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• In predictive coding, unexpected inputs will create hierarchical prediction errors (PE). • We applied local-global oddball auditory paradigm in chronic pain and healthy controls. • Chronic pain is linked to increased lower-level PE and decreased higher-level PE. • Increased theta phase-locking during stimulus-driven PE was correlated with pain perception. The ability to perceive pain presents an interesting evolutionary advantage to adapt to an ever-changing environment. However, in the case of chronic pain (CP), pain perception hinders the capacity of the system to adapt to changing sensory environments. Similar to other chronic perceptual disorders, CP is also proposed to be a maladaptive compensation to aberrant sensory predictive processing. The local-global oddball paradigm relies on learning hierarchical rules and processing environmental irregularities at a local and global level. Prediction errors (PE) between actual and predicted input typically trigger an update of the forward model to limit the probability of encountering future PEs. It has been hypothesised that CP hinders forward model updating, reflected in increased local deviance and decreased global deviance. In the present study, we used the local-global paradigm to examine how CP influences hierarchical learning relative to healthy controls. As hypothesised, we observed that deviance in the stimulus characteristics evoked heightened local deviance and decreased global deviance of the stimulus-driven PE. This is also accompanied by respective changes in theta phase locking that is correlated with the subjective pain perception. Changes in the global deviant in the stimulus-driven-PE could also be explained by dampened attention-related responses. Changing the context of the auditory stimulus did not however show a difference in the context-driven PE. These findings suggest that CP is accompanied by maladaptive forward model updating where the constant presence of pain perception disrupts local deviance in non-nociceptive domains. Furthermore, we hypothesise that the auditory-processing based biomarker identified here could be a marker of domain-general dysfunction that could be confirmed by future research. Graphic abstracts of the PE processing comparison between healthy and chronic pain group. This figure depicts the main principles of predictive coding. (a) In this theory, the brain maintains an active model of the world based on the accumulation of previous experiences and inputs. Based on that, any bottom-up inputs will be matched with top-down predictions. Any discrepancy between input and prediction will create a prediction error (PE). As shown in the figure, the system operates in a hierarchical fashion where lower-level PE will update higher predictions that will cyclically minimise PE at the lower levels. (b) To support that, in this study the healthy controls increased later, more complex attentive responses (P300) while minimising their response to local changes (MMN). (c) However, due to the aberrant predictive processing, the chronic pain group showed a reduced response to global deviants (P300) and an increased response to local deviants (MMN). [Display omitted] [ABSTRACT FROM AUTHOR]

• We re-analyse our previous data to address Mazaheri et al.'s, 2022 criticisms. • Re-analysis partly supports the relationship between the ΔPAF and pain-free state PAF. • It provides weak support to the relationship between pain-free state PAF and perception. • The new analysis reinstates the validity of our previous conclusions. • Methodological differences may account for the lack of conceptual replication. In response to Mazaheri et al.'s critique, we revisited our study (Valentini et al., 2022) on the relationship between peak alpha frequency (PAF) and pain. Their commentary prompted us to reassess our data to address the independence between slow and slowing alpha brain oscillations, as well as the predictivity of slow alpha oscillations in pain perception. Bayesian correlation analyses revealed mixed support for independence. Investigating predictivity, we found inconsistent associations between pre-PAF and unpleasantness ratings. We critically reflected on methodological and theoretical issues on the path to PAF validation as a pain biomarker. We emphasized the need for diversified methodology and analytical approaches as well as robust findings across research groups. [ABSTRACT FROM AUTHOR]

Pain has an inhibitory effect on the corticospinal excitability that has been interpreted as an evolutionary mechanism, directed to down-regulate cortical activity in order to facilitate rapid protective spinal reflexes. Here, we focused on the link between defensive mechanisms and motor system and we asked whether voluntary actions can modulate the corticospinal excitability during painful stimulations. To this aim, we manipulated the volition-related aspects of our paradigm by comparing conditions in which either the participant (self-generated action) or the experimenter (other-generated action) pressed the button to deliver painful high-intensity transcutaneous electric shocks to the right digit V. MEPs to TMS were recorded from the FDI and APB muscles of the stimulated hand. A compelling agent-dependent modulation of the corticospinal excitability was found, showing, in self-generated compared to other-generated actions, a significantly lower inhibitory effect, as measured by greater MEP amplitude. This finding suggests a top-down modulation of volitional actions on defensive mechanisms, promoting the view that predictive information from the motor system attenuates the responses to the foreseeable adverse events generated by one’s own actions as compared to unpredictable events generated by someone else’s actions.

• Pain empathy varies from individual to individual and is related to pain perception. • Electroencephalography showed that both delta and alpha bands were involved in pain empathy regulation. • The average power in the delta band of Fz reflects individual differences in pain empathy. • The phase-locking values of the alpha band between Fz and P3 reflect individual differences in pain sensitivity. Pain empathy is a complex form of psychological inference that enables us to understand how others feel in the context of pain. Since pain empathy may be grounded in our own pain experiences, it exhibits huge inter-individual variability. However, the neural mechanisms behind the individual differences in pain empathy and its association with pain perception are still poorly understood. In this study, we aimed to characterize brain mechanisms associated with individual differences in pain empathy in adult participants (n = 24). The 32-channel electroencephalography (EEG) was recorded at rest and during a pain empathy task, and participants viewed static visual stimuli of the limbs submitted to painful and nonpainful stimulation to solicit empathy. The pain sensitivity of each participant was measured using a series of direct current stimulations. In our results, the N2 of Fz and the LPP of P3 and P4 were affected by painful pictures. We found that both delta and alpha bands in the frontal and parietal cortex were involved in the regulation of pain empathy. For the delta band, a close relationship was found between average power, either in the resting or task state, and individual differences in pain empathy. It suggested that the spectral power in Fz's delta band may reflect subjective pain empathy across individuals. For the alpha band, the functional connectivity between Fz and P3 under painful picture stimulation was correlated to individuals' pain sensitivity. It indicated that the alpha band may reflect individual differences in pain sensitivity and be involved in pain empathy processing. Our results suggested the distinct role of the delta and alpha bands of EEG signals in pain empathy processing and may deepen our understanding of the neural mechanisms underpinning pain empathy. [ABSTRACT FROM AUTHOR]

