Psychophysiology, 51 (2014), 464–477. Wiley Periodicals, Inc. Printed in the USA. Copyright © 2014 Society for Psychophysiological Research DOI: 10.1111/psyp.12157
Shifting attention between the space of the body and external space: Electrophysiological correlates of visual-nociceptive crossmodal spatial attention
LOUIS FAVRIL,a ANDRÉ MOURAUX,b CHIARA F. SAMBO,c and VALÉRY LEGRAINa,b a
Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium c Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK b
Abstract The study tested whether nociceptive stimuli applied to a body limb can orient spatial attention in external space toward visual stimuli delivered close to that limb. Nociceptive stimuli were applied to either the left or the right hand. Task-relevant visual stimuli were delivered at the location adjacent to the stimulated hand (70% valid trials) or adjacent to the other hand (30% invalid trials). Visual stimuli were discriminated with shorter reaction times and elicited ERPs of greater magnitude in the valid as compared to the invalid trials. This enhancement affected the N1 component, suggesting that the location of the nociceptive cue modifies visual processing through a modulation of neural activity in the visual cortex. We hypothesize the existence of a common frame of reference able to coordinate the mapping of the space of the body and the mapping of the external space. Descriptors: Pain, Nociception, Body, Space, Crossmodal, ERPs
among the most consistently activated following the delivery of a nociceptive stimulus (see Tracey & Mantyh, 2007). However, a pure somatotopic representation of the bodily space might be insufficient to localize the source of nociceptive stimuli in the external world. Indeed, in most situations, at least in normal conditions, physical threats represent complex objects that also provide information to our other senses. Therefore, an adaptive control of behavior against potentially damaging objects requires the integration of information conveyed through nociceptive afferents and inputs originating from other sensory systems. In order to adequately localize a threatening object in space, to give it priority for a more in-depth processing, and to select and prepare the most appropriate action, spatial attention needs to be coordinated across the different senses to form a crossmodal link between the different dimensions of space. In other words, an effective localization of bodily threats requires selectively orienting attention not only towards the painful part of the body but also in external space. While the study of crossmodal links between vision and touch has received great interest (see Spence & Driver, 2004), little is known about potential links between vision and nociception in the orientation of spatial attention (see Legrain et al., 2012). The few studies having investigated spatial attention in the context of nociception and pain were confined to the investigation of unimodal spatial selection. For example, we showed that focusing attention on the limb on which nociceptive stimuli were applied significantly increased the magnitude of the event-related potentials (ERPs) elicited by these stimuli, as compared to a condition during which attention was oriented on the opposite limb (Legrain, Guérit, Bruyer, & Plaghki, 2002). Other studies have shown that
Being able to detect and react to stimuli that might have a direct impact on the physical integrity of the body (e.g., threats) is a major function for survival. A nociceptive stimulus is an archetype of physical threat because it has the potential to inflict tissue damage to the body (Loeser & Treede, 2008). Nociceptive processing involves spatial localization in order to detect what part of the body is potentially being damaged and to focus actions towards protecting the threatened body part (Legrain et al., 2012). The ability to localize nociceptive stimuli on the body depends partially on a direct relationship between the spatial organization of the skin receptors and the spatial organization of the neurons in the cortex (e.g., Kenshalo & Isensee, 1983). Numerous studies have shown the existence of such a somatotopic organization of the responses to nociceptive and painful stimuli in the primary (SI) and secondary (SII) somatosensory cortices, as well in the insula (Andersson et al., 1997; Baumgärtner et al., 2010; Bingel et al., 2004; Brooks, Zambreanu, Godinez, Craig, & Tracey, 2005; Disbrow, Robert, & Krubitzer, 2000; Henderson, Gandevia, & Macefield, 2007; Mancini, Haggard, Iannetti, Longo, & Sereno, 2012; Mazzola, Isnard, Peyron, Guénot, & Mauguière, 2009). These brain areas are
VL is supported by the Research Foundation Flanders (FWO, Belgium). We thank Prof. Nathalie Lefèvre (Statistical Methodology and Computing Service, Université catholique de Louvain, Belgium) for statistical assistance. Address correspondence to: Valéry Legrain, Institute of Neuroscience, Université catholique de Louvain, Avenue Mounier 53, COSY boîte B1.53.04, 1200 Brussels, Belgium. E-mail: [email protected]
Visual-nociceptive crossmodal spatial attention directing spatial attention towards the stimulated body part speeds the detection of painful stimuli1 and increases the intensity of the elicited pain percept (Dowman, 2004; Honoré, Hénon, & Naveteur, 1995; Van Damme & Legrain, 2012; Van Ryckeghem et al., 2011). Interestingly, the shifts of spatial attention observed in some of these latter experiments were triggered—overtly or covertly, that is, with or without eye movement—by nonsymbolic lateralized visual stimuli, suggesting a crossmodal link between visuospatial attention and orienting of attention to the surface of the body (Honoré et al., 1995; Van Ryckeghem et al., 2011). The present experiment tested the existence of a crossmodal link between nociception and vision in spatial attention. It is hypothesized that orienting attention at the location of a stimulus belonging to one sensory modality will improve the processing and detection of a stimulus belonging to another modality if there is a spatial congruence between the positions of the two stimuli (Eimer & Driver, 2001; Eimer, van Velzen, & Driver, 2002; Spence, Nicholls, Gillespie, & Driver, 1998). Previous experiments investigated the ability of lateralized visual cues to orient attention selectively to one hemibody and to modify the processing of painful stimuli (Honoré et al., 1995; Van Ryckeghem et al., 2011). Here, we tested the reverse hypothesis according to which the occurrence of a nociceptive stimulus on a certain part of the body is able to shift spatial attention in external space in order to improve the processing of visual stimuli delivered in the side of space adjacent to the stimulated body part. This hypothesis was tested using behavioral and electrophysiological measures in a crossmodal cueing paradigm. The participants were asked to discriminate brief visual stimuli delivered close to either the right or the left hand. Each visual stimulus was preceded by a nociceptive stimulus applied to either the left or the right hand. In most of the trials, the visual stimulus appeared close to the hand onto which the nociceptive stimulus was applied (valid trials). In other trials, the visual stimulus appeared close to the hand opposite to that on which the nociceptive stimulus was applied (invalid trials). It was hypothesized that the magnitude of the event-related potentials to the visual stimuli would be enhanced, and that performance of the visual task would be improved by the spatial validity of the nociceptive cueing stimuli. Method Participants Participants were 10 healthy volunteers (mean age 24.5 ± 2.8 years; 6 women; all right-handed), with normal or corrected-tonormal vision, no prior history of neurological, psychiatric, or chronic pain disorder, and no current use of psychotropic or analgesic drugs. Experimental procedures were approved by the Ethics Committee of the Université catholique de Louvain and conformed to the latest revision of the Declaration of Helsinki. Written informed consent was obtained. Stimuli and Apparatus Intraepidermal electrical stimulation (IES) was used to selectively activate skin nociceptors (Bromm & Meier, 1984). The stimuli
1. The term nociceptive describes a stimulus that activates nociceptors regardless of whether it elicits a perception of pain. In contrast, the term painful describes a stimulus eliciting a perception of pain, regardless of whether it activates nociceptors (see Loeser & Treede, 2008).
