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Pain is strongly modulated by expectations and beliefs. Across species, subregions of ventromedial prefrontal cortex (VMPFC) are implicated in a variety of functions germane to pain, predictions, and learning. Human fMRI studies show that VMPFC activity tracks expectations about pain and mediates expectancy effects on pain-related activity in other brain regions. Prior lesion studies suggest that VMPFC may instead play a more general role in generating affective responses to painful stimuli. To test whether VMPFC is required to generate affective responses to pain or is more specifically involved in expectancy-based pain modulation, we studied responses to heat stimuli in five adults with bilateral surgical lesions of VMPFC and twenty healthy adults without brain damage. All participants underwent a quantitative sensory testing procedure followed by a pain expectancy task in which cues predicting either low or high pain were followed by intermittent medium intensity heat stimuli. Compared to adults without brain damage, individuals with VMPFC lesions reported larger differences in expected pain based on predictive cues and failed to update expectations following the covert introduction of unexpected medium temperature stimuli. Consistent with observed expectancy differences, subjective pain unpleasantness ratings in the VMPFC lesion group were more strongly modulated by cue during thermal stimulation. We found no group differences in overall pain sensitivity, nor in relationships between pain and autonomic arousal, suggesting that VMPFC damage specifically enhances the effect of expectations on pain processing, likely driven by impaired integration of new sensory feedback to update expectations about pain. These results provide essential new data regarding the specific functional contribution of VMPFC to pain modulation., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Published by Elsevier Ltd.)

Treatment outcomes are strongly influenced by expectations, as evidenced by the placebo effect. Meta-analyses of clinical trials reveal that placebo effects are strongest in pain, indicating that psychosocial factors directly influence pain. In this review, I focus on the neural and psychological mechanisms by which instructions, learning, and expectations shape subjective pain. I address new experimental designs that help researchers tease apart the impact of these distinct processes and evaluate the evidence regarding the neural mechanisms by which these cognitive factors shape subjective pain. Studies reveal that expectations modulate pain through parallel circuits that include both pain-specific and domain-general circuits such as those involved in affect and learning. I then review how expectations, learning, and verbal instructions impact clinical outcomes, including placebo analgesia and responses to pharmacological treatments, and discuss implications for future work.

Inequities in pain assessment are well-documented; however, the psychological mechanisms underlying such biases are poorly understood. We investigated potential perceptual biases in the judgments of faces displaying pain-related movements. Across five online studies, 956 adult participants viewed images of computer-generated faces ("targets") that varied in features related to race (Black and White) and gender (women and men). Target identity was manipulated across participants, and each target had equivalent facial movements that displayed varying intensities of movement in facial action-units related to pain (Studies 1-4) or pain and emotion (Study 5). On each trial, participants provided categorical judgments as to whether a target was in pain (Studies 1-4) or which expression the target displayed (Study 5) and then rated the perceived intensity of the expression. Meta-analyses of Studies 1-4 revealed that movement intensity was positively associated with both categorizing a trial as painful and perceived pain intensity. Target race and gender did not consistently affect pain-related judgments, contrary to well-documented clinical inequities. In Study 5, in which pain was equally likely relative to other emotions, pain was the least frequently selected emotion (5%). Our results suggest that perceivers can utilize facial movements to evaluate pain in other individuals, but perceiving pain may depend on contextual factors. Furthermore, assessments of computer-generated, pain-related facial movements online do not replicate sociocultural biases observed in the clinic. These findings provide a foundation for future studies comparing CGI and real images of pain and emphasize the need for further work on the relationship between pain and emotion., Supplementary Information: The online version contains supplementary material available at 10.1007/s42761-023-00181-6., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023.)

