Cogn Affect Behav Neurosci DOI 10.3758/s13415-013-0233-z

Neural mechanisms underlying pain’s ability to reorient attention: Evidence for sensitization of somatic threat detectors Robert Dowman

# Psychonomic Society, Inc. 2013

Abstract Pain typically signals damage to the body, and as such can be perceived as threatening and can elicit a strong emotional response. This ecological significance undoubtedly underlies pain’s well-known ability to demand attention. However, the neural mechanisms underlying this ability are poorly understood. Previous work from the author’s laboratory has reported behavioral evidence suggesting that participants disengage their attention from an incorrectly cued visual target stimulus and reorient it toward a somatic target more rapidly when the somatic target is painful than when it is nonpainful. Furthermore, electrophysiological data suggest that this effect is mediated by a stimulus-driven process, in which somatic threat detectors located in the dorsal posterior insula activate the medial and lateral prefrontal cortex areas involved in reorienting attention toward the painful target. In these previous studies, the painful and nonpainful somatic targets were given in separate experiments involving different participants. Here, the nonpainful and painful somatic targets were presented in random order within the same block of trials. Unlike in the previous studies, both the nonpainful and painful somatic targets activated the somatic threat detectors, and the times taken to disengage and reorient attention were the same for both. These electrophysiological and behavioral data suggest that somatic threat detectors can become sensitized to nonpainful somatic stimuli that are presented in a context that includes painful stimuli. Keywords Pain . Attention . Orienting . Threat

Introduction Pain often signals damage to the body (Millan, 1999; Price, Greenspan, & Dubner, 2003; Wall, 1994), and under some R. Dowman (*) Department of Psychology, Clarkson University, 8 Clarkson Ave, Potsdam, NY 13699-5825, USA e-mail: [email protected]

circumstances can be perceived as threatening and elicit a strong emotional response (Auvray, Myin, & Spence, 2010; Eccleston & Crombez, 1999; Vlaeyen & Linton, 2000). These properties are undoubtedly related to pain’s well-known ability to disengage attention from other ongoing cognitive processes and reorient it toward the damage (Eccleston & Crombez, 1999; Norman & Shallice, 1986). Yet, despite pain’s ecological significance, the neural mechanisms underlying this important cognitive process are poorly understood (Legrain, Iannetti, Plaghki, & Mouraux, 2011; Van Damme, Legrain, Vogt, & Crombez, 2010). Evidence for a stimulus-driven somatic threat detection and reorienting process We have investigated the neural mechanism underlying pain’s ability to disengage and reorient attention using a cross-modal endogenous-cuing paradigm (Dowman, 2007a, b; Dowman & ben-Avraham, 2008). In these studies, a visual task and a somatosensory task were given in random order with equal probabilities in the same block of trials. Two target stimuli were given in each task. For the visual task, participants indicated whether a red or a yellow lightemitting diode (LED) was lit. The target stimuli for the somatosensory task were two perceptually distinct levels of sural nerve electrical stimulation. In one study, both of the sural nerve targets were painful (Dowman, 2007a), and in the other, both were nonpainful (Dowman, 2007b). In the study involving painful sural nerve stimuli, the participants rated the intensity of the target. In the study involving nonpainful sural nerve stimuli, the participants performed an intensity discrimination task, in which they indicated whether the low- or the high-intensity stimulus was presented. A symbolic cue given at the beginning of each trial signaled which task was forthcoming. The interval between the cue offset and target onset was 1.5 s to ensure that any

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involuntary (exogenous) attention effects elicited by the cue had expired and that the participant had ample time to voluntarily direct attention to the cued target (see Van Damme, Crombez, Eccleston, & Goubert, 2004). The cue correctly signaled the upcoming target modality on 75 % of the trials (validly cued). The target modality was invalidly cued on the remaining 25 % of the trials. Note that the invalidly cued condition required participants to disengage attention from the cued target modality and reorient it toward the target stimulus. The visual targets were presented very near the location of the somatic targets; hence, the shifts in attention were largely between sensory modalities, with little change in spatial location. The amplitudes of three components of the painful sural nerve event-related potential (ERP) were unexpectedly larger in the invalidly cued than in the validly cued condition. It is unlikely that this result reflected the effects of attention on perceptual processes, given that the pain ratings were lower in the invalidly cued than in the validly cued condition (Dowman, 2007a; see also Dowman, 2001, 2004b). Rather, these results present the possibility that these three ERP components index the disengagement and reorienting of attention toward the painful target. The earliest of these components is a bilateral negative potential recorded from the fronto-temporal scalp at about 150 ms poststimulus, at which time the negativity is larger on the side contralateral to the evoking stimulus (referred to here as the contralateral temporal negativity, or CTN). The second component is a negative potential located at the frontocentral scalp (FCN) that overlaps temporally with the CTN, and the third is the P3a component. Interestingly, the increases in CTN and FCN amplitudes in the invalidly cued condition, in which the painful sural nerve evoking stimulus was unattended, was also seen in a study involving a distraction task (Dowman, 2004a). In that study, both the CTN and FCN amplitudes were larger when the participants were engaged in a mental arithmetic task and were instructed to ignore the painful sural nerve evoking stimulus than when they were attending to it. The amplitude of the late positive potential, which includes the P1, P2, and P3a components (see Dowman, 2004c, 2007a, b), was smaller in the distraction than in the attend condition. Hence, the increase in the amplitude of the P3a evoked by an unattended painful sural nerve evoking stimulus appears to depend on the task relevance of the stimulus, whereas the increase in the CTN and FCN amplitudes does not. The increase in the CTN and FCN component amplitudes evoked by an unattended painful sural nerve stimulus contrasts sharply with the decrease in the amplitude of comparable midlatency negative components evoked by other types of painful stimuli, such as the N1 and N2 peaks evoked by painful laser (see Lorenz & Garcia-Larrea, 2003, for review) and by intra- and transcutaneous electrical

