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Background: Patients suffering from complex regional pain syndrome (CRPS) are increasingly shown to be affected by cognitive difficulties. While these cognitive symptoms were initially described as limited to the perception, representation and use of the body, that is, the somatic space, they were recently shown to also extend to the perception of extra-somatic space. CRPS patients seem indeed to pay less attention to visual stimuli occurring in the same side of space as their affected limb and especially those occurring close to that limb. The aim of the present study was to more precisely characterize these visuospatial biases, by investigating whether they may be dependent on the visually perceived proximity between the visual stimuli and the affected limb., Methods: Upper-limb CRPS patients and matched control participants performed temporal order judgements on visual stimuli, one presented in either side of space, while they could either see their hands near the visual stimuli or not., Results: Visuospatial biases were not modulated by the availability of visual feedback about the hands. However, secondary analyses revealed that these biases depended on the type of rehabilitation program that the patients followed: whereas patients who did not follow any specific program presented significant biases to the detriment of visual stimuli in the affected side of space, patients who did follow a CRPS-specialized program did not., Conclusions: Patients' cognitive strategies will be important to consider when studying inter-individual differences in the cognitive symptomatology and associated cognitive-based rehabilitation procedures in CRPS., Significance: The existence of biases in visuospatial perception in Complex Regional Pain Syndrome has been reported but not always systematically replicated. We show that these biases might depend on the type of general rehabilitation program that the patients follow. Patients' individual cognitive strategies will be important to consider when studying the cognitive symptomatology of CRPS., (© 2023 European Pain Federation - EFIC ®.)

To protect our body against physical threats, it is important to integrate the somatic and extra-somatic inputs generated by these stimuli. Temporal synchrony is an important parameter determining multisensory interaction, and the time taken by a given sensory input to reach the brain depends on the length and conduction velocity of the specific pathways through which it is transmitted. Nociceptive inputs are transmitted through very slow conducting unmyelinated C and thinly myelinated Aδ nociceptive fibers. It was previously shown that to perceive a visual stimulus and a thermo-nociceptive stimulus applied on the hand as coinciding in time, the nociceptive stimulus must precede the visual one by 76 ms for nociceptive inputs conveyed by Aδ fibers and 577 ms for inputs conveyed by C fibers. Since spatial proximity is also hypothesized to contribute to multisensory interaction, the present study investigated the effect of spatial congruence between visual and nociceptive stimuli. Participants judged the temporal order of visual and nociceptive stimuli, with the visual stimuli flashed either next to the stimulated hand or next to the opposite unstimulated hand, and with nociceptive stimuli evoking responses mediated by either Aδ or C fibers. The amount of time by which the nociceptive stimulus had to precede the visual stimulus for them to be perceived as appearing concomitantly was smaller when the visual stimulus occurred near the hand receiving the nociceptive stimulus as compared to when it occurred near the contralateral hand. This illustrates the challenge for the brain to process the synchrony between nociceptive and non-nociceptive stimuli to enable their efficient interaction to optimize defensive reaction against physical dangers., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Central sensitization refers to the increased responsiveness of nociceptive neurons in the central nervous system after repeated or sustained peripheral nociceptor activation. It is hypothesized to play a key role in the development of chronic pain. A hallmark of central sensitization is an increased sensitivity to noxious mechanical stimuli extending beyond the injured location, known as secondary hyperalgesia. For its ability to modulate the transmission and the processing of nociceptive inputs, attention could constitute a promising target to prevent central sensitization and the development of chronic pain. It was recently shown that the experimental induction of central sensitization at both forearms of healthy volunteers using bilateral high-frequency electrocutaneous stimulation (HFS), can be modulated by encouraging participants to selectively focus their attention to one arm, to the detriment of the other arm, resulting in a greater secondary hyperalgesia on the attended arm as compared to the unattended one. Given the potential value of the question being addressed, we conducted a preregistered replication study in a well-powered independent sample to assess the robustness of the effect, i.e., the modulatory role of spatial attention on the induction of central sensitization. This hypothesis was tested using a double-blind, within-subject design. Sixty-seven healthy volunteers performed a task that required focusing attention toward one forearm to discriminate innocuous vibrotactile stimuli while HFS was applied on both forearms simultaneously. Our results showed a significant increase in mechanical sensitivity directly and 20 min after HFS. However, in contrast to the previous study, we did not find a significant difference in the development of secondary hyperalgesia between the attended vs. unattended arms. Our results question whether spatial selective attention affects the development of secondary hyperalgesia. Alternatively, the non-replication could be because the bottom-up capture of attention caused by the HFS-mediated sensation was too strong in comparison to the top-down modulation exerted by the attentional task. In other words, the task was not engaging enough and the HFS pulses, including those on the unattended arm, were too salient to allow a selective focus on one arm and modulate nociceptive processing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Della Porta, Vilz, Kuzminova, Filbrich, Mouraux and Legrain.)

