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Errors put organisms in danger. Upon error commission, error processing allows for the updating of behavior that proved ineffective in light of the current context and goals, and for the activation of behavioral defensive systems. Pain, on the other hand, signals actual or potential danger to one's physical integrity and, likewise, motivates protective behavior. These parallels suggest the existence of cross-links between pain and error processing but so far their relationship remains elusive. In this review, we tie together findings from the field of pain research with those from electroencephalography studies on error processing [specifically the Error Related Negativity (ERN) and Positivity (Pe)]. More precisely, we discuss three plausible associations: Firstly, pain may enhance error processing as it increases error salience. Secondly, persons fearful of pain may be particularly vigilant towards painful errors and thus show a stronger neural response to them. Thirdly, the ERN as a component of the neural response to error commission is considered an endophenotype of threat sensitivity. As high sensitivity to pain threats is known to incite avoidance behavior, this raises the intriguing possibility that neural signatures of error processing predict pain-related protective behaviors, such as avoidance. We propose an integration of these findings into a common framework to inspire future research. Perspectives Inspired by research in anxiety disorders, we discuss the potential bi-directional relationships between error processing and pain, and identify future directions to examine the neural and psychological processes involved in acute and chronic pain and respective avoidance behavior.

Pain-related fear and -avoidance crucially contribute to pain chronification. People with chronic pain may adopt costly avoidance strategies above and beyond what is necessary, aligning with experimental findings of excessive fear generalization to safe movements in these populations. Furthermore, recent evidence suggests that, when avoidance is costly, it can dissociate from fear. Here, we investigated whether concurrently measured pain-related fear and costly avoidance generalization correspond in one task. We also explored whether healthy participants avoid excessively despite associated costs, and if avoidance would decrease as a function of dissimilarity from a pain -associated movement. In a robotic arm-reaching task, participants could avoid a low-cost, pain-associated movement trajectory (T+), by choosing a high-cost non-painful movement trajectory (T-), at opposite ends of a movement plane. Subsequently, in the absence of pain, we introduced three movement trajectories (G1-3) between T+ and T-, and one movement trajectory on the side of T-opposite to T+ (G4), linearly increasing in costs from T+ to G4. Avoidance was operationalized as maximal deviation from T+, and as trajectory choice. Fear learning was measured using self-reported pain-expectancy, pain-related fear, and startle eye-blink electromyography. Self-reports generalized, both decreasing with increasing distance from T+. In contrast, all generalization trajectories were chosen equally, suggesting that avoidance-costs and previous pain balanced each other out. No effects emerged in the electromyography. These results add to a growing body of literature showing that (pain-related) avoidance, especially when costly, can dissociate from fear, calling for a better under-standing of the factors motivating, and mitigating, disabling avoidance. Perspective: This article presents a comparison of pain-related fear- and avoidance generalization, and an exploration of excessive avoidance in healthy participants. Our findings show that pain -related avoidance can dissociate from fear, especially when avoidance is costly, calling for a better understanding of the factors motivating and mitigating disabling avoidance. (C) 2022 The Author(s). Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc.

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.

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

ispartof: Pain vol:162 issue:4 pages:995-998 ispartof: location:United States status: published

BackgroundA subset of patients with chronic pain who receive exposure in vivo (EXP) treatment experience clinically relevant relief of pain intensity. Although pain relief is not an explicit therapeutic target, it is important to understand how and why this concomitant effect occurs in some patients but not others. This longitudinal study therefore aimed to characterize brain plasticity as well as to explore pretreatment factors related to pain relief.MethodsResting-state functional magnetic resonance imaging data were acquired in 30 patients with chronic pain. Twenty-three patients completed EXP, and 6-month follow-up data were available in 20 patients (magnetic resonance imaging data in 17 patients). Pain-free control data were acquired at two time points (n = 29, n = 21). Seed-based resting-state functional connectivity (rsFC) analyses were performed, with seeds in the amygdala, hippocampus, and nucleus accumbens.ResultsPain relief after EXP was highly variable, with 60% of patients reporting a clinically relevant improvement. Amygdala rsFC with the middle frontal gyrus decreased significantly over time in patients but was not associated with pain relief. In contrast, greater pain relief was associated with greater decreases over time in hippocampus rsFC with the precuneus, which was related to reductions in catastrophizing (EXP therapeutic target) as well. Greater pain relief was also associated with lower pretreatment rsFC between nucleus accumbens and postcentral gyrus.ConclusionsWhile changes in hippocampus rsFC were associated with pain relief after EXP, pretreatment nucleus accumbens rsFC showed potential prognostic value. Our findings further support the importance of corticolimbic circuitry in chronic pain, emphasizing its relation to pain relief and identifying potential underlying mechanisms and prognostic factors, warranting further testing in independent samples.

Pain can be considered as a signal of “bodily error”: Errors – discrepancies between the actual and optimal/targeted state – can put organisms at danger and activate behavioral defensive systems. If the error relates to the body, pain is the warning signal that motivates protective action such as avoidance behavior to safeguard our body’s integrity. Hence, pain shares the functionality of errors. On the neural level, an important error processing component is the error-related negativity (ERN), a negative deflection in the electroencephalographic (EEG) signal generated primarily in the anterior cingulate cortex within 100 ms after error commission. Despite compelling evidence that the ERN plays an important role in the development of various psychopathologies and is implicated in learning and adjustment of behavior, its relation to pain-related avoidance has not yet been examined. Based on findings from anxiety research, it seems conceivable that individuals with elevated ERN amplitudes are more prone to engage in pain-related avoidance behavior, which may, under certain conditions, be a risk factor for developing chronic pain. Consequently, this new line of research promises to contribute to our understanding of human pain. As in most novel research areas, a first crucial step for integrating the scientific fields of ERN and pain is developing a paradigm suited to address the needs from both fields. The present manuscript presents the development and piloting of an experimental task measuring both ERN and avoidance behavior in response to painful mistakes, as well as the challenges encountered herein. A total of 12 participants underwent one of six different task versions. We describe in detail each of these versions, including their results, shortcomings, our solutions, and subsequent steps. Finally, we provide some advice for researchers aiming at developing novel paradigms.Keywords: error-related negativity, avoidance behavior, chronic pain, experimental psychopathology, experimental paradigm

