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The angiotensin receptor blocker losartan has been linked to aspects of aversive learning such as fear acquisition and extinction, inhibition of aversive learning rates and reduced post-traumatic stress disorder (PTSD) symptoms. Here, we investigate the influence of losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized placebo-controlled design, we tested 45 healthy volunteers during a baseline session (session 1), after application of losartan or placebo (session 2) and during a follow-up session (session 3). On each session, participants engaged in a task where they had to predict the likelihood of an electrical stimulation on every trial while the true shock contingencies repeatedly switched between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. Acute administration of losartan significantly reduced participants’ adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates on the drug session compared to baseline. The 50mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out general reduction in attention and engagement. Decreased adjustment of aversive expectations to low-to-high, but not high-to-low, threat change was maintained on a follow up session 24hrs later, suggesting a possible role of losartan in prevention of formation of aversive associations on longer time scales.

Prior expectations can bias how we perceive pain. Using a drift diffusion model, we recently showed that this influence is primarily based on changes in perceptual decision-making (indexed as shift in starting point). Only during unexpected application of high-intensity noxious stimuli, altered information processing (indexed as increase in drift rate) explained the expectancy effect on pain processing. Here, we employed functional magnetic resonance imaging to investigate the neural basis of both these processes in healthy volunteers. On each trial, visual cues induced the expectation of high- or low-intensity noxious stimulation or signaled equal probability for both intensities. Participants categorized a subsequently applied electrical stimulus as either low- or high-intensity pain. A shift in starting point towards high pain correlated negatively with right dorsolateral prefrontal cortex activity during cue presentation underscoring its proposed role of "keeping pain out of mind". This anticipatory right dorsolateral prefrontal cortex signal increase was positively correlated with periaqueductal gray (PAG) activity when the expected high-intensity stimulation was applied. A drift rate increase during unexpected high-intensity pain was reflected in amygdala engagement and increased functional connectivity between amygdala and PAG. Our findings suggest involvement of the PAG in both decision-making bias and altered information processing to implement expectancy effects on pain. PERSPECTIVE: Modulation of pain through expectations has been linked to changes in perceptual decision-making and altered processing of afferent information. Our results suggest involvement of the dorsolateral prefrontal cortex, amygdala, and periaqueductal gray in these processes.

Pain-related learning mechanisms likely play a key role in the development and maintenance of chronic pain. Previous smaller-scale studies have suggested impaired pain-related learning in patients with chronic pain, but results are mixed, and chronic back pain (CBP) particularly has been poorly studied. In a differential conditioning paradigm with painful heat as unconditioned stimuli, we examined pain-related acquisition and extinction learning in 62 patients with CBP and 61 pain-free healthy male and female volunteers using valence and contingency ratings and skin conductance responses. Valence ratings indicate significantly reduced threat and safety learning in patients with CBP, whereas no significant differences were observed in contingency awareness and physiological responding. Moreover, threat learning in this group was more impaired the longer patients had been in pain. State anxiety was linked to increased safety learning in healthy volunteers but enhanced threat learning in the patient group. Our findings corroborate previous evidence of altered pain-related threat and safety learning in patients with chronic pain. Longitudinal studies exploring pain-related learning in (sub)acute and chronic pain are needed to further unravel the role of aberrant pain-related learning in the development and maintenance of chronic pain.

OBJECTIVE: Reliably identifying good placebo responders has pronounced implications for basic research on, and clinical applications of, the placebo response. Multiple studies point to direct verbal suggestibility as a potentially valuable predictor of individual differences in placebo responsiveness, but previous research has produced conflicting results on this association. METHODS: In two double-blind studies, we examined whether behavioral direct verbal suggestibility measures involving a correction for compliance would be associated with individual differences in responsiveness to conditioned and unconditioned placebo hypoalgesia using an established placebo analgesia paradigm. In study 1 (n = 57; mean [standard deviation] age = 23.7 [8.1] years; 77% women), we used behavioral hypnotic suggestibility as a predictor of placebo hypoalgesia induced through conditioning and verbal suggestion, whereas in study 2 (n = 78; mean [standard deviation] = 26.1 [7.4] years; 65% women), we measured nonhypnotic suggestibility and placebo hypoalgesia induced through verbal suggestion without conditioning. RESULTS: In study 1, the placebo hypoalgesia procedure yielded a moderate placebo response (g = 0.63 [95% confidence interval = 0.32 to 0.97]), but the response magnitude did not significantly correlate with hypnotic suggestibility (rs = 0.11 [-0.17 to 0.37]). In study 2, the placebo procedure did not yield a significant placebo response across the full sample (g = 0.11 [-0.11 to 0.33]), but the magnitude of individual placebo responsiveness significantly correlated with nonhypnotic suggestibility (rs = 0.27 [0.03 to 0.48]). CONCLUSIONS: These results suggest that the extent to which direct verbal suggestibility captures variability in placebo responsiveness depends on the use of conditioning and highlights the utility of suggestibility as a potential contributing factor to placebo responding when placebo hypoalgesia is induced through verbal suggestions.