Spatial locations of somatosensory stimuli are coded according to somatotopic (anatomical distribution of the sensory receptors on the skin surface) and spatiotopic (position of the body parts in external space) reference frames. This was mostly evidenced by means of temporal order judgment (TOJ) tasks in which participants discriminate the temporal order of two tactile stimuli, one applied on each hand. Because crossing the hands generates a conflict between anatomical and spatial responses, TOJ performance is decreased in such posture, except for congenitally blind people, suggesting a role of visual experience in somatosensory perception. In previous TOJ studies, stimuli were generally presented using the method of constant stimuli-that is, the repetition of a predefined sample of stimulus-onset asynchronies (SOA) separating the two stimuli. This method has the disadvantage that a large number of trials is needed to obtain reliable data when aiming at dissociating performances of groups characterized by different cognitive abilities. Indeed, each SOA among a large variety of different SOAs should be presented the same number of times irrespective of the participant's performance. This study aimed to replicate previous tactile TOJ data in sighted and blind participants with the adaptive psi method in order to validate a novel method that adapts the presented SOA according to the participant's performance. This allows to precisely estimate the temporal sensitivity of each participant while the presented stimuli are adapted to the participant's individual discrimination threshold. We successfully replicated previous findings in both sighted and blind participants, corroborating previous data using a more suitable psychophysical tool., (© 2021. The Psychonomic Society, Inc.)

Abstract: Complex regional pain syndrome (CRPS) is thought to be characterized by cognitive deficits affecting patients' ability to represent, perceive, and use their affected limb as well as its surrounding space. This has been tested, among others, by straight-ahead tasks testing oneself's egocentric representation, but such experiments lead to inconsistent results. Because spatial cognitive abilities encompass various processes, we completed such evaluations by varying the sensory inputs used to perform the task. Complex regional pain syndrome and matched control participants were asked to assess their own body midline either visually (ie, by means of a moving visual cue) or manually (ie, by straight-ahead pointing with one of their upper limbs) and to reach and point to visual targets at different spatial locations. Although the 2 former tasks only required one single sensory input to be performed (ie, either visual or proprioceptive), the latter task was based on the ability to coordinate perception of the position of one's own limb with visuospatial perception. However, in this latter task, limb position could only be estimated by proprioception, as vision of the limb was prevented. Whereas in the 2 former tasks CRPS participants' performance was not different from that of controls, they made significantly more deviations errors during the visuospatial task, regardless of the limb used to point or the direction of pointing. Results suggest that CRPS patients are not specifically characterized by difficulties in representing their body but, more particularly, in integrating somatic information (ie, proprioception) during visually guided movements of the limb., (Copyright © 2020 International Association for the Study of Pain.)

Multisensory interactions between pain and vision allow us to adapt our behavior to optimize detection and reaction against bodily threats. Interactions between different sensory inputs are enhanced when they are perceived closely in space and time. However, thermo-nociceptive and visual stimuli are conveyed to the cortex through specific pathways with their own conduction velocity. The present experiment aims to measure the necessary asynchrony between a nociceptive stimulus and a visual stimulus for both to be perceived as occurring simultaneously. Healthy volunteers performed a temporal order judgment task during which they discriminated the temporal order between a laser-induced nociceptive stimulus applied on one hand dorsum and a visual stimulus presented next to the stimulated hand. Laser stimulus temperature selectively activated Aδ- and/or C- fiber afferents. In order to be perceived as occurring simultaneously with a visual stimulus, a thermo-nociceptive input selectively conveyed by C-fiber afferents must precede the visual stimulus by 577 ms on average, while the stimulus-evoked input conveyed by Aδ-fiber afferents must precede it by 76 ms on average. This experiment focuses on the necessary asynchrony between thermo-nociceptive and visual inputs for them to be perceived simultaneously, to optimize the conditions under which they interact closely. Since C-fibers are unmyelinated, the asynchrony between a C-fiber stimulus and a visual stimulus is much greater than the asynchrony between a nociceptive stimulus additionally activating Aδ-fibers and that same visual stimulus. It is crucial to consider these discrepancies in further studies interested in multisensory interactions., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Examining the mechanisms underlying crossmodal interaction between nociceptive and visual stimuli is crucial to understand how humans handle potential bodily threats in their environment. It has recently been shown that nociceptive stimuli can affect the perception of visual stimuli, provided that they occur close together in external space. The present study addresses the question whether these crossmodal interactions between nociceptive and visual stimuli are mediated by the visually perceived proximity between the visual stimuli and the limb on which nociceptive stimuli are applied, by manipulating the presence vs. absence of visual feedback about the position of the stimulated limb. Participants performed temporal order judgments on pairs of visual stimuli, shortly preceded by nociceptive stimuli, either applied on one hand or both hands simultaneously. The hands were placed near the visual stimuli and could either be seen directly, seen through a glass barrier, or hidden from sight with a wooden board. Unilateral nociceptive stimuli induced spatial biases to the advantage of visual stimuli presented near the stimulated hand, which were greater in the conditions in which the hands were seen than in the condition in which vision was prevented. Spatial biases were not modulated by the presence of the glass barrier, minimizing the possibility that the differential effect between the vision and no-vision conditions is solely due to the presence of the barrier between the hands and the visual stimuli. These findings highlight the importance of visual feedback for determining spatial mapping between nociceptive and visual stimuli for crossmodal interaction.