stimuli (e.g., Blom, Wiering, & Van der Lubbe, 2012; Yamasaki, Kakigi, Watanabe, & Hoshiyama, 2000). This discrepancy is likely due to the sural nerve evoking stimulus being much better at eliciting an involuntary orienting response than these other stimuli. Indeed, many of the properties of the sural nerve electrical stimulus are ideal for eliciting an orienting response (see Eccleston & Crombez, 1999; Friedman, Cycowicz, & Gaeta, 2001; Näätänen, 1992; Yantis & Jonides, 1990): It is intense (the pain threshold level elicits near-maximal activation of the innocuous Aβ tactile afferents; Dowman, 1993), has an abrupt onset, and produces an unfamiliar (novel) paresthesia/prickling pain sensation. These properties contrast with the lower subjective intensity and familiar sensations produced by the painful laser stimulus, at least at the levels used in most laser ERP studies of attention (Dowman, 2004d). Similarly, intra- and transcutaneous electrical evoking stimuli activate smaller numbers of afferent endings in the skin than does the sural nerve electrical stimulus, resulting in a less intense sensation. (See Dowman, 2004d, for a more detailed comparison of the sural-nerve-evoked and laser-evoked midlatency negative components.) These characteristics, especially intensity and novelty, are critical in the ability of a task-irrelevant painful stimulus to disengage and reorient attention away from (i.e., interrupt) another ongoing task: Pain that is strong and novel, has an abrupt onset, is perceived as being threatening, and/or is unexpected is particularly effective at interfering with the task, whereas pain lacking these qualities seldom results in interference (Crombez, Eccleston, Baeyens, & Eelen, 1998; Eccleston & Crombez, 1999; Vancleef & Peters, 2006; Van Damme, Crombez, Van Nieuwenborgh-De Wever, & Goubert, 2008). It may be the case, therefore, that the unusual effect of attention on the CTN and FCN amplitudes is due to the sural nerve evoking stimulus being more effective at activating the neural mechanism responsible for disengaging and reorienting attention than these other types of painful stimuli. The response properties of the CTN generators are also consistent with this idea. Previous dipole source localization and intracranial recording studies have provided strong evidence that the CTN is generated in part by temporally overlapping activity in the second somatosensory cortex and the adjacent dorsal posterior insula (Dowman & Darcey, 1994; Dowman, Darcey, Barkan, Thadani, & Roberts, 2007). In addition to being activated by noxious stimuli, neurons in the dorsal posterior insula respond to stimuli that are associated with threats to the body, such as air hunger and deviations of body temperature away from homeostasis (Craig, 2002, 2003). These response properties are consistent with the idea that the dorsal posterior insula is involved either directly or indirectly in a somatic threat detection process (Dowman & ben-Avraham, 2008). Indeed, in earlier studies, CTN

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amplitudes were reported as being larger in the invalidly cued than in the validly cued condition when both of the sural nerve targets were painful (Dowman, 2007a), but not when both were nonpainful (Dowman, 2007b). The cue validity effects for the FCN and P3a, on the other hand, were observed for both the nonpainful (Dowman, 2007b) and painful (Dowman, 2007a) sural nerve targets. This result suggests that the FCN and P3a play a more general role in attentional control. The response properties of the FCN and P3a generators are also consistent with this idea. A rather large body of evidence has shown that the P3a recorded from the anterior scalp indexes prefrontal cortical activity involved in orienting attention toward any unexpected, infrequent stimulus (see Friedman et al., 2001; Knight, 1996; and Polich, 2003, for reviews). Previous dipole source localization and intracranial recording studies from this lab have suggested that the FCN is generated in part by the medial prefrontal cortex, including the dorsal anterior cingulate cortex and the overlying presupplementary motor area (Dowman, 2001, 2004b; Dowman & Darcey, 1994; Dowman et al., 2007; Dowman, Glebus, & Shinners, 2006). One of the roles of the medial prefrontal cortex involves monitoring for situations that require a change in attentional control and signaling the lateral prefrontal cortex to execute the change (see Botvinick, Braver, Barch, Carter, & Cohen, 2001; Carter & van Veen, 2007; Yeung, Botvinick, & Cohen, 2004, for reviews). Clearly, an unattended painful stimulus qualifies as a situation that requires a change in attentional control (Bishop, 2008; Eccleston & Crombez, 1999; Van Damme, Legrain, Vogt, & Crombez, 2010).

Behavioral evidence for the somatic threat-detection-and-reorienting hypothesis The electrophysiological data reviewed above suggest that painful sural nerve stimuli facilitate the disengagement and reorienting of attention via a stimulus-driven somatic threatdetection-and-reorienting process. According to this hypothesis, an unattended and/or unexpected painful stimulus activates somatic threat detectors in the dorsal posterior insula (indexed by the CTN). This activation is monitored by the medial prefrontal cortex (indexed by the FCN), which in turn signals the lateral prefrontal cortex to reorient attention toward the pain (indexed by the P3a). The task reaction time data also support this hypothesis, albeit their evidence is not as strong as the electrophysiological data reviewed above. The different sensory modalities, sural nerve target stimulus intensities, and behavioral tasks used in such studies have prevented direct comparisons of the reaction time data between the visual, nonpainful sural nerve, and painful sural nerve targets. Dowman and ben-Avraham (2008) attempted to circumvent these confounds by normalizing the validity effect to the

