Investigating mortality salience as a potential causal influence and moderator of responses to laboratory pain.

Background: Because pain can have profound ramifications for quality of life and daily functioning, understanding nuances in the interplay of psychosocial experiences with pain perception is vital for effective pain management. In separate lines of research, pain resilience and mortality salience have emerged as potentially important psychological correlates of reduced pain severity and increased tolerance of pain. However, to date, there has been a paucity of research examining potentially interactive effects of these factors on pain perception. To address this gap, the present experiment investigated mortality salience as a causal influence on tolerance of laboratory pain and a moderator of associations between pain resilience and pain tolerance within a Chinese sample. Methods: Participants were healthy young Chinese adults (86 women, 84 men) who first completed a brief initial cold pressor test (CPT) followed by measures of demographics and pain resilience. Subsequently, participants randomly assigned to a mortality salience (MS) condition completed two open-ended essay questions in which they wrote about their death as well as a death anxiety scale while those randomly assigned to a control condition completed analogous tasks about watching television. Finally, all participants engaged in a delay task and a second CPT designed to measure post-manipulation pain tolerance and subjective pain intensity levels. Results: MS condition cohorts showed greater pain tolerance than controls on the post-manipulation CPT, though pain intensity levels did not differ between groups. Moderator analyses indicated that the relationship between the behavior perseverance facet of pain resilience and pain tolerance was significantly stronger among MS condition participants than controls. Conclusions: This experiment is the first to document potential causal effects of MS on pain tolerance and Ms as a moderator of the association between self-reported behavior perseverance and behavioral pain tolerance. Findings provide foundations for extensions within clinical pain samples.

Exercise induced hypoalgesia during different intensities of a dynamic resistance exercise: A randomized controlled trial.

INTRODUCTION: Exercise produces an immediate lessening of pain sensitivity (Exercise-Induced Hypoalgesia (EIH)) in healthy individuals at local and distant sites, possibly through a shared mechanism with conditioned pain modulation (CPM). Dynamic resistance exercise is a recommended type of exercise to reduce pain, yet limited research has examined the effects of intensity on EIH during this type of exercise. Therefore, the primary purpose of this study is to compare changes in PPT at a local and distant site during a leg extension exercise at a high intensity, a low intensity, or a quiet rest condition. A secondary purpose is to examine if CPM changes after each intervention. The final purpose is to examine if baseline pain sensitivity measures are correlated with response to each intervention. METHODS: In a randomized controlled trial of 60 healthy participants, participants completed baseline pain sensitivity testing (heat pain threshold, temporal summation, a cold pressor test as measure of CPM) and were randomly assigned to complete a knee extension exercise at: 1) high intensity (75% of a 1 Repetition Maximum (RM), 2) low intensity (30% 1RM), or 3) Quiet Rest. PPT was measured between each set at a local (quadriceps) and distant (trapezius) site during the intervention. CPM was then repeated after the intervention. To test the first purpose of the study, a three-way ANOVA examined for time x site x intervention interaction effects. To examine for changes in CPM by group, a mixed-model ANOVA was performed. Finally, a Pearson Correlation examined the association between baseline pain sensitivity and response to each intervention. RESULTS: Time x site x intervention interaction effects were not significant (F(5.3, 150.97) = 0.87, p = 0.51, partial eta2 = 0.03). CPM did not significantly change after the interventions (time x intervention F(1,38) = 0.81, p = 0.37, partial eta2 = 0.02. EIH effects at the quadriceps displayed a significant, positive moderate association with baseline HPT applied over the trapezius (r = 0.61, p<0.01) and TS (r = 0.46, p = 0.04). DISCUSSION: In healthy participants, PPT and CPM did not significantly differ after a leg extension exercise performed at a high intensity, low intensity, or quiet rest condition. It is possible pre-intervention CPM testing with a noxious stimuli may have impaired inhibitory effects frequently observed during exercise but future research would need to examine this hypothesis.

