The influence of transient spatial attention on the processing of intracutaneous electrical stimuli examined with ERPs

Clinical Neurophysiology 123 (2012) 947–959

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The influence of transient spatial attention on the processing of intracutaneous electrical stimuli examined with ERPs Rob H.J. Van der Lubbe a,b,⇑, Jan R. Buitenweg c, Maria Boschker a, Bernard Gerdes c, Marijtje L.A. Jongsma a,d a

Cognitive Psychology and Ergonomics, University of Twente, Enschede, The Netherlands Department of Cognitive Psychology, University of Finance and Management in Warsaw, Poland c Biomedical Signals and Systems, University of Twente, Enschede, The Netherlands d Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, The Netherlands b

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Article history: Accepted 22 August 2011 Available online 12 October 2011 Keywords: Spatial attention Transient Intracutaneous electrical stimulation ERPs Orienting effect Source localization Nociception

h i g h l i g h t s  Transient spatial attention affects early ERP components elicited by intracutaneous electrical stimuli.  Unattended intracutaneous electrical stimuli seem to induce a ‘‘call for attention’’.  Source analyses suggest that attentional modulation takes place within secondary somatosensory areas and the anterior cingulate cortex.

a b s t r a c t Objective: Determine the influence of transient spatial attention on the processing of intracutaneous electrical stimuli. Methods: Electrical stimuli, a single pulse or five pulses, were presented at the index fingers of the left or right hand. The to-be-attended hand and stimulated finger varied randomly from trial to trial. Participants had to press a foot pedal only when the relevant stimulus, varied between participants, occurred at the attended hand. EEG was measured to extract relevant ERP components. Results: The N100 and N150 were enhanced for attended as compared to unattended stimuli. The N100, N150, P260, and the P500 were enlarged for five pulse as compared to single pulse stimuli. The P260, which is thought to reflect a call for attention, was enhanced for unattended as compared to attended stimuli. Source analyses indicate that attentional effects on the N100, N150, and P260 may be related to changes in activity in secondary somatosensory areas and the anterior cingulate cortex. Conclusions: A transient manipulation of spatial attention increases cortical activity induced by attended relative to unattended intracutaneous electrical stimuli, but initially unattended stimuli appear to induce an enhanced orienting effect. Significance: Initially unattended intracutaneous electrical stimuli seem to induce a call for attention. Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction In the last decades, several electroencephalographic (EEG) studies confirmed that attentional manipulations like distraction modulate the processing of painful stimuli. A common characteristic of nearly all of these studies is that they examined the influence of ⇑ Corresponding author at: Cognitive Psychology and Ergonomics, Faculty of Behavioral Sciences, Universiteit of Twente, Postbus 217, 7500 AE Enschede, The Netherlands. Tel.: +31 53 489 3585; fax: +31 53 489 4241. E-mail address: [email protected] (R.H.J. Van der Lubbe).

sustained attention, either by letting participants perform attention and distraction tasks (e.g., see Dowman, 2004), or by instructing participants to attend to a specific body part or stimulus location during a block of trials (e.g., Legrain et al., 2002). Goal of the current study is rather to establish the influence of transient spatial attention (i.e., the locus of attention varies from trial to trial). In this case, we decided to employ intracutaneous electrical stimuli, which can induce a painful sensation. Given the possible similarities of observed attentional effects with tactile, laser and other electrical stimuli delivered to the left or right hands, we decided to discuss some of their results in our introduction.

1388-2457/$36.00 Ó 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2011.08.034

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Several reasons motivate an exploration of a transient rather than a sustained manipulation of spatial attention. First, an advantage of a transient manipulation is that behavioral measures like reaction time or accuracy of responses can often be used to assess the efficacy of the instruction to orient to a specific side. Numerous studies used this manipulation introduced by Posner (1978) to examine the influence of spatial attention on the processing of visual, auditory, and tactile stimuli by comparing performance for stimuli presented at attended vs. unattended locations (e.g., Posner et al., 1980; Van der Lubbe et al., 2006). In an event related potentials (ERPs) study by Forster and Eimer (2005), central cues indicated the likely side of a weak vibratory tactile stimulus (the target) delivered to the left or right hand, which required a vocal detection response, whereas a stronger vibration (the nontarget) required no response. Responses were much faster when the target occurred on the cued side than when it occurred on the uncued side, thereby revealing the efficacy of the attentional manipulation. Additionally, an increased N140 was observed for cued as compared to uncued nontargets, indicating that attention affected early somatosensory processing. A second reason for examining the effect of a transient manipulation, most relevant for the current study, is that attentional effects may differ from a sustained manipulation of spatial attention. For example, Eimer and Forster (2003) studied attentional effects on ERPs elicited by tactile stimuli delivered to the left or right hand, either by holding the attended side constant throughout an experimental block, or by changing the to-be-attended side across successive trials. In both conditions, attentional modulations were observed on the N140, but an earlier effect on the N80 was observed only in the sustained condition. These findings led Eimer and Forster to suggest that sustained spatial attention may already affect processing within primary somatosensory cortex (SI), whereas transient spatial attention modulates activity in secondary somatosensory cortex (SII) and beyond (but see Zopf et al., 2004). Finally, with regard to behavior, Posner et al. (1980) demonstrated that benefits and costs of attention on detection times may be more pronounced in the case of a transient spatial attention manipulation than in the case of a sustained spatial attention manipulation, which might point to a problem in maintaining attention directed at the intended side in sustained attention conditions. A number of methods have been used to induce a painful experience after stimulus presentation (for a review see Kakigi et al., 2005). Recent studies (e.g., Legrain et al., 2002, 2003, 2005, 2009; Valeriani et al., 2000) employed laser stimuli as they selectively activate the nociceptive1 Ad fibers while cortical activity from C fibers, determined with ERPs is reduced (see Bromm, 1984). Several other studies employed different methods of electrical stimulation. For example, Desmedt and coworkers (e.g., Desmedt and Robertson, 1977; Desmedt and Tomberg, 1989) used low intensity transcutaneous electrical stimuli, which do not induce a painful sensation (see also Garcia-Larrea et al., 1995; Thees et al., 2003), but other researchers employed higher stimulus intensities that induce a painful sensation (e.g., Dowman, 2001, 2004; Yamasaki et al., 2000; Warbrick et al., 2006). Given the painful experience, one might draw the conclusion that these stimuli selectively involve the nociceptive system. However, these stimuli as well induce activation across the fast Aß fibers, which reduces cortical activity resulting from the slower nociceptive Ad fibers, possibly due to a merging of these inputs (see Mouraux and Plaghki, 2007). Thus, observed effects with these stimuli are not purely nociceptive but reflect a mixture of effects of processing along Aß fibers and Ad fibers. 1 Nociceptive refers to the transfer of information about (potential) tissue damage along specialized (Ad and C) neural fibers, whereas pain may be considered as the subjective perceptual result of this transfer. Introduction of the term nociception can be traced back to Sir Charles Sherrington (1906).