Studies on functional and structural changes in the primary somatosensory cortex (S1) have provided important insights into neural mechanisms underlying several chronic pain conditions. However, the role of S1 plasticity in postherpetic neuralgia (PHN) remains elusive. Combining psychophysics and magnetic resonance imaging (MRI), we investigated whether pain in PHN patients is linked to S1 reorganization as compared with healthy controls. Results from voxel-based morphometry showed no structural differences between groups. To characterize functional plasticity, we compared S1 responses to noxious laser stimuli of a fixed intensity between both groups and assessed the relationship between S1 activation and spontaneous pain in PHN patients. Although the intensity of evoked pain was comparable in both groups, PHN patients exhibited greater activation in S1 ipsilateral to the stimulated hand. Pain-related activity was identified in contralateral superior S1 (SS1) in controls as expected, but in bilateral inferior S1 (IS1) in PHN patients with no overlap between SS1 and IS1. Contralateral SS1 engaged during evoked pain in controls encoded spontaneous pain in patients, suggesting functional S1 reorganization in PHN. Resting-state fMRI data showed decreased functional connectivity between left and right SS1 in PHN patients, which scaled with the intensity of spontaneous pain. Finally, multivariate pattern analyses (MVPA) demonstrated that BOLD activity and resting-state functional connectivity of S1 predicted within-subject variations of evoked and spontaneous pain intensities across groups. In summary, functional reorganization in S1 might play a key role in chronic pain related to PHN and could be a potential treatment target in this patient group.

The effects of expectations on pain perception are often studied using large differences in pain probabilities between experimental conditions, although they may be far more subtle in clinical contexts and, therefore, more difficult to detect. The current study aimed to investigate at which point subtle differences in pain probabilities can be detected and lead to differentiable expectations and perceptions. Furthermore, we investigated whether instructions can aid learning from experience and enhance subsequent pain modulatory effects. During a predictive learning task, participants were presented with 5 different cues, followed by either a high and low noxious stimulus. They learned about the different cue-stimulus contingencies either solely through experience (LEARN, N = 40) or a combination of experience and explicit information about the cue-stimulus contingencies (INSTRUCT, N = 40). We found that without explicit information, picking up the different pain probabilities was challenging, while explicit instruction significantly improved their detection. As revealed by drift diffusion modeling, learning from experience was insufficient for the development of a bias towards low pain even when it was highly likely. By contrast, when explicit information was provided, perception became more nuanced with the direction and extent of bias, capturing the subtle differences in pain probabilities. These findings highlight that the use of instructions to foster the detection of subtle pain improvements during pain treatment to enhance their cognitive pain modulatory effects warrant further investigation. ispartof: Pain vol:163 issue:1 pages:137-145 ispartof: location:United States status: published

Psychological distress is prevalent in students and can predispose to psychiatric disorders. Recent findings indicate that distress might be linked to impaired cognitive performance in students. Experimental findings in healthy participants suggest that placebo interventions can improve cognition. However, whether non-deceptive (i.e., open-label, OLP) placebos can enhance cognitive function and emotional well-being is unclear. Using a randomized-controlled design we demonstrate a positive impact of OLP on subjective well-being (i.e., stress, fatigue, and confusion) after a 21-day OLP application in healthy students during midterm exams. OLP did not improve test performance, but, within the OLP group, test performance was positively correlated with measures of general belief in the benefit of medication. These results show that OLP can counteract negative effects of acute stress on psychological well-being and might improve cognitive performance if supported by positive treatment expectations. Additionally, our findings in healthy volunteers warrant further investigation in exploring the potential of OLP in reducing stress-related psychological effects in patients. The trial was preregistered at the German Clinical Trials Register on December 20, 2017 (DRKS00013557).

Updating beliefs in changing environments can be driven by gradually adapting expectations or by relying on inferred hidden states (i.e., contexts), and changes therein. Previous work suggests that increased reliance on context could underly fear relapse phenomena that hinder clinical treatment of anxiety disorders. We test whether trait anxiety variations in a healthy population influence how much individuals rely on hidden-state inference. In a Pavlovian learning task, participants observed cues that predicted an upcoming electrical shock with repeatedly changing probability, and were asked to provide expectancy ratings on every trial. We show that trait anxiety is associated with steeper expectation switches after contingency reversals and reduced oddball learning. Furthermore, trait anxiety is related to better fit of a state inference compared to a gradual learning model when contingency changes are large. Our findings support previous work suggesting hidden-state inference as a mechanism behind anxiety-related to fear relapse phenomena.

ObjectiveTo track the interplay between (micro-) structural changes along the trajectories of nociceptive pathways and its relation to the presence and intensity of neuropathic pain (NP) after spinal cord injury (SCI).MethodsA quantitative neuroimaging approach employing a multiparametric mapping protocol was used, providing indirect measures of myelination (via contrasts such as magnetisation transfer (MT) saturation, longitudinal relaxation (R1)) and iron content (via effective transverse relaxation rate (R2*)) was used to track microstructural changes within nociceptive pathways. In order to characterise concurrent changes along the entire neuroaxis, a combined brain and spinal cord template embedded in the statistical parametric mapping framework was used. Multivariate source-based morphometry was performed to identify naturally grouped patterns of structural variation between individuals with and without NP after SCI.ResultsIn individuals with NP, lower R1 and MT values are evident in the primary motor cortex and dorsolateral prefrontal cortex, while increases in R2* are evident in the cervical cord, periaqueductal grey (PAG), thalamus and anterior cingulate cortex when compared with pain-free individuals. Lower R1 values in the PAG and greater R2* values in the cervical cord are associated with NP intensity.ConclusionsThe degree of microstructural changes across ascending and descending nociceptive pathways is critically implicated in the maintenance of NP. Tracking maladaptive plasticity unravels the intimate relationships between neurodegenerative and compensatory processes in NP states and may facilitate patient monitoring during therapeutic trials related to pain and neuroregeneration.