Abstract The human insula is an important target for spinothalamic input, but there is still no consensus on its role in pain perception and nociception. In this study, we show that the human insula exhibits activity preferential for sustained thermonociception. Using intracerebral EEG recorded from the insula of 8 patients (2 females) undergoing a presurgical evaluation of focal epilepsy (53 contacts: 27 anterior, 26 posterior), we "frequency-tagged" the insular activity elicited by sustained thermonociceptive and vibrotactile stimuli, by periodically modulating stimulation intensity at a fixed frequency of 0.2 Hz during 75 s. Both types of stimuli elicited an insular response at the frequency of stimulation (0.2 Hz) and its harmonics, whose magnitude was significantly greater in the posterior insula compared to the anterior insula. Compared to vibrotactile stimulation, thermonociceptive stimulation exerted a markedly greater 0.2 Hz modulation of ongoing theta-band (4–8 Hz) and alpha-band (8–12 Hz) oscillations. These modulations were also more prominent in the posterior insula compared to the anterior insula. The identification of oscillatory activities preferential for thermonociception could lead to new insights into the physiological mechanisms of nociception and pain perception in humans. [ABSTRACT FROM AUTHOR]

Some individuals are more distracted by pain during a cognitive task than others, representing poor pain coping. We have characterized individuals as A-type (attention dominates) or P-type (pain dominates) based on how pain interferes with task speed. The ability to optimize behavior during pain may relate to the flexibility in communication at rest between the dorsolateral prefrontal cortex (DLPFC) of the executive control network, and the anterior mid-cingulate cortex (aMCC) of the salience network (SN) – regions involved in cognitive-interference. The aMCC and aIns (SN hub) also signify pain salience; flexible communication at rest between them possibly allowing prioritizing task performance during pain. We tested the hypotheses that pain-induced changes in task performance are related to resting-state dynamic functional connectivity (dFC) between these region pairs (DLPFC-aMCC; aMCC-aIns). We found that 1) pain reduces task consistency/speed in P-type individuals, but enhances performance in A-type individuals, 2) task consistency is related to the FC dynamics within DLPFC-aMCC and aMCC-aIns pairs, 3) brain-behavior relationships are driven by dFC within the slow-5 (0.01–0.027 Hz) frequency band, and 4) dFC across the brain decreases at higher frequencies. Our findings point to neural communication dynamics at rest as being associated with prioritizing task performance over pain. [ABSTRACT FROM AUTHOR]

The neural processing and experience of pain are influenced by both expectations and attention. For example, the amplitude of event-related pain responses is enhanced by both novel and unexpected pain, and by moving the focus of attention towards a painful stimulus. Under predictive coding, this congruence can be explained by appeal to a precision-weighting mechanism, which mediates bottom-up and top-down attentional processes by modulating the influence of feedforward and feedback signals throughout the cortical hierarchy. The influence of expectation and attention on pain processing can be mapped onto changes in effective connectivity between or within specific neuronal populations, using a canonical microcircuit (CMC) model of hierarchical processing. We thus implemented a CMC within dynamic causal modelling for magnetoencephalography in human subjects, to investigate how expectation violation and attention to pain modulate intrinsic (within-source) and extrinsic (between-source) connectivity in the somatosensory hierarchy. This enabled us to establish whether both expectancy and attentional processes are mediated by a similar precision-encoding mechanism within a network of somatosensory, frontal and parietal sources. We found that both unexpected and attended pain modulated the gain of superficial pyramidal cells in primary and secondary somatosensory cortex. This modulation occurred in the context of increased lateralized recurrent connectivity between somatosensory and fronto-parietal sources, driven by unexpected painful occurrences. Finally, the strength of effective connectivity parameters in S1, S2 and IFG predicted individual differences in subjective pain modulation ratings. Our findings suggest that neuromodulatory gain control in the somatosensory hierarchy underlies the influence of both expectation violation and attention on cortical processing and pain perception. [ABSTRACT FROM AUTHOR]

Noxious stimuli induce physiological processes which commonly translate into pain. However, under certain conditions, pain intensity can substantially dissociate from stimulus intensity, e.g. during longer-lasting pain in chronic pain syndromes. How stimulus intensity and pain intensity are differentially represented in the human brain is, however, not yet fully understood. We therefore used electroencephalography (EEG) to investigate the cerebral representation of noxious stimulus intensity and pain intensity during 10 min of painful heat stimulation in 39 healthy human participants. Time courses of objective stimulus intensity and subjective pain ratings indicated a dissociation of both measures. EEG data showed that stimulus intensity was encoded by decreases of neuronal oscillations at alpha and beta frequencies in sensorimotor areas. In contrast, pain intensity was encoded by gamma oscillations in the medial prefrontal cortex. Contrasting right versus left hand stimulation revealed that the encoding of stimulus intensity in contralateral sensorimotor areas depended on the stimulation side. In contrast, a conjunction analysis of right and left hand stimulation revealed that the encoding of pain in the medial prefrontal cortex was independent of the side of stimulation. Thus, the translation of noxious stimulus intensity into pain is associated with a change from a spatially specific representation of stimulus intensity by alpha and beta oscillations in sensorimotor areas to a spatially independent representation of pain by gamma oscillations in brain areas related to cognitive and affective-motivational processes. These findings extend the understanding of the brain mechanisms of nociception and pain and their dissociations during longer-lasting pain as a key symptom of chronic pain syndromes. [ABSTRACT FROM AUTHOR]

Decoding the neural representations of pain is essential to obtaining an objective assessment as well as an understanding of its underlying mechanisms. The complexities involved in the subjective experience of pain make it difficult to obtain a quantitative assessment from the induced spatiotemporal patterns of brain activity of high dimensionality. Most previous studies have investigated the perception of pain by analyzing the amplitude or spatial patterns in the response of the brain to external stimulation. This study investigated the decoding of endogenous pain perceptions according to resting-state magnetoencephalographic (MEG) recordings. In our experiments, we applied a beamforming method to calculate the brain activity for every brain region and examined temporal and spectral features of brain activity for predicting the intensity of perceived pain in patients with primary dysmenorrhea undergoing menstrual pain. Our results show that the asymmetric index of sample entropy in the precuneus and the sample entropy in the left posterior cingulate gyrus were the most informative characteristics associated with the perception of menstrual pain. The correlation coefficient ( ρ =0.64, p <0.001) between the predicted and self-reported pain scores demonstrated the high prediction accuracy. In addition to the estimated brain activity, we were able to predict accurate pain scores directly from MEG channel signals ( ρ =0.65, p <0.001). These findings suggest the possibility of using the proposed model based on resting-state MEG to predict the perceived intensity of endogenous pain. [ABSTRACT FROM AUTHOR]