Integration of Prior Expectations and Suppression of Prediction Errors During Expectancy-Induced Pain Modulation: The Influence of Anxiety and Pleasantness.

Pain perception arises from the integration of prior expectations with sensory information. Although recent work has demonstrated that treatment expectancy effects (e.g., placebo hypoalgesia) can be explained by a Bayesian integration framework incorporating the precision level of expectations and sensory inputs, the key factor modulating this integration in stimulus expectancy-induced pain modulation remains unclear. In a stimulus expectancy paradigm combining emotion regulation in healthy male and female adults, we found that participants' voluntary reduction in anticipatory anxiety and pleasantness monotonically reduced the magnitude of pain modulation by negative and positive expectations, respectively, indicating a role of emotion. For both types of expectations, Bayesian model comparisons confirmed that an integration model using the respective emotion of expectations and sensory inputs explained stimulus expectancy effects on pain better than using their respective precision. For negative expectations, the role of anxiety is further supported by our fMRI findings that (1) functional coupling within anxiety-processing brain regions (amygdala and anterior cingulate) reflected the integration of expectations with sensory inputs and (2) anxiety appeared to impair the updating of expectations via suppressed prediction error signals in the anterior cingulate, thus perpetuating negative expectancy effects. Regarding positive expectations, their integration with sensory inputs relied on the functional coupling within brain structures processing positive emotion and inhibiting threat responding (medial orbitofrontal cortex and hippocampus). In summary, different from treatment expectancy, pain modulation by stimulus expectancy emanates from emotion-modulated integration of beliefs with sensory evidence and inadequate belief updating.

Can the neural representation of physical pain predict empathy for pain in others?

The question of whether physical pain and vicarious pain have some shared neural substrates is unresolved. Recent research has argued that physical and vicarious pain are represented by dissociable multivariate brain patterns by creating biomarkers for physical pain (Neurologic Pain Signature, NPS) and vicarious pain (Vicarious Pain Signature, VPS), respectively. In the current research, the NPS and two versions of the VPS were applied to three fMRI datasets (one new, two published) relating to vicarious pain which focused on between-subject differences in vicarious pain (Datasets 1 and 3) and within-subject manipulations of perspective taking (Dataset 2). Results show that (i) NPS can distinguish brain responses to images of pain vs no-pain and to a greater extent in vicarious pain responders who report experiencing pain when observing pain and (ii) neither version of the VPS mapped on to individual differences in vicarious pain and the two versions differed in their success in predicting vicarious pain overall. This study suggests that the NPS (created to detect physical pain) is, under some circumstances, sensitive to vicarious pain and there is significant variability in VPS measures (created to detect vicarious pain) to act as generalizable biomarkers of vicarious pain.

Neuroimaging-based evidence for sympathetic correlation between brain activity and peripheral vasomotion during pain anticipation.

Anticipation of pain engenders anxiety and fear, potentially shaping pain perception and governing bodily responses such as peripheral vasomotion through the sympathetic nervous system (SNS). Sympathetic innervation of vascular tone during pain perception has been quantified using a peripheral arterial stiffness index; however, its innervation role during pain anticipation remains unclear. This paper reports on a neuroimaging-based study designed to investigate the responsivity and attribution of the index at different levels of anticipatory anxiety and pain perception. The index was measured in a functional magnetic resonance imaging experiment that randomly combined three visual anticipation cues and painful stimuli of two intensities. The peripheral and cerebral responses to pain anticipation and perception were quantified to corroborate bodily responsivity, and their temporal correlation was also assessed to identify the response attribution of the index. Contrasting with the high responsivity across levels of pain sensation, a low responsivity of the index across levels of anticipatory anxiety revealed its specificity across pain experiences. Discrepancies between the effects of perception and anticipation were validated across regions and levels of brain activity, providing a brain basis for peripheral response specificity. The index was also characterized by a 1-s lag in both anticipation and perception of pain, implying top-down innervation of the periphery. Our findings suggest that the SNS responds to pain in an emotion-specific and sensation-unbiased manner, thus enabling an early assessment of individual pain perception using this index. This study integrates peripheral and cerebral hemodynamic responses toward a comprehensive understanding of bodily responses to pain.