percentage increase in the invalidly cued condition (i.e., {[invalidly cued−validly cued]/validly cued} * 100). This analysis revealed that the normalized reaction time validity effect for the painful sural nerve target stimulus was about one-half that for the nonpainful sural nerve and visual targets. Similar results were reported by Spence, Bentley, Phillips, McGlone, and Jones (2002) in a cross-modal endogenous cuing experiment that involved painful laser and visual target stimuli presented to the forearm. That is, the reaction time validity effect for the painful target was smaller than that for the visual target. One explanation for the smaller reaction time validity effects reported in these studies is that the painful targets were more effective at disengaging and reorienting attention. This would have reduced the invalidly cued condition reaction times, thereby decreasing the validity effect. Present study The behavioral evidence reviewed above is consistent with the somatic threat-detection-and-reorienting hypothesis. However, these studies were not specifically designed to compare the nonpainful and painful sural nerve target reaction time validity effects, and as a consequence, a number of other explanations could account for these results. One of the goals of this study was to investigate two of the most obvious alternatives. The first involves possible differences in how attention was voluntarily allocated following the cue (i.e., attentional set). The potentially threatening nature of the painful sural nerve target raises the possibility that participants voluntarily allocated some attention to the painful target when the cue signaled that the visual target was forthcoming (pain target invalidly cued condition). This may not have been the case for the nonpainful, and presumably nonthreatening, sural nerve targets. The increase in attention allocated to the uncued painful target would have shortened its invalidly cued reaction time, and thereby reduced its validity effect. Second, the nonpainful and painful sural nerve targets used in previous studies were presented in different tasks: an intensity discrimination task (Dowman, 2007b) and an intensity rating task (Dowman, 2007a), respectively. It might be the case, therefore, that the different reaction time validity effects were due to the different tasks and not the pain. Indeed, studies using visual target stimuli have shown that more complex tasks (e.g., target identification vs. target detection) are associated with longer overall reaction times and smaller reaction time validity effects (Posner, Snyder, & Davidson, 1980). This is consistent with the observation that the overall reaction times were longer, and reaction time validity effects smaller, for the more complex pain intensity rating task (Dowman, 2007a, b). In the present study, the cross-modal endogenous cuing procedure used in the earlier studies was modified to control for the attentional set and task confounds that contaminated

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the Dowman (2007a, b) studies. As in the earlier studies, the participants performed cued color discrimination and sural nerve intensity discrimination tasks. The color discrimination task was identical to that used in the earlier studies, in which participants indicated whether the red or yellow target LED was lit. The sural nerve intensity discrimination task was the same as that used in Dowman (2007b), in which participants indicated whether the low- or high-intensity sural nerve target had been presented. The difference was that nonpainful and painful levels were used as the low and high stimulus intensities. So, instead of the nonpainful and painful sural nerve targets being presented in separate experiments, they were presented together in a random order in the same block of trials. If the effect of pain on the reaction time validity effects reported in earlier studies was due to the somatic threatdetection-and-reorienting process, then the reaction time validity effect would be smaller for the painful than for the nonpainful sural nerve targets. If the pain effect was due to attentional set, then roughly equal amounts of attention would be allocated to both the nonpainful and painful sural nerve targets in the invalidly cued condition, and their reaction time validity effects would be the same. Likewise, if the different reaction time validity effects for the painful and nonpainful sural nerve targets reported in earlier studies were due to the different tasks, then the reaction time validity effects should be the same when both are presented in the same intensity discrimination task. Sural nerve ERPs were also obtained to verify the roles of the CTN, FCN, and P3a in somatic threat detection and reorienting. That is, the CTN amplitude should be larger in the invalidly than in the validly cued condition for the painful but not for the nonpainful sural nerve target stimuli, reflecting the role of the CTN in somatic threat detection, and the FCN and P3a amplitudes should be larger in the invalidly than in the validly cued conditions for both the painful and nonpainful sural nerve stimuli, reflecting the more general roles of these components in attentional control.

Method Participants A group of 22 healthy young adults (mean ± SD age 18.6 ± 1.1 years; three women, 19 men) participated in the study. Each participant was given a detailed explanation of the procedure, and each read and signed an informed consent document prior to participating. The research conformed to the American Psychological Association standards for the ethical treatment of human subjects and was approved by the Clarkson University Institutional Review Board. The participants were comfortably positioned in a recliner chair located in a sound-attenuated and temperature-controlled (21 ±

1 °C) recording chamber. The participant’s lower right leg rested on an L-shaped brace to help maintain foot and lower limb position and to hold the visual target stimuli. Cuing and target stimuli The somatosensory electrical target stimuli were presented to the right sural nerve at the ankle along its retromalleolar path. The electrical stimulus consisted of a five-pulse train of square-wave pulses (1-ms pulse duration, 250-Hz pulse frequency, 17-ms duration) delivered through two electrodes positioned 2-cm apart on the skin overlying the nerve. The stimulating electrode impedances were less than 10,000Ω. The stimulator output was computer controlled, and the stimulus current was measured online throughout the experiment to verify that it did not change appreciably during the recording block. (See Dowman, 2007a, for a more detailed description of the equipment used to deliver and monitor the sural nerve electrical stimuli.) Two sural nerve electrical stimulus intensities were used. One produced a nonpainful tapping and/or paresthesia sensation, and the other produced a moderately painful prickling sensation. Both sensations were largely localized to the dorsolateral surface of the foot, consistent with the distribution of the sural nerve. The stimulus intensities were determined at the beginning of the session using a single ascending series of stimulations to obtain a rough estimate of the stimulus levels, which were then more precisely determined during intensity rating trials. In the intensity rating trials, the two current levels were presented in random order (without replacement) and with a 4-s interstimulus interval, and the participants rated the intensity of each stimulus on a 9-point numerical rating scale (1 = sensory threshold, 5 = pain threshold, and 9 = maximum pain tolerable). At least 50 trials were given at each level during the intensity rating trials, and adjustments were made to the stimulus currents in order to achieve the nonpainful and moderately painful levels used in the cross-modal endogenous cuing task. The mean (± SD) current levels for the nonpainful and painful sural nerve target stimuli were 0.95 ± 0.28 and 8.50 ± 4.88 mA, respectively, and the intensity ratings were 1.2 ± 0.2 and 6.9 ± 0.6, respectively. Other results from this lab have shown that the nonpainful stimulus level can for practical purposes be considered to activate only the large-diameter Aβ tactile afferents (Dowman, 1993), and that the painful stimulus level continues to be rated as painful over the course of a subsequent recording block comparable in duration to that used here (Dowman, 2001, 2004a, b, 2007a). The color target stimuli consisted of two 0.5-cm-diameter light-emitting diodes (LEDs) arranged vertically 2 cm apart in a black plastic box (4 cm wide × 10 cm high × 5 cm deep). The top LED was yellow and the bottom was red. The LEDs were illuminated by a 150-ms, 5-V TTL pulse. The LED box was fixed to the foot brace, with the LEDs located 5 cm

