Role of the Supraspinal Opioidergic Circuit in Prefrontal TMS-Induced Analgesia

Study Overview
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Brief Summary
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Studies have shown that transcranial magnetic stimulation (TMS), a non-invasive form of brain stimulation, can reduce pain in the laboratory and in the clinic. The purpose of this study is to investigate how TMS relieves pain and affects pain circuitry in the brain. One of the primary study hypotheses is that opioid blockade will significantly reduce the pain relief produced by left prefrontal cortex TMS.

Detailed Description
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Non-invasive forms of brain stimulation such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are currently being investigated as alternative or adjunctive therapies for pain. Clinical interest in these techniques continues to grow because of rising opiate abuse and inadequate pain management strategies. Despite this enthusiasm, studies on the efficacy of repetitive TMS (rTMS) for pain have produced mixed results. Some of the most promising and informative research has focused on rTMS for perioperative pain. In two different postoperative studies, a single session of left dorsolateral prefrontal cortex (DLPFC) rTMS after gastric bypass surgery reduced morphine self-administration by 40% when compared to sham stimulation. These data are particularly fascinating given the role of the DLPFC in top-down pain processing. Centered at the juncture of Brodmann Areas (BAs) 9 and 46, the DLPFC remains a popular therapeutic target for rTMS given its accessible location and presumed role in high-order cognition and emotional valence. Animal and human studies suggest that cingulofrontal regions like DLPFC may modulate pain perception via recruitment of opioidergic midbrain and brainstem structures like the periaqueductal gray (PAG) and the rostroventromedial medulla (RVM), respectively. These data outline the functional circuitry that might be involved in the analgesic effects of DLPFC rTMS. While many studies aim to evaluate the clinical efficacy of DLPFC rTMS for pain management, few have examined how it affects pain processing. Imaging the cerebral signature of pain before and after left DLPFC rTMS might reveal information about pain circuitry and help to elucidate the mechanism by which prefrontal rTMS may produce analgesia. Previous studies suggest that opioid blockade abolishes left but not right DLPFC rTMS-induced analgesia. In this study, our a priori hypothesis was that left DLPFC rTMS would attenuate blood oxygenation-level dependent (BOLD) signal response to painful stimuli in pain processing regions. More specifically, we anticipated that midbrain and medulla BOLD signal changes induced by left DLPFC rTMS would be abolished by pretreatment with the μ-opioid antagonist naloxone.

Official Title
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Role of the Supraspinal Opioidergic Circuit in Prefrontal TMS-Induced Analgesia

Conditions
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Pain

Intervention / Treatment
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* Procedure: Sham rTMS
* Procedure: Real rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy volunteers no history of depression or pain no metal in body no medications that lower seizure threshold Exclusion Criteria: history of depression or pain history of seizures or epilepsy metal implants in body medications that lower seizure threshold psychiatric medications

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Saline<br>Participants received intravenous saline immediately prior to sham and real rTMS of the left dorsolateral prefrontal cortex. The parameters of the stimulation paradigm are as follows: 10 Hz, 5 seconds on, 10 seconds off, 20 minutes, 4000 pulses). | Procedure: Sham rTMS<br>* The eSham system was implemented in conjunction with a specialized Neuronetics sham TMS coil. This coil has a metal plate hidden inside of it that blocks the magnetic field from affecting the brain. Scalp electrodes were used to mimic the feel of real rTMS. This approach has been validated in previous studies.<br>* Other names: Neuronetics Model 2100 Therapy System;Procedure: Real rTMS<br>* An iron-core, solid-state figure-of-8 coil was used to stimulate the dorsolateral prefrontal cortex. The site of stimulation was estimated using the Beam F3 method based on the 10-20 EEG system.<br>* Other names: Neuronetics Model 2100 Therapy System;|
| Active Comparator: Naloxone<br>Participants received intravenous naloxone (0.1mg/kg) immediately prior to sham and real rTMS of the left dorsolateral prefrontal cortex. The parameters of the stimulation paradigm are as follows: 10 Hz, 5 seconds on, 10 seconds off, 20 minutes, 4000 pulses). | Procedure: Sham rTMS<br>* The eSham system was implemented in conjunction with a specialized Neuronetics sham TMS coil. This coil has a metal plate hidden inside of it that blocks the magnetic field from affecting the brain. Scalp electrodes were used to mimic the feel of real rTMS. This approach has been validated in previous studies.<br>* Other names: Neuronetics Model 2100 Therapy System;Procedure: Real rTMS<br>* An iron-core, solid-state figure-of-8 coil was used to stimulate the dorsolateral prefrontal cortex. The site of stimulation was estimated using the Beam F3 method based on the 10-20 EEG system.<br>* Other names: Neuronetics Model 2100 Therapy System;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Rating | There are two experimental visits separated by one week. During each experiment, pain ratings will be measured every 30 minutes. Preliminary testing will be done 30 minutes into the experiment. The purpose of preliminary testing is to select the temperature that will be used to induce pain throughout the experiment. Baseline testing will be done 60 minutes into the experiment. After sham rTMS will be done 90 minutes into the experiment. After real rTMS will be done 120 minutes into the study. The pain scale used in a Visual Analog Scale (VAS). There was an 11-point rating system where 0 represented no pain and 10 represented unbearable pain. | Baseline (60 minutes into experiment), Post-Sham (90 minutes), Post-Real (120 minutes) | 
| Change in BOLD Signal in Pain Processing Regions During Pain, Including Supraspinal Opioidergic Structures | There are two experimental visits separated by one week. During each experiment, blood oxygen level dependent (BOLD) signal will be measured at baseline (60 minutes into the experiment), post-sham rTMS (90 minutes into the experiment) and post-real (120 minutes into the experiment). | Baseline (60 minutes into experiment), Post-Sham (90 minutes), Post-Real (120 minutes) |