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The circumstances under which empathy is altered in ASD remain unclear, as previous studies did not systematically find differences in brain activation between ASD and controls in empathy-eliciting paradigms, and did not always monitor whether differences were primarily due to ASD "per se", or to conditions overlapping with ASD, such as alexithymia and anxiety. Here, we collected fMRI data from 47 participants (22 ASD) viewing pictures depicting hands and feet of unknown others in painful, disgusting, or neutral situations. We computed brain activity for painful and disgusting stimuli (vs. neutral) in whole brain and in regions of interest among the brain areas typically activated during the perception of nociceptive stimuli. Group differences in brain activation disappeared when either alexithymia or anxiety - both elevated in the ASD group - were controlled for. Regression analyses indicated that the influence of symptoms was mainly shared between autistic symptomatology, alexithymia and anxiety or driven by unique contributions from alexithymia or anxiety. Our results suggest that affective empathy may be affected in ASD, but that this association is complex. The respective contribution of alexithymia and anxiety to decreased affective empathy of people with ASD may be due to the association of those psychiatric conditions with reduced motor resonance/Theory of Mind.

The extent to which affective empathy is impaired in Autism Spectrum Disorder (ASD) remains unclear, as some-but not all-previous neuroimaging studies investigating empathy for pain in ASD have shown similar activation levels to those of neurotypicals individuals. These inconsistent results could be due to the use of different empathy-eliciting stimuli. While some studies used pictures of faces exhibiting a painful expression, others used pictures of limbs in painful situations. In this study, we used fMRI to compare activation in areas associated with empathy processing (empathy network) for these two types of stimuli in 31 participants (16 with ASD, 15 controls). We found a group difference in the inferior frontal gyrus (IFG) and the thalamus when participants viewed stimuli of limbs in painful situations, but not when they viewed face stimuli with a painful expression. Both groups of participants activated their empathy network more when viewing pictures of limbs in painful situations than when viewing pictures of faces with a painful expression; this increased activation for limbs versus faces was significantly enhanced in controls relative to ASD participants, especially in the secondary somatosensory cortex (SII). Our findings suggest that empathy defect of people with ASD is contingent upon the type of stimuli used, and may be related to the level of Mirror Neuron System involvement, as brain regions showing group differences (IFG, SII) underlie embodiment. We discuss the potential clinical implications of our findings in terms of developing interventions boosting the empathetic abilities of people with ASD., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Despite the flourishing research on the relationships between affect and language, the characteristics of pain-related words, a specific type of negative words, have never been systematically investigated from a psycholinguistic and emotional perspective, despite their psychological relevance. This study offers psycholinguistic, affective, and pain-related norms for words expressing physical and social pain. This may provide a useful tool for the selection of stimulus materials in future studies on negative emotions and/or pain. We explored the relationships between psycholinguistic, affective, and pain-related properties of 512 Italian words (nouns, adjectives, and verbs) conveying physical and social pain by asking 1020 Italian participants to provide ratings of Familiarity, Age of Acquisition, Imageability, Concreteness, Context Availability, Valence, Arousal, Pain-Relatedness, Intensity, and Unpleasantness. We also collected data concerning Length, Written Frequency (Subtlex-IT), N-Size, Orthographic Levenshtein Distance 20, Neighbor Mean Frequency, and Neighbor Maximum Frequency of each word. Interestingly, the words expressing social pain were rated as more negative, arousing, pain-related, and conveying more intense and unpleasant experiences than the words conveying physical pain., Competing Interests: The authors have declared that no competing interests exist.

According to the Scalar Expectancy Theory, humans are equipped with a biological internal clock, possibly modulated by attention and arousal. Both emotions and pain are arousing and can absorb attentional resources, thus causing distortions of temporal perception. The aims of the present single-event fMRI study were to investigate: a) whether observation of facial expressions of pain interferes with time production; and b) the neural network subserving this kind of temporal distortions. Thirty healthy volunteers took part in the study. Subjects were asked to perform a temporal production task and a concurrent gender discrimination task, while viewing faces of unknown people with either pain-related or neutral expressions. Behavioural data showed temporal underestimation (i.e., longer produced intervals) during implicit pain expression processing; this was accompanied by increased activity of right middle temporal gyrus, a region known to be active during the perception of emotional and painful faces. Psycho-Physiological Interaction analyses showed that: 1) the activity of middle temporal gyrus was positively related to that of areas previously reported to play a role in timing: left primary motor cortex, middle cingulate cortex, supplementary motor area, right anterior insula, inferior frontal gyrus, bilateral cerebellum and basal ganglia; 2) the functional connectivity of supplementary motor area with several frontal regions, anterior cingulate cortex and right angular gyrus was correlated to the produced interval during painful expression processing. Our data support the hypothesis that observing emotional expressions distorts subjective time perception through the interaction of the neural network subserving processing of facial expressions with the brain network involved in timing. Within this frame, middle temporal gyrus appears to be the key region of the interplay between the two neural systems.