Test-retest reliability of Bayesian estimations of the effects of stimulation, prior information and individual traits on pain perception.

BACKGROUND: There is inter-individual variability in the influence of different components (e.g. nociception and expectations) on pain perception. Identifying the individual effect of these components could serve for patient stratification, but only if these influences are stable in time. METHODS: In this study, 30 healthy participants underwent a cognitive pain paradigm in which they rated pain after viewing a probabilistic cue informing of forthcoming pain intensity and then receiving electrical stimulation. The trial information was then used in a Bayesian probability model to compute the relative weight each participant put on stimulation, cue, cue uncertainty and trait-like bias. The same procedure was repeated 2 weeks later. Relative and absolute test-retest reliability of all measures was assessed. RESULTS: Intraclass correlation results showed good reliability for the effect of the stimulation (0.83), the effect of the cue (0.75) and the trait-like bias (0.75 and 0.75), and a moderate reliability for the effect of the cue uncertainty (0.55). Absolute reliability measures also supported the temporal stability of the results and indicated that a change in parameters corresponding to a difference in pain ratings ranging between 0.47 and 1.45 (depending on the parameters) would be needed to consider differences in outcomes significant. The comparison of these measures with the closest clinical data we possess supports the reliability of our results. CONCLUSIONS: These findings support the hypothesis that inter-individual differences in the weight placed on different pain factors are stable in time and could therefore be a possible target for patient stratification. SIGNIFICANCE: Our results demonstrate the temporal stability of the weight healthy individuals place on the different factors leading to the pain response. These findings give validity to the idea of using Bayesian estimations of the influence of different factors on pain as a way to stratify patients for treatment personalization.

Electrostimulation of the white matter of the posterior insula and medial operculum: perception of vibrations, heat, and pain.

ABSTRACT: This study aimed to characterize the sensory responses observed when electrically stimulating the white matter surrounding the posterior insula and medial operculum (PIMO). We reviewed patients operated on under awake conditions for a glioma located in the temporoparietal junction. Patients' perceptions were retrieved from operative reports. Stimulation points were registered in the Montreal Neurological Institute template. A total of 12 stimulation points in 8 patients were analyzed. Painful sensations in the contralateral leg were reported (5 sites in 5 patients) when stimulating the white matter close to the parcel OP2/3 of the Glasser atlas. Pain had diverse qualities: burning, tingling, crushing, or electric shock. More laterally, in the white matter of OP1, pain and heat sensations in the upper part of the body were described (5 sites in 2 patients). Intermingled with these sites, vibration sensations were also reported (3 sites in 2 patients). Based on the tractograms of 44 subjects from the Human Connectome Project data set, we built a template of the pathways linking the thalamus to OP2/3 and OP1. Pain sites were located in the thalamo-OP2/3 and thalamo-OP1 tracts. Heat sites were located in the thalamo-OP1 tract. In the 227 awake surgeries performed for a tumor located outside of the PIMO region, no patients ever reported pain or heat sensations when stimulating the white matter. Thus, we propose that the thalamo-PIMO connections constitute the main cortical inputs for nociception and thermoception and emphasize that preserving these fibers is of utmost importance to prevent the postoperative onset of a debilitating insulo-opercular pain syndrome.

Does Active Inference Provide a Comprehensive Theory of Placebo Analgesia?