• Spatial scales of pain-preferential activity pattern were investigated by taking advantage of machine learning techniques. • Pain-preferential information was identified at both fine-grained and coarse-grained spatial scales. • Fine-grained local pain-distinguishing information was widely distributed within the brain. • Spatial distribution of pain-distinguishing information showed large inter-subject variability that was associated with personal pain behavior. How pain emerges from human brain remains an unresolved question in pain neuroscience. Neuroimaging studies have suggested that all brain areas activated by painful stimuli were also activated by tactile stimuli, and vice versa. Nonetheless, pain-preferential spatial patterns of voxel-level activation in the brain have been observed when distinguishing painful and tactile brain activations using multivariate pattern analysis (MVPA). According to two hypotheses, the neural activity pattern preferentially encoding pain could exist at a global, coarse-grained, regional level, corresponding to the "pain connectome" hypothesis proposing that pain-preferential information may be encoded by the synchronized activity across multiple distant brain regions, and/or exist at a local, fine-grained, voxel level, corresponding to the "intermingled specialized/preferential neurons" hypothesis proposing that neurons responding specially or preferentially to pain could be present and intermingled with non-pain neurons within a voxel. Here, we systematically investigated the spatial scales of pain-distinguishing information in the human brain measured by fMRI using machine learning techniques, and found that pain-distinguishing information could be detected at both coarse-grained spatial scales across widely distributed brain regions and fine-grained spatial scales within many local areas. Importantly, the spatial distribution of pain-distinguishing information in the brain varies across individuals and such inter-individual variations may be related to a person's trait about pain perception, particularly the pain vigilance and awareness. These results provide new insights into the longstanding question of how pain is represented in the human brain and help the identification of characteristic neuroimaging measurements of pain. [ABSTRACT FROM AUTHOR]

Humans exhibit substantial inter-individual differences in pain perception, which contributes to variability in analgesic efficacy. Individual differences in pain sensitivity have been linked with variation in the serotonin transporter gene (5-HTTLPR), and selective serotonin reuptake inhibitors (SSRIs) such as citalopram have been increasingly used as treatments for multiple pain conditions. We combined genotyping, pharmacological challenge, and neuroimaging during painful electrical stimulation to reveal how serotonin genetics and pharmacology interact to influence pain perception and its underlying neurobiological mechanisms. In a double-blind, placebo-controlled procedure, we acutely administrated citalopram (30 mg po) to short/short (s/s) and long/long (l/l) healthy male 5-HTTLPR homozygotes during functional MRI with painful and non-painful electrical stimulation. 5-HTTLPR genotype modulated citalopram effects on pain-related brain responses in the thalamus, cerebellum, anterior insula, midcingulate cortex and inferior frontal cortex. Specifically, citalopram significantly reduced pain-related brain responses in l/l but not in s/s homozygotes. Moreover, the interaction between 5-HTTLPR genotype and pain-related brain activity was a good predictor of the citalopram-induced reductions in pain reports. The genetic modulations of citalopram effects on brain-wide pain processing were paralleled by significant effects on the Neurological Pain Signature, a multivariate brain pattern validated to be sensitive and specific to physical pain. This work provides neurobiological mechanism by which genetic variation shapes brain responses to pain perception and treatment efficacy. These findings have important implications for the types of individuals for whom serotonergic treatments provide effective pain relief, which is critical for advancing personalized pain treatment. [ABSTRACT FROM AUTHOR]

The study by Valentini et al. (2022) observed that the peak alpha frequency (PAF) of participants became slower after they were exposed to painful, as well as non-painful but unpleasant stimuli. The authors interpreted this as a challenge to our previous studies which propose that the speed of resting PAF, independently of pain-induced changes to PAF, can be a reliable biomarker marker for gaging individual pain sensitivity. While investigations into the role that PAF plays in pain perception are timely, we have some concerns about the assumptions and methodology employed by Valentini et al. Moreover, we believe the authors here have also misrepresented some of our previous work. In the current commentary, we detail the critical differences between our respective studies, with the ultimate aim of guiding future investigations. [ABSTRACT FROM AUTHOR]

Top-down processes such as expectations play a key role in pain perception. In specific contexts, inferred threat of impending pain can affect perceived pain more than the noxious intensity. This biasing effect of top-down threats can affect some individuals more strongly than others due to differences in fear of pain. The specific characteristics of intrinsic brain characteristics that mediate the effects of top-down threat bias are mainly unknown. In this study, we examined whether threat bias is associated with structural and functional brain connectivity. The variability in the top-down bias was mapped to the microstructure of white matter in diffusion weighted images (DWI) using MRTrix3. Mean functional connectivity of five canonical resting state networks was tested for association with bias scores and with the identified DWI metrics. We found that the fiber density of the splenium of the corpus callosum was significantly low in individuals with high top-down threat bias (FWE corrected with 5000 permutations, p < 0.05). The mean functional connectivity within the language/memory and between language/memory and default mode networks predicted the bias scores. Functional connectivity within language memory networks predicted the splenium fiber density, higher pain catastrophizing and lower mindful awareness. Probabilistic tractography showed that the identified region in the splenium connected several sensory regions and high-order parietal regions between the two hemispheres, indicating the splenium's role in sensory integration. These findings demonstrate that individuals who show more change in pain with changes in the threat of receiving a stronger noxious stimulus have lower structural connectivity in the pathway necessary for integrating top-down cue information with bottom-up sensory information. Conversely, systems involved in memory recall, semantic and self-referential processing are more strongly connected in people with top-down threat bias. [ABSTRACT FROM AUTHOR]