Objective: 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., Methods: We evaluated the 2-point discrimination thresholds for both nociceptive-selective and tactile stimuli across several skin regions. Thresholds were estimated using pairs of simultaneous stimuli, and also using successive stimuli., Results and Interpretation: These two approaches produced convergent results. The fingertip was the area of highest spatial acuity, for both pain and touch. On the glabrous skin of the hand, the gradient of spatial acuity for pain followed that observed for touch. On the hairy skin of the upper limb, spatial acuity for pain and touch followed opposite proximal-distal gradients, consistent with the known innervation density of this body territory. Finally, by testing spatial acuity for pain in a rare participant completely lacking Aβ fibers, we demonstrate that spatial acuity for pain does not rely on a functioning system of tactile primary afferents. This study represents the first systematic characterization of spatial acuity for pain across multiple regions of the body surface., (© 2014 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)

Identifying personality traits and neural signatures that predict placebo responsiveness is important, both on theoretical and practical grounds. In the present functional magnetic resonance imaging (fMRI) study, we performed multiple-regression interaction analysis to investigate whether hypnotic susceptibility (HS), a cognitive trait referring to the responsiveness to suggestions, explains interindividual differences in the neural mechanisms related to conditioned placebo analgesia in healthy volunteers. HS was not related to the overall strength of placebo analgesia. However, we found several HS-related differences in the patterns of fMRI activity and seed-based functional connectivity that accompanied placebo analgesia. Specifically, in subjects with higher HS, the placebo response was related to increased anticipatory activity in a right dorsolateral prefrontal cortex focus, and to reduced functional connectivity of that focus with brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex); an opposite pattern of fMRI activity and functional connectivity was found in subjects with lower HS. During pain perception, activity in the regions reflecting attention/arousal (bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral posterior temporal foci) was negatively related to the strength of the analgesic placebo response in subjects with higher HS, but not in subjects with lower HS. These findings highlight HS influences on brain circuits related to the placebo analgesic effects. More generally, they demonstrate that different neural mechanisms can be involved in placebo responsiveness, depending on individual cognitive traits., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Placebo analgesia (PA) is one of the most studied placebo effects. Brain imaging studies published over the last decade, using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), suggest that multiple brain regions may play a pivotal role in this process. However, there continues to be much debate as to which areas consistently contribute to placebo analgesia-related networks. In the present study, we used activation likelihood estimation (ALE) meta-analysis, a state-of-the-art approach, to search for the cortical areas involved in PA in human experimental pain models. Nine fMRI studies and two PET studies investigating cerebral hemodynamic changes were included in the analysis. During expectation of analgesia, activated foci were found in the left anterior cingulate, right precentral, and lateral prefrontal cortex and in the left periaqueductal gray (PAG). During noxious stimulation, placebo-related activations were detected in the anterior cingulate and medial and lateral prefrontal cortices, in the left inferior parietal lobule and postcentral gyrus, anterior insula, thalamus, hypothalamus, PAG, and pons; deactivations were found in the left mid- and posterior cingulate cortex, superior temporal and precentral gyri, in the left anterior and right posterior insula, in the claustrum and putamen, and in the right thalamus and caudate body. Our results suggest on one hand that the modulatory cortical networks involved in PA largely overlap those involved in the regulation of emotional processes, on the other that brain nociceptive networks are downregulated in parallel with behavioral analgesia., (Copyright © 2011 Wiley Periodicals, Inc.)