OBJECTIVES: Worry is the most common psychological complaint among patients with Inflammatory Bowel Disease (IBD). This study aimed to translate and test the psychometric properties the Rating Form of IBD Patient Concerns (RFIPC) among Dutch-speaking patients with IBD in Belgium. It also aimed to describe worries and concerns, and to examine possible differences in worry patterns between patients with different disease types and disease activities. METHODS: The RFIPC was translated into Dutch following the guidelines of the Rome Foundation and was completed by patients with Crohn's disease (CD, n = 336) and ulcerative colitis (UC, n = 160). To test concurrent validity, the Depression Anxiety Stress Scales (DASS-21) were used. Factor structure was examined with confirmatory factor analysis. RESULTS: The four-factor structure including subscales 'impact of the disease', 'sexual intimacy', 'complications of the disease' and 'body stigma' was confirmed in the Dutch sample. All factors had high internal consistency (>.70). Correlations with DASS-21 suggest good concurrent validity, all rs>.30, ps

Objectives Contemporary fear-avoidance models of chronic pain posit that fear of pain, and overgeneralization of fear to non-threatening stimuli is a potential pathway to chronic pain. While increasing experimental evidence supports this hypothesis, a comprehensive investigation requires testing in multiple modalities due to the diversity of symptomatology among individuals with chronic pain. In the present study we used an established tactile fear conditioning paradigm as an experimental model of allodynia and spontaneous pain fluctuations, to investigate whether stimulus generalization occurs resulting in fear of touch spreading to new locations. Methods In our paradigm, innocuous touch is presented either paired (predictable context) or unpaired (unpredictable context) with a painful electrocutaneous stimulus (pain-US). In the predictable context, vibrotactile stimulation to the index or little finger was paired with the pain-US (CS+), whilst stimulation of the other finger was never paired with pain (CS−). In the unpredictable context, vibrotactile stimulation to the index and little fingers of the opposite hand (CS1 and CS2) was unpaired with pain, but pain-USs occurred unpredictable during the intertrial interval. During the subsequent generalization phase, we tested the spreading of conditioned responses (self-reported fear of touch and pain expectancy) to the (middle and ring) fingers between the CS+ and CS−, and between the CS1 and CS2. Results Differential fear acquisition was evident in the predictable context from increased self-reported pain expectancy and self-reported fear for the CS + compared to the CS−. However, expectancy and fear ratings to the novel generalization stimuli (GS+ and GS−) were comparable to the responses elicited by the CS−. Participants reported equal levels of pain expectancy and fear to the CS1 and CS2 in the unpredictable context. However, the acquired fear did not spread in this context either: participants reported less pain expectancy and fear to the GS1 and GS2 than to the CS1 and CS2. As in our previous study, we did not observe differential acquisition in the startle responses. Conclusions Whilst our findings for the acquisition of fear of touch replicate the results from our previous study (Biggs et al., 2017), there was no evidence of fear generalization. We discuss the limitations of the present study, with a primary focus on procedural issues that were further investigated with post-hoc analyses, concluding that the present results do not show support for the hypothesis that stimulus generalization underlies spreading of fear of touch to new locations, and discuss how this may be the consequence of a context change that prevented transfer of acquisition.

The fear-avoidance model of chronic pain predicts that catastrophic (mis)interpretation of pain elicits pain-related fear that in turn may spur avoidance behaviour leading to chronic pain disability. Here we investigated whether performing a movement to avoid a painful stimulus in the context of a novel movement increases threat and pain-related fear towards this novel movement, and whether avoidance behaviour persisted when given the choice between performing the acquired movement to avoid a painful stimulus or an alternative, novel movement. Applying a robotic arm-reaching task, participants could choose between two movements to reach a target location: a short, but painful movement trajectory, or a longer non-painful movement trajectory. After avoidance acquisition, the option to choose the painful trajectory was removed. The Experimental Group (N=50) could choose between the longest trajectory or a novel intermediate trajectory, whereas the Control Group (N=50) was allowed to only perform the novel trajectory. In a final test, participants of both groups were allowed to choose any of the three trajectories. Post-acquisition, Experimental Group participants showed elevated pain-expectancy and pain-related fear towards the novel trajectory, compared to the Control Group. During test, the Experimental Group participants persisted in performing the longest pain-free (avoidance) trajectory, and were less likely to choose the novel trajectory. In addition, these participants maintained higher levels of pain-related fear for the novel trajectory compared to the Control Group. These findings suggest that avoidance in the context of other neutral activities/movements may lead to the development and maintenance of threat appraisals and irrational fears. ispartof: Pain vol:162 issue:3 pages:875-885 ispartof: location:United States status: published