Placebo interventions generate mismatches between expected pain and sensory signals from which pain states are inferred. Because we lack direct access to bodily states, we can only infer whether nociceptive activity indicates tissue damage or results from noise in sensory channels. Predictive processing models propose to make optimal inferences using prior knowledge given noisy sensory data. However, these models do not provide a satisfactory explanation of how pain relief expectations are translated into physiological manifestations of placebo responses. Furthermore, they do not account for individual differences in the ability to endogenously regulate nociceptive activity in predicting placebo analgesia. The brain not only passively integrates prior pain expectations with nociceptive activity to infer pain states (perceptual inference) but also initiates various types of actions to ensure that sensory data are consistent with prior pain expectations (active inference). We argue that depending on whether the brain interprets conflicting sensory data (prediction errors) as a signal to learn from or noise to be attenuated, the brain initiates opposing types of action to facilitate learning from sensory data or, conversely, to enhance the biasing influence of prior pain expectations on pain perception. Furthermore, we discuss the role of stress, anxiety, and unpredictability of pain in influencing the weighting of prior pain expectations and sensory data and how they relate to the individual ability to regulate nociceptive activity (endogenous pain modulation). Finally, we provide suggestions for future studies to test the implications of the active inference model of placebo analgesia.

Expectations underlie the effects of unpredictable pain: a behavioral and electroencephalogram study.

ABSTRACT: Previous studies on the potential effects of unpredictability on pain perception and its neural correlates yielded divergent results. This study examined whether this may be explained by differences in acquired expectations. We presented 41 healthy volunteers with laser heat stimuli of different intensities. The stimuli were preceded either by predictable low, medium, or high cues or by unpredictable low-medium, medium-high, or low-high cues. We recorded self-reports of pain intensity and unpleasantness and laser-evoked potentials (LEPs). Furthermore, we investigated whether dynamic expectations that evolved throughout the experiment based on past trials were better predictors of pain ratings than fixed (nonevolving) expectations. Our results replicate previous findings that unpredictable pain is higher than predictable pain for low-intensity stimuli but lower for high-intensity stimuli. Moreover, we observed higher ratings for the medium-high unpredictable condition than the medium-low unpredictable condition, in line with an effect of expectation. We found significant interactions (N1, N2) for the LEP components between intensity and unpredictability. However, the few significant differences in LEP peak amplitudes between cue conditions did not survive correction for multiple testing. In line with predictive coding perspectives, pain ratings were best predicted by dynamic expectations. Surprisingly, expectations of reduced precision (increased variance) were associated with lower pain ratings. Our findings provide strong evidence that (dynamic) expectations contribute to the opposing effects of unpredictability on pain perception; therefore, we highlight the importance of controlling for them in pain unpredictability manipulations. We also suggest to conceptualize pain expectations more often as dynamic constructs incorporating previous experiences.

Social cues influence perception of others' pain.

BACKGROUND: Accurately perceiving other people's pain is important in both daily life and healthcare settings. However, judging other's pain is inherently difficult and can be biased by various social and cultural factors. Here, we examined whether perception of others' pain and pain management recommendations are socially influenced by seeing the opinions of other raters. METHODS: In Experiment 1 (N = 50), participants rated pictures depicting injured hands or feet of pre-selected high, medium and low intensities. Each picture was preceded by cues indicating ratings of 10 previous participants. Cues were randomized to indicate low (SocialLOW) or high (SocialHIGH) pain judgements and were not predictive of actual normative pain intensity. In Experiment 2 (N = 209), participants viewed facial video clips of patients with chronic shoulder pain making painful movements. They estimated patients' pain intensity and provided pain management recommendations. RESULTS: Experiment 1 revealed that perceivers' pain estimates were significantly and substantially higher for stimuli following SocialHIGH than SocialLOW cues (Cohen's d = 1.26, p < 0.001) and paralleled by increased skin conductance responses. Experiment 2 replicated the effect of social cues on pain judgements (d = 0.58, p < 0.001). However, social cues did not influence post-study pain management recommendations, potentially due to memory limitations. CONCLUSIONS: Together, these studies reveal that judgements of others' pain are robustly modulated by information about others' opinions. Future research could test the prevalence and strength of such effects in clinical settings. SIGNIFICANCE: The present study shows that even arbitrary opinions of other raters influence the perception of others' pain. This finding adds new insight into the growing evidence of social and cultural biases in pain estimation.

