Flavia Mancini

Visual Distortion of Body Size Modulates Pain Perception

Pain is a complex subjective experience that is shaped by numerous contextual factors. For example, simply viewing the body reduces the reported intensity of acute physical pain. In this study, we investigated whether this visually induced analgesia is modulated by the visual size of the stimulated body part. We measured contact heat-pain thresholds while participants viewed either their own hand or a neutral object in three size conditions: reduced, actual size, or enlarged. Vision of the body was analgesic, increasing heat-pain thresholds by an average of 3.2 °C. We further found that visual enlargement of the viewed hand enhanced analgesia, whereas visual reduction of the hand decreased analgesia. These results demonstrate that pain perception depends on multisensory representations of the body and that visual distortions of body size modulate sensory components of pain.

Linking Pain and the Body: Neural Correlates of Visually Induced Analgesia

The visual context of seeing the body can reduce the experience of acute pain, producing a multisensory analgesia. Here we investigated the neural correlates of this “visually induced analgesia” using fMRI. We induced acute pain with an infrared laser while human participants looked either at their stimulated right hand or at another object. Behavioral results confirmed the expected analgesic effect of seeing the body, while fMRI results revealed an associated reduction of laser-induced activity in ipsilateral primary somatosensory cortex (SI) and contralateral operculoinsular cortex during the visual context of seeing the body. We further identified two known cortical networks activated by sensory stimulation: (1) a set of brain areas consistently activated by painful stimuli (the so-called “pain matrix”), and (2) an extensive set of posterior brain areas activated by the visual perception of the body (“visual body network”). Connectivity analyses via psychophysiological interactions revealed that the visual context of seeing the body increased effective connectivity (i.e., functional coupling) between posterior parietal nodes of the visual body network and the purported pain matrix. Increased connectivity with these posterior parietal nodes was seen for several pain-related regions, including somatosensory area SII, anterior and posterior insula, and anterior cingulate cortex. These findings suggest that visually induced analgesia does not involve an overall reduction of the cortical response elicited by laser stimulation, but is consequent to the interplay between the brains pain network and a posterior network for body perception, resulting in modulation of the experience of pain.

Cognitive aspects of nociception and pain: bridging neurophysiology with cognitive psychology

The event-related brain potentials (ERPs) elicited by nociceptive stimuli are largely influenced by vigilance, emotion, alertness, and attention. Studies that specifically investigated the effects of cognition on nociceptive ERPs support the idea that most of these ERP components can be regarded as the neurophysiological indexes of the processes underlying detection and orientation of attention toward the eliciting stimulus. Such detection is determined both by the salience of the stimulus that makes it pop out from the environmental context (bottom-up capture of attention) and by its relevance according to the subjects goals and motivation (top-down attentional control). The fact that nociceptive ERPs are largely influenced by information from other sensory modalities such as vision and proprioception, as well as from motor preparation, suggests that these ERPs reflect a cortical system involved in the detection of potentially meaningful stimuli for the body, with the purpose to respond adequately to potential threats. In such a theoretical framework, pain is seen as an epiphenomenon of warning processes, encoded in multimodal and multiframe representations of the body, well suited to guide defensive actions. The findings here reviewed highlight that the ERPs elicited by selective activation of nociceptors may reflect an attentional gain apt to bridge a coherent perception of salient sensory events with action selection processes.

Fine-Grained Nociceptive Maps in Primary Somatosensory Cortex

Topographic maps of the receptive surface are a fundamental feature of neural organization in many sensory systems. While touch is finely mapped in the cerebral cortex, it remains controversial how precise any cortical nociceptive map may be. Given that nociceptive innervation density is relatively low on distal skin regions such as the digits, one might conclude that the nociceptive system lacks fine representation of these regions. Indeed, only gross spatial organization of nociceptive maps has been reported so far. However, here we reveal the existence of fine-grained somatotopy for nociceptive inputs to the digits in human primary somatosensory cortex (SI). Using painful nociceptive-selective laser stimuli to the hand, and phase-encoded functional magnetic resonance imaging analysis methods, we observed somatotopic maps of the digits in contralateral SI. These nociceptive maps were highly aligned with maps of non-painful tactile stimuli, suggesting comparable cortical representations for, and possible interactions between, mechanoreceptive and nociceptive signals. Our findings may also be valuable for future studies tracking the time course and the spatial pattern of plastic changes in cortical organization involved in chronic pain.

Endogenous opioids contribute to insensitivity to pain in humans and mice lacking sodium channel Nav1.7

Loss-of-function mutations in the SCN9A gene encoding voltage-gated sodium channel Nav1.7 cause congenital insensitivity to pain in humans and mice. Surprisingly, many potent selective antagonists of Nav1.7 are weak analgesics. We investigated whether Nav1.7, as well as contributing to electrical signalling, may have additional functions. Here we report that Nav1.7 deletion has profound effects on gene expression, leading to an upregulation of enkephalin precursor Penk mRNA and met-enkephalin protein in sensory neurons. In contrast, Nav1.8-null mutant sensory neurons show no upregulated Penk mRNA expression. Application of the opioid antagonist naloxone potentiates noxious peripheral input into the spinal cord and dramatically reduces analgesia in both female and male Nav1.7-null mutant mice, as well as in a human Nav1.7-null mutant. These data suggest that Nav1.7 channel blockers alone may not replicate the analgesic phenotype of null mutant humans and mice, but may be potentiated with exogenous opioids.