Memory retrieval is accompanied by a reactivation of cortical and subcortical areas that have been active during encoding. This neural reinstatement is stronger during retrieval of pain-associated material compared with other unpleasant events. In this functional magnetic resonance imaging study, we investigated the differences in neural reinstatement during recognition of visual stimuli that had been paired with face or hand pain during memory encoding. Body site-specific neural reinstatement was tested in 23 healthy young volunteers who performed a visual categorization and a surprise recognition task. Our data shows increased neural reinstatement in task-specific and encoding-related areas, such as the parahippocampus (left: x = -26, y = -30, z = -18, t = 4.11; right: x = 26, y = -38, z = -6, t = 4.36), precuneus (x = 2, y = -56, z = 2, t = 3.77), fusiform gyrus (left: x = -24, y = -26, z = -20, t = 5.41; right: x = 18, y = -58, z = -14, t = 4.52), and amygdala (x = -34, y = -4, z = -20, t = 4.49) for pictures that were previously presented with face compared with hand pain. These results correlated with the individual's recognition confidence, although recognition rates did not differ between the conditions. Functional connectivity was increased between the amygdala and parahippocampus (x = 34, y = -10, z = -28, t = 5.13) for pictures that had previously been paired with face compared with hand pain. Our results were positively correlated with pain-related fear, represented by neural activation in the thalamus (x = -14, y = -35, z = 4, t = 3.54). The reported results can be interpreted as compensatory resource activation and support the notion of a stronger affective component of face compared with hand pain, potentially in line with its greater biological relevance. Perspective This study demonstrates neural reinstatement of face pain-related information, which might be related to the increased biological and affective component of face pain compared with pain on the extremities. Our results might contribute to the understanding of the development and prevalence of head and face pain conditions.

OBJECTIVE: Expectations are known to be key determinants of placebo and nocebo phenomena. In previous studies, verbal suggestions to induce such expectations have mainly focused on the direction and magnitude of the effect, whereas little is known about the influence of temporal information. METHODS: Using an experimental placebo and nocebo design, we investigated whether information about the expected onset of a treatment effect modulates the start and time course of analgesic and hyperalgesic responses. Healthy volunteers (n = 166) in three placebo and three nocebo groups were informed that the application of an (inert) cream would reduce (placebo groups) or amplify pain (nocebo groups) after 5, 15, or 30 minutes. Two control groups were also included (natural history and no expectations). Participants' pain intensity rating of electrical stimuli administered before and 10, 20, and 35 minutes after cream application was obtained. RESULTS: Mixed-method analysis of variance showed a significant interaction between group and time (F(12,262) = 18.172, p < .001, pη2 = 0.454), suggesting that pain variations differed across time points and between groups. Post hoc comparisons revealed that the placebo and nocebo groups began to show a significantly larger change in perceived pain intensity than the no-expectancy control group at the expected time point (p < .05) but not earlier (p > .05). Once triggered, the analgesic effect remained constant over the course of the experiment, whereas the hyperalgesic effect increased over time. CONCLUSIONS: Our results indicate that temporal suggestions can shape expectancy-related treatment effects, which, if used systematically, could open up new ways to optimize treatment outcome.

Background: Research on placebo analgesia commonly focuses on the impact of information about direction (i.e., increase or decrease of pain) and magnitude of the expected analgesic effect, whereas temporal aspects of expectations have received little attention so far. In a recent study, using short-lasting, low-intensity stimuli, we demonstrated that placebo analgesia onset is influenced by temporal information. Here, we investigate whether the same effect of temporal suggestions can be found in longer lasting, high-intensity pain in a Cold Pressor Test (CPT). Methods: Fifty-three healthy volunteers were allocated to one of three groups. Participants were informed that the application of an (inert-)cream would reduce pain after 5 min (P5) or 30 min (P30). The third group was informed that the cream only had hydrating properties (NE). All participants completed the CPT at baseline and 10 (Test 10) and 35 min (Test 35) following cream application. Percentage change in exposure time (pain tolerance) from baseline to Test 10 (Δ10) and to Test 35 (Δ35) and changes in heart rate (HR) during CPT were compared between the three groups. Results: Δ10 was greater in P5 than in NE and P30, indicating that analgesia was only present in the group that was expecting an early onset of analgesia. Δ35 was greater in P5 and P30 compared to NE, reflecting a delayed onset of analgesia in P30 and maintained analgesia in P5. HR differences between groups were not significant. Conclusions: Our data suggest that ‘externally timing’ of placebo analgesia may be possible for prolonged types of pain. Significance: Research on placebo effects mainly focuses on the influence of information about direction (i.e., increase or decrease of pain) and magnitude (i.e., strong or weak) of the expected effect but ignores temporal aspects of expectations. In our study in healthy volunteers, the reported onset of placebo analgesia followed the temporal information provided. Such ‘external timing’ effects could not only aid the clinical use of placebo treatment (e.g., in open-label placebos) but also support the efficacy of active drugs.