465 were delivered to the hand dorsum using stainless steel concentric bipolar electrodes developed by Inui (Inui, Tran, Hoshiyama, & Kakigi, 2002; Nihon Kohden, Japan). Each electrode consists of a needle cathode (length: 0.1 mm, Ø: 0.2 mm) surrounded by a cylindrical anode (Ø: 1.4 mm). By gently pressing the device against the skin, the needle electrode was inserted in the epidermis, in the sensory territory of the superficial radial nerve. The method relies on the fact that cutaneous nociceptive free nerve endings are located more superficially than encapsulated Aβ fiber mechanoreceptors. In order to guarantee the selectivity of the nociceptive stimulation, a very strict procedure was used to adjust individually the intensity of the stimulus at twice the absolute detection threshold to a single 0.5-ms square-wave pulse (Colon, Nozaradan, Legrain, & Mouraux, 2012; Mouraux, Iannetti, & Plaghki, 2010; see Procedure). It has been shown that this procedure enables the selective activation of capsaicinsensitive Aδ nociceptors without activating more deeply located low-threshold Aβ mechanoreceptors (Mouraux et al., 2010). Conversely, higher intensity of stimulation, such as intensity corresponding to the pain threshold, compromises the selectivity of IES because stronger currents also activate more deeply located Aβ fibers (de Tommaso et al., 2011; Legrain & Mouraux, 2013; Perchet et al., 2012). During the experiment, stimuli consisted of trains of three consecutive pulses separated by a 5-ms interpulse interval (Inui, Tsuji, & Kakigi, 2006). These stimuli were perceived as a pinprick sensation related to the activation of Aδ nociceptors (Bromm, Jahnke, & Treede, 1984; Nahra & Plaghki, 2003). The pinprick sensation was not necessarily qualified as painful. Visual stimuli were generated by means of two white lightemitting diodes (LED) with a 17 lm luminous flux, a 6.40 cd luminous intensity, and a 120° visual angle (GM5BW97330A, Sharp Corporation, Japan). Each LED was placed close to one of the two hands, at a maximum distance of 1 cm from the joint between the metacarpal and the proximal phalange of the index finger. During the experiment, the visual stimuli were either a 5-ms single flash or two consecutive flashes separated by a 100-ms interflash interval. The participants perceived the visual stimuli as a flashing white light. Procedure The experiment started with the instruction and a familiarization procedure to the visual task (see below). After placement of the EEG electrodes and impedance check, the detection threshold to IES was measured for each hand using the method of limits (Churyukanov, Plaghki, Legrain, & Mouraux, 2012). The electrode was placed on the hand dorsum, and single-pulse stimuli were applied using a staircase procedure by increasing or decreasing the intensity of electrical current with steps of 0.10 mA. The intensity was set at twice the detection threshold, with an intensity of ≤ 0.50 mA as restrictive criterion. If this criterion was not met, the electrode was displaced and the staircase procedure was restarted. Intensities of the two electrodes were also adapted in order to obtain an equivalent subjective intensity of perception between the two hands (using the same limit criterion of 0.50 mA). After each experimental block, participants were asked to describe the percept elicited by IES in order to ensure that (1) the subjective intensity of perception was not habituating and disappearing, and (2) the equivalence between the perceptions of IES from the two hands was still respected. If one of these two criteria was not met, stimulus intensity was adjusted with 0.50 mA as the limit. If this
466 limit was reached, the electrodes were displaced and the staircase procedure was restarted. Next, participants were asked to look at a fixation point on the lower edge of an AZERTY keyboard and to place their hands on the keyboard with the top of the left index finger on the key corresponding to the letter W and the top of the right index finger on the key corresponding to the digit 3 of the numeric keypad. The two keys, and the hands, were equidistant from the fixation point and from the sagittal midline of the body. The distance between the two index fingers was ∼35 cm. The LEDs, placed close to each index finger, were also equidistant from the fixation point and the body midline. The distance between the nose and the fixation point was ∼40 cm. After approximately 10 practice trials, participants were presented with 8 blocks of 60 trials per block. Figure 1 illustrates an example of a trial. Each trial started with a nociceptive stimulus applied randomly and equiprobably on one of the two hands. After a constant 800-ms interval, the visual stimulus was flashed by means of the LED placed close to either the left or the right hand. The probability of left and right LED flashes was equivalent. In 70% of the trials, the spatial location of the nociceptive and visual
L. Favril et al. stimuli was congruent; that is, they were delivered on the same hemispace (valid trials). In the remaining 30% of the trials, the nociceptive and the visual stimuli were delivered in opposite hemispaces (invalid trials). Therefore, in most of the trials, the location of the nociceptive stimulus was predictive of the location of the forthcoming visual stimulus. Visual stimuli consisted of a single flash in 2/3 of the trials (nontarget) and a double flash in 1/3 of the trials (target). Hence, in each block, target visual stimuli were presented in 14 out of the 42 valid trials (7 left and 7 right stimuli) and 6 out of the 18 invalid trials (3 left and 3 right stimuli). The nontarget visual stimuli were presented in 28 out of the 42 valid trials (14 left and 14 right stimuli) and 12 out of the 18 invalid trials (6 left and 6 right stimuli). The order of the different types of trials was pseudorandomized with the restriction that none of the two first trials of each block contained a target visual stimulus. The intertrial time interval, measured between the onsets of two consecutive visual stimuli, varied randomly between 2,500 and 3,000 ms. Participants were instructed to keep their gaze on the fixation point and their index fingers on the response keys during the whole stimulation block. They were asked to respond as quickly and as accurately as possible to the occurrence of a target visual stimulus. Responses were given by pressing the key under the corresponding index finger. Because the location of the nociceptive stimulus was predictive of the position of the visual stimulus in most of the trials, participants were encouraged to use the nociceptive stimuli as spatial cues to improve their performance. Measures Performance of the visual task. The percentage of missed responses (i.e., no response to target visual stimuli) and the percentage of false alarms (i.e., response to nontarget visual stimuli) were taken as measures of response accuracy. The mean reaction times (RTs) to target visual stimuli were used as a measure of response speed (excluding RTs associated to false alarms, anticipated responses, RT < 150 ms, and delayed responses, RT > 1,500 ms).
