Expectations about the magnitude of impending pain exert a substantial effect on subsequent perception. However, the neural mechanisms that underlie the predictive processes that modulate pain are poorly understood. In a combined behavioral and high-density electrophysiological study we measured anticipatory neural responses to heat stimuli to determine how predictions of pain intensity, and certainty about those predictions, modulate brain activity and subjective pain ratings. Prior to receiving randomized laser heat stimuli at different intensities (low, medium or high) subjects (n=15) viewed cues that either accurately informed them of forthcoming intensity (certain expectation) or not (uncertain expectation). Pain ratings were biased towards prior expectations of either high or low intensity. Anticipatory neural responses increased with expectations of painful vs. non-painful heat intensity, suggesting the presence of neural responses that represent predicted heat stimulus intensity. These anticipatory responses also correlated with the amplitude of the Laser-Evoked Potential (LEP) response to painful stimuli when the intensity was predictable. Source analysis (LORETA) revealed that uncertainty about expected heat intensity involves an anticipatory cortical network commonly associated with attention (left dorsolateral prefrontal, posterior cingulate and bilateral inferior parietal cortices). Relative certainty, however, involves cortical areas previously associated with semantic and prospective memory (left inferior frontal and inferior temporal cortex, and right anterior prefrontal cortex). This suggests that biasing of pain reports and LEPs by expectation involves temporally precise activity in specific cortical networks.

The aim of mindfulness meditation is to develop present-focused, non-judgmental, attention. Therefore, experience in meditation should be associated with less anticipation and negative appraisal of pain. In this study we compared a group of individuals with meditation experience to a control group to test whether any differences in the affective appraisal of pain could be explained by lower anticipatory neural processing. Anticipatory and pain-evoked ERPs and reported pain unpleasantness were recorded in response to laser stimuli of matched subjective intensity between the two groups. ERP data were analysed after source estimation with LORETA. No group effects were found on the laser energies used to induce pain. More experienced meditators perceived the pain as less unpleasant relative to controls, with meditation experience correlating inversely with unpleasantness ratings. ERP source data for anticipation showed that in meditators, lower activity in midcingulate cortex relative to controls was related to the lower unpleasantness ratings, and was predicted by lifetime meditation experience. Meditators also reversed the normal positive correlation between medial prefrontal cortical activity and pain unpleasantness during anticipation. Meditation was also associated with lower activity in S2 and insula during the pain-evoked response, although the experiment could not disambiguate this activity from the preceding anticipation response. Our data is consistent with the hypothesis that meditation reduces the anticipation and negative appraisal of pain, but effects on pain-evoked activity are less clear and may originate from preceding anticipatory activity. Further work is required to directly test the causal relationship between meditation, pain anticipation, and pain experience.

Increased activity in cognitive control regions of the brain during pain anticipation related to improved mental health and perceived control over pain, but not to decreased pain experience. Greater perceived control may therefore result from improved regulation of the emotional response to pain.

Psychological factors play a major role in exacerbating chronic pain. Effective self-management of pain is often hindered by inaccurate beliefs about the nature of pain which lead to a high degree of emotional reactivity. Probabilistic models of perception state that greater confidence (certainty) in beliefs increases their influence on perception and behavior. In this study, we treat confidence as a metacognitive process dissociable from the content of belief. We hypothesized that confidence is associated with anticipatory activation of areas of the pain matrix involved with top-down modulation of pain. Healthy volunteers rated their beliefs about the emotional distress that experimental pain would cause, and separately rated their level of confidence in this belief. Confidence predicted the influence of anticipation cues on experienced pain. We measured brain activity during anticipation of pain using high-density EEG and used electromagnetic tomography to determine neural substrates of this effect. Confidence correlated with activity in right anterior insula, posterior midcingulate and inferior parietal cortices during the anticipation of pain. Activity in the right anterior insula predicted a greater influence of anticipation cues on pain perception, whereas activity in right inferior parietal cortex predicted a decreased influence of anticipatory cues. The results support probabilistic models of pain perception and suggest that confidence in beliefs is an important determinant of expectancy effects on pain perception.

Supraspinal processes in humans can have a top-down enhancing effect on nociceptive processing in the brain and spinal cord. Studies have begun to suggest that such influences occur in conditions such as fibromyalgia (FM), but it is not clear whether this is unique to FM pain or common to other forms of chronic pain, such as that associated with osteoarthritis (OA). We assessed top-down processes by measuring anticipation-evoked potentials and their estimated sources, just prior (< 500 ms) to laser heat pain stimulation, in 16 patients with FM, 16 patients with OA and 15 healthy participants, by using whole-brain statistical parametric mapping. Clinical pain and psychological coping factors (pain catastrophizing, anxiety, and depression) were well matched between the patient groups, such that these did not confound our comparisons between FM and OA patients. For the same level of heat pain, insula activity was significantly higher in FM patients than in the other two groups during anticipation, and correlated with the intensity and extent of reported clinical pain. However, the same anticipatory insula activity also correlated with OA pain, and with the number of tender points across the two patient groups, suggesting common central mechanisms of tenderness. Activation in the dorsolateral prefrontal cortex was reduced during anticipation in both patient groups, and was related to less effective psychological coping. Our findings suggest common neural correlates of pain and tenderness in FM and OA that are enhanced in FM but not unique to this condition.