BackgroundPain is one of the primary symptoms of endometriosis, a chronic inflammatory condition characterised by the presence of endometrial tissue outside the uterus. Endometriosis-associated pain is commonly considered as nociceptive in nature but its clinical presentation suggests that it might have neuropathic-like properties in a subgroup of patients.MethodsThis is a cross sectional study using an online survey. The survey was distributed by patient support websites. The survey was composed of validated questionnaires assessing pain symptoms, psychological measures and questions about number of surgeries.Main results and the role of chanceWe had 1417 responses which met the inclusion criteria. Using standard painDETECT cut-off scores, we found that pain was classified as neuropathic in 40% of patients and as mixed neuropathic/nociceptive in a further 35%. In line with observations in other neuropathic conditions, the neuropathic subgroup reported higher pain intensities, greater psychological distress and cognitive impairment. Neuropathic pain was also more likely in those with more surgeries to the abdomen and a longer history of pain. As revealed by a cluster analysis, those with a neuropathic pain component could further be divided into two subgroups based on their sensory profile.ConclusionsThe data presented here indicate that endometriosis-associated pain includes a neuropathic-like component in a substantial proportion of women. Although further investigation is required, our finding challenges the current conceptualisation of endometriosis-associated pain as nociceptive and advocates for a new perspective on this type of pain, which is so debilitating to a large number of women.

A growing body of research has identified fear of visceral sensations as a potential mechanism in the development and maintenance of visceral pain disorders. However, the extent to which such learned fear affects visceroception remains unclear. To address this question, we used a differential fear conditioning paradigm with nonpainful esophageal balloon distensions of 2 different intensities as conditioning stimuli (CSs). The experiment comprised of preacquisition, acquisition, and postacquisition phases during which participants categorized the CSs with respect to their intensity. The CS1 was always followed by a painful electrical stimulus (unconditioned stimulus) during the acquisition phase and in 60% of the trials during postacquisition. The second stimulus (CS) was never associated with pain. Analyses of galvanic skin and startle eyeblink responses as physiological markers of successful conditioning showed increased fear responses to the CS1 compared with the CS, but only in the group with the low-intensity stimulus as CS1. Computational modeling of response times and response accuracies revealed that differential fear learning affected perceptual decision-making about the intensities of visceral sensations such that sensations were more likely to be categorized as more intense. These results suggest that associative learning might indeed contribute to visceral hypersensitivity in functional gastrointestinal disorders. Perspective: This study shows that associative fear learning biases intensity judgements of visceral sensations toward perceiving such sensations as more intense. Learning-induced alterations in visceroception might therefore contribute to the development or maintenance of visceral pain. ispartof: The Journal of Pain vol:18 issue:10 pages:1197-1208 ispartof: location:United States status: published

Beliefs and expectations often persist despite disconfirming evidence. We examine two potential mechanisms underlying such ‘self-reinforcing’ expectancy effects in the pain domain: Modulation of perception and biased learning. In two experiments, cues previously associated with symbolic representations of high or low temperatures preceded painful heat. We examined trial-to-trial dynamics in participants’ expected pain, reported pain, and brain activity. Subjective and neural pain responses assimilated towards cue-based expectations, and pain responses in turn predicted subsequent expectations, creating a positive dynamic feedback loop. Furthermore, we found evidence for a confirmation bias in learning: Higher- and lower-than-expected pain triggered greater expectation updating for high- and low-pain cues, respectively. Individual differences in this bias were reflected in the updating of pain-anticipatory brain activity. Computational modeling provided converging evidence that expectations influence both perception and learning. Together, these effects promote self-reinforcing expectations, helping to explain why beliefs can be resistant to change.

As Gligorov (2018) notes, the gate control theory of pain was an important advance over previous accounts of pain. Prior to the gate control theory of pain, prominent theories of pain were committe...

Pain intensity ratings are subject to various cognitive modulations - yet the mechanisms underlying this influence are still not understood. In a conditioning protocol, pain-related expectations were induced through pairing predefined movements with a noxious or innocuous stimulus in either a predictable or unpredictable fashion. Healthy volunteers (N = 37) categorized the stimuli as either painful or nonpainful and rated its perceived intensity. Using a Hierarchical Drift Diffusion model based on the categorization data, we found that an a priori decision-making bias evolved toward the expected sensations (P < .001). In particular, our findings suggest that differences in both the amount of decision-making bias (P = .004) and the speed of sensory processing predict pain intensity ratings (P < .001). As such, changes in pain ratings could be based in either of these processes, which may require a different approach when targeted as part of psychological pain treatment. PERSPECTIVE: Changes in reported pain levels were linked to two distinct mechanisms, suggesting that increased pain reports could be attributed to either enhanced sensory processing or biased inferences. Our results might contribute to the development of person-tailored treatments based on the identification of latent mechanisms using computational models.