Background: The COVID-19 pandemic and its associated restrictions have been a major stressor that has exacerbated mental health worldwide. Qualitative data play a unique role in documenting mental states through both language features and content. Text analysis methods can provide insights into the associations between language use and mental health and reveal relevant themes that emerge organically in open-ended responses., Objective: The aim of this web-based longitudinal study on mental health during the early COVID-19 pandemic was to use text analysis methods to analyze free responses to the question, "Is there anything else you would like to tell us that might be important that we did not ask about?" Our goals were to determine whether individuals who responded to the item differed from nonresponders, to determine whether there were associations between language use and psychological status, and to characterize the content of responses and how responses changed over time., Methods: A total of 3655 individuals enrolled in the study were asked to complete self-reported measures of mental health and COVID-19 pandemic-related questions every 2 weeks for 6 months. Of these 3655 participants, 2497 (68.32%) provided at least 1 free response (9741 total responses). We used various text analysis methods to measure the links between language use and mental health and to characterize response themes over the first year of the pandemic., Results: Response likelihood was influenced by demographic factors and health status: those who were male, Asian, Black, or Hispanic were less likely to respond, and the odds of responding increased with age and education as well as with a history of physical health conditions. Although mental health treatment history did not influence the overall likelihood of responding, it was associated with more negative sentiment, negative word use, and higher use of first-person singular pronouns. Responses were dynamically influenced by psychological status such that distress and loneliness were positively associated with an individual's likelihood to respond at a given time point and were associated with more negativity. Finally, the responses were negative in valence overall and exhibited fluctuations linked with external events. The responses covered a variety of topics, with the most common being mental health and emotion, social or physical distancing, and policy and government., Conclusions: Our results identify trends in language use during the first year of the pandemic and suggest that both the content of responses and overall sentiments are linked to mental health., (©Rachel Weger, Juan Antonio Lossio-Ventura, Margaret Rose-McCandlish, Jacob S Shaw, Stephen Sinclair, Francisco Pereira, Joyce Y Chung, Lauren Yvette Atlas. Originally published in JMIR Mental Health (https://mental.jmir.org), 01.03.2023.)

Recent data suggest that interactions between systems involved in higher order knowledge and associative learning drive responses during value-based learning. However, it is unknown how these systems impact subjective responses, such as pain. We tested how instructions and reversal learning influence pain and pain-evoked brain activation. Healthy volunteers (n=40) were either instructed about contingencies between cues and aversive outcomes or learned through experience in a paradigm where contingencies reversed three times. We measured predictive cue effects on pain and heat-evoked brain responses using functional magnetic resonance imaging. Predictive cues dynamically modulated pain perception as contingencies changed, regardless of whether participants received contingency instructions. Heat-evoked responses in the insula, anterior cingulate, and other regions updated as contingencies changed, and responses in the prefrontal cortex mediated dynamic cue effects on pain, whereas responses in the brainstem's rostroventral medulla (RVM) were shaped by initial contingencies throughout the task. Quantitative modeling revealed that expected value was shaped purely by instructions in the Instructed Group, whereas expected value updated dynamically in the Uninstructed Group as a function of error-based learning. These differences were accompanied by dissociations in the neural correlates of value-based learning in the rostral anterior cingulate, thalamus, and posterior insula, among other regions. These results show how predictions dynamically impact subjective pain. Moreover, imaging data delineate three types of networks involved in pain generation and value-based learning: those that respond to initial contingencies, those that update dynamically during feedback-driven learning as contingencies change, and those that are sensitive to instruction. Together, these findings provide multiple points of entry for therapies designs to impact pain., Competing Interests: LA, TD, EP, QY, RR, LB, SG, DP No competing interests declared

Quantitative sensory testing (QST) allows researchers to evaluate associations between noxious stimuli and acute pain in clinical populations and healthy participants. Despite its widespread use, our understanding of QST's reliability is limited, as reliability studies have used small samples and restricted time windows. We examined the reliability of pain ratings in response to noxious thermal stimulation in 171 healthy volunteers (n = 99 female, n = 72 male) who completed QST on multiple visits ranging from 1 day to 952 days between visits. On each visit, participants underwent an adaptive pain calibration in which they experienced 24 heat trials and rated pain intensity after stimulus offset on a 0 to 10 Visual Analog Scale. We used linear regression to determine pain threshold, pain tolerance, and the correlation between temperature and pain for each session and examined the reliability of these measures. Threshold and tolerance were moderately reliable (Intra-class correlation = .66 and .67, respectively; P < .001), whereas temperature-pain correlations had low reliability (Intra-class correlation = .23). In addition, pain tolerance was significantly more reliable in female participants than male participants, and we observed similar trends for other pain sensitive measures. Our findings indicate that threshold and tolerance are largely consistent across visits, whereas sensitivity to changes in temperature vary over time and may be influenced by contextual factors. PERSPECTIVE: This article assesses the reliability of an adaptive thermal pain calibration procedure. We find that pain threshold and tolerance are moderately reliable whereas the correlation between pain rating and stimulus temperature has low reliability. Female participants were more reliable than male participants on all pain sensitivity measures., (Copyright © 2022. Published by Elsevier Inc.)