Intense or sustained activation of peripheral nociceptors can induce central sensitization. This enhanced responsiveness to nociceptive input of the central nervous system primarily manifests as an increased sensitivity to painful mechanical pinprick stimuli extending beyond the site of injury (secondary mechanical hyperalgesia) and is thought to be a key mechanism in the development of chronic pain, such as persistent post-operative pain. It is increasingly recognized that emotional and cognitive factors can strongly influence the pain experience. Furthermore, through their potential effects on pain modulation circuits including descending pathways to the spinal cord, it has been hypothesized that these emotional and cognitive factors could constitute risk factors for the susceptibility to develop chronic pain. Here, we tested whether, in healthy volunteers, the experimental induction of central sensitization by peripheral nociceptive input can be modulated by selective spatial attention. While participants performed a somatosensory detection task that required focusing attention towards one of the forearms, secondary hyperalgesia was induced at both forearms using bilateral and simultaneous high-frequency electrical stimulation (HFS) of the skin. HFS induced an increased sensitivity to mechanical pinprick stimuli at both forearms, directly (T1) and 20 min (T2) after HFS, confirming the successful induction of secondary hyperalgesia at both forearms. Most importantly, at T2, the HFS-induced increase in pinprick sensitivity as well as the area of secondary hyperalgesia was greater at the attended arm as compared to the non-attended arm. This indicates that top-down attentional factors can modulate the development of central sensitization by peripheral nociceptive input, and that the focus of spatial attention, besides its modulatory effects on perception, can affect activity-dependent neuroplasticity., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Complex Regional Pain Syndrome (CRPS) is characterized by pain, motor and inflammatory symptoms usually affecting one limb. Cognitive difficulties have been reported to affect patients' ability to represent, perceive and use their affected limb. It is debated whether these difficulties result from deficits in controlling goal-directed movements in space or from a learned strategy to protect the affected limb. In order to dissociate the two hypotheses, patients with upper-limb CRPS were asked to move with their unaffected hand towards visual targets projected at different positions on a horizontal semi-reflexive mirror. By means of a robotic handle placed below the screen, they were asked to move a cursor, to reach and cross lines at their estimated midpoint. In some of the stimulation series, the affected hand was placed below the mirror so that some lines appeared projected onto that hand. Vision of the hands and the robotic handle was preserved or prevented by opening or closing a shutter below the mirror. Lines were displayed on the mirror according to which part of the body was affected (ispi- vs. contralateral) and the actual position of the affected hand (inside vs. outside the workspace). Comparatively to control participants, CRPS patients generally biased their estimation by bisecting the lines towards their left side, irrelative of which part of the body was affected and the position of the affected hand, both in ipsi- and contralateral space, with only a few exceptions. Our results are in line with previous studies having described a visuospatial deficit in CRPS patients and discard the explanation of observed symptoms in terms of learned nonuse strategies, as only the unaffected hand was used to perform the task. It is suggested that CRPS patients can display difficulties to perform tasks requesting visuo-motor coordination, reflecting the complex cortical reorganization occurring in CRPS., Competing Interests: The authors have declared that no competing interests exist.