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horizontally to the right of the right foot. The visual angle between the LEDs was 2.0º, and the distance between the dorsolateral side of the foot and the LEDs was 2.1º. The cuing stimuli consisted of the uppercase letters “V” and “S,” presented at the center of a computer monitor. The center of the monitor was about 27 cm distal, 4 cm lateral, and 10 cm superior to the LED box. The letters were 2.5 cm high and were presented for 500 ms. ERP recording parameters The ERPs elicited by the sural nerve electrical and color target stimuli were recorded from 29 electrodes arranged on the scalp in a grid centered on a location 2 cm posterior to the vertex position of the International 10–20 Electrode System (CZ′; Sharbrough et al., 1991). The interelectrode distance along the sagittal and coronal axes was 5 cm, which samples at twice the highest spatial frequency of the mid- and longlatency peaks of the sural nerve ERP (Dowman, 1994). The scalp electrodes were referenced to the noncephalic sternovertebral electrode (Dowman & Goshko, 1992). Eye movement potentials were recorded from two electrodes positioned just lateral to the lateral canthus and over the inferior portion of the orbicularis oculi muscle of the left eye. The recording electrode impedances were less than 5,000Ω. The ERPs and eye movement potentials were amplified 50,000 times, filtered between 0.3 and 100 Hz (−6 dB points), and sampled at 250 Hz. Trials were rejected by computer during data acquisition whenever the scalp potentials exceeded 100μV and/or when the eye movement potentials exceeded 40μ V, to reduce muscle and eye movement artifacts. Procedure Each trial began with a cue consisting of the uppercase letter “V” or “S.” The “V” signaled that a visual target stimulus was forthcoming, and the “S” signaled that a sural nerve electrical target stimulus was forthcoming. The target stimulus onset followed the cue offset by 1,500 ms. For the visual target stimuli, the participants pressed a left response switch with their right index finger if the red LED was lit, and a right response switch with their right middle finger if the yellow LED was lit. For the sural nerve target stimuli, the participants pressed the left response switch with their right index finger if the nonpainful sural nerve target was presented, and the right response switch with their right middle finger if the painful sural nerve target was presented. The trial duration was 4 s, and each trial was immediately followed by the next. The four different target stimuli (two color and two somatic) were given in random order (without replacement) and equal probabilities. Each target was validly cued on a randomly determined (without replacement) 75 % of the trials, so that a visual target followed the “V” cue and a sural nerve target

followed the “S” cue. On the remaining 25 % of the trials, the targets were invalidly cued, so that a visual target followed the “S” cue and a sural nerve target followed the “V” cue. The participants were told that the cues would correctly signal the next target on most, but not all, of the trials, and that they were to focus all of their attention on the cued target. The participants were instructed to keep their eyes fixated on a point on the foot brace that was about midway between their ankle and the LEDs and to covertly shift their attention to the target. The participants were also instructed to make the response to the target as quickly and accurately as possible. Each participant was given a total of 640 artifact-free trials, of which 320 were color targets (160 red, 160 yellow) and 320 were sural nerve targets (160 nonpainful, 160 painful). For each target, 120 validly and 40 invalidly cued trials were presented. A mandatory 5-min break was inserted halfway through the recording block. Participants also had the opportunity to take additional breaks, if needed, though these were seldom requested. Data analysis Trials with reaction times less than 150 ms or greater than 1,200 ms were excluded from the accuracy and reaction time analyses, to eliminate anticipatory and outlier responses, respectively. Anticipatory and outlier responses were made on only 0.1 % and 0.5 % of the trials, respectively. Trials with incorrect responses were excluded from the reaction time analysis. As in the previous studies, the time segments used to measure the amplitudes of the midlatency negative components of the sural nerve ERP, which include the CTN, the FCN, and the central negativity (CN) that immediately precedes the CTN, were determined by visual inspection of the 29-channel grand average ERP scalp topographic patterns, to identify the signature pattern for that component and its maximum location (Dowman, 2011).1 Then the grand average ERP waveform measured from the maximum amplitude location was used to select the onset and offset latencies for that component. The onset and offset latencies for the P1, P2, and P3a components comprising the late positive potential were determined by separating the late positive potential into stable periods, where a stable period refers to consecutive time points having the same 29-channel scalp topographic pattern. The stable periods were defined as those time points whose r 2 with it midpoint was greater than .85 and greater than the r 2 with the adjacent stable period(s). The r 2 analysis ensured that 1 In the previous work, the midlatency negative component onset and offset latencies had been determined using the stable-period analysis described for the P1, P2, and P3a components (Dowman, 1994, 2001, 2007a, b). However, experience has demonstrated that the method used here takes considerably less time and produces equivalent results (Dowman, 2011).