Other researchers used intracutaneous rather than transcutaneous stimulation by employing a method proposed by Bromm and Meier (1984); (e.g., Chapman et al., 1999; Hauck et al., 2007; Miltner et al., 1989; Reinert et al., 2000; Van der Heide et al., 2009). This method more effectively stimulates Ad fibers and might circumvent the problem mentioned with transcutaneous stimulation. There are, however, strong indications that this method does not exclude activation along Aß fibers (Van der Heide et al., 2009). Specifically, Van der Heide et al. observed a clear P50 component when employing intracutaneous stimulation. This component seems due to processing along Aß fibers as it emerges too early for a contribution of Ad fibers (see Plaghki and Mouraux, 2003). A slightly different intracutaneous stimulation method was developed by Inui et al. (2002), which seems to overcome the nonselective activation of neural fibers by use of a bipolar needle electrode that selectively activates the Ad fibers (see Mouraux et al., 2010). In the current study, we employed high intensity intracutaneous stimulation according to the method of Bromm and Meier (1984), which implies that our results should be considered within a broader perspective encompassing the attentional influence on somatosensory evoked potentials (SEPs) and laser evoked potentials (LEPs). The choice for this broader perspective is additionally motivated by results of a recent study showing that LEPs may be entirely explained by a combination of multimodal and somatosensory-specific activities (Mouraux and Iannetti, 2009). Early research on the influence of sustained attention on SEPs with transcutaneous electrical stimuli showed mixed results. Desmedt and Tomberg (1989) delivered electrical stimuli to the fingers in attention conditions, in which infrequent targets had to be detected, or in distraction conditions, in which participants had to read a novel. Earliest signs of an attentional enhancement were already present for a P30 and P40 component, which seem to arise from somatosensory areas. Michie et al. (1987) observed attentional modulations of the N80, but this early effect was not present in the study by Garcia-Larrea et al. (1995), who only observed an attentional effect on the N140. In other studies with attention and distraction tasks with higher stimulus intensities that lead to a painful sensation (Dowman, 2001, 2004; Yamasaki et al., 2000), attentional effects were only present after about 140 ms, which were attributed to the anterior cingulate cortex (ACC) and not to SI, SII, or the insula (see Yamasaki et al., 2000). Hauck et al. (2007) used painful intracutaneous stimuli in a sustained attention/distraction paradigm and measured the magnetoencephalogram (MEG) and focused on oscillations rather than ERPs. In contrast with the previous studies with painful transcutaneous stimuli, they obtained support for an attentional influence on contralateral somatosensory areas, and additionally, increased coupling between the ipsilateral and contralateral somatosensory areas in the case of focused attention. As indicated above, comparable effects of spatial attention on the N140 have been observed with tactile stimuli (Eimer and Forster, 2003; Forster and Eimer, 2005; see also Eimer and Driver, 2000; Forster et al., 2009) whereas effects on earlier components seem to depend on the sustained or transient attention manipulation (Eimer and Forster, 2003). The influence of sustained spatial attention on LEPs was studied by Legrain et al. (2002) by presenting laser pulse stimuli to either the left or the right hand. Participants were instructed to attend to one hand during a block of trials, and to the other hand during another block of trials. The stimulation side and stimulus intensity (weak or high) varied randomly from trial to trial, although one intensity occurred frequently (80%) and the other rarely (20%). Participants had to count the rare stimuli (either of weak or high intensity, which varied per block) on the attended side. EEG analyses revealed that the N1 component, peaking at about 160 ms at the C3 and C4 electrodes, was more negative for attended as compared to unattended stimuli. The same result was observed for the

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slightly later N2 component at about 230 ms. In another report on the same experiment, Legrain et al. (2003) showed that the P22 component (peaking at about 400 ms at Cz) was enhanced for rare as compared to frequent stimuli, but only for rare stimuli of a high intensity and not for rare stimuli of a weak intensity. The latter observation corresponds with the idea that a novel stimulus of high intensity may induce attentional switching, a so-called bottom-up attentional capture effect. This finding also affirms the view that intense painful stimuli, which by definition signal potential tissue damage, have special attention-attracting properties (e.g., Eccleston and Crombez, 1999). The interpretation of observed ERP effects may be facilitated by specifying the likely processes reflected by an ERP component and by relating this component with its underlying neural structure(s). Many authors focused on the meaning of the more anterior P3a component, and concluded that it reflects an orienting effect towards novel and salient stimuli, which may be paraphrased as ‘‘a call for attention’’ (e.g. Escera et al., 2000; Nieuwenhuis et al., 2010; Polich, 2007). Furthermore, a combined EEG-fMRI (functional magnetic resonance imaging) study by Crottaz-Herbette and Menon (2006) strongly suggests that the N2b–P3a complex originates from ACC. If we more closely focus on source localization studies using laser stimuli (Valeriani et al., 2000; Bentley et al., 2002; Garcia-Larrea et al., 2003), then it appears that initial activity related to the N1 component arises from SII and/or the insula although a small part of this activity may be related to SI. Thus, the laser-evoked N1 component mainly reflects somatosensory processes. Most prominent, however, appears to be the contribution of (the caudal part of) the ACC, which accounts for the laserevoked P2 component. Another relevant combined EEG-fMRI study of Thees et al. (2003) focused on the sources implicated in the processing of transcutaneous electrical stimuli. They determined sources in SI (with clear activity from 20 to 140 ms), SII (50–140 ms), the insula (80–140 ms) and the supplementary motor area (SMA) and/or ACC (90–140 ms, and 220–270 ms). In the current study, we were especially interested in the influence of transient spatial attention on the processing of intracutaneous electrical stimuli. Furthermore, we wanted to compare observed effects with results of earlier studies employing attentional manipulations with transcutaneous stimuli, laser stimuli, and tactile stimuli. Spatial attention was manipulated by employing symbolic cues indicating the to-be-attended hand (comparable to the cues used in the study by Van der Lubbe et al. (2006)). A deviation from the method used by Forster and Eimer (2005) concerned the relevance of the cues. In our study, participants only had to respond when the relevant stimulus occurred on the cued side but not when stimuli occurred on the other side. An advantage of the latter procedure is that the cues are mandatory; they have to be used to properly perform the task, which may increase the probability of finding an effect of attention. Secondly, stimuli at the unattended side are never task relevant, therefore they might possibly provide more information on bottom-up attentional capture of intracutaneous stimuli. For example, in the case of the paradoxical observation of increased activity for unattended as compared to attended stimuli, this might mean that initially unattended stimuli captured attention. Furthermore, contribution of motor processes will be minimized due to the low proportion of required responses. A slight disadvantage, however, is that no attentional effect can be assessed on our behavioral measures. To distinguish targets from nontargets we used stimuli with different perceived stimulus intensities, which we manipulated by varying the number 2 Legrain et al. (2002, 2003) denoted this component as the P2 component; however, this component seems to originate from anterior areas and arrives very late, therefore, one could argue that it is identical to the P3a component (for discussions on this issue see Dowman, 2004; Lorenz and Garcia-Larrea, 2003; Legrain et al., 2009).

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of pulses (single vs. five pulses) rather than by increasing stimulus amplitudes. The advantage of this method is that the same fibers will be recruited for the different intensities as increasing the number of pulses should only lead to an increase in the generation of action potentials along the same fibers (Van der Heide et al., 2009). Furthermore, it seems interesting to compare the attentional effect, which according to some authors might lead an increase in signal strength (e.g., see Moran and Desimone, 1985), with a real manipulation of signal strength. EEG was measured from a larger number of electrodes than in most of the aforementioned studies to enable source analyses and additionally, to estimate the activation of these sources over time.