Whether, how, and which cognitive factors modulate the development of secondary hypersensitivity/hyperalgesia after central sensitization is not fully understood. Here, we tested, in 3 subsequent experiments, whether being engaged in non-pain-related cognitive demanding tasks: (1) lessens the amount of hypersensitivity developed after an experimental procedure sensitizing nociceptive pathways; and (2) modulates cortical responses to somatosensory stimuli (measured by electroencephalography, EEG). In the first experiment, we validated a novel model in humans using low-frequency stimulation of the skin and demonstrated that it was able to successfully induce hypersensitivity to mechanical pinprick stimuli in the area surrounding the sensitized site. In the second and third experiments, we engaged participants in tasks of increasing difficulty (the Eriksen Flanker Task in experiment 2, and a modified N-back task in experiment 3). We observed that hypersensitivity to mechanical stimuli still developed in experiment 2, that is, the pinprick stimuli applied on the sensitized arm were perceived as more intense after low-frequency stimulation. By contrast, no statistically significant enhancement of mechanical hypersensitivity was observed in experiment 3, indicating that, at the group level, being engaged in a difficult N-back task may interfere with the development of mechanical hypersensitivity. Contrary to previous studies, which have used different methods to induce sensitization, we did not observe any increase in the cortical response to somatosensory stimuli applied on the sensitized arm. We conclude that (1) the development of pinprick hypersensitivity is modulated by the concomitant execution of a difficult N-back task, and (2) the enhancement of cortical responses to somatosensory stimuli is related to the method used to induce central sensitization. ispartof: Pain vol:161 issue:7 pages:1459-1469 ispartof: location:United States status: published

Experimental data suggest that associative learning can influence defensive avoidance behavior and pain perception in humans. However, whether voluntary movements can become conditioned stimuli and influence pain responses has yet to be evaluated. Forty healthy volunteers participated in this study. Electrocutaneous stimuli applied to the shoulder at pain threshold level (UStest) and at pain tolerance level (US) were determined prior to a movement-conditioning paradigm. First, reaching movements to visual cues shown on one side of a computer screen were associated with the US (CS+ movements) on 80% of trials, whereas reaching movements to visual stimuli shown on the other side were never associated with the nociceptive-US (CS- movements). Next, participants underwent a test phase in which movements to visual cues on both sides were paired with the UStest on 50% of trials. During the test phase, participants were asked to evaluate if the movement was painful (yes/no) and to rate pain intensity after each trial. Movement onset and duration as well as skin conductance responses (SCR) were collected. The UStest stimuli were more likely to be perceived as painful and were also rated as more painful during CS+ movements. Movement onset latency and SCRs were significantly higher in anticipation of the CS+ movement as compared to the CS- movement. These findings suggest that pain can be conditioned to voluntary movements. ispartof: Pain vol:161 issue:10 pages:2321-2329 ispartof: location:United States status: published

Persons with chronic musculoskeletal pain may be hypervigilant for pain-related cues, which paradoxically, may be maintaining their pain. Several randomized controlled trials have assessed whether a modified dot-probe protocol (i.e., attention bias modification; ABM) reduces chronic pain- and pain-related symptoms in persons with several diagnoses, including fibromyalgia. Scalability and economic efficiency potentiates the appeal of ABM protocols; however, research results have been mixed, with only some studies evidencing significant symptom gains from ABM and some evidencing gains for the control group. The current randomized controlled trial sought to replicate and extend previous ABM research using idiosyncratic word stimuli and a 1-month follow-up. Participants included treatment-seeking adult women (n=117) with fibromyalgia who were randomly assigned to a standard (i.e., control) or active (i.e., ABM) condition. The protocol was delivered online and involved twice-weekly 15-min sessions, for 4 weeks, with questionnaires completed at baseline, post-treatment, and 1-month follow-up. Symptom reports were analysed with mixed hierarchical modelling. There was no evidence of differences between the control and ABM groups. Both groups had small significant (ps.05). There were no significant changes for either group on measures of anxiety sensitivity, illness/injury sensitivity, pain-related fear, pain-related anxiety, or attentional biases (ps>.05). The current findings add to the emerging and mixed literature regarding ABM for pain by demonstrating that ABM produces no substantive improvements in pain or pain-related constructs in a large sample of patients with fibromyalgia. ispartof: Pain vol:161 issue:3 pages:584-594 ispartof: location:United States status: published

Avoidance is considered key in the development of chronic pain. However, little is known about how avoidance behaviour subsequently affects pain-related fear and pain. We investigated this using a robotic arm reaching avoidance task to investigate this. In a between-subjects design both Experimental Group (n=30) and Yoked Control Group (n=30) participants perform either of three movement trajectories (T1-T3) to reach a target location. During acquisition, only participants of the Experimental Group could partially or fully avoid a painful electrocutaneous stimulus by choosing the intermediate trajectory (T2; 50% reinforcement) or the longest trajectory (T3; 0% reinforcement) versus the shortest trajectory (T1: 100% reinforcement). After acquisition, contingencies changed (all trajectories 50% reinforced), and the acquired avoidance behaviour no longer effectively prevented pain from occurring. The Yoked Control Group received the same reinforcement schedule as the Experimental Group irrespective of their behaviour. When avoidance behaviour became ineffective for the Experimental Group, pain-related fear increased for the previously safe(r) trajectories (T2 and T3) and remained the same for T1, whereas pain threshold and tolerance declined. For the Yoked Group, pain-related fear increased for all trajectories. The Experimental Group persisted in emitting avoidance behaviour following the contingency change, albeit at a lower frequency than during acquisition. Perspective Results indicate participants become more afraid of and sensitive to pain, when previously acquired avoidance is no longer effective. Also, participants continue to show avoidance behaviour despite it being not adaptive anymore. These findings suggest that ineffective avoidance may play role in the maintenance and development of chronic pain. ispartof: The Journal of Pain vol:21 issue:3-4 pages:494-505 ispartof: location:United States status: published

