Role of the Supraspinal Opioidergic Circuit in Prefrontal TMS-Induced Analgesia
Condition: Pain
Study type: Interventional

Summary: 
      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: 
      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.
    

Intervention name(s): Sham rTMS; Real rTMS
Intervention type(s): Procedure; Procedure
Intervention description(s): 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.; 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.
Other intervention name(s): Neuronetics Model 2100 Therapy System; Neuronetics Model 2100 Therapy System
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science