2. Method 2.1. Participants Sixteen students (9 male and 7 female) from the Faculty of Behavioral Sciences of the University of Twente participated in our experiment (age range: 18–27 years). All right-handed students had normal or corrected-to-normal vision, were free of pain, and did not use psychotropics before participation. They received course credits for their participation, and signed a written informed consent. The study was approved by an ethical committee (the medical board human-related research; Arnhem-Nijmegen: CMO 2006/213).

2.2. Stimuli and procedure Visual stimuli were displayed on a CRT monitor (75 Hz, 17 in., controlled by a Pentium IV computer) located at approximately 60 cm in front of the participant, who was seated at a chair. The start of a trial was signaled by an auditory warning stimulus (1000 Hz, 70 dB, for 400 ms) together with a white fixation point (0.48°  0.48°), which was displayed on a black background at the center of the monitor until the end of a trial. 1400 ms after trial onset the cue, a rhomb (3.62°  1.91°) consisting of a red and a green triangle, exchanged the fixation point for 400 ms. 1100 ms after cue onset, an intracutaneous electrical stimulus was presented at the fingertip of the left or right index finger, being either a single bipolar rectangular pulse of 0.2 ms, or a train of five bipolar pulses with an interpulse interval of 5 ms (see Van der Heide et al., 2009). The inter trial interval was set at 10.5 s. After electrode placement (see Section 2.5), the individual pain threshold (PT) for a single pulse stimulus was determined per finger by employing a visual analog scale (VAS). The values on this scale ranged from ‘‘0’’ (no perceived stimulus) to ‘‘9’’ (a very painful stimulus). A just perceivable sensation (the detection threshold: DT) corresponds with a score of ‘‘1’’, a score of ‘‘4.5’’ corresponds with the pain threshold (PT), and a score of ‘‘7’’ with a really annoying stimulus. Starting at 0.1 mA, the current was increased by 0.1 mA per step to set the DT. The current was subsequently increased until the PT was reached, and this procedure was repeated three times per finger before taking the average of the second and third repetition. The currents of the stimuli employed in the EEG experiment were set halfway the DT and the PT, which resulted in the use of an average of 1.2 (SD: 0.8) and 1.3 (0.7) mA for stimuli delivered at the left and right index fingers, respectively. These values appear highly comparable. A separate repeated measures analysis of variance (ANOVA) with the factors hand and the between-subjects factor group (see below) indeed revealed far from significant effects, F (1, 14) < 0.3, p > 0.62. The use of these amplitude settings implies that the perceived intensity of the single pulse stimulus lies below the pain threshold. The study by Van der Heide et al. (2009) with a

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comparable procedure showed that a train of five pulses with this same intensity likely results in a painful sensation.

for the employed stimuli were examined by using ANOVAs with the factors number of pulses (one or five), time (before or after the experiment), and group (low or high).

2.3. Task In total, 160 intracutaneous electrical stimuli (1 or 5 pulses) were presented, either to the left or to the right index finger. Participants had to attend to the hand indicated by the red (or green) side of the cue, which varied from trial to trial. Halfway the task, this color-dependent instruction was reversed, and participants had to attend to the hand at the green (or red) side. The order of the color instruction was counterbalanced. Participants were divided into a low and a high intensity group. In the low intensity group, single pulse stimuli were relevant, whereas five pulse stimuli were relevant for the high intensity group. Participants had to respond by pressing a foot pedal with their right foot when the relevant stimulus occurred on the tobe-attended side (the Go trials) but not in any of the other conditions (the Nogo trials). Emphasis was laid on response accuracy. Each stimulus combination (attended/unattended, one/five pulses, left/right) was equally likely, varied pseudo-randomly from trial to trial, and occurred on twenty trials. The intensities of the employed stimuli were individually judged for both hands before the start and after the end of the experiment by reporting a VAS score. 2.4. Apparatus The experiment was programmed and controlled with Labview (National Instruments, version 8). The intracutaneous electrical stimuli were delivered by gold electrodes with 1 mm diameter. A small opening was drilled in the upper layer of the skin of the fingertips of the index fingers by employing a dental gimlet with the same diameter as the tip of the stimulation electrode. Two rectangular surface electrodes (4  9 cm) were placed at the upper part of the left and right forearm as an anode, which were connected to prevent current leakage through the body midline. The stimuli were generated by a battery-driven computer-controlled constant current stimulator with two output channels (see Van der Heide et al., 2009). All bipolar pulses consisted of a 200 ls cathodic pulse, followed by a 800 ls anodic charge balancing pulse at 25% of the cathodic pulse amplitude. 2.5. Recordings The EEG and electrooculogram (EOG) were measured with Brain Vision Recorder (Version 1.03). Additionally, pedal presses and digital codes related to the various stimulus events were registered. EEG was acquired from 61 Ag/AgCl electrodes at locations according to the extended 10–20 system with a QuickAmp 72 amplifier (BrainProducts), which has a built-in average reference. Horizontal and vertical EOG were acquired with bipolar Ag/AgCl electrodes located on the outer canthi of the eyes and from above and below the left eye. Electrode resistance was kept below 5 kO. Signals were sampled at a rate of 500 Hz with an online notch filter at 50 Hz, and a high cutoff at 200 Hz.

2.6.2. EEG measures EEG data were analyzed with Brain Vision Analyzer (version 1.05). Eye movements (criteria: hEOG ± 80 lV, vEOG ± 120 lV) were marked. We examined the 100 to 800 ms interval relative to the onset of the intracutaneous electrical stimuli. A 100 to 0 ms baseline was set, and trials with eye movements (from 100 to 300 ms) and EEG artefacts were removed. Next, ocular correction was carried out. This procedure left on average 90.8% of the trials. ERPs were created per participant as a function of stimulation side, number of pulses, and attention. Appropriate time windows and electrodes for analyses on the different ERP components were determined after inspection of the grand means. The following time windows and electrodes were selected: N100: 90–110 ms on C5 and C6; N150: 140–160 ms on C5, C6, and FCz; P260: 240–280 ms on Cz and Pz; P500: 480– 520 ms on Cz and Pz. Obtained averages (across trials without eye movements and EEG artefacts) per individual for each time interval were subjected to ANOVAs with the factors electrode, stimulation side (left or right), number of pulses (one or five), attention (attended vs. unattended, and group (low or high intensity). The Greenhouse-Geisser e correction was applied to adjust the degrees of freedom whenever appropriate. In the case of complex interactions, further statistical tests were carried out to facilitate their interpretation. Source analyses were carried out on the ERPs produced by the intracutaneous stimuli by employing the BESA software package (version 5.1.6, MEGIS Software GmbH). A four-shell spherical head model was used and all EEG electrodes were included. Regional sources (Frishkoff et al., 2004) were determined for the average of the grand means across all stimulus conditions. The number of to be estimated sources was based on anatomical considerations in combination with the outcome of an earlier EEG source localization study on transcutaneous electrical stimuli (Thees et al., 2003). In the latter study, fMRI was measured to validate the source localization results. Thees et al. reported the contribution of sources in SI, SII, the insula, and a more anterior medial area (ACC and/or SMA) for activity in the interval from 20 to 270 ms. Given the rather small distance between SII and the insula, we decided to use only one source pair to account for their summed activities. In total, this amounts to five sources: two bilateral source pairs and a single source. Time windows for the fitting procedure were specified by examining the global field power (GFP: the sum of squares of activity over all EEG channels). An extension of a sequential fitting procedure was applied in which fitting was repeated until a stable solution was obtained (see Van der Lubbe et al., 2010). The solution was subsequently applied to the grand means as a function of attention, number of pulses, and stimulation side to estimate separate source waveforms per condition by computing the root-mean-square (RMS) across the three orthogonal vectors, which is thought to represent an equivalent of neural activity (see Frishkoff et al., 2004).