Figure 1. Experimental design. The paradigm is illustrated by an invalid trial containing a target visual stimulus. In this example, the nociceptive stimulus is delivered to the left hand by means of intraepidermal stimulation using a concentric electrode. The stimulus consisted of three consecutive pulses of 0.5 ms with 5 ms as interpulse time interval (total duration of the stimulus: 15.5 ms). The nociceptive stimulus was followed 800 ms later by a visual stimulus consisting either of a single or a double flash of 5 ms of duration by means of an LED positioned in the vicinity of one of the index fingers. In this example, the right LED was flashed with a double stimulus. The time interval between the two flashes was 100 ms. Participants were asked to react to the occurrence of a double flash at the correct position using the corresponding key (in this example, key 3 of the numerical pad). Performance in the visual task was measured during the 1,500-ms time window running after the onset of the second flash of the double stimulus.
Event-related potentials. The electroencephalogram (EEG) was recorded using 64 Ag-AgCl electrodes placed on the scalp according to the International 10/10 system (Waveguard64 cap, Cephalon A/S, Denmark). Eye blinks and eye movements were monitored using an electrooculogram (EOG) recorded from two pairs of electrodes placed at the upper left and lower right sides of the right eye (vertical EOG) and close to the lateral canthi of the left and right eyes (horizontal EOG). Electrode impedances were kept below 50 kΩ. Signals were recorded using an average reference, amplified, and digitized using a 4,000 Hz sampling rate (ASA-Lab, ANT, The Netherlands). Offline analyses were carried out using Brain Vision Analyzer 1.05 (Brain Products GmbH, Germany) and LetsWave 4.0 (Université catholique de Louvain, Belgium). The continuous EEG recordings were band-pass filtered (0.3–30 Hz, 12 dB/octave) and segmented into 1,500-ms epochs (−500 to 1,000 ms relative to the onset of the nociceptive stimulus) for nociceptive ERPs and 2,000-ms epochs (−1,100 to 900 ms relative to the onset of the visual stimulus) for visual ERPs. Artifacts produced by eye blinks and eye movements were corrected using independent component analysis (ICA; Hyvarinen & Oja, 2000), and epochs with signal amplitude exceeding ± 100 μV were excluded (less than 8% of the total number of epochs per condition). Signals were rereferenced to
Visual-nociceptive crossmodal spatial attention the mastoid electrodes (M1-M2) and baseline corrected (from −500 to 0 ms for nociceptive ERPs; from −1,100 to 800 ms for visual ERPs). ERP data obtained in response to frequent nontarget visual stimuli and to rare target visual stimuli were analyzed separately. The dataset obtained from the nontarget trials was used to test the effect of spatial attention on the early stages of visual processing; the exclusion of target trials was used to avoid contamination by decision- and movement-related processes. The dataset obtained from the target trials was used to test the effect of spatial attention on late decisional processes (e.g., processes reflected by the parietal P3 wave) and to correlate these data to the behavioral data. In order to obtain a good signal-to-noise ratio of the ERPs to rare visual targets of the invalid condition, the data obtained in response to left- and right-sided visual stimuli were merged. Then, epochs were sorted and averaged according to the experimental conditions: left versus right hand for nociceptive ERPs; left versus right side*valid versus invalid trials for visual ERPs to nontargets; valid versus invalid for visual ERPs to targets. The identification of ERP components was based on the latency and scalp topography of the obtained peaks. Regarding nociceptive ERPs, a positive component was first identified between 250 and 400 ms after stimulus onset and measured at Cz, C3, and C4 (Legrain et al., 2002). This positive component was labeled according to its peak latency at Cz, that is, P320. Next, a negative component was isolated at the contralateral temporal electrode (T7 or T8) between 100 and 200 ms after stimulus onset. This negative component was labeled N150 and was also measured at the ipsilateral temporal electrode (T8 or T7) (Legrain et al., 2002). Electrocortical activities elicited by nociceptive stimuli at latencies greater than the P320 were also characterized. For this purpose, six successive time windows of 50 ms were arbitrarily defined between 500 and 800 ms (W1: 500–550 ms; W2: 550–600 ms; W3: 600–650 ms; W4: 650–700 ms; W5: 700– 750 ms; W6: 750–800 ms). Mean ERP amplitudes were measured for each time window over four scalp locations, obtained by pooling the following electrodes: frontal left (F3/F5/FC3/FC5), frontal right (F4/F6/FC4/FC6), parietal left (CP3/CP5/P3/P5), and parietal right (CP4/CP6/P4/P6). Regarding visual ERPs in response to nontarget stimuli, six components were successfully identified in most of the participants: C1 (or NP80; Rauss, Schwartz, & Pourtois, 2011) in 7 out of 10 participants, P1, N1, and P2 in all participants, N2 and P3 in 9 out of 10 participants. C1 was isolated as a negative peak at Pz and/or Oz at 70–90 ms after the onset of the visual stimulus. For each subject and experimental condition, an estimate of C1 magnitude was obtained by pooling and averaging separately amplitudes from electrodes over the left hemisphere (P3/O1), the midline (Pz/Oz), and the right hemisphere (P4/O2). P1 was identified as a positive component around 80–120 ms at contralateral occipital (O1/O2) and parieto-occipital (PO7/PO8) electrodes. P1 magnitude was measured by pooling and averaging separately amplitudes from electrodes over the left (PO7/O1) and right (PO8/O2) hemispheres. N1 was identified as a negative component around 100– 200 ms at contralateral parietal electrodes (CP5/CP6, P5/P6, and P7/P8). N1 magnitude was measured by pooling and averaging separately amplitudes from electrodes over the left (CP5/P5/P7) and right (CP6/P6/P8) hemispheres. P2 was identified as a positive component around 150–250 ms at Cz. Fz and Pz were also taken into account for analyses. Finally N2 (200–300 ms) and P3 (250– 500 ms) were identified at Fz and Cz, respectively. For these two late components, Fz, Cz, and Pz were taken into account for analyses. For all ERP components, peak latencies were measured
