Distinct patterns of brain activity mediate perceptual and motor and autonomic responses to noxious stimuli

Fig. 1. Paradigm. The paradigm comprised three core conditions (perception, motor, and autonomic) and an additional combined condition, which were presented in pseudorandomized order. In each condition, 60 painful laser stimuli were applied to the dorsum of the left hand. Stimulus intensity was varied in a pseudorandomized sequence between three individually adjusted levels (low, medium, and high). The interstimulus interval was varied between 8 and 12 s. In the perception condition, participants were prompted to verbally rate the perceived pain intensity on a numerical rating scale (0–100). Pain ratings served as a measure of the perceptual dimension of pain. In the motor condition, participants were instructed to release a button pressed with the index finger of the right hand as fast as possible in response to noxious stimuli. Reaction times served as a measure of the motor dimension of pain. In the autonomic condition, participants were instructed to focus on the painful stimulation without any particular task while skin conductance responses (SCRs) were recorded. SCRs served as a measure of the autonomic dimension of pain. In the combined condition, the participants were asked to…

Fig. 2. Perceptual, motor, and autonomic responses to noxious stimuli. Box plots of pain ratings (0–100, NRS), reaction times (ms), and skin conductance responses (µS) to noxious stimuli of low, medium, and high intensity in the perception, motor, and autonomic conditions, respectively. The band inside the box indicates the median, and the bottom and top edges of the box indicate the 25th and 75th percentiles, respectively. The whiskers extend to the most extreme data points not considered outliers, and the outliers are plotted individually using the “+” symbol. **p < 0.01, ***p < 0.001, n.s. not significant, dependent samples t-tests; NRS numerical rating scale, SCR skin conductance response

Fig. 3. Brain responses to noxious stimuli. Mean time courses and time-frequency representation (TFR, right panel) of brain responses averaged across conditions and participants. Marked time periods and time-frequency windows indicate periods/windows chosen to quantify N1, N2, P2, and gamma responses. Topographies depict the scalp distribution of neural activity in these periods/windows, electrodes used for the quantification of the different responses are marked. For visualization only, the TFR is displayed as %-signal change relative to a prestimulus baseline (−1000 to 0 ms)

Fig. 4. Mediation analysis. a Two-path mediation model with a representing the relation of X to M, b the relation of M to Y controlled for X, and c′ the relation of X to Y controlled for M. Mediation effects are calculated by multiplying coefficients of path a and path b and tested for significance using a bootstrap approach. b Three-path mediation model linking stimulus intensity (X) and the perceptual, motor, or autonomic dimension of pain (Y) via two sequential mediators (M1 and M2)

Fig. 5. Brain mediators of perceptual, motor, and autonomic responses to noxious stimuli. Mediation effects in the perception (a), motor (b), and autonomic (c) conditions. The thickness of the arrows reflects the size of the regression coefficients and thus, represents the strength of mediation effects. Significant mediation effects are indicated by continuous arrows

Fig. 6. Patterns of mediation effects in the different conditions. The radar chart depicts the relative mediation effect for each brain response and condition. The relative mediation effect of a brain response in a certain condition was calculated as the mediation effect divided by the sum of the mediation effects of all brain responses in that condition

Fig. 7. Brain mediators of perceptual, motor, and autonomic responses—three-path mediation analysis. Three-path mediation analyses were performed whenever more than one brain response significantly mediated in the two-path mediation models. Thus, three-path mediation analyses were performed for the N2 and P2 waves in the perception condition as well as for the N1 and P2, N1 and gamma, gamma and P2 responses in the motor condition. A schematic overview of potential mediation effects (path a1 × d × b2) in the perception (a) and motor (b) condition is depicted. Dashed arrows indicate that no significant three-path mediation effects were found