2.6. Data analysis 3. Results 2.6.1. Behavioral measures Although emphasis was laid on response accuracy, we determined average response speed on correct hit trials as well to have an indication of the moment of responding. The individual hit rate (P(H)) was determined by dividing the number of correct hits by the total number of Go trials. The false alarm rate (P(F)) was computed by dividing the number of false alarms by the total number of Nogo trials. VAS scores obtained before and after the experiment

3.1. Behavioral data The speed of pedal presses with the right foot on correct hit trials was relatively low with mean response times for left and right hand stimuli of 985 (SD: 348) and 934 (326) ms. This observation suggests that, in line with the instructions, participants laid emphasis on the accuracy of their responses, which may indicate

R.H.J. Van der Lubbe et al. / Clinical Neurophysiology 123 (2012) 947–959 Table 1 Visual analog scale (VAS) scores (standard errors within brackets) as a function of time (before and after the EEG experiment) hand, and number of pulses of the intracutaneous stimuli. Single pulse Before

Five pulses After

Before

After

Low intensity group Left 2.5 (0.3) Right 1.9 (0.3)

1.4 (0.4) 1.3 (0.3)

4.8 (0.4) 5.1 (0.5)

3.3 (0.4) 2.4 (0.5)

High intensity group Left 3.3 (0.3) Right 3.1 (0.3)

2.5 (0.4) 2.9 (0.3)

6.3 (0.4) 6.5 (0.5)

4.0 (0.3) 4.2 (0.3)

that the extent of motor inhibition on Nogo trials was limited. The hit rates for left and right hand stimuli of 95 (5) and 92 (8)%, and false-alarm rates for left and right stimuli of 4 (2)% and 5 (4)% additionally revealed that participants were well able to adapt to trial wise changes in the required locus of attention. No effect of the factor hand was observed. ANOVAs performed on VAS scores (see Table 1) indicated that five pulse stimuli were judged as more painful than single pulse stimuli (4.6 vs. 2.4) and that the perceived pain intensity decreased over time (4.2 before, and 2.7 after the experiment); F(1, 14) > 31.8, p < 0.001). This attenuation over time was more pronounced for five pulse (5.7–3.5) than for single pulse stimuli (2.7–2.0; number of pulses  time, F(1, 14) = 28.4, p < 0.001). The interaction between number of pulses, time, and hand, F(1, 14) = 4.6, p = 0.05, seems to reflect the stronger decrease over time for the five pulse stimulus delivered on the right hand. Finally, the high intensity group reported overall higher VAS scores than the low intensity group (4.1 vs. 2.8; F(1, 14) = 12.8, p = 0.003). It is tempting to interpret this effect as increased sensitivity for the group of participants for whom high intensity stimuli were made task relevant. Inspection of Table 1, however, shows that group differences were already present before the start of the experiment (group  time, group  time  number of pulses group; F(1, 14) < 0.7) suggesting that this effect is probably accidental. 3.2. EEG data Grand average ERPs and topographical maps (after application of a low cutoff filter set at 16 Hz 12 dB/oct for display purposes) as a function of number of pulses, stimulation side, and attention are displayed in Figs. 1–4. In Fig. 1, an early peak is present at approximately 20 ms after stimulus onset at FCz, which appears to be an artifact caused by our stimulation procedure. This interpretation was confirmed by our source analyses (see below, see also Van der Heide et al., 2009). Thereafter, a small positive peak is visible around 60 ms. This component was of low amplitude and not well circumscribed, probably due to the too low number of stimulus repetitions for this component. Therefore, we decided not to analyze this early component. Inspection of the topographical maps in Fig. 2a and b shows that the later N100 was maximal at the C6 and C5 electrode for left and right stimuli, respectively. Therefore, these electrodes were selected for display in Fig. 1 and for the statistical analyses. Regarding the N150, an additional maximum is visible at FCz in the case of five pulse stimuli (see Fig. 2a). The electrodes selected for display of the P260 and the P500 in Fig. 3 were based on inspection of the topographical maps concerning these components in Fig. 4. These electrodes were also selected for the statistical analyses. Inspection of Figs. 3 and 4 additionally shows that a distinction was made between the low intensity and the high intensity group, who had to detect the presence of either the single pulse or the five pulse stimuli on the to-be-attended side. This was done as our analyses on the P500 (see below) revealed strong interactions with the factor group.

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3.2.1. The N100 Analyses on the N100 with the factors electrode (C5/C6), attention, side of stimulation, number of pulses, and the between-subjects factor group showed main effects of attention (F (1, 14) = 17.4, p = 0.001) and number of pulses (F (1, 14) = 30.6, p < 0.001). Increased negativity was found for attended as compared to unattended stimuli ( 2.7 vs. 2.3 lV), and for five pulse as compared to single pulse stimuli ( 2.9 vs. 2.1 lV). An interaction between side of stimulation and electrode was found (F (1, 14) = 78.6, p < 0.001), and this effect additionally depended on number of pulses, (side  electrode  number of pulses: F(1, 14) = 40.9, p < 0.001). The latter effect may indicate that the effect of number of pulses was more pronounced at the electrode contralateral to the stimulated finger. In line with this idea, separate analyses for left stimuli revealed no effect of number of pulses at the ipsilateral C5 electrode, F(1, 14) = 0.3, but a clear effect of this factor at the contralateral C6 electrode, F (1, 14) = 47.9, p < 0.001. The same pattern of results was observed for right stimuli; no effect of number of pulses was present at the ipsilateral (now C6) electrode, F(1, 14) = 2.6, but an effect of this factor was present at the contralateral (now C5) electrode, F (1, 14) = 12.0, p = 0.003. The overall analysis on the N100 further revealed that the interaction between electrode and attention just failed to reach the level of significance, F(1, 14) = 4.4, p = 0.055. 3.2.2. The N150 Analyses performed on the N150 (including the C5, FCz, and C6 electrodes) revealed main effects of attention, F (1, 14) = 13.0, p = 0.003, and number of pulses (F(1, 14) = 38.2, p < 0.001), reflecting increased negativity for attended as compared to unattended stimuli ( 2.5 vs. 2.1 lV), and increased negativity for five pulse as compared to single pulse stimuli ( 3.1 vs. 1.6 lV). An interaction was observed between electrode and number of pulses, F(2, 28) = 7.6, e = 0.86, p = 0.006, which may indicate that the effect of number of pulses was more pronounced at FCz (see Fig. 1). Indeed, this effect appeared to be larger at FCz ( 0.1 vs. 2.8 lV) than at the C5 ( 2.3 vs. 3.4 lV) and the C6 ( 2.3 vs. 3.0 lV) electrodes, which was confirmed by separate statistical comparisons on the effect of number of pulses between these electrodes, F(1, 14) > 7.5, p < 0.016. Furthermore, an interaction was observed between electrode and side, F(2, 28) = 8.7, e = 1.0, p = 0.002, which seems to reflect the contralateral maximum of the N150. A separate analysis without inclusion of the FCz electrode revealed this same interaction, F (1, 14) = 14.2, p = 0.002. Separate analyses for left and right stimuli showed that amplitudes tended to be larger at the contralateral (C6) than at the ipsilateral electrode (C5) for left stimuli ( 3.7 vs. 2.2 lV; F(1, 14) = 4.5, p = 0.053), whereas a clear lateralization effect was observed for right stimuli ( 3.6 lV at C5 vs. 1.6 lV at C6; F(1, 14) = 9.8, p = 0.007). 3.2.3. The P260 Analyses on the P260 including the factors electrode (Cz, Pz), attention, side of stimulation, number of pulses, and the factor group revealed main effects of electrode, F(1, 14) = 24.6, p < 0.001, and number of pulses, F(1, 14) = 60.2, p < 0.001. These effects indicated that the P260 was larger at Cz than at Pz (10.5 vs. 5.6 lV), and larger for five pulse than for single pulse stimuli (10.0 vs. 5.6 lV; see Fig. 3). An interaction was observed between electrode and attention, F (1, 14) = 30.3, p < 0.001, which indicated that an enhancement for unattended as compared to attended stimuli was only present at Cz (11.5 vs. 9.5 lV; F(1, 14) = 6.4, p = 0.024), and not at Pz (5.3 vs. 6.0 lV; F(1, 14) = 1.5, p = 0.24). The interaction between electrode and number of pulses, F(1, 14) = 10.1, p = 0.007, indicated that the enlargement for five pulse as compared to single pulse stimuli was more pronounced at Cz (12.9 vs. 8.2 lV; F