Vicarious facilitation of facial responses to pain.

INTRODUCTION: Observing facial expressions of pain has been shown to lead to increased subjective, neural and autonomic pain responses. Surprisingly, these vicarious facilitation effects on its corresponding response channel, namely facial responses to pain have mostly been neglected. We aim to examine whether the prior exposure to facial expressions of pain leads to a facilitation of facial responses to experimental pain; and whether this facilitation is linked to the valence (pain vs. neutral expression) or also linked to specific motor-features of the facial pain expressions (different facial muscle movements). METHOD: Subjective (intensity and unpleasantness ratings) and facial responses (Facial Action Coding System) of 64 participants (34 female) to painful and non-painful heat stimuli were assessed. Before each heat stimulus, video clips of computer-generated facial expressions (three different pain expressions and a neutral expression) were presented. RESULTS: The prior exposure to facial expressions of pain led to increased subjective and facial responses to pain. Further, vicarious pain facilitation of facial responses was significantly correlated with facilitation of unpleasantness ratings. We also found evidence that this vicarious facilitation of facial responses was not only linked to the presentation of pain versus neutral expressions but also to specific motor-features of the pain cue (increase in congruent facial muscle movements). DISCUSSION: Vicarious pain facilitation was found for subjective and facial responses to pain. The results are discussed with reference to the motivational priming hypothesis as well as with reference to motor priming. SIGNIFICANCE: Our study uncovers evidence that facial pain responses are not only influenced by motivational priming (similar to other types of pain responses), but also by motor-priming. These findings shed light on the complexity - ranging from social, affective and motor mechanisms - underling vicarious facilitation of pain.

Relationship between individual differences in pain empathy and task- and resting-state EEG.

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.

Objective Measurement of Subjective Pain Perception with Autonomic Body Reactions in Healthy Subjects and Chronic Back Pain Patients: An Experimental Heat Pain Study.

Multiple attempts to quantify pain objectively using single measures of physiological body responses have been performed in the past, but the variability across participants reduces the usefulness of such methods. Therefore, this study aims to evaluate whether combining multiple autonomic parameters is more appropriate to quantify the perceived pain intensity of healthy subjects (HSs) and chronic back pain patients (CBPPs) during experimental heat pain stimulation. HS and CBPP received different heat pain stimuli adjusted for individual pain tolerance via a CE-certified thermode. Different sensors measured physiological responses. Machine learning models were trained to evaluate performance in distinguishing pain levels and identify key sensors and features for the classification task. The results show that distinguishing between no and severe pain is significantly easier than discriminating lower pain levels. Electrodermal activity is the best marker for distinguishing between low and high pain levels. However, recursive feature elimination showed that an optimal subset of features for all modalities includes characteristics retrieved from several modalities. Moreover, the study's findings indicate that differences in physiological responses to pain in HS and CBPP remain small.

Modulation of pain perceptions following treadmill running with different intensities in females.

We aimed to compare the effects of three intensities of treadmill running on exercise-induced hypoalgesia (EIH) in healthy individuals. We anticipated that the primary and secondary changes in pain perception and modulation may differ between running intensities. Sixty-six women were randomly assigned to one of three treadmill running intensities for 35 min: 40% reserved heart rate (HRR), 55% HRR, or 70% HRR. The effects of EIH were assessed using pressure pain thresholds (PPT) and tolerance thresholds (PPTol). We measured conditional pain modulation (CPM). Compared with baseline, PPT and PPTol significantly increased in all groups during running and at the 5-10-min follow-up. The PPT and PPTol changes in the moderate- and low-intensity groups were significantly higher than those in the high-intensity group during running and 24 h after running, while the CPM responses of the high-intensity group were significantly reduced at the 24-h follow-up. Moderate- and low-intensity running may elicit significant primary and secondary (persisting over 24 h) EIH effects and increase CPM responses in females. However, high-intensity running induced only limited analgesic effects and reduced CPM responses, which may be attributed to the activation of endogenous pain modulation.