Pain is considered a hardwired signal of bodily disturbance belonging to a basic motivational system that urges the individual to act and to restore the body's integrity, rather than just a sensory and emotional experience. Given its eminent survival value, pain is a strong motivator for learning. Response to repeated pain increases when harm risks are high (sensitization) and decreases in the absence of such risks (habituation). Discovering relations between pain and other events provides the possibility to predict (Pavlovian conditioning) and control (operant conditioning) harmful events. Avoidance is adaptive in the short term but paradoxically may have detrimental long-term effects. Pain and pain-related responses compete with other demands in the environment. Exposure-based treatments share the aim of facilitating or restoring the pursuit of individual valued life goals in the face of persistent pain, and further improvements in pain treatment may require a paradigm shift toward more personalized approaches. ispartof: Annual Review Of Clinical Psychology vol:16 pages:187-212 ispartof: location:United States status: published

OBJECTIVES: This systematic review examined studies that used mediation analysis to investigate the mechanisms of action of cognitive-behavioral, mind-body, and exercise-based interventions for pain and disability in people with chronic primary musculoskeletal pain. MATERIALS AND METHODS: We searched 5 electronic databases for articles that conducted mediation analyses of randomized controlled trials to either test or estimate indirect effects. RESULTS: We found 17 studies (n=4423), including 90 mediation models examining the role of 22 putative mediators on pain or disability, of which 4 had partially mediated treatment effect; 8 had mixed results, and 10 did not mediate treatment effect. The conditions studied were chronic whiplash-associated pain, chronic low back pain, chronic knee pain, and mixed group of chronic primary musculoskeletal pain. DISCUSSION: We observed that several of the studies included in our systematic review identified similar mechanisms of action, even between different interventions and conditions. However, methodological limitations were common. In conclusion, there are still substantial gaps with respect to understanding how cognitive-behavioral, mind-body, and exercise-based interventions work to reduce pain and disability in people with chronic primary musculoskeletal pain.

Background and Aims Disease-related behaviours that may maintain or worsen symptom burden remain largely unexplored in inflammatory bowel disease [IBD]. In this study, we developed and validated an instrument assessing IBD-related, modifiable behaviours and explored which behaviours prospectively correlate with fatigue, a debilitating and common symptom in IBD. Methods Initially, 72 items reflecting IBD-related behaviours were generated based on literature review and input from clinicians and people diagnosed with IBD. During wave 1, 495 IBD patients rated to what extent each behaviour was applicable to them. Additionally, disease activity, fatigue, IBD-related concerns and psychological variables were assessed. During a follow-up visit 4–12 weeks later [wave 2], a random selection of 92 patients from wave 1 completed the measures assessing the IBD-related behaviours, disease activity and fatigue once more. Results A principal component analysis with oblique rotation revealed seven components in the 72 IBD behaviours, which could be interpreted as: [1] Avoiding food and activities, [2] Access to toilets, [3] Avoidance of sex, [4] Cognitive avoidance, [5] Not sharing with others, [6] Alternative treatments and [7] Disease management. Each component was reduced to three to five representative items, resulting in a final, 25-item IBD-Bx questionnaire showing good concurrent validity [alphas > 0.63] and reliability. Almost all components were cross-sectionally related to levels of fatigue. Avoiding food and activities and Access to toilets significantly predicted fatigue at wave 2 when controlling for baseline fatigue. Conclusions The IBD-Bx is a valid and reliable questionnaire of IBD-related behaviours, some of which predict future fatigue burden.

Slow, deep breathing (SDB) is a common pain self-management technique. Stimulation of the arterial baroreceptors and vagal modulation are suggested, among others, as potential mechanisms underlying the hypoalgesic effects of SDB. We tested whether adding an inspiratory load to SDB, which results in a stronger baroreceptor stimulation and vagal modulation, enhances its hypoalgesic effects. Healthy volunteers performed SDB (controlled at 0.1 Hz) with and without an inspiratory threshold load. Controlled breathing (CB) at a normal frequency (0.23 Hz) was used as an active control. Each condition lasted 90 s, included an electrical pain stimulation on the hand, and was repeated four times in a randomized order. Pain intensity, self-reported emotional responses (arousal, valence, dominance), and cardiovascular parameters (including vagally-mediated heart rate variability) were measured per trial. A cover story was used to limit the potential effect of outcome expectancy. Pain intensity was slightly lower during SDB with load compared with normal-frequency CB, but the effect was negligible (Cohens d

In this article we briefly examine the unique features of Single-Case Designs (SCDs) (studies in a single participant), their history and current trends, and real-world clinical applications. The International Collaborative Network for N-of-1 Trials and Single-Case Designs (ICN) is a formal collaborative network for individuals with an interest in SCDs. The ICN was established in 2017 to support the SCD scientific community and provide opportunities for collaboration, a global communication channel, resource sharing and knowledge exchange. In May 2021, there were more than 420 members in 31 countries. A member survey was undertaken in 2019 to identify priorities for the ICN for the following few years. This article outlines the key priorities identified and the ICN's progress to date in these key areas including network activities (developing a communications strategy to increase awareness, collecting/sharing a comprehensive set of resources, guidelines and tips, and incorporating the consumer perspective) and scientific activities (writing position papers and guest editing special journal issues, exploring key stakeholder perspectives about SCDs, and working to streamline ethical approval processes for SCDs). The ICN provides a practical means to engage with this methodology through membership. We encourage clinicians, researchers, industry, and healthcare consumers to learn more about and conduct SCDs, and to join us in our mission of using SCDs to improve health outcomes for individuals and populations. ispartof: Contemporary Clinical Trials Communications vol:23 pages:1-8 ispartof: location:Netherlands status: published