In several biomedical fields, researchers are faced with regression problems that can be stated as Statistical Learning problems. One example is given by decoding brain states from functional magnetic resonance imaging (fMRI) data. Recently, it has been shown that the general Statistical Learning problem can be restated as a linear inverse problem. Hence, new algorithms were proposed to solve this inverse problem in the context of Reproducing Kernel Hilbert Spaces. In this paper, we detail one iterative learning algorithm belonging to this class, called ν-method, and test its effectiveness in a between-subjects regression framework. Specifically, our goal was to predict the perceived pain intensity based on fMRI signals, during an experimental model of acute prolonged noxious stimulation. We found that, using a linear kernel, the psychophysical time profile was well reconstructed, while pain intensity was in some cases significantly over/underestimated. No substantial differences in terms of accuracy were found between the proposed approach and one of the state-of-the-art learning methods, the Support Vector Machines. Nonetheless, adopting the ν-method yielded a significant reduction in computational time, an advantage that became more evident when a relevant feature selection procedure was implemented. The ν-method can be easily extended and included in typical approaches for binary or multiple classification problems, and therefore it seems well-suited to build effective brain activity estimators., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Despite growing interest in the placebo effect, the neural correlates of conditioned analgesia are still incompletely understood. We investigated herein on brain activity during the conditioning and post-conditioning phases of a placebo experimental paradigm, using event-related fMRI in 31 healthy volunteers. Brief laser heat stimuli delivered to one foot (either right or left) were preceded by different visual cues, signalling either painful stimuli alone, or painful stimuli accompanied by a (sham) analgesic procedure. Cues signalling the analgesic procedure were followed by stimuli of lower intensity in the conditioning session, whereas in the test session both cues were followed by painful stimuli of the same intensity. During the first conditioning trials, progressive signal increases over time were found during anticipation of analgesia compared to anticipation of pain, in a medial prefrontal focus centered on medial area BA8, and in bilateral lateral prefrontal foci. These frontal foci were adjacent to, and partially overlapped, those active during anticipation of analgesia in the test session, whose signal changes were related to the magnitude of the placebo behavioral response, and those active during placebo analgesia. Specifically, a large focus in the right prefrontal cortex showed activity related to analgesia, irrespective of the expected side of stimulation. Analgesia was also related to decreased activity, detectable immediately following noxious stimulation, in parietal, insular and cingulate pain-related clusters. Our findings of dynamic changes in prefrontal areas during placebo conditioning, and of direct placebo effects on cortical nociceptive processing, add new insights into the neural bases of conditioned placebo analgesia., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Recent studies have shown that functional magnetic resonance imaging (fMRI) can non-invasively assess spinal cord activity. Yet, a quantitative description of nociceptive and non-nociceptive responses in the human spinal cord, compared with random signal fluctuations in resting state data, is still lacking. Here we have investigated the intensity and spatial extent of blood oxygenation level dependent (BOLD) fMRI responses in the cervical spinal cord of healthy volunteers, elicited by stimulation of the hand dorsum (C6-C7 dermatomes). In a block design fMRI paradigm, periods (20 s each) of repetitive noxious (laser heat) or innocuous (brushing) stimulation were alternated with rest. To estimate the level of false positive responses, functional images were acquired during a separate run while subjects were at rest. In a first analysis of averaged peristimulus signals from all voxels within each half of the spinal cord, we found bilateral fMRI responses to both stimuli. These responses were significantly larger during noxious than during innocuous stimulation. No significant fMRI signal change was evident over corresponding time periods during the Rest run. In a second, general linear model analysis, we identified a voxel population preferentially responding to noxious stimulation, which extended rostro-caudally over the length (4 cm) of the explored spinal cord region. By contrast, we found no evidence of voxel populations responding uniquely to innocuous stimuli, or showing decreased activity following either kind of somatosensory stimulus. These results provide the first false-positive-controlled comparison of spinal BOLD fMRI responses to noxious and innocuous stimuli in humans, confirming and extending physiological information obtained in other species., (2010 Elsevier Inc. All rights reserved.)

Most imaging studies on the human pain system have concentrated so far on the spatial distribution of pain-related activity. In the present study, we investigated similarities and differences between the spatial and temporal patterns of brain activity related to touch vs. pain perception. To this end, we adopted an event-related functional magnetic resonance imaging (fMRI) paradigm allowing us to separately assess the activity related to stimulus anticipation, perception, and coding. The fMRI signal increases following brief mechanical noxious or non-noxious stimulation of the hand dorsum were largely overlapping in the contralateral and ipsilateral hemispheres, including portions of the parietal, insular, frontal and cingulate cortices. Higher activity following noxious stimulation was found in the contralateral mid-anterior insular cortex, in the anterior mid-cingulate cortex (aMCC) and in the adjacent dorso-medial frontal cortex. Significant decreases in fMRI signals following both tactile and painful stimuli were found in perigenual cingulate (pACC)/medial prefrontal cortex (MPF) and in the posterior cingulate/precuneus/paracentral lobule; more intense decreases were found in the pACC/MPF following painful stimuli. fMRI signal increases in the contralateral insula and in aMCC, but not in the parietal cortex, were more prolonged following painful than tactile stimuli. Moreover, a second peak of signal increases (albeit of lower intensity) was found in anterior insula and aMCC during pain intensity rating. These results show specific spatio-temporal patterns of cortical activity related to processing noxious vs. non-noxious mechanical stimuli.