Electrophysiological markers for anticipatory processing of nocebo-augmented pain.

Nocebo effects on pain are widely thought to be driven by negative expectations. This suggests that anticipatory processing, or some other form of top-down cognitive activity prior to the experience of pain, takes place to form sensory-augmenting expectations. However, little is known about the neural markers of anticipatory processing for nocebo effects. In this event-related potential study on healthy participants (n = 42), we tested whether anticipatory processing for classically conditioned nocebo-augmented pain differed from pain without nocebo augmentation using stimulus preceding negativity (SPN), and Granger Causality (GC). SPN is a slow-wave ERP component thought to measure top-down processing, and GC is a multivariate time series analysis used to measure functional connectivity between brain regions. Fear of pain was assessed with the Fear of Pain Questionnaire-III and tested for correlation with SPN and GC metrics. We found evidence that both anticipatory processing measured with SPN and functional connectivity from frontal to temporoparietal brain regions measured with GC were increased for nocebo pain stimuli relative to control pain stimuli. Other GC node pairs did not yield significant effects, and a lag in the timing of nocebo pain stimuli limited interpretation of the results. No correlations with trait fear of pain measured after the conditioning procedure were detected, indicating that while differences in neural activity could be detected between the anticipation of nocebo and control pain trials, they likely were not related to fear. These results highlight the role that top-down processes play in augmenting sensory perception based on negative expectations before sensation occurs.

The role of spontaneous vs. experimentally induced attentional strategies for the pain response to a single bout of exercise in healthy individuals.

OBJECTIVES: Exercise-induced pain and exercise-induced hypoalgesia (EIH) are well described phenomena involving physiological and cognitive mechanisms. Two experiments explored whether spontaneous and instructed mindful monitoring (MM) were associated with reduced exercise-induced pain and unpleasantness, and increased EIH compared with spontaneous and instructed thought suppression (TS) in pain-free individuals. METHODS: Eighty pain-free individuals participated in one of two randomized crossover experiments. Pressure pain thresholds (PPTs) were assessed at the leg, back and hand before and after 15 min of moderate-to-high intensity bicycling and a non-exercise control condition. Exercise-induced pain and unpleasantness were rated after bicycling. In experiment 1 (n=40), spontaneous attentional strategies were assessed with questionnaires. In experiment 2, participants (n=40) were randomly allocated to use either a TS or MM strategy during bicycling. RESULTS: In experiment 1, the change in PPTs was significantly larger after exercise compared with quiet rest (p<0.05). Higher spontaneous MM was associated with less exercise-induced unpleasantness (r=-0.41, p<0.001), whereas higher spontaneous TS was associated with higher ratings of exercise-induced unpleasantness (r=0.35, p<0.05), but not with pain intensity or EIH. In experiment 2, EIH at the back was increased in participants using instructed TS compared with participants using instructed MM (p<0.05). CONCLUSIONS: These findings suggest that spontaneous and presumably habitual (or dispositional) attentional strategies may primarily affect cognitive-evaluative aspects of exercise, such as feelings of exercise-induced unpleasantness. MM was related to less unpleasantness, whereas TS was related to higher unpleasantness. In terms of brief experimentally-induced instructions, TS seems to have an impact on physiological aspects of EIH; however, these preliminary findings need further research.

Counterirritation by Pain Inhibits Responses to and Perception of Aversive Loud Tones.