Low back pain affects individuals of all ages and is a leading contributor to disease burden worldwide. Despite advancements in assessment and treatment methods, the management of low back pain remains a challenge for researchers and clinicians alike. One reason for the limited success in identifying effective treatments is the large variation in the manifestations, possible causes, precipitating and maintaining factors, course, prognosis and consequences in terms of activity interference and quality of life. However, despite these challenges, steady progress has been achieved in the understanding of back pain, and important steps in the understanding of the psychological and social risk factors, genetics and brain mechanisms of low back pain have been made. These new findings have given impetus to the development of new diagnostic procedures, evidence-based screening methods and more targeted interventions, which underscore the need for a multidisciplinary approach to the management of low back pain that integrates biological, psychological and social aspects.

OBJECTIVE: The extent to which pain-related expectations, known to affect pain perception, also affect perception of non-painful sensations remains unclear, as well as the potential role of unpredictability in this context.METHODS: In a proprioceptive fear conditioning paradigm, various arm extension movements were associated with predictable and unpredictable electrocutaneous pain or its absence. During a subsequent test phase non-painful electrocutaneous stimuli with a high or low intensity were presented during movement execution. We used hierarchical drift diffusion modeling to examine the influence of expecting pain on the perceptual decision-making process underlying intensity perception of non-painful sensations. In the first experiment (n=36), the pain stimulus was never presented during the test phase after conditioning. In the second experiment (n=39), partial reinforcement was adopted to prevent extinction of pain expectations.RESULTS: In both experiments, movements that were associated with (un)predictable pain led to higher pain-expectancy, self-reported fear, unpleasantness and arousal, as compared to movements that were never paired with pain (effect sizes ηp ranging from .119 - .557; all p-values < .05). Only in the second experiment - when the threat of the pain US remained present - we found that the expectation of pain affected decision-making. Compared to the no pain condition, an a priori decision-making bias towards the high intensity decision threshold was found with the strongest bias during unpredictable pain (effect sizes ηp ranging from .469 - .504; all p-values < .001).CONCLUSIONS: Thus, the expectation of pain not only affects inferential processes for subsequent painful but also for non-painful bodily stimuli, with unpredictability moderating these effects, and only when the threat of pain remains present due to partial reinforcement.

BackgroundBreathlessness in chronic obstructive pulmonary disease (COPD) is often discordant with airway pathophysiology (“over-perception”). Pulmonary rehabilitation has profound effects upon breathlessness, without influencing lung function. Learned associations can influence brain mechanisms of sensory perception. We therefore hypothesised that improvements in breathlessness with pulmonary rehabilitation may be explained by changing neural representations of learned associations, reducing “over-perception”.MethodsIn 31 patients with COPD, we tested how pulmonary rehabilitation altered the relationship between brain activity during learned associations with a word-cue task (using functional magnetic resonance imaging), clinical, and psychological measures of breathlessness.ResultsImprovements in breathlessness and breathlessness-anxiety correlated with reductions in word-cue related activity in the insula and anterior cingulate cortex (ACC) (breathlessness), and increased activations in attention regulation and motor networks (breathlessness-anxiety). Greater baseline (pre-rehabilitation) activity in the insula, ACC and prefrontal cortex correlated with the magnitude of improvement in breathlessness and breathlessness anxiety.ConclusionsPulmonary rehabilitation reduces the influence of learned associations upon neural processes that generate breathlessness. Patients with stronger word-cue related activity at baseline benefitted more from pulmonary rehabilitation. These findings highlight the importance of targeting learned associations within treatments for COPD, demonstrating how neuroimaging may contribute to patient stratification and more successful personalised therapy.

Individuals in pain often face the choice between avoiding pain and pursuing other equally valued goals. However, little is known about pain-related choice behavior and pain perception in goal conflict situations. Seventy-eight healthy volunteers performed a computerized task requiring repeated choices between incompatible options, differing in their effect on probability to receive painful stimulation and money. Depending on group assignment, participants chose between increased pain probability versus decreased money probability (avoidance-avoidance conflict situation); decreased pain probability versus increased money probability (approach-approach conflict situation); or decrease versus increase in both probabilities (double approach/avoidance conflict situation). During the choice task, participants rated painfulness, unpleasantness, threat, and fearfulness associated with the painful stimulation and how they felt. Longer choice latency and more choice switching were associated with higher retrospective ratings of conflict and of decision difficulty, and more equal importance placed on pain avoidance and earning money. Groups did not differ in choice behavior, pain stimulus ratings, or affect. Across groups, longer choice latencies were nonsignificantly associated with higher pain, unpleasantness, threat, and fearfulness. In the avoidance-avoidance group, more choice switching was associated with higher pain-related threat and fearfulness, and with more negative affect. These results of this study suggest that associations between choice behaviors, pain perception, and affect depend on conflict situation. Perspective: We present a first experimental demonstration of the relationship between pain-related choice behaviors, pain, and affect in different goal conflict situations. This experimental approach allows us to examine these relationships in a controlled fashion. Better understanding of pain-related goal conflicts and their resolution may lead to more effective pain treatment. (C) 2014 by the American Pain Society