Looking at still images of body parts in situations that are likely to cause pain has been shown to be associated with activation in some brain areas involved in pain processing. Because pain involves both sensory components and negative affect, it is of interest to explore whether the visually evoked representations of pain and of other negative emotions overlap. By means of event-related functional magnetic resonance imaging, here we compare the brain areas recruited, in female volunteers, by the observation of painful, disgusting, or neutral stimuli delivered to one hand or foot. Several cortical foci were activated by the observation of both painful and disgusting video clips, including portions of the medial prefrontal cortex, anterior, mid-, and posterior cingulate cortex, left posterior insula, and right parietal operculum. Signal changes in perigenual cingulate and left anterior insula were linearly related to the perceived unpleasantness, when the individual differences in susceptibility to aversive stimuli were taken into account. Painful scenes selectively induced activation of left parietal foci, including the parietal operculum, the postcentral gyrus, and adjacent portions of the posterior parietal cortex. In contrast, brain foci specific for disgusting scenes were found in the posterior cingulate cortex. These data show both similarities and differences between the brain patterns of activity related to the observation of noxious or disgusting stimuli. Namely, the parietal cortex appears to be particularly involved in the recognition of noxious environmental stimuli, suggesting that areas involved in sensory aspects of pain are specifically triggered by observing noxious events.

Diurnal variations in tonic pain reactions have been described in mice tested in Spring, but the underlying mechanisms are still unknown. We tested the potential role of melatonin, a key hormone in the control of neuro-endocrine circadian rhythms. The experiments were performed in male CBA/J mice housed under controlled temperature, humidity, and light (12/12 dark/light cycle) conditions, during the Light (7-10a.m.) or Dark (7-10p.m.) phases of the diurnal cycle. In a first group of experiments, animals were either pretreated with i.p. saline (controls) or with the melatonin receptor antagonist, luzindole (30 mg/kg), before the s.c. injection of a dilute formalin solution into a hindpaw. In control animals, pain-related behavioral reactions (licking and flinching) were higher in the evening (Dark) than in the morning (Light), both during the first (0-10 min) and the second (11-55 min) phase of the response to s.c. formalin. In animals pre-treated with luzindole, no diurnal changes occurred, pain reactions in the Dark being similar to those of the Light Control group. In a second group of experiments, artificial pinealectomy, obtained by exposing animals to continuous light for 48 h, also reduced pain reactions in the evening to levels comparable to those in the morning. Receptor autoradiography showed lower binding availability at spinal cord level in mice sacrificed during the Dark, as expected from the circadian pattern of melatonin secretion. A further significant decrease of melatonin receptor binding was induced by noxious stimulation. These results suggest a proalgesic role of endogenous melatonin in tonic pain.

We investigated changes in the corticospinal pattern of activity in healthy volunteers during sustained noxious and non-noxious mechanical stimulation of the first hand digit, resulting from active (self-stimulation) or passive (externally-induced) pressing against a sharp or blunted tip. The results indicate that, in order to press a finger onto a noxious stimulus with the same force generated to press onto a non-noxious one, the motor cortex adopts a peculiar strategy in terms of recruitment of motor units. This is reflected by an increase of corticospinal excitability (as revealed by motor potentials evoked by transcranial magnetic stimulation of the contralateral primary motor cortex) and EMG activity of agonist muscles, possibly related to an increase of motor unit synchronization.

