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. 2009 Jun 17;29(24):7909-16.
doi: 10.1523/JNEUROSCI.0014-09.2009.

Characterizing the cortical activity through which pain emerges from nociception

Michael C Lee  1 , André Mouraux, Gian Domenico Iannetti
Affiliations

Characterizing the cortical activity through which pain emerges from nociception

Michael C Lee et al. J Neurosci. .

Abstract

Nociception begins when Adelta- and C-nociceptors are activated. However, the processing of nociceptive input by the cortex is required before pain can be consciously experienced from nociception. To characterize the cortical activity related to the emergence of this experience, we recorded, in humans, laser-evoked potentials elicited by physically identical nociceptive stimuli that were either perceived or unperceived. Infrared laser pulses, which selectively activate skin nociceptors, were delivered to the hand dorsum either as a pair of rapidly succeeding and spatially displaced stimuli (two-thirds of trials) or as a single stimulus (one-third of trials). After each trial, subjects reported whether one or two distinct painful pinprick sensations, associated with Adelta-nociceptor activation, had been perceived. The psychophysical feedback after each pair of stimuli was used to adjust the interstimulus interval (ISI) of the subsequent pair: when a single percept was reported, ISI was increased by 40 ms; when two distinct percepts were reported, ISI was decreased by 40 ms. This adaptive algorithm ensured that the probability of perceiving the second stimulus of the pair tended toward 0.5. We found that the magnitude of the early-latency N1 wave was similar between perceived and unperceived stimuli, whereas the magnitudes of the later N2 and P2 waves were reduced when stimuli were unperceived. These findings suggest that the N1 wave represents an early stage of sensory processing related to the ascending nociceptive input, whereas the N2 and P2 waves represent a later stage of processing related, directly or indirectly, to the perceptual outcome of this nociceptive input.

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Figures

Figure 1.
Figure 1.
Experimental design. Top, Nociceptive stimuli were presented in blocks. Each block (30 trials) consisted of 20 trials during which two stimuli were applied close in space and in rapid temporal succession (green and red circles) and 10 trials during which a single stimulus was applied (gray circles). x-Axis, Trial number; y-axis, ISI. Bottom, After each trial, the subject was asked whether one or two temporally distinct pricking sensations had been perceived. The ISI of each double-stimulus trial was determined by the number of pricking sensations perceived in the preceding double-stimulus trial. If a single pricking sensation had been perceived (green), the ISI of the following double-stimulus trial was increased by 40 ms, thus making the detection of the second stimulus easier. If two pricking sensations had been perceived (red), the ISI of the following double-stimulus trial was reduced by 40 ms, thus making the detection of the second stimulus harder. This adaptive staircase algorithm ensured that the ISI of double-stimulus trials was maintained, throughout the experiment, at a value at which the likelihood of perceiving the second stimulus was equal to the likelihood of not perceiving the second stimulus.
Figure 2.
Figure 2.
Spatial distribution of laser stimuli. Left, Target location of the second stimulus in trials in which the second stimulus was not perceived (red) and was perceived (green). Each spot location was assigned a pair of relative coordinates on a 4 × 4 cm plane, whose area was adjusted to fit within the left-hand dorsum. Data from a representative subject are shown. Right, To ensure that differences between perceived and unperceived trials did not result from differences in peripheral nociceptive input, an iterative trial selection procedure was used to successively remove trials from the pools of perceived and unperceived trials, until their spatial distribution was homogeneous (see also Materials and Methods). Note how, in this subject, the procedure rejected a small, spatially isolated cluster of trials in which the second stimulus was not perceived (dashed circle).
Figure 3.
Figure 3.
Time course and scalp topography of LEPs elicited by two rapidly succeeding laser stimuli. Left column, LEPs elicited by the first stimulus (S1). Right column, LEPs elicited by the second stimulus (S2). Top row, LEPs obtained when the second stimulus was not perceived (P1). Bottom row, LEPs obtained when the second stimulus was perceived (P2). The average interstimulus interval was 553 ± 285 ms. The colored waveforms represent single subjects, whereas the black waveforms represent the group-level average (Cz vs nose reference). x-Axis, Time (in seconds). The vertical calibration bar represents amplitude (10 μV; negativity plotted upward). All stimuli elicited a negative wave (N2) followed by a positive wave (P2), maximal at Cz. The topographies of both waves are displayed in the corresponding scalp maps. The gray circles mark the position of electrode Cz. Note that the magnitudes of the N2 and P2 waves elicited by the second stimulus were greater when the second stimulus was perceived. Also note that the magnitudes of N2 and P2 waves elicited by the first stimulus were greater than those elicited by the second stimulus.
Figure 4.
Figure 4.
Effect of stimulus perception on LEPs elicited by two rapidly succeeding stimuli. x-Axis, Time (in seconds). The vertical calibration bar represents amplitude (5 μV; negativity plotted upward). Top graphs, N2 and P2 waves recorded at the vertex (Cz vs nose reference). Bottom graphs, N1 wave recorded at the temporal region contralateral to the stimulated side (Tc vs Fz). Full waveforms, LEPs obtained when the second stimulus was perceived. Dashed waveforms, LEPs obtained when the second stimulus was not perceived. The main effect of perception is shown in the left column. Note that the magnitudes of the N2 and P2 waves were significantly greater when the second stimulus was perceived, whereas the magnitude of the N1 wave was not significantly affected by whether or not the stimulus was perceived. The effect of perception on the LEPs elicited by the first stimulus is shown in the middle column, and its effect on the LEPs elicited by the second stimulus is shown in the right column. Note how the amplitude of the P2 wave elicited by both the first and the second stimulus was significantly greater when the second stimulus was perceived. The bar graphs represent the average (± SD) amplitudes of N1, N2, and P2 waves in each condition. *p < 0.05; **p < 0.01.
Figure 5.
Figure 5.
Effect of stimulus repetition on LEPs elicited by two rapidly succeeding stimuli. x-axis, Time (in seconds). The vertical calibration bar represents amplitude (5 μV; negativity plotted upward). Top graphs, N2 and P2 waves recorded at the vertex (Cz vs nose reference). Bottom graphs, N1 wave recorded at the temporal region contralateral to the stimulated side (Tc vs Fz). Full waveforms, LEPs elicited by the first stimulus. Dashed waveforms, LEPs elicited by the second stimulus. The main effect of stimulus repetition is shown in the left column. Note that the magnitudes of all three waves were significantly reduced by stimulus repetition. The effect of stimulus repetition on the LEPs obtained when the second stimulus was not perceived is shown in the middle column, whereas its effect on the LEPs obtained when the second stimulus was perceived is shown in the right column. The bar graphs represent the average (± SD) amplitudes of N1, N2, and P2 waves in each condition. *p < 0.05; **p < 0.01.
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