467 from stimulus onset, and peak amplitudes were measured from baseline to peak. Regarding visual ERPs in response to target stimuli, N2 (200– 300 ms) was identified in 9 out of the 10 participants and P3 (250–500 ms) was identified in all participants, at electrodes Fz, Cz, and Pz. Analyses Intensity of the nociceptive stimuli. In order to ensure that the intensity of IES delivered to each of the two hands was equivalent between the two hands, the maximum intensities used during the experiment were compared by means of a paired Student t test (left vs. right hand). Performance of the visual task. RTs, percentages of missed responses, and percentages of false alarms were compared using a 2-factor analysis of variance (ANOVA) for repeated measures with location of the visual stimuli (left vs. right) and spatial validity of the nociceptive cue (valid vs. invalid) as within-subject factors. Nociceptive ERPs. Amplitudes and latencies of the N150 and P320 components of nociceptive ERPs were compared using a 2-factor ANOVA for repeated measures with location of the nociceptive stimuli (left vs. right) and topography (contralateral [T7/T8] vs. ipsilateral [T8/T7] for N150; contralateral [C3/C4] vs. ipsilateral [C4/C3] vs. vertex [Cz] for P320) as within-subject factors. In order to characterize the topography of the ERPs elicited during the late time windows, the amplitudes measured at each time window (W1 to W6) were compared using ANOVA with location of the stimuli (left vs. right), coronal distribution (frontal vs. parietal), and lateral distribution (contralateral vs. ipsilateral) as within-subject factors (see Legrain, Perchet, & Garcia-Larrea, 2009, for the use of two topographic distribution factors with ANOVA). Visual ERPs. Amplitudes and latencies of the C1, P1, N1, P2, N2, and P3 components of visual ERPs to nontargets were compared using a 3-factor ANOVA for repeated measures with location of the visual stimuli (left vs. right), topography, and validity of the nociceptive cue (valid vs. invalid) as within-subject factors. The levels of the factor topography were contralateral versus ipsilateral versus midline for C1, contralateral versus ipsilateral for P1 and N1, frontal (Fz) versus central (Cz) versus parietal (Pz) for P2, N2, and P3. Amplitudes and latencies of the N2 and P3 components of the visual ERPs to targets were compared using a 2-factor ANOVA for repeated measures with topography (Fz vs. Cz vs. Pz) and validity (valid vs. invalid) as factors. In addition, correlation analyses were performed between N2 and P3 latencies and amplitudes and performance (percentage of missed responses, percentage of false alarms, RT). To achieve this, difference scores were computed by subtracting the data of the invalid condition from the data of the valid condition (left and right conditions were merged together). Pearson’s correlation coefficient was used. Significance level was set at p < .05. When appropriate, Greenhouse-Geisser corrections of degrees of freedom and tests of within-subjects contrasts were used. For contrasts, a Bonferroni correction was applied to ensure an overall Type I error below 0.05. Effect sizes were measured with partial eta-squared ( η2p ) for ANOVAs and Cohen’s d for t tests.
L. Favril et al. Results
Intensity of the Nociceptive Stimuli The maximal intensity of IES used during the experiment was 0.39 ± 0.09 mA for left-hand stimulation and 0.38 ± 0.11 mA for right-hand stimulation. This difference was not significant (t9 = .275, p = .790, d = .090) suggesting the intensity of IES was physically equivalent between the two hands. These values correspond to those used in previous studies that succeeded to selectively activate nociceptors (Colon et al., 2012; Inui et al., 2006; Mouraux et al., 2010), and are much lower than those used in studies that failed to show selective activation (de Tommaso et al., 2011). Performance of the Visual Task Figure 2 illustrates the performance of the visual task. Overall, participants made few errors (2.84% of missed responses, 2.42% of false alarms). Conversely to the results observed on the percentages of missed responses, F(1,9) = .110, p = .747, η2p = .012, and false alarms, F(1,9) = .678, p = .432, η2p = .070, there was a significant effect of the validity of the nociceptive cue on RTs, F(1,9) = 25.462, p = .001, η2p = .739, showing that participants responded with shorter RTs to visual targets preceded by a valid nociceptive cue than to visual targets preceded by an invalid nociceptive cue. Nociceptive ERPs Group-level average waveforms are shown in Figure 3. The mean latencies of the N150 and P320 components were not affected by any experimental factors (all p ≥ .057, all η2p ≤ .273 ). The location of the nociceptive stimulus had a nearly significant effect on the amplitude of the N150 component, F(1,9) = 5.042, p = .051, η2p = .359, suggesting slightly greater amplitudes following stimulation of the left hand as compared to the right hand. There was a significant effect of topography, F(1,9) = 11.095, p = .009, η2p = .552, showing that N150 amplitude was greater over the contralateral temporal electrode as compared to the ipsilateral temporal electrode. The amplitude of P320 was significantly affected by the factor topography, F(2,18) = 33.905, p < .001, η2p = .790: P320 amplitude was greater at Cz than at the contralateral, F(1,9) = 23.538, p = .003, η2p = .723, and ipsilateral, F(1,9) = 54.467, p < .001, η2p = .858, central electrodes. Interestingly, P320 amplitude was also greater at the contralateral than at the ipsilateral electrodes, F(1,9) = 9.724, p = .036, η2p = .519. Regarding the ERP signal elicited at later latencies (W1–W6), the analyses revealed that the factor coronal distribution was significant for the latest time windows (W5: F(1,9) = 5.332, p = .046, η2p = .372; W6: F(1,9) = 5.760, p = .040, η2p = .390) and not for the early ones (all p > .062, all η2p < .336 ). This is explained by the fact that the ERP signal was significantly more negative over parietal than over frontal sites between 700 and 800 ms. The factor lateral distribution was also significant during late time windows (W3: F(1,9) = 12.465, p = .006, η2p = .581; W4: F(1,9) = 10.720, p = .010, η2p = .544; W5: F(1,9) = 13.113, p = .006, η2p = .593; W6: F(1,9) = 10.474, p = .010, η2p = .538) and not during the earliest time windows (all p > .087, all η2p < .290 ), suggesting greater ERP signal over the contralateral than the ipsilateral hemisphere during the 600–800 ms time window. To summarize, nociceptive stimuli randomly applied to the left and right hands elicited ERPs characterized by a lateralized tem-
Figure 2. Behavioral performance in the visual task. The graphics illustrate (A) the percentages of missed responses (i.e., absence of response to target visual stimuli), (B) the percentages of false alarms (i.e., responses to nontarget visual stimuli), and (C) the mean RTs to target visual stimuli, in response to left-sided (left) and right-sided (right) visual stimuli, following either a valid cueing (in white) and an invalid cueing (in dark gray) nociceptive stimulus. Error bars represent standard deviations corrected according to the method of Cousineau (2005).