BACKGROUND: Studies using somatic pain models have shown the hypoalgesic effects of slow, deep breathing. We evaluated the effect of slow, deep breathing on visceral pain and explored putative mediating mechanisms including autonomic and emotional responses.METHODS: Fifty-seven healthy volunteers (36 females, mean age = 22.0 years) performed controlled, deep breathing at a slow frequency (6 breaths per minute), controlled breathing at a normal frequency (14 breaths per minute; active control), and uncontrolled breathing (no-treatment control) in randomized order. Moderate painful stimuli were given during each condition by delivering electrical stimulation in the distal esophagus. Participants rated pain intensity after each stimulation. Heart rate variability and self-reported arousal were measured during each condition.KEY RESULTS: Compared to uncontrolled breathing, pain intensity was lower during slow, deep breathing (Cohen's d = 0.40) and normal controlled breathing (d = 0.47), but not different between slow, deep breathing and normal controlled breathing. Arousal was lower (d = 0.53, 0.55) and heart rate variability was higher (d = 0.70, 0.86) during slow, deep breathing compared to the two control conditions. The effect of slow, deep breathing on pain was not mediated by alterations in heart rate variability or arousal but was moderated by pain catastrophizing.CONCLUSIONS AND INFERENCES: Slow, deep breathing can reduce visceral pain intensity. However, the effect is not specific to the slow breathing frequency and is not mediated by autonomic or emotional responses, suggesting other underlying mechanisms (notably distraction). Whether a long-term practice of slow, deep breathing can influence (clinical) visceral pain warrants to be investigated.

Background A substantial group of patients with inflammatory bowel disease (IBD) experience fatigue, even while in clinical remission. At present, disease-specific behaviours that maintain or worsen symptom burden including fatigue have not been explored. We developed a questionnaire evaluating IBD-specific avoidance behaviour and investigated how this relates to self-reported fatigue. Methods This study was a close collaboration between the psychology and gastroenterology department of our tertiary referral centre. A 72-item IBD-specific avoidance behaviour questionnaire (IBD-B) was generated based on literature review and input from clinicians and a patient focus group (n = 10). Between July 2018 and March 2019, 500 consecutive IBD patients were included at our infusion unit (wave 1) (participation rate 79%, 48% male, 66% Crohn’s disease (CD), median age 40). Patients completed the 72-item IBD-B, a demographic questionnaire, patient-reported outcome assessing disease activity (PRO2) and a Visual Analogue Scale (VAS) for fatigue. Test–retest reliability was assessed in 89 patients (54% male, 70% CD, median age of 40) who completed the IBD-B, PRO2 and VAS fatigue scale a second time after 4–12 weeks (wave 2). Clinical remission was defined as an abdominal pain score ≤1 and a liquid to very soft stool frequency ≤1.5 in CD patients and as no rectal bleeding and a stool frequency ≤1 in patients with ulcerative colitis (UC). A principal component analysis (PCA) was then used to reduce the number of items and investigate the underlying factor structure of the IBD-B. The predictive value of IBD-specific behaviours for fatigue was finally investigated both cross-sectionally and prospectively. Results At wave 1, 46% and 69% of CD and UC patients, respectively, were in clinical remission. PCA suggested a reduction of the 72-item to a final 25-item IBD-B and a seven-factor solution for use in clinical practice (loading factors >0.5, Table 1). The final 25-item IBD-B showed good psychometric properties. The median (IQR) total IBD-B and fatigue scores were, respectively, 29 (40-20) and 52 (77-25) for patients in clinical remission compared with 38 (48-28) and 74 (87-50) for patients not in clinical remission (both p < 0.01). Both cross-sectional and prospective significant correlations between IBD-B factors and fatigue were demonstrated (Table 2). Conclusion The IBD-B is a valuable tool to accurately measure IBD-specific avoidance behaviour in IBD patients. IBD patients without clinical remission report higher IBD-B values and show a higher correlation between avoidance behaviour and fatigue. Further research should now focus on identifying predictors for fatigue in IBD patients in clinical remission.

Activity interruptions, namely temporary suspensions of an ongoing task with the intention to resume it later, are common in pain. First, pain is a threat signal that urges us to interrupt ongoing activities in order to manage the pain and its cause. Second, activity interruptions are used in chronic pain management. However, activity interruptions by pain may carry costs for activity performance. These costs have recently started to be systematically investigated.We review the evidence on the consequences of activity interruptions by pain for the performance of the interrupted activity. Further, inspired by literature on interruptions from other research fields, we suggest ways to improve interruption management in the field of pain, and provide a future research agenda. ispartof: Pain Management vol:9 issue:1 pages:81-91 ispartof: location:England status: Published online

BackgroundAlthough pain-related avoidance is mainly intended to reduce the accompanying anticipatory fear, avoidance behavior may paradoxically increase fear when a previous avoidance response is no longer available, suggesting that there is a bidirectional relationship between pain-related fear and avoidance.PurposeWe hypothesized that avoidance can serve as a source of information that fuels irrational pain-related threat appraisals, which, in turn, increases pain-related fear.MethodsParticipants (N = 66) were exposed to a painful heat stimulus and randomly assigned to the avoidance or control group. They were instructed to avoid the full heat intensity by pressing a stop button in the presence of a stop cue. Only avoidance group participants received a stop cue and were allowed to press the stop button, while control group participants received the same instructions but never had the opportunity to avoid the full heat intensity. In reality and unknown to participants, the intensity and duration of the heat stimulus was independent of the avoidance response. In the subsequent test phase, the avoidance response was unavailable for both groups. We measured pain-related fear, threat appraisals/harmfulness, and pain intensity.ResultsIn line with our expectations, pain-related fear levels were higher when the avoidance response was no longer available compared to those when the avoidance response was available. Increased threat appraisals mediated the relationship between avoidance behavior and increased pain-related fear.ConclusionsThe perceived opportunity to avoid increased pain-related fear through threat appraisals, suggesting a more complicated relationship between pain-related fear, threat appraisals, and avoidance behavior than the unidirectional relationships proposed in the fear-avoidance model. Clinical implications are discussed.