Acute and chronic pain automatically attract attention and thus interfere with cognitive functioning. Impaired memory is a prominent complaint of patients with chronic pain that substantially contributes to pain-related disability. In this fMRI study, we investigated the specific influence of pain on neural processes of memory encoding in healthy human volunteers using a visual task. To investigate the specificity of the interruptive effect of pain on the encoding of visual objects, objects were presented (1) alone, (2) with painful heat stimuli, or (3) with auditory stimuli that were matched for unpleasantness to the heat stimuli. The interruptive effect of concomitant aversive stimulation on behavioral measures and neural processing was assessed in a categorization task during encoding and in a subsequent recognition task. Pain interfered with object processing and encoding of visual stimuli. On the behavioral level, this resulted in slower reaction times during the categorization task for pain compared with auditory stimuli and in a lower recognition rate in the pain condition but not in the tone condition. Pain catastrophizing amplified this interruptive effect of pain. On the neural level, this pain-related disruption of encoding was associated with reduced activity in the right anterior hippocampus during encoding. Moreover, the hippocampus exhibited reduced functional connectivity with extrastriate regions during painful stimulation relative to auditory stimulation. In summary, our results show a pain-related disruption of visual encoding over and above the unpleasantness of a stimulus, suggesting a pain-specific interruptive mechanism that interferes with an early stage of memory formation.

Relief from pain in humans is frequently measured by computing the reduction on an 11-point pain intensity scale. However, this definition of relief may be insufficient to capture the utility of pain relief for the individual. Based on pain literature and evidence from studies examining relief and reward, it is clear that pain relief is a broad concept comprising several factors, only one of which is pain intensity reduction. According to opponent process theory, all sensations consist of a primary process and a slow 'opponent process' of opposite valence, the purpose of which is to reduce the deviation from homeostatic balance. Here, opponent process theory provided a framework to explore the interaction between pain, relief and reward. We devised three psychophysical studies examining the temporal (Experiment I) and magnitude (Experiments I and II) relationships between pain severity and its subsequent relief. In Experiment III, we further manipulated the magnitude and pleasantness of relief experienced by applying innocuous cooling following noxious heat stimulation of capsaicin-sensitized skin. Results confirmed predictions from opponent process theory and showed that pain intensity reduction was significantly stronger than relief intensity ratings. Furthermore, continuous relief ratings appeared to reflect the speed of pain intensity reduction. Varying pain intensity parametrically confirmed that relief increases with pain intensity. That innocuous cooling following primary hyperalgesia intervention significantly increased the intensity, pleasantness and duration of relief provides further evidence that pain relief encapsulates more than a reduction in pain intensity. Importantly, the high relief pleasantness ratings confirmed the hypothesized link between relief and reward.

The decision as to whether a sensation is perceived as painful does not only depend on sensory input but also on the significance of the stimulus. Here, we show that the degree to which an impending stimulus is interpreted as threatening biases perceptual decisions about pain and that this bias toward pain manifests before stimulus encounter. Using functional magnetic resonance imaging we investigated the neural mechanisms underlying the influence of an experimental manipulation of threat on the perception of laser stimuli as painful. In a near-threshold pain detection paradigm, physically identical stimuli were applied under the participants' assumption that the stimulation is entirely safe (low threat) or potentially harmful (high threat). As hypothesized, significantly more stimuli were rated as painful in the high threat condition. This context-dependent classification of a stimulus as painful was predicted by the prestimulus signal level in the anterior insula, suggesting that this structure integrates information about the significance of a stimulus into the decision about pain. The anticipation of pain increased the prestimulus functional connectivity between the anterior insula and the midcingulate cortex (MCC), a region that was significantly more active during stimulation the more a participant was biased to rate the stimulation as painful under high threat. These findings provide evidence that the anterior insula and MCC as a “salience network” integrate information about the significance of an impending stimulation into perceptual decision-making in the context of pain.

Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.

The idea that pain can lead to feelings of frustration, worry, anxiety and depression seems obvious, particularly if it is of a chronic nature. However, there is also evidence for the reverse causal relationship in which negative mood and emotion can lead to pain or exacerbate it. Here, we review findings from studies on the modulation of pain by experimentally induced mood changes and clinical mood disorders. We discuss possible neural mechanisms underlying this modulatory influence focusing on the periaqueductal grey (PAG), amygdala, anterior cingulate cortex (ACC) and anterior insula as key players in both, pain and affective processing.

The perception of pain can be significantly modulated by the behavioral context. Here, we investigated how contextual modulations of pain are subserved in the human brain. We independently modulated the attentional and emotional context of painful stimuli and recorded brain activity by using functional magnetic resonance imaging. Our results confirm that attention to pain and a negative emotional context increases pain perception and this is concomitantly associated with increased neural activity in the anterior insular cortex. Connectivity analyses further reveal that during attentional and emotional modulations of pain, the anterior insula selectively and flexibly connects to attentional and emotional brain networks in frontoparietal and medial temporal lobe areas, respectively. We conclude that the flexible functional connectivity of the anterior insula to other functional systems of the brain, for example, attentional and emotional brain networks, subserves the extraordinary sensitivity of the pain experience to contextual modulations.

