Mechanism of Analgesic Effect on Prolonged Continuous Theta Burst Stimulation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Mechanism of Analgesic Effect on Prolonged Continuous Theta Burst Stimulation

Conditions
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Chronic Pain, rTMS

Intervention / Treatment
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* Drug: Naloxone
* Drug: Saline
* Drug: Ketamine Hydrochloride
* Device: pcTBS of M1
* Device: pcTBS of DLPFC
* Device: SHAM stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1）woman or man over 18 and under 85 years old; 2）Clinical diagnosis of physical and mental health people; 3) able to cooperate in completing questionnaire. Exclusion Criteria: 1)Clinical diagnosis of psychiatric disorder including major depression; 2) History of substance abuse (alcohol, drugs); 3) Past treatment with repetitive transcranial magnetic stimulation (rTMS); 4) Contraindications to rTMS (previous severe head trauma or neurosurgical intervention, past or current epilepsy, active brain tumor, intracranial hypertension, implanted ferromagnetic devices, e.g., cardiac pacemaker, neurostimulator, or cochlear implants); 5) Any difficulty to fill out questionnaires (due to language or cognitive problems);

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: active stimulation of M1<br>pcTBS was administered to the left M1 at 80% resting motor threshold (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. | Drug: Naloxone<br>* The volunteer received an intravenous bolus followed by a continuous infusion of naloxone, which was continued throughout the pcTBS session<br>Drug: Saline<br>* The volunteer received an intravenous bolus followed by a continuous infusion of placebo (saline), which was continued throughout the pcTBS session<br>Drug: Ketamine Hydrochloride<br>* The volunteer received an intravenous bolus followed by a continuous infusion of ketamine, which was continued throughout the pcTBS session<br>Device: pcTBS of M1<br>* 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<br>|
| Experimental: active stimulation of DLPFC<br>pcTBS was administered to the left DLPFC at 80% resting motor threshold (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. | Drug: Naloxone<br>* The volunteer received an intravenous bolus followed by a continuous infusion of naloxone, which was continued throughout the pcTBS session<br>Drug: Saline<br>* The volunteer received an intravenous bolus followed by a continuous infusion of placebo (saline), which was continued throughout the pcTBS session<br>Drug: Ketamine Hydrochloride<br>* The volunteer received an intravenous bolus followed by a continuous infusion of ketamine, which was continued throughout the pcTBS session<br>Device: pcTBS of DLPFC<br>* 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<br>|
| Sham Comparator: SHAM stimulation<br>The Sham stimulation was delivered using the same protocol, with the coil being orientated at 90° to the scalp so that the magnetic field would be delivered away from the scal | Drug: Naloxone<br>* The volunteer received an intravenous bolus followed by a continuous infusion of naloxone, which was continued throughout the pcTBS session<br>Drug: Saline<br>* The volunteer received an intravenous bolus followed by a continuous infusion of placebo (saline), which was continued throughout the pcTBS session<br>Drug: Ketamine Hydrochloride<br>* The volunteer received an intravenous bolus followed by a continuous infusion of ketamine, which was continued throughout the pcTBS session<br>Device: SHAM stimulation<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| pain intensity at baseline | pain intensity on a 10-cm visual analogue scale (VAS) extending from 0 (no pain) to 100 (maximal pain possible) at baseline. | Baseline | 
| pain intensity at the posttreatment of pcTBS | pain intensity on a 10-cm visual analogue scale (VAS) extending from 0 (no pain) to 100 (maximal pain possible) at the posttreatment of pcTBS. | through study completion, an average of 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor-evoked potential (MEP) | Corticospinal excitability will be measured with MEP at rest of the first dorsal interosseous (FDI) muscle, A total of 20 single pulses were consecutively delivered to the hand region of the left M1 at 120% RMT (45° to the midline, handle pointing backward). | through study completion, an average of 8 months | 
| Cortical silent period (CSP) | Corticospinal excitability will be measured with CSP during a sustained voluntary FDI muscle contraction, A total of 20 single pulses were consecutively delivered to the hand region of the left M1 at 120% RMT (45° to the midline, handle pointing backward). | through study completion, an average of 8 months | 
| Maximum plasma concentration of opioid peptide at baseline | plasma opioid peptide concentrations will be measured using ELISA at baseline. | baseline | 
| Maximum plasma concentration of opioid peptide at the posttreatment of pcTBS | plasma opioid peptide concentrations will be measured using ELISA at the last posttreatment of pcTBS. | through study completion, an average of 8 months |