunteer received an intravenous bolus followed by a continuous infusion of naloxone, which was continued throughout the pcTBS session; The volunteer received an intravenous bolus followed by a continuous infusion of placebo (saline), which was continued throughout the pcTBS session; The volunteer received an intravenous bolus followed by a continuous infusion of ketamine, which was continued throughout the pcTBS session; Prolonged continuous theta-burst stimulation (pcTBS) was administered to the left M1 at 80% RMT, consisting of a burst of 3 pulses given at 50 Hz repeated every 5 Hz. A total of 1,200 pulses were delivered with the TMS coil positioned in a posterior-anterior (PA) direction parallel to the midline; Prolonged continuous theta-burst stimulation (pcTBS) was administered to the left DLPFC at 80% RMT, consisting of a burst of 3 pulses given at 50 Hz repeated every 5 Hz. A total of 1,200 pulses were delivered with the TMS coil positioned in a posterior-anterior (PA) direction parallel to the midline; The Sham stimulation was delivered using the same pcTBS protocol, with the coil being flipped 90◦to the scalp so that the magnetic field would be delivered away from the scalp
Intervention MeSH terms: Ketamine; Naloxone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Diagnostic