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the topographic pattern, and by implication the source configuration, was the same throughout the time segment (Dowman, 1994). The amplitude of each sural nerve ERP component was computed by averaging the potential across its onset and offset latencies. The amplitudes of the CN, CTN, and FCN components were obtained from their maximum scalp locations. The amplitudes of the P1, P2, and P3a components were obtained from the five sagittal midline electrodes. Previous work has demonstrated that the amplitudes obtained from these midline locations adequately capture the components of interest (Dowman, 2007a, b, 2011). This method was also used to measure the visual ERP component amplitudes. The effects of cue validity on the visual ERP were the essentially the same as those reported in earlier studies (Dowman, 2007a, b), and hence will not be reported here. A repeated measures analysis of variance was used to evaluate the effects of evoking stimulus intensity and/or cue validity on the ERP amplitudes and the task reaction times and accuracies. The red and yellow visual target reaction times were combined, since there was no a priori reason to expect differences between them, and because variables that might affect reaction time, such as stimulus intensity, were not controlled. Greenhouse–Geisser corrections were applied when the numerator degrees of freedom were greater than 1, to correct for violations of the sphericity assumption. In reporting the significance levels, the uncorrected degrees of freedom are given, along with the epsilon (ε) values used to adjust the significance level.

Results Eye movements The eye movement potentials and the scalp topographic pattern of the negative visual ERP peak occurring at 190 ms poststimulus (N190) demonstrate that participants did not shift their gaze toward the target stimulus (Fig. 1): The eye potentials show little or no eye movement before or following the target stimulus, and the N190 maximum was located on the left side, as would be expected from a visual stimulus presented to the right of the fixation point (Dowman, 2007a). Task reaction time and accuracy Color discrimination task The color discrimination task accuracy was the same across the validly (mean ± SD = 0.99 ± 0.02) and invalidly (0.98 ± 0.02) cued conditions [F(1, 21) = 3.00, p = .10], and the reaction times were faster in the validly cued (479.4 ± 66.5 ms) than in the invalidly cued (539.3 ± 83.3 ms) condition [F (1, 21) = 32.87, p < .0001].

Sural nerve intensity discrimination task Although a trend emerged for the sural nerve intensity discrimination task accuracy to be greater in the validly cued than in the invalidly cued condition [0.98 ± 0.02 vs. 0.97 ± 0.03, respectively; validity main effect, F (1, 21) = 3.32, p = .09; Stimulus Intensity × Validity interaction, F (1, 21) = 0.17, p > .10] and greater for the nonpainful than for the painful targets [0.98 ± 0.02 vs. 0.97 ± 0.03, respectively; stimulus intensity main effect, F(1, 21) = 3.44, p = .08], these differences were small and did not reach statistical significance. The sural nerve intensity discrimination task reaction times trended toward being faster for the painful than for the nonpainful sural nerve targets [F(1, 21) = 4.14, p = .055] (Fig. 2), as has been reported elsewhere (Bushnell, Duncan, Dubner, Jones, & Maixner, 1985; Dowman, 2001, 2004b; Miron, Duncan, & Bushnell, 1989). The sural nerve intensity discrimination task reaction times were also affected by cue validity [validity main effect, F(1, 21) = 43.22, p < .0001], where reaction times were faster in the validly than in the invalidly cued condition. However, the effect of cue validity on the sural nerve target reaction times was the same for the nonpainful and painful sural nerve targets [Stimulus Intensity × Validity interaction, F (1, 21) = 0.29, p > .10]. Electrophysiological measures Sural nerve ERP The grand average scalp topographic patterns and waveforms of the three sural nerve ERP components of interest here—the CTN, FCN, and P3a—are shown in Figs. 3 and 4. As has been reported elsewhere (e.g., Dowman, 2007a, b, 2011), the increase in FCN amplitude in the invalidly cued relative to the validly cued condition is focused over the fronto-central scalp (Fig. 3, lower row), consistent with its putative medial prefrontal cortex generator (Dowman & benAvraham, 2008; Dowman et al., 2007). Consequently, the average of the two most anterior midline electrodes was used to measure the FCN amplitude. The effects of cue validity on the CTN, FCN, and P3a components are shown in Figs. 4 and 5. As was previously reported (Dowman, 2007a, b), the difference between the validly and invalidly cued conditions was not evident throughout the entire component interval, but rather was restricted to an epoch within the interval (Fig. 4). Hence, to maximize statistical power, the component amplitudes were computed as the average amplitudes of the epoch in which the invalidly and validly cued grand average waveforms differed. For the nonpainful and painful CTN components, the amplitude epochs were 137–153 ms and 145–161 ms, respectively; for the nonpainful and painful FCNs, the amplitude epoch was 153–169 ms; and for the nonpainful and painful P3as, the amplitude epoch was 353–385 ms. The CTN amplitude was larger in the invalidly cued than in the validly cued condition [validity main effect, F(1, 21) =

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Fig. 1 a Grand average eye movement potentials evoked by the visual (averaged across red and yellow light -emitting diodes) and the nonpainful and painful sural nerve target stimuli obtained in the validly and invalidly cued conditions. b Grand average scalp topographic patterns for the N190 peak in the visual event-related potential. The small solid circles in each topography identify the recording electrode

locations, where CZ′ (2 cm posterior to the vertex [CZ] position of the 10–20 Electrode System; Sharbrough et al., 1991) is the third electrode from the bottom along the sagittal midline. The lines are isovoltage contours. The shading was adjusted in each of the topographies to best illustrate the topographic pattern