Objectives Interoceptive fear learning and generalization have been hypothesized to play a key role in unexplained abdominal and esophageal pain in patients with functional gastrointestinal disorders. However, there is no experimental evidence demonstrating that fear learning and generalization to visceral sensations can be established in humans and alter visceral perception. Methods In a novel fear learning-generalization paradigm, an innocuous esophageal balloon distension served as conditioned stimulus (CS), and distensions at three different pressure levels around the pain detection threshold were used as generalization stimuli. During fear learning, the CS was paired with a painful electrical stimulus (unconditioned stimulus) in the conditioning group (n = 30), whereas in the control group (n = 30), the unconditioned stimulus was delivered alone. Before and after fear learning, visceral perception thresholds for first sensation, discomfort, and pain and visceral discrimination sensitivity were assessed. Results Fear learning was established in the conditioning group only (potentiated eye-blink startle to the CS (t(464.06) = 3.17, p = .002), and fear generalization to other stimulus intensities was observed (t(469.12) = 2.97, p = .003; t(464.29) = 4.17, p

Phenomena such as placebo analgesia or pain relief through distraction highlight the powerful influence cognitive processes and learning mechanisms have on the way we perceive pain. Although contemporary models of pain acknowledge that pain is not a direct readout of nociceptive input, the neuronal processes underlying cognitive modulation are not yet fully understood. Modern concepts of perception—which include computational modeling to quantify the influence of cognitive processes—suggest that perception is critically determined by expectations and their modification through learning. Research on pain has just begun to embrace this view. Insights into these processes promise to open up new avenues to pain prevention and treatment by harnessing the power of the mind.

The observation that cognitive factors such as beliefs and expectations not only modulate the perception of pain, but also the therapeutic benefit and adverse effects of any pharmacological treatment is not new. However, the contribution of cognitive factors to pharmacotherapy is still poorly understood and far from being systematically exploited to maximize treatment outcome. Recent insights into placebo and nocebo phenomena and their underlying neurobiological mechanisms have, however, rekindled the interest in interactions between pharmacological effects and cognitive factors. In this review, we argue that modern non-invasive neuroimaging techniques exploring structure and function of the brain as well as neurochemical processes can aid in understanding these potential interactions at a more fundamental level. Taking pain as an example, we portrait recent advances in this field and discuss basic science and clinical implications. © 2012.

This meeting report highlights the main topics presented at the conference "Chronic Inflammatory and Neuropathic Pain," convened jointly by the New York Academy of Sciences, MedImmune, and Grunenthal GmbH, on June 2-3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from academia, industry, clinical practice, and government to explore new frontiers in our understanding and treatment of chronic and neuropathic pain. The program included leading and emerging investigators studying the pathophysiological mechanisms underlying neuropathic and chronic pain, and experts in the clinical development of pain therapies. Discussion included novel issues, current challenges, and future directions of basic research in pain and preclinical and clinical development of new therapies for chronic pain.

SummaryChronic dyspnoea is a devastating symptom that debilitates millions of people worldwide. It causes a large burden on both patient and carer, and significant costs to society and health services. Treatment options are limited. Much effort has been directed at optimising lung function and improving exercise capacity, however, the brain mechanisms underlying dyspnoea perception have received less attention.In this review, we focus on cognitive and affective aspects of dyspnoea and discuss how novel neuroimaging methods can provide quantitative measures of these subjective sensations. We draw parallels with the more advanced field of chronic pain, and explain some of the challenges faced when imaging dyspnoea.To date, brain mechanisms of dyspnoea have been investigated in a handful of studies by a limited number of authors. These have found consistent activation in the insular cortex, the anterior cingulate cortex and the amygdala. Novel neuroimaging methods and an improved understanding of perceptual mechanisms underlying dyspnoea now position us to transform dyspnoea research. Future research should investigate how brain regions associated with dyspnoea interact, as well as accurately correlate this neuronal activation with reliable behavioural measures.A better understanding of the brain processes underlying dyspnoea perception will lead to new therapies that will improve quality of life for a very large group of patients.

The biopsychosocial model treats pain as resulting from a complex interaction of biological, psychological, and social factors. Individual differences in approaches to coping with pain-related symptoms are important determinants of pain-related outcomes, and are often classified under the “psychological” category within the biopsychosocial model. However, engagement in various cognitive, affective, and behavioral pain-coping strategies appears to exert biological effects, which we review here. Pain-coping activities such as catastrophizing, distracting oneself from pain sensations, or reappraisal of pain may exert effects on activity in a variety of pain-processing and pain-modulatory circuits within the brain, as well affect the functioning of neuromuscular, immune, and neuroendocrine systems. The interface between pain-related neurobiology and the use of specific pain-coping techniques represents an important avenue for future pain research.

Background Hyperexcitability of N -methyl- d -aspartate acid (NMDA) receptors may play an important role in the development of phantom limb pain (PLP). Aim of the study To investigate whether early treatment with the NMDA antagonist memantine attenuates phantom pain memory formation in traumatic amputees. Methods In a randomized, double-blind, controlled trial 19 patients with acute traumatic amputation of the upper extremity were investigated. All patients received postoperative analgesia by continuous brachial plexus anesthesia (ropivacaine 0.375% 5 ml/h) for at least 7 days. In addition, the patients received either memantine (20–30 mg daily, n = 10) or placebo ( n = 9) for 4 weeks. Results Memantine treatment reduced the number of requested ropivacacine bolus injections during the first week and resulted in a significant decrease of PLP prevalence and intensity at 4 weeks and 6 months follow up, but not at 12 months follow up. Conclusions We conclude that memantine can reduce intensity of phantom limb pain and might also prevent the development of PLP. However, despite the very early begin of treatment; no long-term effect on established PLP was evident.