The application of a noxious stimulus reduces the perception of other noxious stimuli, which can be assessed by an experimental method called "counterirritation." The question arises whether this type of inhibition also affects the processing of other aversive (but not nociceptive) stimuli, such as loud tones. If aversiveness or, in other words, negative emotional valence qualifies a stimulus to be affected by counterirritation, the general emotional context may also play a role in modulating counterirritation effects. We involved 63 participants in this study (M age = 38.8, SD = 10.5 years; 33 males, 30 females). We tried to counterirritate their perceptual and startle reactions to aversively loud tones (105 db) by immersing the hand into a painful hot water bath (46°C) in two emotional valence conditions (i.e., a neutral and a negative valence block in which we showed either neutral pictures or pictures of burn wounds). We assessed Inhibition by loudness ratings and startle reflex amplitudes. Counterirritation significantly reduced both loudness ratings and startle reflex amplitudes. The emotional context manipulation did not affect this clear inhibitory effect, showing that counterirritation by a noxious stimulus affects aversive sensations not induced by nociceptive stimuli. Thus, the assumption that "pain inhibits pain" should be widened to "pain inhibits the processing of aversive stimuli." This broadened understanding of counterirritation leads to a questioning of the postulate of clear pain specificity in paradigms like "conditioned pain modulation" (CPM) or "diffuse noxious inhibitory controls" (DNIC).

Dysfunctional Activation of the Dorsolateral Prefrontal Cortex During Pain Anticipation Is Associated With Altered Subsequent Pain Experience in Fibromyalgia Patients.

The ability to accurately predict pain is an adaptive feature in healthy individuals. However, in chronic pain, this mechanism may be selectively impaired and can lead to increased anxiety and excessive avoidance behavior. Recently, we reported the first data demonstrating brain activation in fibromyalgia (FM) patients during conditioned pain responses, in which FM patients revealed a tendency to form new pain-related associations rather than extinguishing irrelevant ones. The aim of the present study was to extend our previous analysis, to elucidate potential neural divergences between subjects with FM (n = 65) and healthy controls (HCs) (n = 33) during anticipatory information (ie, prior to painful stimulus onset). Using functional magnetic resonance imaging (fMRI), the current analyses include 1) a congruently cued paradigm of low and high pain predictive cues, followed by 2) an incongruently cued paradigm where low and high pain predictive cues were followed by an identical mid-intensity painful pressure. During incongruently cued high-pain associations, FM exhibited reduced left dorsolateral prefrontal cortex (dlPFC) activation compared to HCs, which was followed by an altered subsequent pain experience in FM, as patients continued to rate the following painful stimuli as high, even though the pressure had been lowered. During congruently cued low pain anticipation, FM exhibited decreased right dlPFC activation compared to HCs, as well as decreased brain connectivity between brain regions implicated in cognitive modulation of pain (dlPFC) and nociceptive processing (primary somatosensory cortex/postcentral gyrus [S1] and supplementary motor area [SMA]/midcingulate cortex [MCC]). These results may reflect an important feature of validating low pain expectations in HCs and help elucidate behavioral reports of impaired safety processing in FM patients. PERSPECTIVE: FM exhibited a stronger conditioned pain response for high-pain associations, which was associated with reduced dlPFC activation during the incongruent trial. During (congruent and incongruent) low pain associations, FM dlPFC brain activation remained indifferent. Imbalances in threat and safety pain perception may be an important target for psychotherapeutic interventions.

Prefrontal engrams of long-term fear memory perpetuate pain perception.

A painful episode can lead to a life-long increase in an individual's experience of pain. Fearful anticipation of imminent pain could play a role in this phenomenon, but the neurobiological underpinnings are unclear because fear can both suppress and enhance pain. Here, we show in mice that long-term associative fear memory stored in neuronal engrams in the prefrontal cortex determines whether a painful episode shapes pain experience later in life. Furthermore, under conditions of inflammatory and neuropathic pain, prefrontal fear engrams expand to encompass neurons representing nociception and tactile sensation, leading to pronounced changes in prefrontal connectivity to fear-relevant brain areas. Conversely, silencing prefrontal fear engrams reverses chronically established hyperalgesia and allodynia. These results reveal that a discrete subset of prefrontal cortex neurons can account for the debilitating comorbidity of fear and chronic pain and show that attenuating the fear memory of pain can alleviate chronic pain itself.

Both fine-grained and coarse-grained spatial patterns of neural activity measured by functional MRI show preferential encoding of pain in the human brain.

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.