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Fig. 1. Grand average ERPs are displayed, with time in milliseconds (ms) along the abscissa and amplitudes in microvolts (lV) along the ordinate. The N100 and N150 produced by intracutaneous electrical stimuli are most pronounced above lateral central (C5 and C6) and medial frontocentral (FCz) sites (see Fig. 2), which were selected for display. Time windows selected for statistical analyses for these components are indicated with dotted lines. The stimuli were presented to the index fingers of either the left or the right hand, and ERPs for these conditions are depicted in the left and right panel, respectively. The stimuli were presented either as single pulse or as five pulses, and were presented at either the attended or the unattended hand (attend vs. unattend), which varied from trial to trial.

(1, 14) = 57.2, p < 0.001) than at Pz (7.1 vs. 4.2 lV; F(1, 14) = 34.6, p < 0.001). 3.2.4. The P500 Analyses on the P500 with the same factors as the P260 revealed a main effect of attention, F(1, 14) = 16.2, p = 0.001, an interaction between attention and electrode, F (1, 14) = 12.8, p = 0.003, and an interaction between number of pulses and electrode, F(1, 14) = 4.8, p = 0.046. The latter interactions indicate (see below) that the attention effect was only present at Cz, whereas the effect of number of pulses was only present at Pz (see Fig. 3). Several higher-order interactions were observed including the factors electrode and group, F (1, 14) > 28.7, p < 0.001. To clarify these effects, we performed separate analyses for the Cz and the Pz electrodes. Regarding the Cz electrode, a main effect of attention, an interaction between number of pulses and group, and an interaction between attention, number of pulses and group was found, F(1, 14) > 30.3, p < 0.003, but no main effect of number of pulses was observed, F < 0.3. The interaction between attention, number of pulses and group appears to reflect a Go/Nogo difference; for the low intensity group, a reduced central P500

is present for attended single pulse stimuli (see upper left panel Fig. 3), whereas for the high intensity group, a reduced central P500 is present for attended five pulse stimuli (see upper right panel Fig. 3). Separate analyses for the high intensity group displayed a significant interaction between attention and number of pulses, F(1, 7) = 18.7, p = 0.003, which confirmed a reduction of the P500 for attended vs. unattended five pulse stimuli, F (1, 7) = 24.5, p = 0.002, and no significant effect of attention for single pulse stimuli. Separate analyses for the low intensity group displayed an interaction between attention and number of pulses as well, F(1, 7) = 12.0, p = 0.01. For those participants, an attention effect was found for single pulse stimuli, F (1, 7) = 13.3, p = 0.008, whereas no attention effect was observed for five pulse stimuli. Regarding the Pz electrode, a main effect of number of pulses, F (1, 14) = 20.0, p = 0.001, and a just insignificant interaction between number of pulses and group was observed, F(1, 14) = 4.5, p = 0.051. The parietal P500 was larger for five pulse than for single pulse stimuli (7.8 vs. 5.9 lV), but this effect was only significant for the high intensity group (9.3 vs. 6.5 lV; F(1, 7) = 22.6, p = 0.002) and not for the low intensity group (6.3 vs. 5.3 lV; F(1, 7) = 2.6).

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Fig. 2. Topview of isopotential maps of the grand averages for the N100 (from 90 to 110 ms after stimulus onset) and N150 components (from 140 to 160 ms) as a function of stimulated index finger (left or right) and attention (attend or unattend). In the upper panel (a) the topographic maps for the five pulses stimuli are displayed and in the lower panel (b) the topographic maps for the single pulse stimuli are displayed. The maps were created by using interpolation by spherical splines (4th order, maximal degree of legendre potentials 10, default lambda 1e 5).

3.3. Source analyses Source analyses were carried out on activity from 40 to 250 ms after stimulus onset, just before the P260 reached its maximum.3 Inspection of the GFP (not displayed) of the overall average (including low and high intensity, left and right, and attended and unattended stimuli) revealed four peaks. A first peak rose directly from stimulus onset until a maximum at 18 ms, which seems to reflect a stimulus artifact due to electrical stimulation. A source analysis indicated that this activity probably does not arise from somatosensory areas but from the forehead. As we wanted to avoid any interference from this artefact, this interval was excluded from our final source modeling. A 3 An attempt to include the later P500 resulted in unstable solutions; therefore, we restricted the final source analyses to the 40–250 ms interval.

second peak started to rise from about 40 ms and reached a maximum at 100 ms, which accounts for the activity until the peak of the N100. A subsequent intermediate peak was identified that started shortly after the N100 and became maximal at 130 ms. A fourth peak started from about 130 ms and reached a maximum at 250 ms, which accounts for the downward flank of the N150 and the rise of the P260. The latter three time intervals (40–100 ms, 100–130 ms, and 130– 250 ms) were selected for the source localization analyses with two symmetrical sources for the first and the second interval and a single source for the final time interval. This procedure resulted in a residual variance for the overall averages for the 40–250 ms interval of 1.3%. The resulting source configuration is displayed in Fig. 5. MNI coordinates of the sources were determined on the ground of affine transformations performed within Matlab. The first source pair ( 38 21 81) roughly corresponds with SI in the left and right

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Fig. 3. Grand average ERPs for the low intensity (left panel) and the high intensity (right panel) group are displayed, with each average being based on eight participants. The P260 and P500 produced by the intracutaneous stimuli were largest above Cz and Pz (see Fig. 6), which were selected for display. Time windows selected for statistical analyses are indicated with dotted lines. For each group, ERPs are displayed as a function of number of pulses (single pulse vs. five pulses) and attention (attend vs. unattend).

hemisphere, the second source pair ( 60 14 17) probably reflects the combined activity from SII and the insula. The fifth source (11 4 51) seems to account for activity from the ACC and/or the SMA. These sources (see Fig. 5) can very well account for the observed ERPs within the 40–250 ms interval, and therefore facilitate our understanding of effects on the ERP components in this time window. Inspection of the source activities over time (the source waveforms, see Fig. 6) indicates that the aforementioned attentional effect on the N100 probably concerns modulation within SII, whereas the effect of number of pulses seems present within SI and SII. Furthermore, the effects of attention and number of pulses on the N150 and especially the P260 seem to involve the ACC. Most interesting is the development of effects of attention and the number of pulses over time. Initially, attended and five pulse stimuli seem to induce increased activity in somatosensory areas (N100) as compared to unattended and single pulse stimuli. Thereafter, an effect of number of pulses remains for activity that appears to be related to the ACC (N150). Finally, attention and number of pulses result in opposite effects (P260), with enlarged activity for the five pulse as compared to the single pulse stimuli, and enlarged activity for unattended as compared to attended stimuli, which can also be traced back to the ACC.