Over the recent years, neuroimaging studies have investigated the neural mechanisms underlying the influence of expectations on perception. However, it seems equally reasonable to assume that expectations impact cognitive functions. Here we used fMRI to explore the role of expectations on task performance and its underlying neural mechanisms. 43 healthy participants were randomly assigned to two groups. Using verbal instructions, group 1 was led to believe that pain enhances task performance while group 2 was instructed that pain hampers their performance. All participants performed a Rapid-Serial-Visual-Presentation (RSVP) Task (target detection and short-term memory component) with or without concomitant painful heat stimulation during 3T fMRI scanning. As hypothesized, short-term memory performance showed an interaction between painful stimulation and expectation. Positive expectations induced stronger neural activation in the right inferior parietal cortex (IPC) during painful stimulation than negative expectation. Moreover, IPC displayed differential functional coupling with the left inferior occipital cortex under pain as a function of expectancy. Our data show that an individual's expectation can influence cognitive performance in a visual short-term memory task which is associated with activity and connectivity changes in brain areas implicated in attentional processing and task performance.

BACKGROUND: Dyspnea is the major source of disability in COPD. In COPD, environmental cues (eg, the prospect of having to climb stairs) become associated with dyspnea and may trigger dyspnea even before physical activity commences. We hypothesized that brain activation relating to such cues would be different between patients with COPD and healthy control subjects, reflecting greater engagement of emotional mechanisms in patients. METHODS: Using functional MRI (FMRI), we investigated brain responses to dyspnea-related word cues in 41 patients with COPD and 40 healthy age-matched control subjects. We combined these findings with scores on self-report questionnaires, thus linking the FMRI task with clinically relevant measures. This approach was adapted from studies in pain that enabled identification of brain networks responsible for pain processing despite absence of a physical challenge. RESULTS: Patients with COPD demonstrated activation in the medial prefrontal cortex and anterior cingulate cortex, which correlated with the visual analog scale (VAS) response to word cues. This activity independently correlated with patient responses on questionnaires of depression, fatigue, and dyspnea vigilance. Activation in the anterior insula, lateral prefrontal cortex, and precuneus correlated with the VAS dyspnea scale but not with the questionnaires. CONCLUSIONS: The findings suggest that engagement of the emotional circuitry of the brain is important for interpretation of dyspnea-related cues in COPD and is influenced by depression, fatigue, and vigilance. A heightened response to salient cues is associated with increased symptom perception in chronic pain and asthma, and the findings suggest that such mechanisms may be relevant in COPD.

Remembering an event partially reactivates cortical and subcortical brain regions that were engaged during its experience and encoding. Such reinstatement of neuronal activation has been observed in different sensory systems, including the visual, auditory, olfactory, and somatosensory domain. However, so far, this phenomenon of incidental memory has not been explored in the context of pain. In this functional magnetic resonance imaging study, we investigated the neural reinstatement of pain-related and tone-related activations during the recognition of neutral images that had been encoded during (1) painful stimulation, (2) auditory stimulation of comparable unpleasantness, or (3) no additional stimulation. Stimulus-specific reinstatement was tested in 24 healthy male and female participants who performed a visual categorization task (encoding) that was immediately followed by a surprise recognition task. Neural responses were acquired in both sessions. Our data show a partial reinstatement of brain regions frequently associated with pain processing, including the left posterior insula, bilateral putamen, and right operculum, during the presentation of images previously paired with painful heat. This effect was specific to painful stimuli. Moreover, the bilateral ventral striatum showed stronger responses for remembered pain-associated images as compared with tone-associated images, suggesting a higher behavioral relevance of remembering neutral pictures previously paired with pain. Our results support the biological relevance of pain in that only painful but not equally unpleasant auditory stimuli were able to "tag" neutral images during their simultaneous presentation and reactivate pain-related brain regions. Such mechanisms might contribute to the development or maintenance of chronic pain and deserve further investigation in clinical populations.

There is little information regarding changes in placebo responsiveness with age, although first predictors of placebo responders such as psychological and physiological processes have been identified. Reviews and meta-analyses indicate that placebo response rates in randomized controlled trials (RCTs) are higher in children and adolescents compared with adults. As these studies cannot control for age-dependent differences in the natural course of the disease, biases might contribute to different placebo rates in RCTs. To avoid these biases, this study investigated age-related differences in placebo responsiveness between children and adults in a well-established experimental model of placebo analgesia combining classic conditioning and expectation. Our data confirm placebo analgesic responses in children, which did not differ in magnitude from those of adults. The influence of previous experience on subsequent treatment outcome was stronger in children than in adults, indicating an increased relevance of learning processes for treatment outcomes in children. Further studies are needed to understand the influence of treatment-related learning processes in children and adolescents, which might critically determine treatment responsiveness during adulthood. Perspective This study is the first to experimentally explore placebo analgesia and influences of previous experience on placebo responses in children compared with adults. We found comparable placebo responses in both groups and an increased relevance of learning processes for treatment outcomes in children.