Nociception, the physiological mechanisms specifically processing information about noxious and potentially painful stimuli, has the double function to warn about potential body damages (interoception) and about the cause of such potential damages (exteroception). The exteroceptive function is thought to rely on multisensory integration between somatic and extra-somatic stimuli, provided that extra-somatic stimuli occur near the stimulated body area. To corroborate this hypothesis, we succeeded to show in healthy volunteers that the perception of nociceptive stimuli applied on one hand can be extinguished, as compared to single presentation, by the simultaneous application of nociceptive stimuli on the opposite hand, as well as by the presentation of visual stimuli near the opposite hand. On the contrary, visual stimuli presented near the same stimulated hand facilitated the perception of nociceptive stimuli. This nociceptive extinction phenomenon indicates that the perception of noxious events does not merely rely on the specific activation of the nociceptive system, but also depends on other sensory experiences about the body and the space around it., (Copyright © 2019 Elsevier B.V. All rights reserved.)

How we perceive our body is shaped by sensory experiences with our surrounding environment, as witnessed by poor performance in tasks during which participants judge with their hands crossed the temporal order between two somatosensory stimuli, one applied on each hand. This suggests that somatosensory stimuli are not only processed according to a somatotopic representation but also a spatiotopic representation of the body. We investigated whether the perception of stimuli occurring in external space, such as visual stimuli, can also be influenced by the body posture and somatosensory stimuli. Participants performed temporal order judgements on pairs of visual stimuli, one in each side of space, with their hands uncrossed or crossed. In Experiment 1, participants' hands were placed either near or far from the visual stimuli. In Experiment 2, the visual stimuli were preceded, either by 60 ms or 360 ms, by tactile stimuli applied on the hands placed near the visual stimuli. Manipulating the time interval was intended to activate either a somatotopic or a spatiotopic representation of somatic inputs. We did not obtain any evidence for an influence of body posture on visual temporal order judgment, suggesting that body perception is less relevant for processing extrabody stimuli than the reverse.

The present study investigated the influence of nociceptive stimuli on visual stimuli processing according to the relative spatial congruence between the two stimuli of different sensory modalities. Participants performed temporal order judgments on pairs of visual stimuli, one presented near the hand on which nociceptive stimuli were occasionally applied, the other one either to its left or to its right. The visual hemifield in which the stimulated hand and the near visual stimulus appeared was manipulated by changing gaze direction. The stimulated hemibody and the stimulated visual hemifield were therefore either congruent or incongruent, in terms of anatomical locations. Despite the changes in anatomical congruence, judgments were always biased in favor of the visual stimuli presented near the stimulated hand. This indicates that nociceptive-visual interaction may rely on a realignment of the respective initial anatomical representations of the somatic and retinotopic spaces toward an integrated, multimodal representation of external space., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS) is a chronic pain condition associating sensory, motor, trophic and autonomic symptoms in one limb. Cognitive difficulties have also been reported, affecting the patients' ability to mentally represent, perceive and use their affected limb. However, the nature of these deficits is still a matter of debate. Recent studies suggest that cognitive deficits are limited to body-related information and body perception, while not extending to external space. Here we challenge that statement, by using temporal order judgment (TOJ) tasks with tactile (i.e. body) or visual (i.e. extra-body) stimuli in patients with upper-limb CRPS. TOJ tasks allow characterizing cognitive biases to the advantage of one of the two sides of space. While the tactile TOJ tasks did not show any significant results, significant cognitive biases were observed in the visual TOJ tasks, affecting mostly the perception of visual stimuli occurring in the immediate vicinity of the affected limb. Our results clearly demonstrate the presence of visuospatial deficits in CRPS, corroborating the cortical contribution to the CRPS pathophysiology, and supporting the utility of developing rehabilitation techniques modifying visuospatial abilities to treat chronic pain.

Coordinating spatial perception between body space and its external surrounding space is essential to adapt behaviors to objects, especially when they are noxious. Such coherent multisensory representation of the body extended into external space is conceptualized by the notion of peripersonal reference frame, mapping the portion of space in which somatic and extra-somatic inputs interact closely. Studies on crossmodal interactions between nociception and vision have been scarce. Here we investigated how the perception of visual stimuli, especially those surrounding the body, can be impacted by a nociceptive and potentially harmful stimulus inflicted on a particular body part. In two temporal order judgment tasks, participants judged which of two lateralized visual stimuli, presented either near or far from the body, had been presented first. Visual stimuli were preceded by nociceptive stimuli, either applied unilaterally (on one single hand) or bilaterally (on both hands simultaneously). In Experiment 1 participants' hands were always placed next to the visual stimuli presented near the trunk, while in Experiment 2 they could also be placed next to the visual stimuli presented far from the trunk. In Experiment 1, the presence of unilateral nociceptive stimuli prioritized the perception of visual stimuli presented in the same side of space as the stimulated hand, with a significantly larger effect when visual stimuli were presented near the body than when presented farther away. Experiment 2 showed that these visuospatial biases were related to the spatial congruency between the hand on which nociceptive stimuli were applied and the visual stimuli, independently of the relative distance of both the stimulated hand and the visual stimuli from the trunk. Indeed, nociceptive stimuli mostly impacted the perception of the closest visual stimuli. It is hypothesized that these crossmodal interactions may rely on representations of the space directly surrounding specific body parts.