Although the small-diameter primary afferent fibers in the skin promptly respond to nociceptive stimuli and convey sensory inputs to the central nervous system, the neural signatures that underpin the relationship between cutaneous afferent fibers and pain perception remain elusive. We combined skin biopsy at the lateral aspect of the distal leg, which is used to quantify cutaneous afferent fibers, with fMRI, which is used to assess brain responses and functional connectivity, to investigate the relationship between cutaneous sensory nerves and the corresponding pain perception in the brain after applying heat pain stimulation to the dorsum of the right foot in healthy subjects. During painful stimulation, the degree of cutaneous innervation, as measured by epidermal nerve fiber density, was correlated with individual blood oxygen level-dependent (BOLD) signals of the posterior insular cortex and of the thalamus, periaqueductal gray, and rostral ventromedial medulla. Pain perception was associated with the activation of the anterior insular cortex and with the functional connectivity from the anterior insular cortex to the primary somatosensory cortex during painful stimulation. Most importantly, both epidermal nerve fiber density and activity in the posterior insular cortex showed a positive correlation with the strength of coupling under pain between the anterior insular cortex and the primary somatosensory cortex. Thus, our findings support the notion that the neural circuitry subserving pain perception interacts with the cerebral correlates of peripheral nociceptive fibers, which implicates an indirect role for skin nerves in human pain perception. [ABSTRACT FROM AUTHOR]

Abstract: Persistent pain is a central characteristic of neuropathic pain conditions in humans. Knowing whether rodent models of neuropathic pain produce persistent pain is therefore crucial to their translational applicability. We investigated the spared nerve injury (SNI) model of neuropathic pain and the formalin pain model in rats using positron emission tomography (PET) with the metabolic tracer [18F]fluorodeoxyglucose (FDG) to determine if there is ongoing brain activity suggestive of persistent pain. For the formalin model, under brief anesthesia we injected one hindpaw with 5% formalin and the FDG tracer into a tail vein. We then allowed the animals to awaken and observed pain behavior for 30min during the FDG uptake period. The rat was then anesthetized and placed in the scanner for static image acquisition, which took place between minutes 45 and 75 post-tracer injection. A single reference rat brain magnetic resonance image (MRI) was used to align the PET images with the Paxinos and Watson rat brain atlas. Increased glucose metabolism was observed in the somatosensory region associated with the injection site (S1 hindlimb contralateral), S1 jaw/upper lip and cingulate cortex. Decreases were observed in the prelimbic cortex and hippocampus. Second, SNI rats were scanned 3weeks post-surgery using the same scanning paradigm, and region-of-interest analyses revealed increased metabolic activity in the contralateral S1 hindlimb. Finally, a second cohort of SNI rats was scanned while anesthetized during the tracer uptake period, and the S1 hindlimb increase was not observed. Increased brain activity in the somatosensory cortex of SNI rats resembled the activity produced with the injection of formalin, suggesting that the SNI model may produce persistent pain. The lack of increased activity in S1 hindlimb with general anesthetic demonstrates that this effect can be blocked, as well as highlights the importance of investigating brain activity in awake and behaving rodents. [Copyright &y& Elsevier]

Abstract: Pain perception is thought to emerge from the integrated activity of a distributed brain system, but the relative contribution of the different network nodes is still incompletely understood. In the present functional magnetic resonance imaging (fMRI) study, we aimed to identify the more relevant brain regions to explain the time profile of the perceived pain intensity in healthy volunteers, during noxious chemical stimulation (ascorbic acid injection) of the left hand. To this end, we performed multi-way partial least squares regression of fMRI data from twenty-two a-priori defined brain regions of interest (ROI) in each hemisphere, to build a model that could efficiently reproduce the psychophysical pain profiles in the same individuals; moreover, we applied a novel three-way extension of the variable importance in projection (VIP) method to summarize each ROI contribution to the model. Brain regions showing the highest VIP scores included the bilateral mid-cingulate, anterior and posterior insular, and parietal operculum cortices, the contralateral paracentral lobule, bilateral putamen and ipsilateral medial thalamus. Most of these regions, with the exception of medial thalamus, were also identified by a statistical analysis on mean ROI beta values estimated using the time course of the psychophysical rating as a regressor at the voxel level. Our results provide the first rank-ordering of brain regions involved in coding the perceived level of pain. These findings in a model of acute prolonged pain confirm and extend previous data, suggesting that a bilateral array of cortical areas and subcortical structures is involved in pain perception. [Copyright &y& Elsevier]

Pain is a subjective first-person experience, and self-report is the gold standard for pain assessment in clinical practice. However, self-report of pain is not available in some vulnerable populations (e.g., patients with disorders of consciousness), which leads to an inadequate or suboptimal treatment of pain. Therefore, the availability of a physiology-based and objective assessment of pain that complements the self-report would be of great importance in various applications. Here, we aimed to develop a novel and practice-oriented approach to predict pain perception from single-trial laser-evoked potentials (LEPs). We applied a novel single-trial analysis approach that combined common spatial pattern and multiple linear regression to automatically and reliably estimate single-trial LEP features. Further, we adopted a Naïve Bayes classifier to discretely predict low and high pain and a multiple linear prediction model to continuously predict the intensity of pain perception from single-trial LEP features, at both within- and cross-individual levels. Our results showed that the proposed approach provided a binary prediction of pain (classification of low pain and high pain) with an accuracy of 86.3±8.4% (within-individual) and 80.3±8.5% (cross-individual), and a continuous prediction of pain (regression on a continuous scale from 0 to 10) with a mean absolute error of 1.031±0.136 (within-individual) and 1.821±0.202 (cross-individual). Thus, the proposed approach may help establish a fast and reliable tool for automated prediction of pain, which could be potentially adopted in various basic and clinical applications. [ABSTRACT FROM AUTHOR]

Abstract: The stimulus-evoked response is the principle measure used to elucidate the timing and spatial location of human brain activity. Brain and behavioural responses to pain are influenced by multiple intrinsic and extrinsic factors and display considerable, natural trial-by-trial variability. However, because the neuronal sources of this variability are poorly understood the functional information it contains is under-exploited for understanding the relationship between brain function and behaviour. We recorded simultaneous EEG–fMRI during rest and noxious thermal stimulation to characterise the relationship between natural fluctuations in behavioural pain-ratings, the spatiotemporal dynamics of brain network responses and intrinsic connectivity. We demonstrate that fMRI response variability in the pain network is: dependent upon its resting-state functional connectivity; modulated by behaviour; and correlated with EEG evoked-potential amplitude. The pre-stimulus default-mode network (DMN) fMRI signal predicts the subsequent magnitude of pain ratings, evoked-potentials and pain network BOLD responses. Additionally, the power of the ongoing EEG alpha oscillation, an index of cortical excitability, modulates the DMN fMRI response to pain. The complex interaction between alpha-power, DMN activity and both the behavioural report of pain and the brain's response to pain demonstrates the neurobiological significance of trial-by-trial variability. Furthermore, we show that multiple, interconnected factors contribute to both the brain's response to stimulation and the psychophysiological emergence of the subjective experience of pain. [Copyright &y& Elsevier]