Pain can be considered as a signal of "bodily error": errors put organisms at danger and activate behavioral defensive systems. If the error is of physical nature, pain is the warning signal that motivates protective action such as avoidance behavior to safeguard our body's integrity. Interestingly, an important component of neural error processing, the error-related negativity (ERN), has been found to be related to avoidance in anxiety disorders. The present study is the first to extend these findings to pain and investigate the relationship between ERN and pain-related avoidance behavior. It was hypothesized that individuals with larger ERN amplitudes would show more pain-related avoidance behavior and would be more persistent in their avoidance despite changes in the environment. Fifty-three healthy individuals performed the Eriksen flanker task during which their brain activity on correct and erroneous motor responses was recorded by means of high-density electroencephalography. Avoidance behavior was assessed with an arm reaching task using the HapticMaster robot arm. The results showed that, in contrast to our hypothesis, avoidance was not related to ERN amplitudes. Surprisingly, persons with elevated ERN amplitudes showed low levels of avoidance specifically during early acquisition trials. In contrast to earlier findings in anxiety disorders, individuals with elevated ERN amplitudes did not engage in more pain-related avoidance behavior. In fact, the opposite pattern was found at the start of acquisition: individuals with higher compared with lower ERN amplitudes were slower in learning to avoid pain. Replications and future studies on the relationship between ERN and avoidance behavior are needed. ispartof: Pain vol:163 issue:2 pages:E190-E201 ispartof: location:United States status: Published online

Tinnitus is the perception of a phantom sound and the patient's reaction to it. Although much progress has been made, tinnitus remains a scientific and clinical enigma of high prevalence and high economic burden, with an estimated prevalence of 10%-20% among the adult population. The EU is funding a new collaborative project entitled "Unification of Treatments and Interventions for Tinnitus Patients" (UNITI, grant no. 848261) under its Horizon 2020 framework. The main goal of the UNITI project is to set the ground for a predictive computational model based on existing and longitudinal data attempting to address the question of which treatment or combination of treatments is optimal for a specific patient group based on certain parameters. Clinical, epidemiological, genetic and audiological data, including signals reflecting ear-brain communication, as well as patients' medical history, will be analyzed making use of existing databases. Predictive factors for different patient groups will be extracted and their prognostic relevance validated through a Randomized Clinical Trial (RCT) in which different patient groups will undergo a combination of tinnitus therapies targeting both auditory and central nervous systems. From a scientific point of view, the UNITI project can be summarized into the following research goals: (1) Analysis of existing data: Results of existing clinical studies will be analyzed to identify subgroups of patients with specific treatment responses and to identify systematic differences between the patient groups at the participating clinical centers. (2) Genetic and blood biomarker analysis: High throughput Whole Exome Sequencing (WES) will be performed in well-characterized chronic tinnitus cases, together with Proximity Extension Assays (PEA) for the identification of blood biomarkers for tinnitus. (3) RCT: A total of 500 patients will be recruited at five clinical centers across Europe comparing single treatments against combinational treatments. The four main treatments are Cognitive Behavioral Therapy (CBT), hearing aids, sound stimulation, and structured counseling. The consortium will also make use of e/m-health applications for the treatment and assessment of tinnitus. (4) Decision Support System: An innovative Decision Support System will be implemented, integrating all available parameters (epidemiological, clinical, audiometry, genetics, socioeconomic and medical history) to suggest specific examinations and the optimal intervention strategy based on the collected data. (5) Financial estimation analysis: A cost-effectiveness analysis for the respective interventions will be calculated to investigate the economic effects of the interventions based on quality-adjusted life years. In this paper, we will present the UNITI project, the scientific questions that it aims to address, the research consortium, and the organizational structure.

ispartof: Pain vol:163 issue:4 pages:604-609 ispartof: location:United States status: published

With the objective of increasing the magnitude of treatment effects in behavioral health, there is steadily growing interest in tailoring assessments and interventions to better match individual needs. This aligns with the central idea that behavior can be adequately understood by considering the unique characteristics of the individual and context. Thus, data collected at an individual level provides critical evidence that can be used to inform health care decisions, improve treatment, or refine theories. Yet, the majority of research in behavioral health is based on group-level analyses. Recent developments in the field of single-case experimental design (SCED) has provided new opportunities to utilize individual data. The present article provides a state-of-the art overview regarding key aspects of SCED, including a historical background to why and how SCED emerged, declined, and recently reemerged as well as methodological aspects such as design issues, challenges related to reliability and validity of repeated observations, innovations in visual and statistical analyses of individual data, strategies to deal with missing values, methodology to examine effect size, and approaches to summarize data from a large number of SCEDs using multilevel models and meta-analyses of replication data. Finally, the article discusses key concerns and actions needed to move the field forward.

Compared to the field of anxiety research, the use of fear conditioning paradigms for studying chronic pain is relatively novel. Developments in identifying the neural correlates of pain-related fear are important for understanding the mechanisms underlying chronic pain and warrant synthesis to establish the state-of-the-art. Using effect-size signed differential mapping, this meta-analysis combined nine MRI studies and compared the overlap in these correlates of pain-related fear to those of other non-pain-related conditioned fears (55 studies). Pain-related fear was characterized by neural activation of the supramarginal gyrus, middle temporal gyrus, inferior/middle frontal gyri, frontal operculum and insula, pre-/post-central gyri, medial frontal and (para-)cingulate cortex, hippocampus, thalamus, and putamen. There were differences with other non-pain-related conditioned fears, specifically in the inferior frontal gyrus, medial superior frontal gyrus, post-central gyrus, middle temporal gyrus, parieto-occipital sulcus, and striatum. We conclude that pain-related and non-pain-related conditioned fears recruit overlapping but distinguishable networks, with potential implications for understanding the mechanisms underlying different psychopathologies. ispartof: Neuroscience And Biobehavioral Reviews vol:119 pages:52-65 ispartof: location:United States status: published

