Schematic of experimental apparatus.

This consisted of transcranial magnetic stimulation (TMS) during concurrent electroencephalography (EEG) to simultaneously record motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). MEPs were recorded using electromyographic (EMG) electrodes placed over the distal region of the extensor carpi radialis brevis (ECRB) while thermal pain was delivered over the proximal region of the ECRB.

Schematic of the experimental protocols.

In Experiment 1, participants experienced three blocks of thermal stimuli: a pre-pain, pain, and post-pain block, with each block consisting of multiple thermal stimuli delivered 40s at a time, and during which TMS measurements (indicated by blue arrows) and verbal pain ratings were obtained. The pre-pain and post-pain blocks involved thermal stimuli delivered at the warm threshold (i.e., the temperature that leads to any perceived change in skin temperature from baseline). In the pain block, thermal stimuli were delivered at 46°C. For Experiment 2, the post-pain block was excluded, and an additional sham TMS condition was intermixed within both the pre-pain and pain blocks. For Experiment 3, the post-pain block was also excluded, and an additional subthreshold TMS condition intermixed within both the pre-pain and pain blocks.

No conclusive evidence of a difference in pain ratings between successive 46°C 40s thermal stimuli.

Mean (± SD) pain ratings during the 6 thermal stimuli delivered during the pain block (thermal stimuli delivered at 46°C) of Experiment 1. 10 pain ratings were collected over each 40 second thermal stimulus ∼ every 4 second.

No conclusive evidence of MEP amplitude differences between conditions; however individual pain sensitivity was predicted by changes in MEP amplitude.

A: Mean (± SD) MEP amplitude during the pre-pain, pain and post-pain blocks of Experiment 1. B: Individual-level Relationship between change in MEP amplitude during pain (proportion of pre-pain) and mean verbal pain rating provided by each participant.

Pain led to increased negative and positive amplitude in frontocentral and parietal-occipital sites respectively, 43-90ms after the TMS pulse.

A: Grand-average TEPs during the pre-pain, pain and post-pain blocks of Experiment 1. The grey shaded area represents the window of interpolation around the TMS pulse. B: Scalp topographies and estimated source activity at timepoints where TEP peaks are commonly observed, including the N15, P30, N45, P60, N100 and P180. A cluster plot is also shown on the right comparing signal amplitude between the pain and pre-pain conditions at a representative timepoint (48ms) between 43-90ms, which is where significant amplitude differences were observed. The black stars demonstrate the presence of significant positive (yellow) or negative (blue) clusters.

Pain led to increases in N45, P60 and N100 peak amplitude, and individual pain sensitivity was predicted by changes in the N45 peak.

TEPs across pain and pre-pain condition for the frontocentral electrodes (A) and parietal-occipital electrodes (C) identified from the cluster analysis of Experiment 1. The grey shaded area represents the window of interpolation around the transcranial magnetic stimulation (TMS) pulse. For the frontocentral electrodes, two significantly stronger negative peaks were identified at ∼45 and 85ms post-TMS. For the parietal-occipital electrodes, a significantly stronger positive peak was identified at ∼50ms post-TMS. * indicates at least moderate evidence the alternative hypothesis that the amplitude is larger in pain vs. pre-pain (BF10 > 3). Individual-level relationship between mean verbal pain ratings provided by each participant and change in peak amplitudes at ∼45ms (N45), ∼85ms (N100) post-TMS (B), and ∼50ms (P60) post-TMS (D).

TMS-evoked potentials for Active and Sham TMS.

A: Schematics showing the delivery of active and sham TMS of Experiment 2. Sham TMS involved scalp electrical stimulation (in red) beneath a sham coil (in dotted blue) to mimic somatosensory stimulation associated with active TMS, and concurrent delivery of active TMS 90 degrees to the scalp (in shaded blue) to mimic auditory stimulation associated with TMS. B: Left: TEPs during the pre-pain and pain blocks, for both active and sham stimulation. The grey shaded area represents the window of interpolation around the TMS pulse. Right: Scalp topographies and estimated source activity at timepoints where TEP peaks are commonly observed, including the N15, P30, N45, P60, N100 and P180.

Pain led to an increase in the N45 peak amplitude during active TMS but not sham TMS.

TEPs during pain and pre-pain blocks, across active and sham TMS conditions of Experiment 2, for the frontocentral electrodes (left) and parietal occipital electrodes (right) identified from the cluster analysis in the main experiment. A significantly stronger frontocentral negative peak was identified ∼45ms post-TMS during pain compared to pre-pain, for the active TMS condition. * indicates at least moderate evidence the alternative hypothesis that the amplitude is larger in pain vs. pre-pain (BF10 > 3). The dotted line shows the timing of the peak.

TMS-evoked potentials for supra- and subthreshold TMS.

Left: TEPs during the pre-pain and pain blocks, for both supra- and subthreshold TMS of Experiment 3. The grey shaded area represents the window of interpolation around the transcranial magnetic stimulation TMS pulse. Right: Scalp topographies and estimated source activity at timepoints where TEP peaks are commonly observed, including the N15, P30, N45, P60, N100 and P180.

Pain led to an increase in the N45 peak amplitude for both suprathreshold and subthreshold TMS.

TEPs during pain and pre-pain blocks of Experiment 3, across supra- and subthreshold TMS conditions, for the frontocentral electrodes (left) and parietal occipital electrodes (right) identified from the cluster analysis in Experiment 1. A significantly stronger frontocentral negative peak was identified ∼45ms post-TMS during pain compared to pre-pain for both supra- and subthreshold stimulation. * indicates at least moderate evidence the alternative hypothesis that the amplitude is larger in pain vs. pre-pain (BF10 > 3). The dotted line shows the timing of the peak.