Whole-body mapping of spatial acuity for pain and touch

Tactile spatial acuity is routinely tested in neurology to assess the state of the dorsal column system. In contrast, spatial acuity for pain is not assessed, having never been systematically characterized. More than a century after the initial description of tactile acuity across the body, we provide the first systematic whole‐body mapping of spatial acuity for pain.

Pain relief by touch: A quantitative approach

Summary We tested whether, how, and where intrasegmental touch modulates the perception of laser‐evoked, acute pain. We provide evidence for a spatial organisation of touch–pain interactions within a single dermatome. ABSTRACT Pain relief by touch has been studied for decades in pain neuroscience. Human perceptual studies revealed analgesic effects of segmental tactile stimulation, as compared to extrasegmental touch. However, the spatial organisation of touch–pain interactions within a single human dermatome has not been investigated yet. In 2 experiments we tested whether, how, and where within a dermatome touch modulates the perception of laser‐evoked pain. We measured pain perception using intensity ratings, qualitative descriptors, and signal detection measures of sensitivity and response bias. Touch concurrent with laser pulses produced a significant analgesia, and reduced the sensitivity in detecting the energy of laser stimulation, implying a functional loss of information within the ascending A&dgr; pathway. Touch also produced a bias to judge laser stimuli as less painful. This bias decreased linearly when the distance between the laser and tactile stimuli increased. Thus, our study provides evidence for a spatial organisation of intrasegmental touch–pain interactions.

Touch inhibits subcortical and cortical nociceptive responses.

Abstract The neural mechanisms of the powerful analgesia induced by touching a painful body part are controversial. A long tradition of neurophysiologic studies in anaesthetized spinal animals indicate that touch can gate nociceptive input at spinal level. In contrast, recent studies in awake humans have suggested that supraspinal mechanisms can be sufficient to drive touch-induced analgesia. To investigate this issue, we evaluated the modulation exerted by touch on established electrophysiologic markers of nociceptive function at both subcortical and cortical levels in humans. A&dgr; and C skin nociceptors were selectively activated by high-power laser pulses. As markers of subcortical and cortical function, we recorded the laser blink reflex, which is generated by brainstem circuits before the arrival of nociceptive signals at the cortex, and laser-evoked potentials, which reflect neural activity of a wide array of cortical areas. If subcortical nociceptive responses are inhibited by concomitant touch, supraspinal mechanisms alone are unlikely to be sufficient to drive touch-induced analgesia. Touch induced a clear analgesic effect, suppressed the laser blink reflex, and inhibited both A&dgr;-fibre and C-fibre laser-evoked potentials. Thus, we conclude that touch-induced analgesia is likely to be mediated by a subcortical gating of the ascending nociceptive input, which in turn results in a modulation of cortical responses. Hence, supraspinal mechanisms alone are not sufficient to mediate touch-induced analgesia.

Changes in cortical oscillations linked to multisensory modulation of nociception

Pain can be modulated by several contextual factors. For example, simply viewing ones own body can reduce pain, suggesting that the visual context may influence the processing of nociceptive stimuli. We studied changes in electroencephalographic (EEG) oscillatory activity related to visual modulation of nociception, comparing cortical oscillations during innocuous or noxious contact heat, while participants viewed either their own hand or a neutral object at the same location. Viewing the body compared with viewing the object reduced the intensity ratings of noxious stimuli, but not of innocuous heat. Time–frequency analysis of EEG data revealed that noxious, as opposed to warm, stimulation was associated with reduced beta (15–25 Hz) power. Classically, such decreases in oscillatory power indicate increases in sensory cortical activation. These event‐related oscillatory changes were moreover modulated by the visual context; viewing ones own body increased noxious stimulation‐induced beta oscillatory activity bilaterally, relative to viewing a neutral object, possibly indicating inhibition of cortical nociceptive processing. These results demonstrate that visual–nociceptive interactions involve changes in sensorimotor EEG rhythms.

A Fovea for Pain at the Fingertips

Summary The spatial resolution of sensory systems is not homogeneous across their receptive surfaces. For example, tactile acuity is greatest on the fingertips, reflecting the high innervation density and small mechanoreceptive fields in this area [1, 2]. In contrast, pain is considered to lack any equivalent to the tactile fovea on the fingertips, where the density of nociceptive fibers is remarkably low [3]. Here, by combining psychophysics with histology, we show that this established notion is incorrect. By delivering small-diameter nociceptive-specific laser pulses to human volunteers, we discovered that (1) the spatial acuity for pain is higher on the fingertips than on proximal skin regions such as the hand dorsum, and (2) this distal-proximal gradient for pain is comparable to that for touch. In contrast, skin biopsies in the same participants showed that the intraepidermal nerve fiber density is lower in the fingertips than in the hand dorsum. The increased spatial acuity for pain on the fingertips therefore cannot be explained simply by peripheral innervation density. This finding is, however, consistent with the existence of fine-grained maps of nociceptive input to individual digits in the human primary somatosensory cortex [4]. Video Abstract