4. Discussion Several studies examined the influence of sustained attention with transcutaneous electrical stimuli with different stimulus intensities. These studies revealed somewhat mixed results, showing either attentional effects on very early (P30/40), early (N80), intermediate (N140), or even late (P2) SEP components (e.g., see Desmedt and Tomberg, 1989; Dowman, 2001, 2004; Garcia-Larrea et al., 1995; Michie et al., 1987). In the current study, the primary aim was to asses the influence of a transient rather than a sustained manipulation of spatial attention on ERP components elicited by intracutaneous rather than transcutaneous electrical stimuli, and to consider our results within a broader perspective encompassing attentional effects on SEPs and LEPs. A task variant was chosen in which unattended stimuli were never relevant, which might provide information on attentional capture of our stimuli. The perceived intensity of our intracutaneous stimuli was manipulated by varying the number of pulses, which additionally enables the possibility to asses whether observed attentional effects are in some way comparable to a change in signal strength. To facilitate the interpretation of observed effects on specific ERP components, we performed

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Fig. 4. Topview of isopotential maps determined for the P260 and P500 for the grand averages of the low intensity and the high intensity groups are displayed in the left and right panel, respectively. Maps are displayed as a function of attention (attend vs. unattend) and as a function of number of pulses (five pulses vs. single pulse) in the upper and lower panel, respectively.

source analyses and estimated neural activity of the identified sources over time. Our behavioral data indicate that participants were well able to attend to the cued side and discriminate between the single and five pulse stimuli, as high hit rates and low false-alarm rates were observed. Furthermore, analyses on our VAS scores confirmed that the perceived pain intensity for the intracutaneous electrical stimuli was higher for five pulse stimuli than for single pulse stimuli. The values reported before the start of the EEG experiment indicate that the five pulse stimuli can be considered as painful, although the perceived intensity decreased over time, which corre-

sponds with earlier observations (e.g., see LeBlanc and Potvin, 1966). Together, these data indicate that the manipulation of attention was effective, and additionally that varying the number of pulses resulted in differences in perceived pain intensity. In the following, we will consider the effects on ERP components in their order of appearance after presenting the intracutaneous stimuli. Inspection of Fig. 1 shows a very early positive peak around 20 ms at FCz, which seems to reflect an artefact due to our stimulation procedure (see Van der Heide et al., 2009). This impression was confirmed by a source analysis on this peak, which did not

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Fig. 5. Activity from 40 to 250 ms after stimulus onset was attributed to sources that were localized in contralateral (contra) and ipsilateral (ipsi) somatosensory areas (SI and SII/insula) and the ACC/SMA. The locations of the sources largely accord with the estimations reported in the combined EEG-fMRI study by Thees et al. (2003).

point to a cortical origin. Slightly later, around 60 ms, we see a small positive peak at the C5 or C6 electrode contralateral to the stimulated hand. It seems likely, given the results of previous studies (e.g., Van der Heide et al., 2009) that this P60 reflects the arrival at a cortical level of intracutaneous stimulation due to processing along Aß fibers. This component may very well be the same as the slightly earlier component observed by Desmedt and Tomberg (1989). In comparison with the subsequent components, the P60 was of small magnitude and could not well be distinguished in individual participants (probably due to the relatively low number of stimulus repetitions). Therefore, no statistical analysis was carried out. Inspection of our source waveforms (see Fig. 6), however, suggests that activity around this moment in time arises from SI and SII/insula, which accords with the interpretation of Desmedt and Tomberg (1989) and the results of the combined EEG-fMRI study of Thees et al. (2003). More conspicuous than the previous peaks is the N100, being maximal at the C5/6 electrode contralateral to the side of stimulation (see Figs. 1 and 2). This component was enhanced for attended as compared to unattended stimuli, and also enlarged for five pulse stimuli as compared to a single pulse stimulus. This attentional modulation seems not fully in line with the results of sustained attention studies with transcutaneous electrical stimulation as in most of these studies (e.g., see Garcia-Larrea et al., 1995; but see Michie et al., 1987) effects occurred later. The results do correspond with the influence of sustained attention on tactile stimuli but not with the influence of transient attention, which was only present for the later N140 (Eimer and Forster, 2003). However, this effect seems in line with the sustained attention effect on laser stimuli reported by Legrain et al. (2002), although the N1 component in that study peaked about 60 ms later than our N100, which may be attributed to the slower conduction times along Ad fibers. Together, it appears that in our study, transient spatial attention affected the processing of intracutaneous stimuli at an earlier moment in time than might have been expected on the basis of the transient-sustained spatial attention comparison of Eimer and Forster (2003). This observation obviously motivates further research on the influence of transient as compared to sustained attentional manipulations with painful stimuli. The effect of number of pulses was most pronounced at the electrode contralateral to the side of stimulation whereas the attentional effect appeared more diffuse. This pattern of results might indicate that the attentional modulation concerns a more global phenomenon, for example by affecting other areas (e.g., visual, multimodal) as well. Thus, the influence of spatial attention cannot be equated with a change in signal strength. Our source analyses additionally suggest that neural activity within this time window largely arises from sources in SI and SII/insula (in line with Thees et al., 2003). Inspection of our source waveforms further suggests that the effect of number