Characterizing cerebral contributions to individual variability in pain processing is crucial for personalized pain medicine, but has yet to be done. In the present study, we address this problem by identifying brain regions with high versus low interindividual variability in their relationship with pain. We trained idiographic pain-predictive models with 13 single-trial functional MRI datasets (n = 404, discovery set) and quantified voxel-level importance for individualized pain prediction. With 21 regions identified as important pain predictors, we examined the interindividual variability of local pain-predictive weights in these regions. Higher-order transmodal regions, such as ventromedial and ventrolateral prefrontal cortices, showed larger individual variability, whereas unimodal regions, such as somatomotor cortices, showed more stable pain representations across individuals. We replicated this result in an independent dataset (n = 124). Overall, our study identifies cerebral sources of individual differences in pain processing, providing potential targets for personalized assessment and treatment of pain., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Information is coded in the brain at multiple anatomical scales: locally, distributed across regions and networks, and globally. For pain, the scale of representation has not been formally tested, and quantitative comparisons of pain representations across regions and networks are lacking. In this multistudy analysis of 376 participants across 11 studies, we compared multivariate predictive models to investigate the spatial scale and location of evoked heat pain intensity representation. We compared models based on (a) a single most pain-predictive region or resting-state network; (b) pain-associated cortical-subcortical systems developed from prior literature ("multisystem models"); and (c) a model spanning the full brain. We estimated model accuracy using leave-one-study-out cross-validation (CV; 7 studies) and subsequently validated in 4 independent holdout studies. All spatial scales conveyed information about pain intensity, but distributed, multisystem models predicted pain 20% more accurately than any individual region or network and were more generalizable to multimodal pain (thermal, visceral, and mechanical) and specific to pain. Full brain models showed no predictive advantage over multisystem models. These findings show that multiple cortical and subcortical systems are needed to decode pain intensity, especially heat pain, and that representation of pain experience may not be circumscribed by any elementary region or canonical network. Finally, the learner generalization methods we employ provide a blueprint for evaluating the spatial scale of information in other domains., Competing Interests: The authors have declared that no competing interests exist.

The process of learning allows organisms to develop predictions about outcomes in the environment, and learning is sensitive to both simple associations and higher order knowledge. However, it is unknown whether consciously attending to expectations shapes the learning process itself. Here, we directly tested whether rating expectations shapes arousal during classical conditioning. Participants performed an aversive learning paradigm wherein one image (CS+) was paired with shock on 50% of trials, while a second image (CS-) was never paired with shock. Halfway through the task, contingencies reversed. One group of participants rated the probability of upcoming shock on each trial, while the other group made no online ratings. We measured skin conductance response (SCR) evoked in response to the CS and used traditional analyses as well as quantitative models of reinforcement learning to test whether rating expectations influenced arousal and aversive reversal learning. Participants who provided online expectancy ratings displayed slower learning based on a hybrid model of adaptive learning and reduced reversal of SCR relative to those who did not rate expectations. Mediation analysis revealed that the effect of associative learning on SCR could be fully explained through its effects on subjective expectancy within the group who provided ratings. This suggests that the act of rating expectations reduces the speed of learning, likely through changes in attention, and that expectations directly influence arousal. Our findings indicate that higher order expectancy judgments can alter associative learning., (© 2021 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Identifying biomarkers that predict mental states with large effect sizes and high test-retest reliability is a growing priority for fMRI research. We examined a well-established multivariate brain measure that tracks pain induced by nociceptive input, the Neurologic Pain Signature (NPS). In N = 295 participants across eight studies, NPS responses showed a very large effect size in predicting within-person single-trial pain reports (d = 1.45) and medium effect size in predicting individual differences in pain reports (d = 0.49). The NPS showed excellent short-term (within-day) test-retest reliability (ICC = 0.84, with average 69.5 trials/person). Reliability scaled with the number of trials within-person, with ≥60 trials required for excellent test-retest reliability. Reliability was tested in two additional studies across 5-day (N = 29, ICC = 0.74, 30 trials/person) and 1-month (N = 40, ICC = 0.46, 5 trials/person) test-retest intervals. The combination of strong within-person correlations and only modest between-person correlations between the NPS and pain reports indicate that the two measures have different sources of between-person variance. The NPS is not a surrogate for individual differences in pain reports but can serve as a reliable measure of pain-related physiology and mechanistic target for interventions., (Copyright © 2021. Published by Elsevier Inc.)