Ketamine is a dissociative anesthetic with complex actions on the CNS. We investigated here the effects of ketamine anesthesia on somatosensory processing in the rat spinal cord, thalamus, and cerebral cortex, using the quantitative 2-deoxyglucose mapping technique. Unanesthetized or ketamine-anesthetized male Sprague-Dawley rats received a s.c. injection of a dilute formaldehyde solution (5%, 0.08 ml) into a forepaw, inducing prolonged noxious afferent input, or an equal volume of isotonic saline as a control stimulus. The 2-deoxyglucose experiments started 30 min after the injection. In the cervical enlargement of the spinal cord, ketamine had no significant effect on glucose metabolic rates in saline-injected animals, whereas it prevented the metabolic increases elicited by prolonged noxious stimulation in unanesthetized animals. At the thalamic level, ketamine increased glucose uptake in both saline- and formalin-injected rats in the lateral posterior, lateral dorsal, medial dorsal, gelatinosus, antero-ventral and antero-medial thalamic nuclei, whereas it decreased metabolic activity in the ventro-basal complex. At the cortical level, the drug increased metabolic activity in both control and formalin groups in the lacunosus-molecularis layer of the dorsal hippocampus, posterior parietal, retrosplenial, cingulate and frontal cortex; significant metabolic decreases were found in the CA1 region of the dorsal hippocampus and in the parietal 1 and 2 cortical areas. In the investigated brain regions, ketamine did not abolish noxious-evoked increases in glucose uptake, which were in fact enhanced in the forelimb cortex and in the lacunosus-molecularis layer of the hippocampus. The dissociation between the spinal and supraspinal effects of ketamine suggests a specific antinociceptive action on spinal circuits, in parallel with complex changes of the activity of brain circuits involved in somatosensory processing. More generally, this study shows that functional imaging techniques are able to quantitatively assess the effects of anesthetic drugs on nociceptive processing at different levels of the neuraxis.

Time-dependent increases of local metabolic or blood flow rates have been described in spinal cord and brain during acute and chronic pain states in experimental animals, in parallel with changes of different behavioral endpoints of pain and hyperalgesia. In healthy human volunteers, pain intensity-related hemodynamic changes have been identified in a widespread, bilateral brain system including parietal, insular, cingulate, and frontal cortical areas, as well as thalamus, amygdala, and midbrain. Specific patterns of activity may characterize hyperalgesic states and some chronic pain conditions. Forebrain nociceptive systems are under inhibitory control by endogenous opioids and can be affected by acute administration of mu-opioid receptor agonists. Anticipation of pain may in itself induce changes in brain nociceptive networks. Moreover, pain-related cortical activity can be modulated by hypnotic suggestions, focusing or diverting attention, and placebo. These findings begin to disclose the spatio-temporal dynamics of brain networks underlying pain perception and modulation.

The relative contributions of autonomic arousal and of cognitive processing to cortical activity during anticipation of pain, and the role of changes in thalamic outflow, are still largely unknown. To address these issues, we investigated with functional magnetic resonance imaging (fMRI) the activity of the contralateral mesial hemispheric wall in 56 healthy volunteers while they expected the stimulation of one foot, which could be either painful or innocuous. The waiting period was characterized by emotional arousal, a moderate rise in heart rate, and by increases in mean fMRI signals in the medial thalamus, mid- and posterior cingulate cortex, and in the putative foot area of the primary somatosensory and motor cortex. The same brain regions, excepting posterior cingulate, were also activated by somatosensory stimulation. We identified by cross-correlation analysis a cluster population whose fMRI signal time course was related to the mean heart rate (HR) profile, showing selective changes of activity during the waiting period. Positively correlated clusters were found mainly in sensorimotor areas, mid- and posterior cingulate, and dorsomedial prefrontal cortex. Negatively correlated clusters predominated in the perigenual anterior cingulate and ventromedial prefrontal cortex. HR clusters had different characteristics from, and showed limited spatial overlap with, clusters whose fMRI signals were related to the psychophysical pain intensity profile; however, both cluster populations were affected by anticipation. These findings unravel a complex pattern of brain activity during uncertain anticipation of noxious input, likely related both to changes in the level of arousal and to cognitive modulation of the pain system.