Abstract: Trigeminal neuralgia (TN) is supposedly caused by an ectatic blood vessel affecting the trigeminal nerve at the root entry zone of the brain stem. Recent evidence suggests an additional central component within trigeminal pain-processing in the pathophysiology of TN. Therefore, we aimed to identify specific brain regions possibly associated with the development or maintenance of TN using magnetic resonance imaging (MRI) voxel-based morphometry (VBM). Sixty patients with classical TN were compared to 49 healthy controls. Eighteen patients had TN with concomitant constant facial pain, a condition previously described as a predictor of worse treatment outcome. We found gray matter (GM) volume reduction in TN patients compared to healthy controls in the primary somatosensory and orbitofrontal cortices, as well as the in the secondary somatosensory cortex, thalamus, insula, anterior cingulate cortex (ACC), cerebellum, and dorsolateral prefrontal cortex. GM volume decrease within the ACC, parahippocampus, and temporal lobe correlated with increasing disease duration in TN. There were no differences comparing patients with and without concomitant constant facial pain. No GM increase was found comparing patient subgroups with each other and with healthy controls. The observed changes probably reflect the impact of multiple, daily attacks of trigeminal pain in these patients similar to what was previously described in other chronic pain conditions and may be interpreted as adaptation mechanism to chronic pain in regard to neuronal plasticity. The ACC, parahippocampus and temporal lobe volume reduction in parallel with disease duration may point to a pivotal role of these structures in chronic pain. [Copyright &y& Elsevier]

Abstract: The nature of interactions between observing pain in others (other-pain) and subjective pain perception (self-pain) has been debated. To test whether other-pain and self-pain primes increase or decrease responsiveness to complementary self-pain or other-pain targets, two ERP studies were conducted. In Study 1, twenty participants (10 women, 10 men) were exposed to pictures depicting other-pain or other non-painful situations, followed by self-pain or non-nociceptive heat stimulation delivered to the forearm. Significant visual prime×sensory target interactions indicated that compared to other non-painful primes, other-pain visual primes predicted faster reaction times (RTs) and smaller P2 amplitudes in response to self-pain stimuli while responses to self-heat stimuli were not affected by priming images. However, effects of other-pain primes on elevations in intensity ratings were not specific to self-pain and extended to self-heat targets. In Study 2, self-pain and self-heat stimuli were applied to the same participants followed by other-pain and other non-painful visual targets. Similar to the pattern for Study 1, sensory prime×visual target interactions indicated that compared to self-heat primes, self-pain sensory primes predicted marginally faster RTs and smaller P3 amplitudes in response to other-pain targets while responses to other non-painful targets were unaffected by sensory priming stimuli. Again, self-pain primes predicted higher intensity ratings for both target types compared to self-heat primes. Together, findings supported the shared-representation model of pain empathy more strongly than the threat value of pain hypothesis. [Copyright &y& Elsevier]

Abstract: In our environment, acute pain is often accompanied by input from other sensory modalities, like visual stimuli, which can facilitate pain processing. To date, it is not well understood how these inputs influence the perception and processing of pain. Previous studies on integrative processing between sensory modalities other than pain have shown that multisensory response gains are strongest when the constituent unimodal stimuli are minimally effective in evoking responses. This finding has been termed the principle of inverse effectiveness (IE). In this high-density electroencephalography study, we investigated the influence of Gabor patches of low and high contrast levels on the perception and processing of spatially and temporally aligned painful electrical stimuli of low and high intensities. Subjective pain ratings, event-related potentials (ERPs) and oscillatory responses served as dependent measures. In line with the principle of IE, stronger crossmodal biasing effects of visual input on subjective pain ratings were found for low compared to high intensity painful stimuli. This effect was paralleled by stronger bimodal interactions in right-central ERPs (150–200ms) for low compared to high intensity pain stimuli. Moreover, an enhanced suppression of medio-central beta-band activity (12–24Hz, 200–400ms) was found for low compared to high intensity pain stimuli. Our findings possibly reflect a facilitation of stimulus processing that serves to enhance response readiness of the sensorimotor system following painful stimulation. Taken together, our study demonstrates that multisensory processing between visual and painful stimuli follows the principle of IE and suggests a role for beta-band oscillations in the crossmodal modulation of pain. [Copyright &y& Elsevier]

Abstract: Human empathy is an important component of social cognition that involves complex processes of emotional perspective taking and the issue of self/other distinction. Empathic perception enables us to experience negative emotions when someone else undergoes painful events. We investigated the influence of an extended time interval (10s) and subjective performance evaluation (following each trial) of perspective taking on the cortical and subcortical correlates of pain empathy in eighteen healthy subjects using functional magnetic resonance imaging (fMRI). Subjects were presented pictures of hands and feet in painful and non-painful situations. They were instructed to simply view the picture (View) or adopt either their own perspective (Self) or the perspective of a third-person (Other). Prolonged time intervals of stimulus presentation enabled the analysis of different perspective taking processes (Self versus Other). Enhanced activation in the left supramarginal gyrus was detected for adopting the Self compared to the Other perspective. Time course analysis showed an early peak in the trials, suggesting that taking the first-person perspective is an intuitive more automatic process. The comparison between the Other and Self condition evoked stronger activity in dorso- and ventrolateral prefrontal areas and the superior temporal sulcus (STS). For these areas, a peak in the later phase of the trials was found, suggesting that taking the third-person perspective requires more effort and is an ongoing process. This was also supported by the fact that the participants were subjectively more successful in adopting the Self perspective compared to the Other. Our findings support that especially during the Other condition, prolonged time periods seem to facilitate empathic responses. Individual ratings of performance enabled the comparison between subjects that were successful and unsuccessful at taking the Self or Other perspective. For Self, differential activations were found in the left insula and postcentral gyrus. For Other, differential activations were mainly observed in the left pallidum, bilateral VLPFC, the right middle orbitofrontal cortex OFC and the middle cingulate cortex (MCC). These results suggest that trial-specific success ratings allow us to disentangle differences between effort-related and successful engagement in perspective taking. These two adjustments to the well-known paradigm showed new insight into the aspects of perspective taking during pain perception. [Copyright &y& Elsevier]