poral negativity and a vertex positivity (N150 and P320) whose magnitudes were greater over the hemisphere contralateral to the stimulated hand. Furthermore, following P320, the elicited ERP signals were characterized by a long-lasting negative potential more prominent over the contralateral parietal region of the scalp. Visual ERPs Group-level average ERPs to nontarget visual stimuli are shown in Figure 4. None of the latencies of the visual ERP components were
Visual-nociceptive crossmodal spatial attention
Figure 3. Nociceptive event-related potentials. Green, dark gray, and orange waveforms represent the ERPs recorded, respectively, over the contralateral hemisphere, the vertex, and the ipsilateral hemisphere, in response to nociceptive stimuli applied to the left hand (left) and the right hand (right). Activities recorded at frontocentral (FC5/FC6), temporal (T7/T8), vertex (Cz), and parietal (P3/P4) electrodes are illustrated. The two main ERP components, N150 and P320, are outlined by the gray boxes and depicted by their respective scalp topography. At a later latency, the ERP signal delimited by a gray box was divided into six time windows of 50 ms, from 500 to 800 ms (W1 to W6). Such ERP signal was characterized by the progressive appearance of a sustained negative-going activity mainly over the contralateral parietal part of the scalp. The topographies of the mean amplitude of each successive time window are illustrated at the bottom.
significantly affected by experimental factors (all p ≥ .214, all η2p ≤ .166 ). Figure 5 illustrates the mean amplitudes for each component of the visual ERPs. Regarding C1 amplitude, there was a main effect of the factor topography, F(2,12) = 10.408, p = .002, η2p = .634, suggesting that C1 amplitude was smaller at contralateral than at midline, F(1,6) = 16.291, p = .014, η2p = .731, and ipsilateral, F(1,6) = 10.741, p = .034, η2p = .642, electrodes. The P1 amplitude was unaffected by the experimental factors (all p ≥ .096; all η2p ≤ .279 ). Conversely, N1 amplitude was greater over the contralateral hemisphere as compared to the ipsilateral hemisphere, F(1,9) = 28.261, p < .001, η2p = .758, and, most importantly, was significantly affected by the validity of the nociceptive cue: N1 amplitude was greater when the visual stimuli appeared on the validly cued side as compared to when they appeared on the invalidly cued side, F(1,9) = 10.642, p = .010, η2p = .542. P2 amplitude was also affected by the validity of the nociceptive cue with a smaller (i.e., less positive) amplitude for stimuli presented on the validly cued side as compared to stimuli presented on the invalidly cued side, F(1,9) = 13.855, p = .005, η2p = .606. N2 amplitude was affected by the validity of the nociceptive cue, F(1,8) = 9.852, p = .014, η2p = .552, and this factor significantly interacted with the factor topography, F(2,16) = 6.688, p = .008, η2p = .455. This suggests that the difference between valid and invalid trials was not
similar at the different electrodes. Indeed, valid trials increased N2 amplitude at electrodes Fz, F(1,8) = 9.798, p = .042, η2p = .5511, and Cz, F(1,8) = 12.875, p = .021, η2p = .617, but not at electrode Pz, F(1,9) = 2.635, p = .429, η2p = .288. Finally the only significant result regarding P3 amplitude was the effect of the factor topography, F(2,16) = 12.716, p < .001, η2p = .614, reflecting a greater P3 amplitude at Cz than at Fz, F(1,8) = 16.357, p = .008, η2p = .672, and Pz, F(1,8) = 24.692, p = .002, η2p = .755. Group-level average ERPs to visual target stimuli are shown in Figure 6. Only the latency of the P3 was significantly affected by the factor topography, F(2,18) = 5.041, p = .018, η2p = .359: P3 latency was shorter at Fz than at Pz, F(1,9) = 13.822, p = .010, η2p = .606. Regarding amplitudes, N2 and P3 were not affected by the validity of the nociceptive cue (respectively, F(1,8) = .418, p = .536, η2p = .050; F(1,9) = .886, p = .371, η2p = .090. The significant effect of topography on P3 amplitude, F(1,9) = 15.567, p < .001, η2p = .634, is explained by a greater P3 amplitude at Pz than at Fz, F(1,9) = 18.874, p = .004, η2p = .677, and Cz, F(1,9) = 19.863, p = .004, η2p = .688. None of the ERP data correlated significantly with behavioral data (all |r| ≤ .543, all p ≥ .131) with the exception of the amplitude of P3 at Pz and the percentage of missed response (r = −.759, p = .018) suggesting that the larger the difference in P3 amplitude between valid and invalid