5.99, p < .05], and this effect was the same for the nonpainful and painful sural nerve targets [Stimulus Intensity × Validity interaction, F (1, 21) = 0.04, p > .10] (Fig. 5a). The FCN showed the same cue validity effect as the CTN [validity main effect, F (1, 21) = 4.99, p < .05; Stimulus Intensity × Validity interaction, F(1, 21) = 0.99, p > .10] (Fig. 5b). The Stimulus Intensity × Cue Validity interaction term for the P3a amplitude approached statistical significance [F(1, 21) = 3.85, p = .06]. Inspection of Figs. 4 and 5c and d suggests that the P3a amplitude was larger in the invalidly cued than in the validly cued condition for the painful sural nerve targets, but not for the nonpainful targets. This was confirmed in post-hoc analyses showing a significant cue validity simple main effect for P3a amplitudes evoked by the painful sural nerve target [F (1, 21) = 5.63, p < .05], but not for those evoked by the nonpainful target [F (1, 21) = 0.18 p > .10]. The cue validity effects for the painful sural nerve target P3a were the same across the five midline electrode locations [Electrode × Validity interaction, F(4, 84) = 2.27, p > .10, ε = .42] (Fig. 5d). The effect of cue validity on the other sural nerve ERP components was the same as that reported in Dowman (2007a,

b) (see Fig. 4): The central negativity (CN) was larger in the invalidly cued than in the validly cued condition for both the nonpainful and painful sural nerve targets [validity main effect, F (1, 21) = 4.09 p = .056; Stimulus Intensity × Validity interaction, F (1, 21) = 0.17, p > .1]; the P1 amplitude was smallest in the invalidly cued condition [validity main effect, F(1, 21) = 11.77, p < .01] for both the nonpainful and painful sural nerve targets [Stimulus Intensity × Validity interaction, F(1, 21) = 0.45 p > .10], and the P2 was unaffected by cue

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Fig. 2 Effects of cue validity and stimulus intensity on the sural nerve intensity discrimination task reaction times. *p < .05 in a comparison of the sural nerve stimulus intensities

Fig. 3 Grand average event-related potential (ERP) scalp topographic patterns for the CTN, FCN, and P3a components evoked by the painful sural nerve target stimulus in the validly cued (VC) and invalidly cued (IC) conditions, as well as the invalidly cued–validly cued difference potentials (IC-VC). Essentially the same topographic patterns were seen for the nonpainful sural nerve targets. The numbers above each of the topographies are the onset and offset times of the epoch having that topographic pattern. The small solid circles in each topography identify the recording electrode locations, where CZ′ (2 cm posterior to the vertex [CZ] position of the 10–20 Electrode System; Sharbrough et al., 1991) is the third electrode from the bottom along the sagittal midline. The lines are isovoltage contours. The shading was adjusted in each of the topographies to best illustrate the topographic pattern

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validity (validity main and interaction effects, F s ≤ 1.36, p > .10). Note that the validity effects for the CN and P1 amplitudes evoked by the nonpainful and painful sural nerve target stimuli are also seen when the nonpainful and painful sural nerve targets are presented in separate experiments (Dowman, 2007a, b). It is unlikely, therefore, that these effects are specific to pain. A detailed discussion of the functional significance of the cue validity effects for the CN, P1, and P2 components can be found in Dowman (2007a, b, 2011).

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Fig. 4 Grand average sural nerve event-related potential (ERP) waveforms recorded from the CTN maximum location at the contralateral temporal scalp (TEMPORAL) and from two locations along the sagittal midline: CZ′ (2 cm posterior to the vertex [CZ] position of the 10–20 Electrode System; Sharbrough et al., 1991) and 10 cm anterior to CZ′ (CZ′ + 10). The left panels show the ERPs evoked by the nonpainful sural nerve target stimuli, and the right panels show the ERPs evoked by the painful sural nerve target stimuli. The sural nerve evoking stimulus was given at time 0

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The effects of cue validity on the visual and somatosensory ERPs were for the most part the same as those reported in the earlier studies from this lab, including the cue validity effect for the P3a being evident for the painful but not the nonpainful sural nerve targets. Dowman (2007a, b) reported a P3a validity effect for sural nerve targets that were painful and that produced a nonpainful tactile sensation, but not for those that produced a nonpainful paresthesia sensation similar to that used here. Likewise, the P3a evoked by the visual target stimuli in this study (data not shown) and in Dowman (2007a, b) were all larger in the invalidly cued than in the validly cued condition. Therefore, the absence of a P3a validity effect for the nonpainful paresthesia sural nerve target

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Fig. 5 Effects of stimulus intensity and cue validity on the sural-nerveevoked CTN (a) and FCN (b) component amplitudes, as well as the effects of cue validity on the P3a amplitudes evoked by nonpainful (c) and painful (d) sural nerve targets. P3a amplitudes were recorded from the five midline electrode sites: CZ′ (2 cm posterior to the vertex [CZ]

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position of the 10–20 Electrode System; Sharbrough et al. 1991), 5 and 10 cm anterior to CZ′ (CZ′ + 5 and CZ′ + 10, respectively), and 5 and 10 cm posterior to CZ′ (CZ′-5 and CZ′-10, respectively). *p < .05 in a comparison of the invalidly and validly cued conditions