Abstract: Pain is known to comprise sensory, cognitive, and affective aspects. Despite numerous previous fMRI studies, however, it remains open which spatial distribution of activity is sufficient to encode whether a stimulus is perceived as painful or not. In this study, we analyzed fMRI data from a perceptual decision-making task in which participants were exposed to near-threshold laser pulses. Using multivariate analyses on different spatial scales, we investigated the predictive capacity of fMRI data for decoding whether a stimulus had been perceived as painful. Our analysis yielded a rank order of brain regions: during pain anticipation, activity in the periaqueductal gray (PAG) and orbitofrontal cortex (OFC) afforded the most accurate trial-by-trial discrimination between painful and non-painful experiences; whereas during the actual stimulation, primary and secondary somatosensory cortex, anterior insula, dorsolateral and ventrolateral prefrontal cortex, and OFC were most discriminative. The most accurate prediction of pain perception from the stimulation period, however, was enabled by the combined activity in pain regions commonly referred to as the ‘pain matrix’. Our results demonstrate that the neural representation of (near-threshold) pain is spatially distributed and can be best described at an intermediate spatial scale. In addition to its utility in establishing structure-function mappings, our approach affords trial-by-trial predictions and thus represents a step towards the goal of establishing an objective neuronal marker of pain perception. [Copyright &y& Elsevier]

Abstract: The specific neural processes underlying vicarious pain perception are not fully understood. In this functional imaging study, 20 participants viewed pain-evoking or neutral images displaying either sensory or emotional-communicative information. The pain images displayed nociceptive agents applied to the hand or the foot (sensory information) or facial expressions of pain (emotional-communicative information) and were matched with their neutral counterparts. Combining pain-evoking and neutral images showed that body limbs elicited greater activity in sensory motor regions, whereas midline frontal and parietal cortices and the amygdala responded more strongly to faces. The pain-evoking images elicited greater activity than their neutral counterparts in the bilateral inferior frontal gyrus (IFG), the left inferior parietal lobule (IPL) and the bilateral extrastriate body area. However, greater pain-related activity was observed in the rostral IPL when images depicted a hand or foot compared to a facial expression of pain, suggesting a more specific involvement in the coding of somato-motor information. Posterior probability maps enabling Bayesian inferences further showed that the anterior IFG (BA 45 and 47) was the only region showing no intrinsic probability of activation by the neutral images, consistent with a role in the extraction of the meaning of pain-related visual cues. Finally, inter-individual empathy traits correlated with responses in the supracallosal mid/anterior cingulate cortex and the anterior insula when pain-evoking images of body limbs or facial expressions were presented, suggesting that these regions regulated the observer''s affective-motivational response independent from the channels from which vicarious pain is perceived. [Copyright &y& Elsevier]

Abstract: Stimulation of acupuncture point Pc6, located above the median nerve, has been shown to be effective in treating nausea and vomiting. It has also frequently been reported to cause a heart rate reduction. The mechanism behind this autonomic reaction has not been clarified, so far. We combined brainstem-sensitive functional magnetic resonance imaging with heart rate recording and time-resolved rating of the needling sensation to measure neuronal correlates of sensations and autonomic reactions during acupuncture. On the cortical level, needling sensation activated typical pain-related areas, of which the ventromedial and dorsolateral prefrontal cortex and perigenual anterior cingulate cortex were further involved in mediating the heart rate response. In the brainstem, needling sensation activated nuclei of the descending pain control system, in which a network of hypothalamus, periaqueductal gray, rostral ventromedial medulla, and ventrolateral medulla was identified as the source of the heart rate changes. Our findings indicate that acupuncture may be a special pain stimulus, whose autonomic concomitants could explain its non-analgesic effects and in some cases even have a therapeutic potential. [Copyright &y& Elsevier]

Abstract: The role of operculo-insular region in the processing of somato-sensory inputs, painful or not, is now well established. However, available maps from previous literature show a substantial overlap of cortical areas activated by these stimuli, and the region referred to as the “secondary somatosensory area (SII)” is widely distributed in the parietal operculum. Differentiating SII from posterior insula cortex, which is anatomically contiguous, is not easy, explaining why the “operculo-insular” label has been introduced to describe activations by somatosensory stimuli in this cortical region. Based on the recent cyto-architectural parcellation of the human insular/SII cortices (Eickhoff et al., 2006, Kurth et al., 2010), the present study investigates with functional MRI (fMRI), whether these structural subdivisions could subserve distinct aspects of discriminative somato-sensory functions, including pain. Responses to five types of stimuli applied on the left hand of 25 healthy volunteers were considered: i) tactile stimuli; ii) passive movements; iii) innocuous cold stimuli; iv) non-noxious warm and v) heat pain. Our results show different patterns of activation depending on the type of somato-sensory stimulation. The posterior part of SII (OP1 area), contralateral to stimuli, was the only sub-region activated by all type of stimuli and might therefore be considered as a common cortical target for different types of somato-sensory inputs. Proprioceptive stimulation by passive finger movements activated the posterior part of SII (OP1 sub-region) bilaterally and the contralateral median part of insula (PreCG and MSG). Innocuous cooling activated the contralateral posterior part of SII (OP1) and the dorsal posterior and median part of insula (OP2, PostCG). Pain stimuli induced the most widespread and intense activation that was bilateral in SII (OP1, OP4) and distributed to all sub-regions of contralateral insula (except OP2) and to the anterior part of the ipsilateral insula (PreCG, MSG, ASG). However, the posterior granular part of insula contralateral to stimulus (Ig area) and the anterior part of SII bilaterally (OP4) were specifically activated during pain stimulation. This raises the question whether these latter areas could be the anatomical substrate of the sensory-discriminative processing of thermal pain. [Copyright &y& Elsevier]