L. Favril et al.
Figure 4. Visual event-related potentials induced by the nontarget stimuli. Blue and red waveforms represent the ERPs recorded in response to nontarget visual stimuli in the valid and the invalid conditions, respectively; that is, when the preceding nociceptive stimulus was delivered either to the same side or to the opposite side of space. Left: ERPs elicited by visual stimuli delivered in the vicinity of left hand. Right: ERPs elicited by visual stimuli delivered in the vicinity of right hand. Activities recorded at frontal and central electrodes over the midline (Fz and Cz) as well as at lateral parietal (P5/P6) and occipital (O1/O2) electrodes are illustrated. The different components of the visual ERPs are outlined by the gray boxes. Their respective topographies are illustrated at the bottom according to the cueing conditions: valid trials in the blue squares, invalid trials in the red squares. Note that the topography of the N2 component was masked by those of the P2 and P3 components in most of the conditions and could not be clearly illustrated.
conditions, the smaller the difference in the percentage of missed responses. To summarize, the magnitude of the N1, P2, and N2 components of ERPs obtained in response to the nontarget visual stimuli were significantly modulated by the validity of the preceding nociceptive cue. In contrast, the earlier (C1, P1) and later (P3) components of visual ERPs were not affected by the location of the nociceptive cue. Discussion The present experiment tested the existence of a crossmodal link between nociception and vision in spatial attention. More specifi-
cally, we tested whether nociceptive stimuli applied to one hand were able to orient spatial attention in the external space and to modify the processing and the response to visual stimuli delivered in the proximity of the stimulated hand. In accordance with our hypothesis, participants responded more quickly to a visual target when it was preceded by a valid nociceptive cue, and the magnitude of the visual ERPs was significantly modulated by its location relative to that of the nociceptive cue. The effect of the validity of the nociceptive cue on the response to the visual stimulus was characterized by a more negative ERP signal from 150 ms to 300 ms after stimulus onset (i.e., at latencies corresponding to the visual N1, P2, and N2 components). Additionally, we found that the magnitude of the ERPs elicited by nociceptive
▶ Figure 5. Mean peak amplitudes of the visual ERPs induced by the nontarget stimuli. The graphics illustrate the mean peak amplitude of each component of the visual ERPs in response to nontarget visual stimuli, delivered in the vicinity of the left hand (left) and in the vicinity of the right hand (right), in the valid (white) and the invalid (dark gray) conditions, respectively, measured over different scalp sites. LHM = pooled mean amplitude of the electrodes over left hemisphere (C1: P3/O1; P1: PO7/O1; N1: CP5/P5/P7); MID = pooled mean amplitude of the electrodes of the sagittal midline (C1: Pz/Oz); RHM = pooled mean amplitude of the electrodes over right hemisphere (C1: P4/O2; P1: PO8/O2; N1: CP5/P5/P7). The components for which the mean amplitude was significantly modulated by the validity of the nociceptive cue are outlined by the gray box. Error bars represent standard deviations corrected according to the method of Cousineau (2005).
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L. Favril et al. cues was significantly greater over the hemisphere contralateral to the stimulated hand. Taken together, these behavioral and electrophysiological observations support the notion that nociceptive stimuli delivered to a given body part draw attention towards the adjacent side in the visual external space.
Behavioral Responses to the Visual Cued Stimuli Cueing paradigms have been extensively used to explore the mechanisms of spatial attention. Studies using such paradigms have contributed to dissociate two types of spatial attention mechanism: stimulus-driven exogenous attention and expectancydirected endogenous attention (see Posner & Cohen, 1984). Typically, the former is explored using nonpredictive lateralized cues (i.e., the location of the cue is not predictive of the location of the forthcoming target) and is observed within a short time interval following the onset of the cue (often less than 200 ms; Klein, 2000). The latter is effective at longer time intervals and is investigated using symbolic central cues (e.g., an arrow) or lateralized cues that are actually predictive of the most probable location of the forthcoming target, although those cues can also orient attention exogenously. Here, in response to visual targets, RTs were shorter when the visual targets were flashed at the side of the stimulated hand as compared to when they were flashed at the side of the opposite hand. This is highly consistent with data observed in previous studies, both in unimodal (Posner, 1980) and crossmodal (Spence, McDonald, & Driver, 2004) cueing paradigms. In experiments using tactile cues, behavioral responses to visual or auditory targets were faster when they were delivered near the stimulated hand as compared to conditions in which the opposite hand was stimulated (Kennett, Eimer, Spence, & Driver, 2001; Spence et al., 1998). It should be noted that, in the present experiment, the time interval between the nociceptive and visual stimuli was relatively long (800 ms) and the location of the cue was predictive of the location of the visual stimulus. Therefore, the observed effect was probably mainly the result of endogenous (i.e., goal-directed) spatial orienting mechanisms (Müller & Rabbit, 1989).
ERPs Elicited by the Cued Nontarget Visual Stimuli
Figure 6. Visual event-related potentials induced by the target stimuli. Blue and red waveforms represent the ERPs recorded at Fz, Cz, and Pz in response to target visual stimuli in the valid and the invalid conditions, respectively. ERPs recorded in response to the stimulation of the left and the right hands are pooled together. The respective topographies of the N2 and P3 components are illustrated at the bottom according to the cueing conditions: valid trials in blue squares, invalid trials in red squares. Note that the topography of the P3 component evoked by the target visual stimuli is more posterior than the topography of the P3 component evoked by the nontarget visual stimuli (see Figure 5). Because the topography of the N2 component was masked by those of the P2 and P3 components in the invalid condition, its topography could not be clearly illustrated in that condition.