In order to adapt behavior to a potentially body damaging threat, it is crucial to coordinate the perception of the location of the threat in external space and that of the location of the potential damage on the body surface. Such ability presupposes interactions between nociceptive stimuli and visual stimuli occurring close to the body. We hypothesized that these interactions would rely on multisensory representations of each limb itself, extending its boundaries slightly into external space, with less influence of the global representation of the body as a whole. In most studies investigating such representations, spatial organization of the somatic and extra-somatic stimuli is made according to an egocentric frame of reference centered on the main axes of the participant's whole body (e.g. the trunk), dissociating the left vs. the right side of space. Here, the contribution of such a body-centered frame was minimized, by placing participants' hands in front of them along their anteroposterior body axis, one at a proximal, the other at a distal location. They performed a temporal order judgment task on pairs of visual stimuli, one delivered close to each hand. Visual stimuli were preceded by nociceptive stimuli applied either on one hand, or on both hands simultaneously (control condition). Results showed that, as compared to the control condition, participants' judgements were biased in favor of the visual stimuli the closest to the stimulated hand, irrespective of their distance from the trunk. This finding supports the idea that the mechanisms underlying nociceptive-visual interactions are based on spatial representations that primarily use the stimulated limb rather than the whole body as a coordinate system., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Despite their high relevance for defending the integrity of the body, crossmodal links between nociception, the neural system specifically coding potentially painful information, and vision are still poorly studied, especially the effects of nociception on visual perception. This study investigated if, and in which time window, a nociceptive stimulus can attract attention to its location on the body, independently of voluntary control, to facilitate the processing of visual stimuli occurring in the same side of space as the limb on which the visual stimulus was applied. In a temporal order judgment task based on an adaptive procedure, participants judged which of two visual stimuli, one presented next to either hand in either side of space, had been perceived first. Each pair of visual stimuli was preceded (by 200, 400, or 600 ms) by a nociceptive stimulus applied either unilaterally on one single hand, or bilaterally, on both hands simultaneously. Results show that, as compared to the bilateral condition, participants' judgments were biased to the advantage of the visual stimuli that occurred in the same side of space as the hand on which a unilateral, nociceptive stimulus was applied. This effect was present in a time window ranging from 200 to 600 ms, but importantly, biases increased with decreasing time interval. These results suggest that nociceptive stimuli can affect the perceptual processing of spatially congruent visual inputs.

Sensitization is a form of implicit learning produced by the exposure to a harmful stimulus. In humans and other mammals, sensitization after skin injury increases the responsiveness of peripheral nociceptors and enhances the synaptic transmission of nociceptive input in the central nervous system. Here, we show that sensitization-related changes in the central nervous system are not restricted to nociceptive pathways and, instead, also affect other sensory modalities, especially if that modality conveys information relevant for the sensitized body part. Specifically, we show that after sensitizing the forearm using high-frequency electrical stimulation (HFS) of the skin, visual stimuli projected onto the sensitized forearm elicit significantly enhanced brain responses. Whereas mechanical hyperalgesia was present both 20 and 45 minutes after HFS, the enhanced responsiveness to visual stimuli was present only 20 minutes after HFS. Taken together, our results indicate that sensitization involves both nociceptive-specific and multimodal mechanisms, having distinct time courses.

Recently, Vanden Bulcke, Crombez, Durnez, and Van Damme (2015) investigated whether the attentional prioritization of a specific location due to the anticipation of pain is modality specific or multisensory. They used a temporal order judgment task in which participants judged the order of either two tactile or two visual stimuli, one presented on each hand. Additionally, participants either expected the occurrence of a painful stimulus on one hand or the absence of any pain. Results showed that participants' judgments were biased to the advantage of the stimuli, tactile or visual, presented at the location where pain was expected. The authors concluded that the anticipation of pain leads to a multisensory prioritization of information presented at the threatened spatial location. Here, we would like to question their conclusion in terms of a genuine attentional modulation of multisensory nature, based on methodological and theoretical grounds., (Copyright © 2016 Elsevier Inc. All rights reserved.)