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Randomized Controlled Trial
. 2013 Jun;38(7):1189-97.
doi: 10.1038/npp.2013.13. Epub 2013 Jan 11.

Naloxone-reversible modulation of pain circuitry by left prefrontal rTMS

Joseph J Taylor  1 , Jeffrey J Borckardt, Melanie Canterberry, Xingbao Li, Colleen A Hanlon, Truman R Brown, Mark S George
Affiliations
Randomized Controlled Trial

Naloxone-reversible modulation of pain circuitry by left prefrontal rTMS

Joseph J Taylor et al. Neuropsychopharmacology. 2013 Jun.

Abstract

A 20-minute session of 10 Hz repetitive transcranial magnetic stimulation (rTMS) of Brodmann Area (BA) nine of the left dorsolateral prefrontal cortex (DLPFC) can produce analgesic effects on postoperative and laboratory-induced pain. This analgesia is blocked by pretreatment with naloxone, a μ-opioid antagonist. The purpose of this sham-controlled, double-blind, crossover study was to identify the neural circuitry that underlies the analgesic effects of left DLPFC rTMS, and to examine how the function of this circuit, including midbrain and medulla, changes during opioid blockade. Fourteen healthy volunteers were randomized to receive intravenous saline or naloxone immediately before sham and real left DLPFC rTMS on the same experimental visit. One week later, each participant received the novel pretreatment but the same stimulation paradigm. Using short sessions of heat on capsaicin-sensitized skin, hot allodynia was assessed during 3 Tesla functional magnetic resonance imaging (fMRI) scanning at baseline, post-sham rTMS, and post-real rTMS. Data were analyzed using whole-brain voxel-based analysis, as well as time series extractions from anatomically-defined regions of interest representing midbrain and medulla. Consistent with previous findings, real rTMS significantly reduced hot allodynia pain ratings. This analgesia was associated with elevated blood oxygenation-level dependent (BOLD) signal in BAs 9 and 10, and diminished BOLD signal in the anterior cingulate, thalamus, midbrain, and medulla during pain. Naloxone pretreatment largely abolished rTMS-induced analgesia, as well as rTMS-induced attenuation of BOLD signal response to painful stimuli throughout pain processing regions, including midbrain and medulla. These preliminary results suggest that left DLPFC rTMS drives top-down opioidergic analgesia.

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Figures

Figure 1
Figure 1
Schematic representation of study methodology. The vertical line separates preparatory steps (left) from experimental steps (right). After rMT assessment via parameter estimation by sequential testing and BA 9 localization via BEAM F3 method, participants underwent preliminary pain testing on capsaicin-sensitized skin. The temperature reported as ‘7 out of 10' on a VAS during preliminary testing was used during fMRI scanning at baseline, post-sham rTMS and post-real rTMS (gray boxes). Participants were randomized to I.V. saline on one visit and naloxone on the other visit.
Figure 2
Figure 2
Comparison of block pain intensity ratings (mean±SE). Twelve 22-second blocks of a fixed temperature reported as ‘7 out of 10' on a VAS during preliminary testing were applied to capsaicin-sensitized skin during fMRI scanning at baseline, post-sham rTMS, and post-real rTMS. Asterisks (*P<0.05, **P<0.001) indicate Bonferroni corrected significant within-group differences between ratings after real rTMS and all prior ratings. The asterisks to the right of the bar indicate a Bonferroni corrected significant between-group difference after real rTMS.
Figure 3
Figure 3
Visual of whole-brain analysis. Participants received 12 22 s blocks of rest alternating with 12 22 s blocks of a fixed temperature reported as ‘7 out of 10' on a VAS during preliminary pain testing at baseline, post-sham rTMS, and post-real rTMS. Rest block data were subtracted from pain block data for all analyses. Panel (a) shows significant BOLD signal elevations during baseline testing before any intervention. This baseline pain contrast was used as a comprehensive (P<0.05 uncorrected voxel level threshold) inclusive mask for evaluation of post-sham and post-real pain contrasts (P<0.005 uncorrected voxel level threshold; P<0.005 cluster level threshold; cluster size of five or greater). Panel (b) shows the brain regions that exhibit significantly less BOLD signal activation during pain after real rTMS than during pain after sham rTMS with saline pretreatment. Panel (c) shows how naloxone pretreatment largely abolishes the BOLD signal decreases driven by real rTMS shown in Panel (b).
Figure 4
Figure 4
Graphs of midbrain and medulla PSC (mean±SEM). Midbrain (Panel (a): green) and medulla (Panel (b); purple) ROIs were extracted from a Talairach atlas overlay and used for time series extractions via MarsBaR. An asterisk (* P<0.05) above a bar indicates a significant difference as measured via ANOVA.
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