Background: Alpha power is believed to have an inverse relationship with the perception of pain. Increasing alpha power through an external stimulus may, therefore, induce an analgesic effect. Here, we attempt to modulate the perception of a moderately painful acute laser stimulus by separately entraining three frequencies across the alpha band: 8, 10 and 12 Hz. Methods: Participants were exposed to either visual or auditory stimulation at three frequencies in the alpha-band range and a control frequency. We collected verbal pain ratings of laser stimuli from participants following 10 minutes of flashing LED goggle stimulation and 10 minutes of binaural beat stimulation across the alpha range. Alterations in sleepiness, anxiety and negative mood were recorded following each auditory or visual alpha-rhythm stimulation session. Results: A significant reduction in pain ratings was found after both the visual and the auditory stimulation across all three frequencies compared with the control condition. In the visual group, a significantly larger reduction was recorded following the 10-Hz stimulation than succeeding the 8-and 12-Hz conditions. Conclusions: This study suggests that a short presentation of auditory and visual stimuli, oscillating in the alpha range, have an analgesic effect on acute laser pain, with the largest effect following the 10-Hz visual stimulation. Pain reductions following stimulation in the alpha range are independent of sleepiness, anxiety, and negative moods. Significance: This study provides new behavioural evidence showing that visual and auditory entrainment of frequencies in the alpha-wave range can influence the perception of acute pain in humans.

We present evidence of altered but highly variable cognitive processing (124-268 ms latency) in response to mechanical tactile stimuli in patients with CRPS compared with healthy controls. Such mid- to late-latency responses could potentially provide convenient and robust biomarkers of abnormal perceptual decision-making mechanisms in CRPS to aid in clinical detection and treatment.

IntroductionChronic pain is frequently reported by patients with arthritis [58]. However, there is no correlation between pain and structural joint damage in osteoarthritis [5]. The basis of variability between pathophysiology and pain outcomes is unknown. One possibility is natural variability in pain regulation within the central nervous system (CNS).The ascending spinothalamic pathways that mediate nociception terminate in multiple thalamic nuclei and cortical brain regions [20]. Cortical sites modulate nociception partly by projecting to the basal ganglia including the striatum, which also receives afferent nociceptive inputs from the spinal cord via the globus pallidus [6]. Striatal nuclei, including the caudate, putamen and nucleus accumbens, are the most densely populated regions for opioid receptors in the brain [4,14,34], and are thought to be important for opioid-mediated endogenous analgesia [12,21]. The possibility of opioid mechanisms being involved in determining individual differences in pain states has been a key topic of recent research [28,41,60], but the functional consequences of chronic pain on OpR physiology are largely unknown.Correspondence to: Dr Christopher A Brown, CamPain group, Division of Anaesthesia, Box 93, Addenbrooke's Hospital, Cambridge, CB2 0QQ, cb802@cam.ac.uk. The authors declare no competing financial interests. It has long been known that prolonged nociception results in the release of endogenous opioid peptides and subsequent agonism of OpRs in the CNS [19]. However, a relatively unexplored hypothesis is that chronic pain could potentially adjust OpR physiology to provide more efficient dampening of the pain response as part of a homeostatic control mechanism. There is evidence from animal studies that delta and kappa-OpRs, found in the brain and spinal cord [8,11], can be up-regulated in response to mu-OpR agonism [56], thereby increasing the anti-nociceptive potency of delta-OpR agonists [38,44]. Animal models of chronic inflammatory pain have shown an increase in cell membrane expression of delta-OpRs both postsynaptically [9] and presynaptically [22] in the dorsal spinal cord ipsilateral to the site of injury. Stimulus-evoked translocation of delta-OpRs to neuronal plasma membranes may have evolved as part of a homeostatic mechanism to maintain control of nociceptive transmission [7]. However, evidence for such a mechanism in humans is lacking. Europe PMC Funders GroupPositron Emission Tomography (PET) receptor binding studies enable assessment of the endogenous opioid system in humans via radiotracers that bind to opioid receptors (OpRs), such as carbon-11 labelled diprenorphine ([ 11 C]-DPN), an antagonist that binds equally well to mu, delta and kappa OpRs [31,33]. Here we measured OpR availability in patients with arthritis and healthy controls with [ 11 C]-DPN PET imaging, to identify relationships between OpR availability and the level of perceived acute and chronic pain. Our analysis revealed associations between the striatum and the perception of both acute a...