BackgroundMaladaptive defensive responses such as excessive avoidance behavior have received increasing attention as a main mechanism for the development and maintenance of chronic pain complaints. However, another defensive response which is commonly studied in animals as a proxy for fear is freezing behavior. No research to date has investigated human freezing behavior in the context of pain. In addition, there is an increasing realization that social context can affect pain-relevant processes such as pain experience and pain behavior but less is known about the effects of social context on defensive responses to pain. Hence, this study investigated freezing behavior and facial pain expression in the context of pain, and their modulation by social context.MethodsHealthy, pain-free participants (N = 39) stood on a stabilometric force platform in a threatening or safe social context, which was manipulated using angry or happy facial stimuli. In some trials, an auditory cue (conditioned stimulus; CS) predicted the occurrence of painful electrocutaneous stimulus (unconditioned stimulus; pain-US). We assessed body sway (an index of freezing), heart rate, facial pain expression, self-reported pain intensity, unpleasantness, and pain-US expectancy during the CS and the context alone (no CS).ResultsThe results were mixed. Neither the anticipation of pain, nor social context affected body sway. Heart rate and painful facial expression were reduced in the threatening social context at high anxiety levels. A threatening social context also elicited higher pain-US expectancy ratings. In sum, a threatening social context increases the expectation of pain, but reduces the facial expression of pain and lowers heart rate in highly anxious individuals.

Deep breathing exercises are commonly used for several health conditions including pain and hypertension. Various techniques are available to practice deep breathing, whereas possible differential psychophysiological effects have not been investigated. We compared four deep breathing techniques and examined outcomes in blood pressure variability, respiratory sinus arrhythmia, baroreflex function, and emotional state. Healthy adult volunteers performed pursed-lips breathing, left and right unilateral nostril breathing, and deep breathing with an inspiratory threshold load (loaded breathing), all at a frequency of 0.1 Hz (i.e., controlled breathing) and for three minutes each. Results showed that blood pressure variability was higher during loaded breathing versus other conditions and higher during pursed-lips breathing versus left and right unilateral nostril breathing. Respiratory sinus arrhythmia was higher during loaded breathing versus other conditions and higher during pursed-lips breathing versus left unilateral nostril breathing. The effect of breathing condition on respiratory sinus arrhythmia was mediated by alterations in blood pressure variability. There was no difference between the breathing conditions in baroreflex sensitivity or effectiveness. Participants rated pursed-lips breathing as more calming and pleasant and with more sense of control (vs. other conditions). Overall, among the four tested deep breathing techniques, loaded breathing was associated with enhanced cardiovascular effects and pursed-lips breathing with better emotional responses, while also enhancing cardiovascular effects (albeit less than loaded breathing). These findings can be informative in applying deep breathing techniques as self-management interventions for health conditions, in which baroreceptors stimulation and autonomic and emotional modulations can be beneficial, such as pain and hypertension.

The International Classification of Diseases-11 (ICD-11) chronic pain classification includes about 100 chronic pain diagnoses on different diagnostic levels. Each of these diagnoses requires specific operationalized diagnostic criteria to be present. The classification comprises more than 200 diagnostic criteria. The aim of the Classification Algorithm for Chronic Pain in ICD-11 (CAL-CP) is to facilitate the use of the classification by guiding users through these diagnostic criteria. The diagnostic criteria were ordered hierarchically and visualized in accordance with the standards defined by the Society for Medical Decision Making Committee on Standardization of Clinical Algorithms. The resulting linear decision tree underwent several rounds of iterative checks and feedback by its developers, as well as other pain experts. A preliminary pilot evaluation was conducted in the context of an ecological implementation field study of the classification itself. The resulting algorithm consists of a linear decision tree, an introduction form, and an appendix. The initial decision trunk can be used as a standalone algorithm in primary care. Each diagnostic criterion is represented in a decision box. The user needs to decide for each criterion whether it is present or not, and then follow the respective yes or no arrows to arrive at the corresponding ICD-11 diagnosis. The results of the pilot evaluation showed good clinical utility of the algorithm. The CAL-CP can contribute to reliable diagnoses by structuring a way through the classification and by increasing adherence to the criteria. Future studies need to evaluate its utility further and analyze its impact on the accuracy of the assigned diagnoses. ispartof: Pain vol:162 issue:7 pages:2087-2096 ispartof: location:United States status: published

Avoidance behavior is a key contributor to the transition from acute pain to chronic pain disability. Yet, there has been a lack of ecologically valid paradigms to experimentally investigate pain-related avoidance. To fill this gap, we developed a paradigm (the robotic arm-reaching paradigm) to investigate the mechanisms underlying the development of pain-related avoidance behavior. Existing avoidance paradigms (mostly in the context of anxiety research) have often operationalized avoidance as an experimenter-instructed, low-cost response, superimposed on stimuli associated with threat during a Pavlovian fear conditioning procedure. In contrast, the current method offers increased ecological validity in terms of instrumental learning (acquisition) of avoidance, and by adding a cost to the avoidance response. In the paradigm, participants perform arm-reaching movements from a starting point to a target using a robotic arm, and freely choose between three different movement trajectories to do so. The movement trajectories differ in probability of being paired with a painful electrocutaneous stimulus, and in required effort in terms of deviation and resistance. Specifically, the painful stimulus can be (partly) avoided at the cost of performing movements requiring increased effort. Avoidance behavior is operationalized as the maximal deviation from the shortest trajectory on each trial. In addition to explaining how the new paradigm can help understand the acquisition of avoidance, we describe adaptations of the robotic arm-reaching paradigm for (1) examining the spread of avoidance to other stimuli (generalization), (2) modeling clinical treatment in the lab (extinction of avoidance using response prevention), as well as (3) modeling relapse, and return of avoidance following extinction (spontaneous recovery). Given the increased ecological validity, and numerous possibilities for extensions and/or adaptations, the robotic arm-reaching paradigm offers a promising tool to facilitate the investigation of avoidance behavior and to further our understanding of its underlying processes.