The behavioral response to acute tissue injury is usually characterized by different phases, but the brain mechanisms underlying changes in pain-related behavior over time are still poorly understood. We aimed to analyze time-dependent changes in metabolic activity levels of 49 forebrain structures in the formalin pain model, using the autoradiographic 2-deoxyglucose method in unanesthetized, freely moving rats. We examined rats during the first phase of pain-related reactions ('early' groups), or during the third recovery phase, 60 min later, when the supraspinally mediated behavioral responses were reduced ('late' group). In the early groups, metabolic rates were bilaterally increased over control values in the periaqueductal gray, zona incerta and in several thalamic nuclei (anteroventral, centrolateral, lateral dorsal, parafascicular, posteromedial, submedius, ventromedial, and ventrobasal complex), as well as in the habenulae and in the parietal, cingulate, antero-dorsal insular, and anterior piriform cortex. A contralateral, somatotopically specific activation was found in the putative hindlimb representation area of the somatosensory cortex. In the late group, noxious-induced activation declined in most structures. However, metabolic rates were higher than controls in the periaqueductal gray and zona incerta and in two other structures not previously active: the prerubral area/field of Forel and the arcuate hypothalamic nucleus. These findings provide a time-dependent functional map of nociceptive and anti-nociceptive forebrain circuits during tonic pain. The parallel decrease in licking behavior and forebrain activity, at times when spinally mediated limb flexion responses were still present, suggests that endogenous antinociceptive systems may differently modulate spinal and supraspinal nociceptive networks following acute tissue injury.

Seasonal and diurnal variations in tonic pain reactions were examined in female and male CBA/J mice maintained in a 12/12 dark/light cycle, at controlled temperature and humidity conditions. Animals were injected into the dorsum of one hindpaw with a dilute (20 microl, 1%) formalin solution. Pain-related behaviors were quantified as the time spent licking the injected paw and the number of flinching episodes. The experiments were performed during the first part of the light phase (Light: from 7 to 10 a.m.) or during the first part of the dark phase of the diurnal cycle (Dark: from 7 to 10 p.m.), in two different periods of the year: Spring (March-June) and Winter (November-January). Considering all data, females showed a slightly enhanced licking response, as well as an increase in the time spent in self-grooming, in comparison with males. In Spring, the licking and flinching responses were higher during the Dark phase than during the Light phase. This held for both sexes and for both phases of the behavioral response to formalin injection. By contrast, no significant diurnal variation in pain reactions was found in Winter. These seasonal and diurnal differences were not due to nonspecific changes in motor behavior, inasmuch as locomotor activity and self-grooming showed a different pattern: during the second phase after formalin, self-grooming was higher in the Light period in the experiments performed in Spring, whereas locomotor activity showed no significant seasonal changes. These results show that the behavioral reactions to prolonged noxious input, integrated both at spinal and supraspinal sites, undergo similar seasonal and diurnal variations in both sexes, strengthening the importance of chronobiological factors in the modulation of nociception.

Anticipation of pain is a complex state that may influence the perception of subsequent noxious stimuli. We used functional magnetic resonance imaging (fMRI) to study changes of activity of cortical nociceptive networks in healthy volunteers while they expected the somatosensory stimulation of one foot, which might be painful (subcutaneous injection of ascorbic acid) or not. Subjects had no previous experience of the noxious stimulus. Mean fMRI signal intensity increased over baseline values during anticipation and during actual stimulation in the putative foot representation area of the contralateral primary somatosensory cortex (SI). Mean fMRI signals decreased during anticipation in other portions of the contralateral and ipsilateral SI, as well as in the anteroventral cingulate cortex. The activity of cortical clusters whose signal time courses showed positive or negative correlations with the individual psychophysical pain intensity curve was also significantly affected during the waiting period. Positively correlated clusters were found in the contralateral SI and bilaterally in the anterior cingulate, anterior insula, and medial prefrontal cortex. Negatively correlated clusters were found in the anteroventral cingulate bilaterally. In all of these areas, changes during anticipation were of the same sign as those observed during pain but less intense ( approximately 30-40% as large as peak changes during actual noxious stimulation). These results provide evidence for top-down mechanisms, triggered by anticipation, modulating cortical systems involved in sensory and affective components of pain even in the absence of actual noxious input and suggest that the activity of cortical nociceptive networks may be directly influenced by cognitive factors.