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reported here and in Dowman (2007b) cannot be due to the nonpainful nature of the target stimuli. Both here (Fig. 4) and in Dowman (2007b, Fig. 4), the positive peak and trough that immediately preceded the P3a evoked by the nonpainful paresthesia sural nerve target were considerably smaller in the invalidly cued than in the validly cued condition. This was not the case for the P3a evoked by the painful sural nerve target (Fig. 4; see also Dowman, 2007a), the nonpainful sural nerve target that elicited a tactile sensation (Dowman, 2007b), or the visual targets (Dowman, 2007a). This raises the possibility that the absence of a validity effect for the P3a evoked by the nonpainful paresthesia sural nerve target was a spurious result of the overlap between the preceding positive potential and the P3a. The only difference between the electrophysiological results reported here and in previous work involves the CTN. Here, the CTN was larger in the invalidly cued than in the validly cued condition for both the nonpainful and painful sural nerve target stimuli, whereas in the previous work the CTN validity effect was observed when both were painful (Dowman, 2007a) but not when both were nonpainful (Dowman, 2007b). It seems unlikely that this is a spurious result, given that the effects of cue validity on all of the other sural nerve and visual ERP component amplitudes were identical to those reported in the previous studies (Dowman, 2007a, b). The CTN validity effect appears to be closely related to the reaction time validity effect: When the nonpainful and painful sural nerve targets were given in separate experiments, only the painful sural nerve target exhibited a CTN validity effect, and the reaction time validity effect was smaller for the painful than for the nonpainful sural nerve target (Dowman, 2007a, b; Dowman & ben-Avraham 2008). But here, when the nonpainful and painful sural nerve targets were presented in the same block of trials, both yielded a CTN validity effect, and both exhibited comparable reaction time validity effects. Together, the behavioral and electrophysiological results presented here are consistent with the somatic threatdetection-and-reorienting hypothesis and reveal an unexpected new finding: Namely, that the somatic threat detectors will respond to a nonpainful sural nerve target when it is presented in a pain context, but not when it is presented in a pain-absent context. A possible mechanism underlying the sensitization of somatic threat detectors is presented below. Mechanisms underlying the activation of somatic threat detectors by nonpainful stimuli The mechanism underlying the sensitization of the putative somatic threat detectors indexed by the CTN might be related to the guidance-by-features framework proposed by Cave and Batty (2006). This framework posits that an elementary

stimulus feature or combination of stimulus features that are consistently paired with a threat will enhance the ability of those features to capture attention, presumably through associative learning. Several lines of evidence in the visual search literature support this hypothesis (see Cave & Batty, 2006, for review), as do the results of this study. Both the painful and nonpainful sural nerve target stimuli share the same stimulus feature—namely, activation of the Aβ tactile afferents (Dowman, 1993). Furthermore, neurons in the CTN’s putative dorsal posterior insula generator have been shown to respond to both noxious and tactile somatic stimuli (Dong & Chudler, 1995; Robinson & Burton, 1980). It is possible, therefore, that the dorsal posterior insula activity evoked by Aβ afferent input is enhanced when it is associated with the pain experience. This, in turn, would increase the medial and lateral prefrontal cortex activations responsible for disengaging and reorienting attention. Different mechanisms for reorienting spatial and cross-modal attention toward pain In the cross-modal endogenous-cuing studies reported here and in previous work, the participants voluntarily directed their attention toward targets in different sensory modalities and presented at very similar locations. Work based on the spatial attention endogenous-cuing paradigm has suggested an attentional bias toward painful somatic targets and nonpainful somatic targets presented in a pain context that does not appear to involve somatic threat detectors. In the spatial-attention cuing studies, nonpainful and painful sural nerve targets were presented to the left and right sides in a random order within the same block of trials (Dowman, 2011). A symbolic cue presented at the beginning of each trial signaled which side the upcoming sural nerve target would be presented on, where the ratio of validly to invalidly cued trials was the same as the one used here. The reaction time validity effects for the nonpainful and painful sural nerve target stimuli were the same, and both were smaller than that for the nonpainful sural nerve target given in a pain-absent context in the cross-modal endogenous-cuing studies (see Dowman, 2011). However, spatial cue validity had no effect on the CTN evoked by the nonpainful or the painful sural nerve targets. The same result was reported in Dowman (2004b), where all of the sural nerve targets were painful. The absence of a CTN validity effect in the spatial-attention cuing studies implies that the disengagement and reorienting of attention toward the sural nerve targets did not involve somatic threat detectors. Furthermore, the protocol used in the Dowman (2011) spatial-cuing study specifically eliminated the contribution of attentional set. Rather, these results were best explained by contingent attention capture. Most contingent attention capture studies have involved the visual search paradigm, where it has been shown that task-irrelevant

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distractor stimuli that share an elementary stimulus feature with the target (e.g., color) are more effective at capturing attention than distractors that do not share this feature (Folk & Remington, 2008; Kiss & Eimer, 2011; Remington, Folk, & McLean, 2001; Theeuwes & Van der Burg, 2011). Importantly, the ability of these features to capture attention does not depend on their spatial location (Yantis, 2008). Since nonpainful and painful sural nerve target stimuli share a common stimulus feature—both activate the Aβ tactile afferents (Dowman, 1993)—contingent attention capture would be expected to facilitate the ability of the nonpainful sural nerve target to engage attention when the participant was expecting a painful sural nerve target at another location, as was the case in the spatial-attention cuing study (Dowman, 2011). It is unlikely that contingent attention capture played a role in the reaction time data reported here, however, since the sural nerve targets did not share any stimulus features with the visual targets.

Mechanism underlying the CTN validity effect The different effects of cue validity on the CTN observed in the cross-modal and spatial-attention cuing studies raises the possibility that the CTN validity effect involves a mismatch between the target template held in working memory and the sural nerve evoking stimulus (Dowman & ben-Avraham, 2008; see also Friedman et al., 2001, for examples in other sensory modalities). In the invalidly cued condition of the cross-modal cuing experiments, there would have been a large mismatch between the visual target template held in working memory and the sural nerve target. In the spatial-attention cuing experiments, on the other hand, there would have been a much smaller mismatch between the painful (or nonpainful) sural nerve target template held in working memory and the nonpainful (or painful) sural nerve target presented, given that both share a common stimulus feature—activation of the Aβ afferents. The putative working memory template mismatch response indexed by the CTN appears to be specific to painful somatic stimuli and to nonpainful somatic stimuli that are presented in a pain context. We have proposed elsewhere that the abrupt, unexpected onset of any somatic stimulus activates transient detectors located in the primary somatosensory cortex that are indexed by the CN component of the sural nerve ERP (Dowman, 2007b), similar to what has been proposed for the auditory system (Näätänen, 1990, 1992; Näätänen & Picton, 1987). The transient detectors, in turn, activate the medial and lateral prefrontal areas involved in reorienting attention toward the somatic stimulus (Dowman & benAvraham, 2008). The proposal here is that the activation of somatic threat detectors provides an additional boost to this process.