of pulses is manifested in SI and SII/insula whereas the attentional effect seems present in SII/insula, but not in SI. Thus, although attentional and stimulus intensity effects may be present on the same ERP component they appear to originate from different brain areas. Slightly later, another negative component, the N150, was observed, which again peaks at the C5/6 electrode contralateral to the stimulated hand (see Figs. 1 and 2). Although the analyses for the greater part confirmed the presence of a contralateral maximum, activity now seems present above both contralateral and ipsilateral sites (see Fig. 2), probably due to interhemispheric transfer of stimulus-evoked activity along the corpus callosum. Furthermore, in the case of five pulse stimuli, an additional peak is present above frontocentral areas, which may point to the extra involvement of anterior areas. Our N150 seems equivalent to the N140 observed by Garcia-Larrea et al. (1995), Michie et al. (1987), Dowman (2001, 2004), Yamasaki et al. (2000), Eimer and Forster (2003), and others, and might even be similar to the N2 LEP component around 230 ms observed by Legrain et al. (2002). In line with the majority of these studies, we observed an attentional enhancement of this component. If we incorporate the results of our source analyses then it may additionally be suggested that neural activity at this moment in time largely arises from SII/insula, but also from ACC/SMA (in line with Thees et al., 2003). Furthermore, it may be suggested that the attentional modulation on the N150 largely concerns SII/insula whereas more intense stimuli especially boost activity in ACC/SMA. Thus, again, the influence of spatial attention seems to deviate from a change in signal strength. Furthermore, regarding the intensity effect, it may be argued that the more anterior effect is due to the triggering of ACC/SMA by the five pulse stimuli, which might be a first step in ‘‘a call for attention’’. The next and most conspicuous ERP component in our data is the P260 (according to our view most likely an early P3a, but see footnote 2), which peaked between 240 to 280 ms, and was maximal at Cz (see Figs. 3 and 4). Interestingly, the P260 at Cz was enlarged for unattended as compared to attended stimuli. This result deviates from the results with transcutaneous stimulation reported by Dowman (2004), and also from the results with laser stimuli of Legrain et al. (2002, 2003). At the same time, the P260 was much larger for five pulse stimuli than for a single pulse stimulus. Source analyses (see Fig. 6, notice the scale difference at the bottom) suggest that activity within this time window mainly arises from ACC/SMA. Given the estimated enhanced activity of ACC for unattended stimuli and its presumed role in attentional orienting it may be suggested that unattended stimuli in our paradigm induce a ‘‘call for attention’’. Furthermore, in our experiment this effect appears to be independent from the perceived intensity, which contrasts with the LEP results from Legrain et al.

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t(ms) SINGLE PULSE FIVE PULSES ATTEND UNATTEND Fig. 6. Estimated neural activity averaged across all participants as a function of attention and number of pulses evoked by intracutaneous electrical stimuli, averaged across hands. Activity was attributed to sources that were localized in contralateral (contra) and ipsilateral (ipsi) somatosensory areas (SI and SII/ the insula) and the ACC (see Fig. 5). Notice that the scaling of the activity attributed to ACC/SMA has been adapted to include the high activity of ACC starting around 120 ms after stimulus onset. The time course of activation of the distinguished sources resembles the result reported in the combined EEG-fMRI study by Thees et al. (2003).

(2003). Several explanations may account for this discrepancy, as there are multiple differences between this study and ours, like the employed stimuli, the attentional manipulation, and the context in which stimuli are presented. In line with the previous attentional suggestion, recent review papers on nociception (Iannetti and Mouraux, 2010; Legrain et al., 2011) argue that the activity arising from ACC indeed does not reflect the affective aspect of pain perception or another property specific to nociceptive stimuli but rather a reaction to stimulus saliency; the extent to which a stimulus contrasts with its surrounding input and draws attention.

Thus, although we cannot fully exclude the possibility that the observed effect of number of pulses on the P260 in our study reflects a pure stimulus intensity effect (this applies as well to the N150), it seems more likely to reflect differences in the attentional properties of the employed stimuli. The final ERP component to be considered is the P500. The P500 had a more posterior focus than the P260, and seems most likely the equivalent of the P3b component. The posterior focus is most clearly visible in the conditions in which the relevant target appeared at the attended side (see Figs. 3 and 4). In contrast with

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the previous components the analyses revealed strong dependencies on action relevance of the stimuli, which was varied between groups. A strong reduction of the central P500 was observed when a stimulus required a deliberate foot pedal press, independent of the number of pulses of that stimulus. This observation corresponds with P3b findings from several studies employing visual and auditory stimuli, signifying again that this effect is unlikely to be specific for electrical or nociceptive stimuli (e.g., see Smith et al., 2008; Verleger et al., 2006). This reduction of the P500 may be due to the overlap of anterior motor-related negativity on Go trials, or response inhibition on Nogo trials (see Bruin and Wijers, 2002; Bekker et al., 2004; Pfefferbaum et al., 1985) or a combination of these processes. However, the need for motor inhibition in our study seems not very high as no speeded responses were to be made; therefore, we tend to favor an interpretation in terms of increased motor activity on Go trials. Thus, the final effect on the P500 seems related to the preparation of an action rather than being due to attention-related properties of the employed stimuli. In conclusion, a transient manipulation of spatial attention and an increase in the number of pulses both resulted in enhanced N100 and N150 components elicited by intracutaneous stimuli. On the ground of our source analyses, it may be argued that the attentional modulation concerns increased processing within SII and/or the insula, whereas the effect of number of pulses already involves SI. Furthermore, the attentional modulation was less well circumscribed than the effect of number of pulses, suggesting that the attentional effect cannot simply be conceived of as a change in signal strength. The influence of spatial attention on the P260 was unexpected, as this component was enlarged for unattended relative to attended stimuli, which may be interpreted as ‘‘a call for attention’’ by initially unattended intracutaneous stimuli. The source analyses suggest that the latter effect is possibly due to involvement of ACC. Finally, the effect on the P3b component seems due to action relevance, and seems not specifically related to the use of intracutaneous stimuli. Acknowledgement This work was supported by the Institute of Behavioral Research (IBR) at the University of Twente, the Netherlands. References Bekker EM, Kenemans JL, Verbaten MN. Electrophysiological correlates of attention, inhibition, sensitivity and bias in a continuous performance task. Clin Neurophysiol 2004;115:2001–13. Bentley DE, Youell PD, Jones AKP. Anatomical localization and intra-subject reproducibility of laser evoked potential source in cingulate cortex, using a realistic head model. Clin Neurophysiol 2002;113:1351–6. Bromm B. Neurophysiological correlates of pain. In: Bromm B, editor. Pain measurement in man. Amsterdam: Elsevier; 1984. p. 3–13. Bromm B, Meier W. The intracutaneous stimulus: a new pain model for algesimetric studies. Methods Find Exp Clin Pharmacol 1984;6:405–10. Bruin KJ, Wijers AA. Inhibition, response mode, and stimulus probability: a comparative event-related potential study. Clin Neurophysiol 2002;113:1172–82. Chapman CR, Oka S, Bradshaw DH, Jacobson RC, Donaldson GW. Phasic pupil dilatation response to noxious stimulation in normal volunteers: relationship to brain evoked potentials and pain report. Psychophysiology 1999;36:44–52. Crottaz-Herbette S, Menon V. Where and when the anterior cingulate cortex modulates attentional response: combined fMRI and ERP evidence. J Cogn Neurosci 2006;18:766–80. Desmedt JE, Robertson D. Differential enhancement of early and late components of the cerebral somatosensory evoked potentials during forced-paced cognitive tasks in man. J Physiol 1977;271:761–82. Desmedt JE, Tomberg C. Mapping early somatosensory evoked potentials in selective attention: critical evaluation of control conditions used for titrating by difference the cognitive P30, P40, P100 and N140. Electroencephalogr Clin Neurophysiol 1989;74:321–46. Dowman R. Attentional set effects on spinal and supraspinal responses to pain. Psychophysiology 2001;38:451–64.