Abstract: Introduction: Several brain structures have been consistently found to be involved in visceral pain processing. However, recent research questions the specificity of these regions and it has been suggested that it is not singular activations of brain areas, but their cross-communication that results in perception of pain. Moreover, frequency at which neurons are firing could be what separates pain from other sensory modalities which otherwise involve the same anatomical locations. In this test/retest study, we identified the network of sources and their frequencies following visceral pain. Methods: 62-channel evoked potentials following electrical stimulation in oesophagus were recorded in twelve healthy volunteers on two separate days. Multichannel matching pursuit (MMP) and dipolar source localisation were used. Multiple sources responsible for one MMP component were considered to act synchronously as each MMP component is mono-frequency and has a single topography. We first identified components that were reproducible within subjects over recording sessions. These components were then analysed across subjects. Results: MMP and source localisation showed three main brain networks; an early network at ~8.3Hz and ~3.5Hz involving brainstem, operculum, and pre-frontal cortex peaking at ~77ms. This was followed by an operculum, amygdale, mid-cingulate, and anterior-cingulate network at ~4.5Hz. Finally, there was an operculum and mid-cingulate network that persisted over the entire time interval, peaking at 245.5±51.4ms at ~2.1Hz. Conclusion: This study gives evidence of operculum''s central integrative role for perception of pain and shows that MMP is a reliable method to study upstream brain activity. [Copyright &y& Elsevier]

Abstract: The experience of pain occurs when the level of a stimulus is sufficient to elicit a marked affective response, putatively to warn the organism of potential danger and motivate appropriate behavioral responses. Understanding the biological mechanisms of the transition from innocuous to painful levels of sensation is essential to understanding pain perception as well as clinical conditions characterized by abnormal relationships between stimulation and pain response. Thus, the primary objective of this study was to characterize the neural response associated with this transition and the correspondence between that response and subjective reports of pain. Towards this goal, this study examined BOLD response profiles across a range of temperatures spanning the pain threshold. 14 healthy adults underwent functional magnetic resonance imaging (fMRI) while a range of thermal stimuli (44–49°C) were applied. BOLD responses showed a sigmoidal profile along the range of temperatures in a network of brain regions including insula and mid-cingulate, as well as a number of regions associated with motor responses including ventral lateral nuclei of the thalamus, globus pallidus and premotor cortex. A sigmoid function fit to the BOLD responses in these regions explained up to 85% of the variance in individual pain ratings, and yielded an estimate of the temperature of steepest transition from non-painful to painful heat that was nearly identical to that generated by subjective ratings. These results demonstrate a precise characterization of the relationship between objective levels of stimulation, resulting neural activation, and subjective experience of pain and provide direct evidence for a neural mechanism supporting the nonlinear transition from innocuous to painful levels along the sensory continuum. [Copyright &y& Elsevier]

Abstract: Two quantification methods for light reflectance spectroscopy (LRS) were developed and validated to determine absolute and relative values of hemodynamic parameters and light scattering, followed by a specific application using in vivo animal experiments. A single-channel LRS system consisted of a light source, CCD-array detector, and a computer along with a bifurcated, 2-mm-diameter optical probe; this system was utilized to perform laboratory tissue phantoms for validation of the algorithms. In the animal study, a multi-channel, multisite approach was used to measure several reflectance spectra from rat brain and spinal cord on both the ipsi-lateral and contra-lateral sides, using thin 800-μm-diameter optic probes. The neuro-hemodynamic changes were induced by 10-V electrical stimulation in rat hind paw. The LRS data of the animals were analyzed using both absolute and relative methods. The results show that the relative method is computation-efficient and offers a quick estimation of changes in oxy-hemoglobin concentration for real-time monitoring. The absolute quantification method, on the other hand, provides us with an accurate computational tool to calculate absolute values of oxy-, deoxy-, total hemoglobin concentrations, and light scattering coefficients. We also observe that the hemodynamic responses in rat spinal cord were delayed with a few seconds and have an overall broader full width at half maximum, as compared to those from rat somatosensory cortex. LRS as a measurement system provides a robust method for studying local hemodynamic changes and a potential technique to investigate hemo-neural mechanisms in pain processing. [Copyright &y& Elsevier]

Abstract: 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 &y& Elsevier]

Abstract: The communication of pain requires the perception of pain-related signals and the extraction of their meaning and magnitude to infer the state of the expresser. Here, BOLD responses were measured in healthy volunteers while they evaluated the amount of pain expressed (pain task) or discriminated movements (movement task) in one-second video clips displaying facial expressions of various levels of pain. Regression analysis using subjects'' ratings of pain confirmed the parametric response of several regions previously involved in the coding of self-pain, including the anterior cingulate cortex (ACC) and anterior insula (aINS), as well as areas implicated in action observation, and motor mirroring, such as the inferior frontal gyrus (IFG) and inferior parietal lobule (IPL). Furthermore, the pain task produced stronger activation in the ventral IFG, as well as in areas of the medial prefrontal cortex (mPFC) associated with social cognition and emotional mirroring, whereas stronger activation during the movement task predominated in the IPL. These results suggest that perception of the pain of another via facial expression recruits limbic regions involved in the coding of self-pain, prefrontal areas underlying social and emotional cognition (i.e. ‘mentalizing’), and premotor and parietal areas involved in motor mirroring. [Copyright &y& Elsevier]

Abstract: Watching or imagining other people experiencing pain activates the central nervous system''s pain matrix in the observer. Without emotion regulation skills, repeated exposure to the suffering of others in healthcare professionals may be associated with the adverse consequences of personal distress, burnout and compassion fatigue, which are detrimental to their wellbeing. Here, we recorded event-related potentials (ERP) from physicians and matched controls as they were presented with visual stimuli depicting body parts pricked by a needle (pain) or touched by a Q-tip (no-pain). The results showed early N110 differentiation between pain and no-pain over the frontal area as well as late P3 over the centro-parietal regions were observed in the control participants. In contrast, no such early and late ERP responses were detected in the physicians. Our results indicate that emotion regulation in physicians has very early effects, inhibiting the bottom-up processing of the perception of pain in others. It is suggested that physicians'' down-regulation of the pain response dampens their negative arousal in response to the pain of others and thus may have many beneficial consequences including freeing up cognitive resources necessary for being of assistance. [Copyright &y& Elsevier]

Abstract: Pain is a multidimensional experience. Human pain perception can be modulated by subjective emotional responses. We examined this association within the context of a neuroimaging study, using functional MRI to examine neural responses to electrical pain-inducing stimuli in 15 healthy subjects (6 females; age range=20–30 years). Pain-inducing stimuli were presented during different emotional contexts, which were induced via the continuous presentation (5 s) of sad, happy, or neutral pictures of faces. We found that subjective pain ratings were higher in the sad emotional context than in the happy and neutral contexts, and that pain-related activation in the ACC was more pronounced in the sad context relative to the happy and neutral contexts. Psychophysiological interaction (PPI) and dynamic causal modeling (DCM) analyses demonstrated amygdala to ACC connections during the experience of pain in the sad context. These findings serve to highlight the neural mechanisms that may be relevant to understanding the broader relationship between somatic complaints and negative emotion. [Copyright &y& Elsevier]