Background Frozen shoulder is a painful glenohumeral joint condition. Pain-related beliefs are recognized drivers of function in musculoskeletal conditions. This cross-sectional study investigates associations between pain-related beliefs and arm function in frozen shoulder. Methods Pain intensity, arm function (Disabilities of the Arm, Shoulder and Hand Questionnaire (DASH)), pain catastrophizing (Pain Catastrophizing Scale (PCS)), pain-related fear (Tampa Scale for Kinesiophobia (TSK-11)) and pain self-efficacy (Pain Self-Efficacy Questionnaire (PSEQ)) were administered in 85 persons with frozen shoulder. Correlation analyses assessed associations between pain-related beliefs and arm function. Regression analysis calculated the explained variance in arm function by pain-related beliefs. Results Pain-related fear, pain catastrophizing and pain self-efficacy were significantly associated with arm function (r = 0.51; r = 0.45 and r = −0.69, all p 2 = 0.57). Conclusions Attention should be paid towards the negative effect of pain-related fear on outcomes in frozen shoulder and towards building one’s pain self-efficacy given its protective value in pain management.

The aim of the study reported in this paper is to investigate the effect of slow-deep breathing (SDB) on self-reported pain, heart rate variability, and baroreflex sensitivity (BRS). These effects are examined in 3 separate experiments, each using a different phasic pain modality. For each experiment, different subjects were recruited. Eighty-three healthy female participants were instructed to breathe guided by a visual cue at a slow frequency (SDB: .1 Hz), and at a frequency close to the spontaneous breathing frequency (normal paced breathing, .2 Hz). Pain was induced during instructed breathing using electrocutaneous (experiment 1, n .31), thermal (experiment 2, n . 28), or mechanical stimuli (experiment 3, n = 24). Participants were requested to rate the intensity of each painful stimulus (Numerical Rating Scale) and subjective level of pleasantness, arousal, and dominance (self-assessment manikin). During the experiment, R-R interval, blood pressure, tidal volume, and end-tidal CO2 were continuously measured. Results for self-reported pain, self-assessment manikin, and physiological measurements were consistent across the 3 experiments. Although SDB significantly increased baroreflex sensitivity and heart rate variability, self-reported pain did not differ between breathing conditions, regardless of pain modality. Other potential mechanisms or components should be considered such as behavioral modulators including relaxation and treatment expectation.Perspective: Merely slowing down the breathing frequency to .1 Hz is not sufficient to induce hypoalgesia, despite the significant physiological effects associated with SDB compared to spontaneous breathing. (C) 2020 U.S. Association for the Study of Pain. Published by Elsevier Inc. All rights reserved.

Pain-related fear is typically associated with avoidance behavior and pain-related disability in youth with chronic pain. Youth with elevated pain-related fear have attenuated treatment responses, thus targeted treatment is highly warranted. Evidence supporting graded in-vivo exposure treatment (GET) for adults with chronic pain is considerable, but just emerging for youth. The current investigation represents the first sequential replicated and randomized single-case experimental phase design with multiple measures evaluating GET for youth with chronic pain, entitled GET Living. A cohort 27 youth (81% female) with mixed chronic pain completed GET Living. For each participant, a no-treatment randomized baseline period was compared with GET Living and 3- and 6-month follow-ups. Daily changes in primary outcomes fear and avoidance and secondary outcomes pain catastrophizing, pain intensity, and pain acceptance were assessed using electronic diaries and subjected to descriptive and model-based inference analyses (MLM). Based on individual effect size calculations, a third of participants significantly improved by the end of treatment on fear, avoidance, and pain acceptance. By follow-up over 80% of participants had improved across all primary and secondary outcomes. MLM results to examine the series of replicated cases were generally consistent. Improvements during GET Living was superior to the no-treatment randomized baseline period for avoidance, pain acceptance, and pain intensity, whereas fear and pain catastrophizing did not improve. All five outcomes emerged as significantly improved at 3-and 6-month follow-up. The results of this replicated SCED support the effectiveness of graded exposure for youth with chronic pain and elevated pain-related fear avoidance. ispartof: Pain vol:161 issue:3 pages:520-531 ispartof: location:United States status: published

Exposure in vivo has been found successful in reducing pain-related fear, disability, and experienced pain in chronic pain patients. Despite the success of exposure treatment, experimental studies show that extinction learning is fragile, raising doubts whether extinction of pain-related fear generalizes to new threatening activities after treatment. This study examined whether a particular exposure treatment, in which patients are exposed to a variety of activities (Multiple Exposure condition), promotes generalization of extinction to new threatening situations, compared to an exposure treatment in which subjects are repeatedly exposed to the same set of activities (Repeated Exposure condition). Generalization tests were combined with randomized replicated single case experimental designs (N=8). Included were patients with Complex Regional Pain Syndrome type I reporting elevated levels of pain-related fear. The Multiple Exposure treatment condition consisted of at least 15 activities to which patients were exposed once. The Repeated Exposure treatment condition exposed patients to only three activities during five sessions each. Generalization was tested by exposing patients to new fearful activities post-treatment and 6-months follow-up. Patients from both conditions performed equally well at both generalization tests. Daily measures showed that the Multiple Exposure condition is preferred to reduce fear of movement/(re)injury, pain catastrophizing and pain experience. ispartof: Behaviour Research And Therapy vol:124 ispartof: location:England status: published