Dowman R. Distraction produces an increase in pain-evoked anterior cingulated activity. Psychophysiology 2004a;41:613–24. Dowman R. The pain-evoked P2 is not a P3a event-related potential. Brain Topogr 2004b;17:3–12. Eccleston C, Crombez G. Pain demands attention: a cognitive-affective model of the interruptive function of pain. Psychol Bull 1999;125:356–66. Eimer M, Driver J. An event-related brain potential study of cross-modal links in spatial attention between vision and touch. Psychophysiology 2000;37:697–705. Eimer M, Forster B. Modulations of early somatosensory ERP components by transient and sustained spatial attention. Exp Brain Res 2003;151:24–31. Escera C, Alho K, Schröger E, Winkler I. Involuntary attention and distractibility as evaluated with event-related brain potentials. Audiol Neurootol 2000;5:151–66. Forster B, Eimer M. Covert attention in touch: behavioral and ERP evidence for costs and benefits. Psychophysiology 2005;42:171–9. Forster B, Sambo CF, Pavone EF. ERP correlates of tactile spatial attention differ under intra- and intermodal conditions. Biol Psychol 2009;82:227–33. Frishkoff GA, Tucker DM, Davey C, Scherg M. Frontal and posterior sources of event-related potentials in semantic comprehension. Cogn Brain Res 2004;20: 329–54. Garcia-Larrea L, Lukaszewicz AC, Mauguière F. Somatosensory responses during selective spatial attention: the N120-to-N140 transition. Psychophysiology 1995;32:526–37. Garcia-Larrea L, Frot M, Valeriani M. Brain generators of laser-evoked potentials: from dipoles to functional significance. Clin Neurophysiol 2003;33:279–92. Hauck M, Lorenz J, Engel AK. Attention to painful stimulation enhances c-band activity and synchronization in human sensorimotor cortex. J Neurosci 2007;27:9270–7. Iannetti GD, Mouraux A. From the neuromatrix to the pain matrix (and back). Exp Brain Res 2010;205:1–12. Inui K, Tran TD, Hoshiyama M, Kakigi R. Preferential stimulation of Ad fibers by intra-epidermal needle electrode in humans. Pain 2002;96:247–52. Kakigi R, Inui K, Tamura Y. Electrophysiological studies on human pain perception. Clin Neurophysiol 2005;116:743–63. LeBlanc J, Potvin P. Studies on habituation to cold pain. Can J Physiol Pharmacol 1966;44:287–93. Legrain V, Guérit JM, Bruyer R, Plaghki L. Attentional modulation of the nociceptive processing into the human brain: selective spatial attention, probability of stimulus occurrence, and target detection effects on laser evoked potentials. Pain 2002;99:21–39. Legrain V, Guérit JM, Bruyer R, Plaghki L. Electrophysiological correlates of attentional orientation in humans to strong intensity deviant nociceptive stimuli, inside and outside the focus of spatial attention. Neurosci Lett 2003;339:107–10. Legrain V, Bruyer R, Guérit J-M, Plaghki L. Involuntary orientation of attention to unattended deviant nociceptive stimuli is modulated by concomitant visual task difficulty. Evidence from laser evoked potentials. Clin Neurophysiol 2005;116:2165–74. Legrain V, Perchet C, Garcia-Larrea L. Involuntary orienting of attention to nociceptive events: neural and behavioral signatures. J Neurophysiol 2009;102:2423–34. Legrain V, Iannetti GD, Plaghki L, Mouraux A. The pain matrix reloaded: a salience detection system for the body. Prog Neurobiol 2011;93:111–4. Lorenz J, Garcia-Larrea L. Contribution of attentional and cognitive factors to laser evoked brain potentials. Clin Neurophysiol 2003;33:293–301. Michie PT, Bearpark HM, Crawford JM, Glue LCT. The effects of spatial selective attention on the somatosensory event-related potential. Psychophysiology 1987;24:449–63. Miltner W, Johnson Jr R, Braun C, Larbig W. Somatosensory event-related potentials to painful and non-painful stimuli: effects of attention. Pain 1989;38:303–12. Moran J, Desimone R. Selective attention gates visual processing in the extrastriate cortex. Science 1985;229:782–4. Mouraux A, Plaghki L. Cortical interactions and integration of nociceptive and non-nociceptive somatosensory inputs in humans. Neuroscience 2007;150: 72–81. Mouraux A, Iannetti GD. Nociceptive laser-evoked brain potentials do not reflect nociceptive-specific neural activity. J Neurophysiol 2009;101:3258–69. Mouraux A, Iannetti GD, Plaghki L. Low intensity intra-epidermal electrical stimulation can activate Ad-nociceptors selectively. Pain 2010;150:199–207. Nieuwenhuis S, DeGeus EJ, Aston-Jones G. The anatomical and functional relationship between the P3 and autonomic components of the orienting response. Psychophysiology 2010;3:4. Pfefferbaum A, Ford JM, Weller BJ, Kopell BS. ERPs to response production and inhibition. Electroencephalogr Clin Neurophysiol 1985;60:423–34. Plaghki L, Mouraux A. How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation. Clin Neurophysiol 2003;33:269–77. Polich J. Updating P300: an integrative theory of P3a and P3b. Clin Neurophysiol 2007;118:2128–48. Posner MI. Chronometric explorations of mind. New York: Laurence Erlbaum Associates; 1978. Posner MI, Snyder CRR, Davidson BJ. Attention and the detection of signals. J Exp Psychol Gen 1980;109:160–74. Reinert A, Treede RD, Bromm B. The pain inhibiting pain effect: an electrophysiological study in humans. Brain Res 2000;862:103–10.

R.H.J. Van der Lubbe et al. / Clinical Neurophysiology 123 (2012) 947–959 Sherrington C. The integrative action of the nervous system. Oxford: Oxford University Press; 1906. Smith JL, Johnstone SJ, Barry RJ. Movement-related potentials in the Go/NoGo task: the P3 reflects both cognitive and motor inhibition. Clin Neurophysiol 2008;119:704–14. Thees S, Blankenburg F, Taskin B, Curio G, Villringer A. Dipole source localization and fMRI of simultaneously recorded data applied to somatosensory categorization. NeuroImage 2003;18:707–19. Valeriani M, Restuccia D, Barba C, Le Pera D, Tonali P, Mauguiere F. Sources of cortical responses to painful CO2 laser skin stimulation of the hand and foot in the human brain. Clin Neurophysiol 2000;111:1103–12. Van der Heide EM, Buitenweg JR, Marani E, Rutten WLC. Single pulse and pulse train modulation of cutaneous electrical stimulation: a comparison of methods. J Clin Neurophysiol 2009;26:54–60. Van der Lubbe RHJ, Neggers SFW, Verleger R, Kenemans JL. Spatiotemporal overlap between brain activation related to saccade preparation and attentional orienting. Brain Res 2006;1072:133–52.

959

Van der Lubbe RHJ, Van Mierlo CM, Postma A. The involvement of occipital cortex in the early blind in auditory and tactile duration discrimination tasks. J Cogn Neurosci 2010;22:1541–56. Verleger R, Paehge T, Kolev V, Yordanova J, Jas´kowski P. On the relation of movement-related potentials to the go/no-go effect on P3. Biol Psychol 2006;73:298–313. Warbrick T, Sheffield D, Nouwen A. Effects of pain-related anxiety on components of the pain event-related potential. Psychophysiol 2006;43:481–5. Yamasaki H, Kakigi R, Watanabe S, Hoshiyama M. Effects of distraction on painrelated somatosensory evoked magnetic fields and potentials following painful electrical stimulation. Cogn Brain Res 2000;9:165–75. Zopf R, Giabbiconi CM, Gruber T, Müller MM. Attentional modulation of the human somatosensory evoked potential in a trial-by-trial cueing and sustained spatial attention task measured with high density 128 channels EEG. Cogn Brain Res 2004;20:491–509.