Abstract: Spinal cord stimulation (SCS) is an effective therapy for chronic neuropathic pain. However, the detailed mechanisms underlying its effects are not well understood. Positron emission tomography (PET) with H2 15O was applied to clarify these mechanisms. Nine patients with intractable neuropathic pain in the lower limbs were included in the study. All patients underwent SCS therapy for intractable pain, which was due to failed back surgery syndrome in three patients, complex regional pain syndrome in two, cerebral hemorrhage in two, spinal infarction in one, and spinal cord injury in one. Regional cerebral blood flow (rCBF) was measured by H2 15O PET before and after SCS. The images were analyzed with statistical parametric mapping software (SPM2). SCS reduced pain; visual analog scale values for pain decreased from 76.1±25.2 before SCS to 40.6±4.5 after SCS (mean±SE). Significant rCBF increases were identified after SCS in the thalamus contralateral to the painful limb and in the bilateral parietal association area. The anterior cingulate cortex (ACC) and prefrontal areas were also activated after SCS. These results suggest that SCS modulates supraspinal neuronal activities. The contralateral thalamus and parietal association area would regulate the pain threshold. The ACC and prefrontal areas would control the emotional aspects of intractable pain, resulting in the reduction of neuropathic pain after SCS. [Copyright &y& Elsevier]

Abstract: Electrophysiological investigations of the spinal cord in animals have shown that pain sensitizes the central nervous system via glutamate receptor dependent long-term potentiation (LTP) related to an enhancement of pain perception. To expand these findings, we used functional magnetic resonance (fMRI), blood oxygen level dependent (BOLD) and perfusion imaging in combination with repeated electrical stimulation in humans. Specifically we monitored modulation of somatosensory processing during inhibition of excitatory transmission by ocular application of the glutamate receptor antagonist xenon. BOLD responses upon secondary stimulation increased in mid insular and in primary/secondary sensory cortices under placebo and decreased under xenon treatments. Xenon-induced decreases in regional perfusion were confined to stimulation responsive brain regions and correlated with time courses of xenon concentrations in the cranial blood. Moreover, effects of xenon on behavioral, fMRI and perfusion data scaled with stimulus intensity. The dependence of pain sensitization on sufficient pre-activation reflects a multistage process which is characteristic for glutamate receptor related processes of LTP. This study demonstrates how LTP related processes known from the cellular level can be investigated at the brain systems level. [Copyright &y& Elsevier]

Abstract: Studying of the impact of social context on the perception of pain in others is important for understanding the role of intentionality in interpersonal sensitivity, empathy, and implicit moral reasoning. Here we used an event-related fMRI with pain and social context (i.e., the number of individuals in the stimuli) as the two factors to investigate how different social contexts and resulting perceived agency modulate the neural response to the perception of pain in others. Twenty-six healthy participants were scanned while presented with short dynamic visual stimuli depicting painful situations accidentally caused by or intentionally caused by another individual. The main effect of perception of pain was associated with signal increase in the aMCC, insula, somatosensory cortex, SMA and PAG. Importantly, perceiving the presence of another individual led to specific hemodynamic increase in regions involved in representing social interaction and emotion regulation including the temporoparietal junction, medial prefrontal cortex, inferior frontal gyrus, and orbitofrontal cortex. Furthermore, the functional connectivity pattern between the left amygdala and other brain areas was modulated by the perceived agency. Our study demonstrates that the social context in which pain occurs modulate the brain response to other''s pain. This modulation may reflect successful adaptation to potential danger present in a social interaction. Our results contribute to a better understanding of the neural mechanisms underpinning implicit moral reasoning that concern actions that can harm other people. [Copyright &y& Elsevier]

Abstract: Primary dysmenorrhea (PDM, menstrual pain without pelvic abnormality) is the most common gynecological disorder for women in the reproductive age. It is characterized by cramping pain and enhanced pain sensitivity during the menstruation period. PDM has been associated with peripheral and central sensitization. Abnormal brain mechanisms may further contribute to development and maintenance of the state. Using fluoro-deoxyglucose positron emission tomography, increased activity was observed in prefrontal/orbitofrontal regions and left ventral posterior thalamus while decreased activity mainly was observed in sensorimotor regions of the left hemisphere at onset compared to offset of PDM. These results were specific to menstrual pain and were not found in menstrual matched controls. Orbitofrontal activities were positively related to while somatosensory activities where negatively related to subjective pain ratings. These results show that ongoing menstrual pain in PDM is accompanied by abnormal brain metabolism. Disinhibition of thalamo-orbitofrontal-prefrontal networks may contribute to the generation of pain and hyperalgesia in PDM possibly by maintaining spinal and thalamic sensitization while increasing negative affect. Excessive excitatory input during menstrual pain may induce compensatory inhibitory mechanism in several somatic sensorimotor regions. [Copyright &y& Elsevier]

Abstract: There is a large body of evidence that serotonin [5-hydroxytryptamine (5-HT)] plays an important role in the transmission and regulation of pain. Here we used positron emission tomography (PET) to study the relationship between baseline 5-HT2A binding in the brain and responses to noxious heat stimulation in a group of young healthy volunteers. Twenty-one healthy subjects underwent PET scanning with the 5-HT2A antagonist, [18F]altanserin. In addition, participants underwent a battery of pain tests using noxious heat stimulation to assess pain threshold, pain tolerance and response to short-lasting phasic and long-lasting (7-minute) tonic painful stimulation. Significant positive correlations were found between tonic pain ratings and [18F]altanserin binding in orbitofrontal (r = 0.66; p = 0.005), medial inferior frontal (r = 0.60; p = 0.014), primary sensory–motor (r = 0.61; p = 0.012) and posterior cingulate (r = 0.63; p = 0.009) cortices. In contrast, measures of regional [18F]altanserin binding did not correlate with pain threshold, pain tolerance, or suprathreshold phasic pain responses. These data suggest that cortical 5-HT2A receptor availability co-varies with responses to tonic pain. The correlation between [18F]altanserin binding in prefrontal cortex and tonic pain suggests a possible role of this brain region in the modulation and/or cognitive-evaluative appreciation of pain. [Copyright &y& Elsevier]