Diurnal changes in the behavioural reactions to subcutaneous formalin injection (20 microl, 1%) into the dorsum of an hindpaw were examined in female CBA/J mice aged 70-75 days, maintained in a 12/12 dark/ light cycle (light on at 07.00 h; light off at 19.00 h). Mice showed higher pain scores, as expressed by the amount of time spent licking the injected paw and by the number of flinching episodes, when tested under red light at the beginning of the dark phase (19.00-22.00: Dark group) than when tested either under white or red light at the beginning of the light phase of the diurnal cycle (7.00-10.00). The increases in pain reactions at night were found both during the first (0-10 min) and the second (11-55 min) phase of the behavioural response to formalin injection. They were not due to aspecific increases in motor behaviour, since self-grooming actually decreased in the Dark group during the second phase of the response, and the amount of locomotor activity after the injection was similar to, or lower than, that found in mice tested in the morning under white or red light, respectively. In another group of female CBA/J mice tested in the hotplate apparatus (at a temperature of 52 degrees), paw-lick latencies were significantly higher in mice tested at dark during the night, whereas jump (escape) latencies were higher in the morning. These results demonstrate different diurnal variations in the reactions to brief or prolonged noxious stimulation in mice, with greater responses to tonic pain at the onset of the dark phase.

CNS correlates of acute prolonged pain, and the effects of partial blockade of the central beta-endorphin system, were investigated by the quantitative 2-deoxyglucose technique in unanaesthetized, freely moving rats. Experiments were performed during the second, tonic phase of the behavioural response to a prolonged chemical noxious stimulus (s.c. injection of dilute formalin into a forepaw), or after minor tissue injury (s.c. saline injection). During formalin-induced pain, local glucose utilization rates in the CNS were bilaterally increased in the grey matter of the cervical spinal cord, in spinal white matter tracts and in several supraspinal structures, including portions of the medullary reticular formation, locus coeruleus, lateral parabrachial region, anterior pretectal nucleus, the medial, lateral and posterior thalamic regions, basal ganglia, and the parietal, cingulate, frontal, insular and orbital cortical areas. Pretreatment with anti-beta-endorphin antibodies, injected i.c.v., led to increased metabolism in the tegmental nuclei, locus coeruleus, hypothalamic and thalamic structures, putamen, nucleus accumbens, diagonal band nuclei and dentate gyrus, and in portions of the parietal, cingulate, insular, frontal and orbital cortex. In formalin-injected rats, pretreated with anti-beta-endorphin, behavioural changes indicative of hyperalgesia (increased licking response) were found, which were paralleled by a significant enhancement of functional activity in the anterior pretectal nucleus and in thalamo-cortical systems. A positive correlation was found between the duration of the licking response and metabolic activity of several forebrain regions. These results provide a map of the CNS pattern of metabolic activity during tonic somatic pain, and demonstrate a modulatory role for beta-endorphin in central networks that process somatosensory inputs.

Temporal and intensity coding of pain in human cortex. J. Neurophysiol. 80:3312-3320, 1998. We used a high-resolution functional magnetic resonance imaging (fMRI) technique in healthy right-handed volunteers to demonstrate cortical areas displaying changes of activity significantly related to the time profile of the perceived intensity of experimental somatic pain over the course of several minutes. Twenty-four subjects (ascorbic acid group) received a subcutaneous injection of a dilute ascorbic acid solution into the dorsum of one foot, inducing prolonged burning pain (peak pain intensity on a 0-100 scale: 48 +/- 3, mean +/- SE; duration: 11.9 +/- 0.8 min). fMRI data sets were continuously acquired for approximately 20 min, beginning 5 min before and lasting 15 min after the onset of stimulation, from two sagittal planes on the medial hemispheric wall contralateral to the stimulated site, including the cingulate cortex and the putative foot representation area of the primary somatosensory cortex (SI). Neural clusters whose fMRI signal time courses were positively or negatively correlated (P < 0.0005) with the individual pain intensity curve were identified by cross-correlation statistics in all 24 volunteers. The spatial extent of the identified clusters was linearly related (P < 0.0001) to peak pain intensity. Regional analyses showed that positively correlated clusters were present in the majority of subjects in SI, cingulate, motor, and premotor cortex. Negative correlations were found predominantly in medial parietal, perigenual cingulate, and medial prefrontal regions. To test whether these neural changes were due to aspecific arousal or emotional reactions, related either to anticipation or presence of pain, fMRI experiments were performed with the same protocol in two additional groups of volunteers, subjected either to subcutaneous saline injection (saline: n = 16), inducing mild short-lasting pain (peak pain intensity 23 +/- 4; duration 2.8 +/- 0.6 min) or to nonnoxious mechanical stimulation of the skin (controls: n = 16) at the same body site. Subjects did not know in advance which stimulus would occur. The spatial extent of neural clusters whose signal time courses were positively or negatively correlated with the mean pain intensity curve of subjects injected with ascorbic acid was significantly larger (P < 0.001) in the ascorbic acid group than both saline and controls, suggesting that the observed responses were specifically related to pain intensity and duration. These findings reveal distributed cortical systems, including parietal areas as well as cingulate and frontal regions, involved in dynamic encoding of pain intensity over time, a process of great biological and clinical relevance.