In addition to the observed behavioral effects, the ERPs elicited by the visual stimuli were significantly affected by the congruency between the spatial location of the nociceptive cue and the spatial location of the visual stimulus. When the visual stimulus was delivered in the vicinity of the hand onto which the nociceptive stimulus was applied, the magnitude of the visual ERP signal was more negative during the 150–300 ms time interval following the presentation of the visual stimulus (i.e., at the latencies of the N1, P2, and N2 components of visual ERPs), as compared to when the visual stimulus was delivered to the opposite hand. Crucially, the fact that earlier C1 and P1 components were not modulated by the location of the nociceptive cues rules out the possibility that the effect of the nociceptive cue on the magnitude of the visual ERPs was artifactually produced by late overlapping responses to the nociceptive stimulus. Studies using predictive lateralized cues in unimodal visuospatial attention paradigms have also shown an enhancement of the ERPs elicited by validly cued visual stimuli in the latency range of N1 and N2 components, but have reported inconsistent results regarding the earlier P1 component (Anllo-Vento, 1995; Doallo et al., 2004,
Visual-nociceptive crossmodal spatial attention 2005; Fu, Fan, Chen, & Zhuo, 2001; Hillyard, Luck, & Mangun, 1994; Luck et al., 1994). To our knowledge, the only ERP study that has investigated the effect of somatosensory cues on the processing of nonsomatic stimuli was conducted by Kennett et al. (2001). This study showed that nonpredictive tactile stimulation of the hands speeded the RTs and enhanced the magnitude of the ERPs elicited by visual stimuli presented near the stimulated hand. Importantly, although the paradigm used by Kennett et al. induced exogenous shifts of spatial attention whereas the present paradigm induced endogenous shifts of spatial attention, the enhancement of the magnitude of the ERPs by spatial congruency was observed in the same time intervals. Similarly, Eimer & van Velzen (2005) showed that the enhancement of the visual N1 component at the cued side was dependent on the spatial proximity between the stimulated body limb and the visual stimulus. The modulation of visual ERPs as early as the N1 component confirms that the location of a nociceptive stimulus can modulate the sensory processing of visual inputs and is compatible with the hypothesis of a crossmodal modulation of unimodal processing (Eimer & Driver, 2001; Macaluso & Driver, 2001; Macaluso, Frith, & Driver, 2005). Indeed, there is evidence that the visual N1 component is partially generated in the extrastriate cortex in ventral occipitotemporal and occipitoparietal areas (Clark, Fan, & Hillyard, 1995; Clark & Hillyard, 1996; Gomez Gonzales, Clark, Fan, Luck, & Hillyard, 1994). The present modulation of the amplitude of the visual N1 component by the location of nociceptive cues, without any significant change of its latency or topography, is in favor of a sensory gain control hypothesis according to which selective attention amplifies neural activity involved in processing the attended inputs (Hillyard, Vogel, & Luck, 1998). This is in accordance with fMRI studies showing that tactile attention affects the activity of the visual cortex (Macaluso, Frith, & Driver, 2000, 2002). An alternative explanation to the enhancement of N1 magnitude could be that this enhancement was not the consequence of a genuine enhancement of the activity of its generators. Instead, it could be due to an overlap of so-called selection negativities generated in separate brain areas (Johannes, Münte, Heinze, & Mangun, 1995; Kennett et al., 2001). These negativities have been interpreted as being equivalent to the processing negativity, largely explored in the auditory modality and thought to reflect filtering and matching operations between incoming sensory inputs and mnesic traces of the task-relevant features of the expected target (Näätänen, 1990). According to this hypothesis, attentional selection would act by maintaining a mnesic template of the attended features of the stimuli. Each new sensory input would be compared to the template. The processing negativity would reflect a period of increased cortical excitation induced by the matching operation, while its absence would reflect the rejection of the unattended stimuli. This second explanation would be supported by the finding that the magnitude of the P2 component was not increased, but decreased by the validity of the nociceptive cue. In other words, the amplitude of the P2 component could be more negative due to the overlap of a negative component.
ERPs Elicited by the Cued Target Visual Stimuli We might have expected that the amplitude of the N2 component and, even more so, the amplitude of the P3 component elicited by the visual target stimuli would be enhanced when the target
473 occurred at the validly cued side, as compared to when it occurred at the invalidly cued side. Indeed, this would mean that the late decision processes—reflected by P3 (Donchin & Coles, 1988; Verleger, 1988)—benefited from early attentional selection (Mangun, 1995). However, the absence of a significant effect on P3 amplitude is not surprising when one considers the results of previous studies (e.g., Fu et al., 2001), having found the opposite, that is, significantly enhanced P3 amplitudes in response to invalid targets as compared to valid targets (Eimer, 1994; Hillyard et al., 1994; Mangun & Hillyard, 1991). Several hypotheses can be put forward. First, some compensation mechanisms are possible at late processing stages in order to correctly identify targets at the uncued sides. Second, the effect on P3 could have been masked too by the possible selection negativities (see paragraph 2 of the previous section). However, these interpretations must be taken with caution, especially because of the difference in probability of occurrence between valid versus invalid trials. Indeed, the probability of occurrence of a sensory event contributes largely to the amplitude of the P3 component (Donchin, 1981). Therefore, it could be that the benefit of early attentional selection on the P3 evoked by the visual targets delivered at the validly cued side were masked by the effect of novelty on the P3 evoked by the visual targets delivered at the invalidly cued side.