Study limitations and future directions The evidence reported here and in the earlier studies suggests a close correspondence between the amplitude of the CTN evoked by an unexpected and unattended (e.g., invalidly cued) sural nerve stimulus and the time required to disengage and reorient attention away from some other target stimulus and/or task. Although these results suggest that this effect is mediated by somatic threat detectors located in the dorsal posterior insula, other explanations for these results need to be evaluated in future studies. For example, the present study did not eliminate the possibility that the reaction time validity effect was due to attentional set. It might be the case that the reaction time validity effect was related to attentional set, and that the CTN validity effect involved some other, unrelated phenomenon. The present study was also unable to eliminate the possibility that the different reaction time validity effects for the nonpainful and painful sural nerve targets reported in previous studies were due to task differences, since participants performed an intensity rating task for the painful sural nerve targets in one study (Dowman, 2007a) and an intensity discrimination task for the nonpainful sural nerve targets in the other (Dowman, 2007b). It might be the case, for example, that the comparable reaction times for the nonpainful and painful sural nerve targets observed here emerged because they were presented in the same task. To explore this possibility, the reaction times for the nonpainful sural nerve target obtained here (pain context) were compared to reactions times from the stimuli of comparable intensity evoked by the nonpainful sural nerve targets in Dowman (2007b), where both of the sural nerve targets were nonpainful (pain-absent context). Note that both studies used the same number and probability of cue validity conditions, the same number of trials, and the same intensity discrimination task. This comparison revealed that the nonpainful sural nerve target reaction times were faster in the pain context than the pain-absent context [F (1, 40) = 21.33, p < .0001], and that this effect was largest in the invalidly cued condition [Pain Context × Cue Validity interaction, F(1, 40) = 25.06, p < .0001]. Although these results support the somatic threat-detection-andreorienting hypothesis, they must be interpreted with caution. Importantly, the participants were not randomly assigned to the pain and pain-absent contexts; hence, the reaction time differences could be due to individual differences related, for example, to the willingness to participate in an experiment that involved painful stimuli. This important question will be addressed in future studies. It will also be important to determine the role of general arousal in the effects of pain context on the reaction time validity effect. The presence of a painful sural nerve target might have increased general arousal levels, which in turn could result in a nonspecific decrease in reaction times for all

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of the target stimuli. If that were the case, the reaction time validity effect for the visual task should also have been smaller in the pain context. The visual task reaction times obtained here could not be compared to those obtained in the study in which all of the sural nerve targets were nonpainful (Dowman, 2007b), because of differences in the visual task protocols. That is, in Dowman (2007b) the participants were instructed to look at the cued target, whereas here participants maintained their gaze on a central fixation point and shifted their attention covertly. This difference might have resulted in differences in the visual target reaction times that would be independent of the pain context. It is worth noting, however, that in previous studies (Dowman, 2007a, b) in which the visual task protocols were identical, the validity effect for the visual targets presented in the study in which both of the sural nerve targets were painful (Dowman, 2007a) was the same as that in the study in which both were nonpainful (Dowman, 2007b) [mean ± SD = 132.6 + 91.1 ms and 108.1 ± 59.5 ms, respectively; t(39) = 1.02, p > .10]. These data argue against the idea that the effects of pain context on the nonpainful sural nerve target reaction times were merely due to general arousal. Nevertheless, it will be important to verify this result in studies in which both the visual and the sural nerve tasks are identical in the pain and pain-absent contexts. It is also not clear whether the effects of pain context on reaction times were due to attention being reoriented toward perceptual, decision (e.g., S–R mapping; Nieuwenhuis, Aston-Jones, & Cohen, 2005), and/or response processes. Although a computational modeling study has suggested that the effects of pain on reaction times are primarily due to attention being reoriented toward decision and response processes (Dowman & ben-Avraham, 2008), this has not been confirmed in experimental studies. Redirecting attentional resources to decision and response processes is not a trivial outcome, given that successfully coping with an unexpected threat usually requires action (Eccleston & Crombez, 1999; Lang & Davis, 2006). It is important, therefore, that this question be addressed in future work. Conclusions and clinical implications The electrophysiological and behavioral reaction time data presented here provide further support for the somatic threatdetection-and-reorienting hypothesis and provide new information suggesting that a nonpainful sural nerve stimulus will activate the somatic threat detectors when it is presented in the same context as a painful target. The adaptive value of this process is clear: If there are potential threats to the body in a given situation, then sensitizing the somatic threat detectors to the unexpected, abrupt onset of a tactile stimulus might increase the probability of detecting and avoiding a somatic threat. The sensitization of somatic threat detectors may also play a role in the hypervigilance toward body sensations that is

seen with some types of chronic pain (Van Damme et al., 2010; Vlaeyen & Linton, 2000). It is not clear whether the activation of somatic threat detectors by nonpainful somatic stimuli requires that the painful stimulus be present in that context, or whether expecting that pain might occur in the context is sufficient. If the latter is true, the sensitization of somatic threat detectors might occur in situations in which a patient merely expects pain (e.g., rehabilitation exercises). The activation of the somatic threat detectors by nonpainful somatic stimuli would, in turn, facilitate the shift in attention away from other, ongoing cognitive processes and toward the body, perhaps contributing to a hypervigilance toward body sensations. Indeed, Crombez et al. (1998) reported that a lowintensity electrocutaneous stimulus was more effective at capturing attention when the participants were told that a highintensity painful stimulus might also be given. More work will be necessary to evaluate this possibility. Author note The superb technical assistance of Nina Carey and Gregory Dorchies is greatly appreciated. The author has no conflicts of interest, financial or otherwise.

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