Several studies have described changes in beta-endorphin-like immunoreactivity (beta-ELI) in the rat brain in response to pain and stress stimuli. In order to ascertain the components of beta-ELI, brain samples of rats experiencing acute prolonged (tonic) pain were evaluated for their beta-ELI and later submitted to a chromatographic purification allowing the measurement of beta-endorphin (beta-EP) and acetyl beta-EP. The chromatographic analysis of both ventromedial hypothalamus (VMH) and periaqueductal grey (PAG) homogenates indicates that beta-ELI is distributed in several fractions including shortened forms of beta-EP and their respective acetylated compounds. Quantitatively, while beta-ELI in formalin-injected animals was increased by 48% in VMH and 45% in PAG in respect to controls, the net increase of purified beta-EP was 1100% and 470%, respectively, for VMH and PAG. Moreover, the maximal increase of beta-ELI was evident at 120 min, in both tissues. In contrast, the beta-EP peak was reached at 30 min in VMH and at 60 min in PAG. Acetyl beta-EP was unchanged by treatment in both central areas. No correlation of beta-ELI and beta-EP was found in VMH. These data demonstrate that the evaluation of beta-ELI gives a poor estimate of beta-EP changes, due to several components of the endorphin family.

The involvement of the beta-endorphin (B-EP) system during acute prolonged (tonic) pain was investigated by biochemical and behavioral approaches in freely-moving rats after subcutaneous injection of a small amount of a dilute formaldehyde solution (0.08 ml, 5%) in a forepaw. Beta-endorphin-like immunoreactivity levels were increased over the respective control groups in rats killed 30, 60 and 120 min after injection in discrete regions of the rat brain, namely ventro-medial hypothalamus, ventro-basal thalamus and periaqueductal gray matter, and at 30 and 60 min in postero-medial thalamus. In a separate group of experiments a small amount of anti-B-EP or normal rabbit serum was injected in the lateral ventricle; 6 h later rats received formalin injection as in previous groups and their behavior was scored over the following 2 h. A significant hyperalgesia (as expressed by an increase in the amount of time rats spent licking or chewing the injected paw) was observed 10-50 min and 70-80 min after formalin in the anti-B-EP icv-injected group. Other behavioral parameters such as general motor activity, grooming and limb flexion were not different in the two groups, nor was animal behavior prior to formalin injection. Altogether these data suggest that the central beta-endorphin system is triggered by prolonged noxious stimulation in freely-moving animals, and in turn plays a physiological role in the modulation of the reaction to, or perception of, tonic pain.

beta-Endorphin-like immunoreactivity (B-EP-LI) levels have been investigated in the ventral periaqueductal gray matter (vPAG) of rats killed 30, 60 or 120 min after the subcutaneous injection of dilute formalin (0.08 ml, 5%) in one fore- or hindpaw, or comparable handling. B-EP-LI was estimated by radioimmunoassay, using an anti-camel B-EP serum directed against the C-terminal portion of B-EP molecule. In both fore- and hindlimb groups vPAG B-EP-LI values were significantly increased 60 and 120 min after the injection relative to controls. Values from animals killed 120 min after formalin injection were higher than the ones at 30 and 60 min, forelimb effects being quantitatively more pronounced. The increase in B-EP-LI appeared distributed along the whole rostrocaudal extent of the region.

Acute physical restraint represents a potent stressor in several animal species and is accompanied by a complex pattern of hormonal responses and functional changes in the central nervous system. Repeated immobilization leads to partial blunting of the behavioral and hormonal responses, with transient modifications of neurotransmitter systems in the brain. Pain reactions, as investigated by different kinds of nociceptive tests, are usually attenuated both during and immediately following acute immobilization and the analgesic effect of opiate compounds potentiated; these behavioral alterations may be attributed at least in part to activation of an endogenous opioid system. In some species, restraint may induce a reflex immobility (animal hypnosis or tonic immobility) which is also characterized by suppression of pain reactions in rabbits, probably subserved by different mechanisms. Analysis of available data suggests that pain testing in unanesthetized, restrained animals may involve alterations of the animal's reactivity to noxious stimuli.