ERPs Elicited by the Nociceptive Cueing Stimulus In the present experiment, nociceptive ERPs were elicited by IES (Inui et al., 2002), a method allowing selective activation of skin nociceptors, provided that a very strict stimulation procedure is followed to avoid coactivation of mechanoreceptors involved in the perception of innocuous vibrotactile sensations (Colon et al., 2012; Legrain & Mouraux, 2013; Mouraux et al., 2010). Nociceptive IES induced mainly a negative ERP component (N150) followed by a positive component (P320), occurring approximately 130 and 330 ms after stimulus onset. The topography of the N150 component was maximal over the contralateral temporal region of the scalp, whereas the P320 component was mainly localized at the vertex. The latency and the topography of the P320 of the present ERPs are highly similar to those of the P2 component elicited by infrared laser stimulation of heat-sensitive skin nociceptors (Kakigi, Shibasaki, & Ikeda, 1989; Kunde & Treede, 1993; Miyazaki et al., 1994; Spiegel, Hansen, & Treede, 1996; Treede, Kief, Hölzer, & Bromm, 1988; Valeriani, Rambaud, & Mauguière, 1996; Xu et al., 1995). Conversely, the scalp topography of the N150 component, that is, the main negative component of the present nociceptive ERPs, contrasts with the symmetrical distribution of the N2 component of the nociceptive laser-evoked potentials (the lateralized component, N1, is often masked in the ascending slope of N2). However, the N2 component of laser-evoked potentials is most likely to reflect activity generated in bilateral cortical structures (Garcia-Larrea, Frot, & Valeriani, 2003), and has been shown to exhibit a lateralized topography contralateral to the stimulation site (e.g., Kanda et al., 1999), especially when the spatial location of the nociceptive stimuli constitutes a relevant feature of the task (Bentley et al., 2004; Legrain et al., 2002; Legrain, Bruyer, Guérit, & Plaghki, 2003). Similarly, the scalp topography of the present P320 component, despite its maximum amplitude at the scalp vertex, was also greater over the contralateral than over the ipsilateral hemisphere. It suggests that, in the present experimental conditions, because of the relevance of space for the task, the contralateral sources of nociceptive ERPs were the
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dominant contributors, more than the other sources, to the scalprecorded waveforms. Interestingly, we identified a late-latency component of nociceptive ERPs consisting in a sustained negative signal occurring approximately 700–800 ms after stimulus onset, with contralateral parietal scalp topography. In unimodal visual cueing paradigms, such late lateralized signals have been shown following the occurrence of a visual cue, and have been suggested to index mechanisms involved in the control and direction of spatial attention (Harter & Anllo-Vento, 1991; Harter, Miller, Price, LaLonde, & Keyes, 1989; Hopf & Mangun, 2000; Mangun, 1994; Nobre, Sebestyen, & Miniussi, 2000). Such late lateralized activities have also been described in crossmodal cueing paradigms, over the hemisphere contralateral to the cued side whatever the sensory modality of the cue and target stimuli, suggesting that these ERP signals reflect supramodal attentional mechanisms (Eimer et al., 2002; Eimer, Forster, Fieger, & Harbich, 2004; Eimer, Forster, & van Velzen, 2003; Eimer, van Velzen, Forster, & Driver, 2003). According to these authors, the parietal response could reflect mapping mechanisms using an egocentric frame of reference based on external space. Therefore, we might hypothesize that the late lateralized negative signal observed following presentation of the nociceptive cue could reflect cortical mechanisms underlying the displacement of spatial attention on the basis of nonanatomical spatial coordinates in order to integrate direct stimulation of the body and nearby external stimuli in the same mapping frame. Possible Mechanisms for Crossmodal Spatial Attention Between Nociception and Vision A possible mechanism underlying the crossmodal effect of spatial attention could rely on the existence of multimodal frames of reference integrating the space of the body and the proximal part of external space (Làdavas, di Pellegrino, Farnè, & Zeloni, 1998; Rizzolatti, Fadiga, Fogassi, & Gallese, 1997; Sambo & Forster, 2009; Spence, Pavani, & Driver, 2004). Regarding touch, such a hypothesis is supported by the identification of multimodal neurons in the monkey premotor and parietal cortices (Duhamel, Colby, & Goldberg, 1998; Graziano & Gross, 1994; Graziano, Hu, & Gross, 1997; Graziano, Yap, & Gross, 1994; Rizzolatti, Scandolara, Matelli, & Gentilucci, 1981). In humans, motor/premotor and parietal areas have been found to respond to nociceptive and painful stimulation (e.g., Bornhövd et al., 2002; Coghill, Sang, Maisog, & Iadarola, 1999; Longo, Iannetti, Mancini, Driver, & Haggard, 2012; Nakata et al., 2008; Peyron et al., 2007). Dong, Chudler, Sugiyama, Roberts, and Hayashi (1994) found neurons responding to both nociceptive and proximal visual stimuli in the monkey inferior parietal lobe (area 7b). Until now, such evidence is lacking in
humans, despite the fact that several studies have emphasized that the posture and the vision of the limb on which a noxious stimulus is applied modulates the stimulus-evoked neural responses and pain perception (Longo, Betti, Aglioti, & Haggard, 2009; Longo et al., 2012; Mancini, Longo, Kammers, & Haggard, 2011; Moseley, Parsons, & Spence, 2008; Sambo, Forster, Williams, & Iannetti, 2012; Sambo, Liang, Cruccu, & Iannetti, 2012). Importantly, the present results should not be considered as conclusive evidence for the existence of a peripersonal frame for coding the spatial location of nociceptive inputs. In the present experiment, we used a cueing paradigm with a long cue-to-target time interval. Because stimulus-driven exogenous attention is short-lived, it cannot be observed with a long time interval (Hopfinger & Mangun, 1998; Klein, 2000; Müller & Rabbit, 1989). For this reason, we induced expectancy-driven endogenous attention by rendering the cues predictive of the actual location of the upcoming target (the target visual stimuli occurred more often at the cued side than at the opposite side) (Hillyard et al., 1994; Luck et al., 1994). This approach was preferred to the use of shorter interstimulus intervals, as the temporal overlap of activities elicited by the nociceptive cue and activities elicited by the visual target would have rendered the interpretation of results very difficult. In addition, the use of long interstimulus intervals allowed us to explore the long-latency activities induced by the nociceptive cues (Eimer et al., 2002, 2004; Eimer, Forster, & van Velzen, 2003; Eimer, van Velzen et al., 2003). Therefore, the results of this study do not allow us to definitively conclude that the observed effect of the cue on the behavioral and electrophysiological responses to the visual stimuli were due to direct stimulus-driven capture of attention by the nociceptive stimuli or by knowledge that the location of a nociceptive stimulus predicted the location of the upcoming visual target. Conclusion The present study demonstrates a crossmodal interaction in spatial attention between nociception and vision. More specifically, the study shows that a nociceptive stimulus can orient attention toward the space beyond the body. Such an interaction between vision and nociception could improve the ability to localize and act efficiently against potentially damaging stimuli. Further investigations are needed to understand which frames of reference are responsible for such crossmodal interactions. Because it has been shown that modification of spatial perception is able to alleviate pain and improve sensory-motor functioning in chronic pain patients (Bultitude & Rafal, 2010; Sumitani et al., 2007), understanding the interactions may open new perspectives to develop pain rehabilitation techniques grounded on evidence-based models of cognitive psychology.
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