Excessive expression of fear responses in anticipation of threat occurs in anxiety, but understanding of underlying pathophysiological mechanisms is limited. Animal research indicates that threat-anticipatory defensive responses are dynamically organized by threat imminence and rely on conserved circuitry. Insight from basic neuroscience research in animals on threat imminence could guide mechanistic research in humans mapping abnormal function in this circuitry to aberrant defensive responses in pathological anxiety. 50 pediatric anxiety patients and healthy-comparisons (33 females) completed an instructed threat-anticipation task whereby cues signaled delivery of painful (threat) or non-painful (safety) thermal stimulation. Temporal changes in skin-conductance indexed anxiety effects on anticipatory responding as function of threat imminence. Multivariate network analyses of resting-state functional connectivity data from a subsample were used to identify intrinsic-function correlates of anticipatory-response dynamics, within a specific, distributed network derived from translational research on defensive responding. By considering threat imminence, analyses revealed specific anxiety effects. Importantly, pathological anxiety was associated with excessive deployment of anticipatory physiological response as threat, but not safety, outcomes became more imminent. Magnitude of increase in threat-anticipatory physiological responses corresponded with magnitude of intrinsic connectivity within a cortical-subcortical circuit. Moreover, more severe anxiety was associated with stronger associations between anticipatory physiological responding and connectivity that ventromedial prefrontal cortex showed with hippocampus and basolateral amygdala, regions implicated in animal models of anxiety. These findings link basic and clinical research, highlighting variations in intrinsic function in conserved defensive circuitry as a potential pathophysiological mechanism in anxiety., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)

Pain is a fundamental experience that promotes survival. In humans, pain stands at the intersection of multiple health crises: chronic pain, the opioid epidemic, and health disparities. The study of placebo analgesia highlights how social, cognitive, and affective processes can directly shape pain, and identifies potential paths for mitigating these crises. This review examines recent progress in the study of placebo analgesia through affective science. It focuses on how placebo effects are shaped by expectations, affect, and the social context surrounding treatment, and discusses neurobiological mechanisms of placebo, highlighting unanswered questions and implications for health. Collaborations between clinicians and social and affective scientists can address outstanding questions and leverage placebo to reduce pain and improve human health., Competing Interests: Declaration of interests The author declares no conflict of interest., (Published by Elsevier Ltd.)

Objective: Dispositional mindfulness is associated with reduced pain in clinical and experimental settings. However, researchers have neglected the type of pain assessment, as dispositional mindfulness may have unique benefits for reduced pain sensitivity when relying on summary pain assessments, in contrast to assessing the pain of each noxious stimulus. Here, we test the association between dispositional mindfulness and pain using both trial-by-trial pain assessments and overall summary ratings after acute pain tasks., Methods: One hundred thirty-one healthy adult volunteers (mean age = 29.09 [8.00] years, 55.7% female) underwent two experimental thermal pain paradigms. We tested whether dispositional mindfulness measured with the Mindful Attention Awareness Scale was related to a) heat-evoked pain sensitivity, as measured by pain threshold, pain tolerance, average pain, trial-by-trial ratings, and heat-evoked skin conductance response, and b) summary judgments of sensory and affective pain assessed using the McGill Pain Questionnaire (MPQ)., Results: Mindful Attention Awareness Scale ratings were associated with decreased pain on the MPQ sensory (B = -0.18, SE = 0.05, 95% confidence interval = -0.29 to -0.07, t = -3.28, p = .001) and affective (B = -0.11, SE = 0.03, 95% confidence interval = -0.18 to -0.05, t = -3.32, p = .001) dimensions but not with experimental thermal pain assessments, including threshold, tolerance, heat-evoked pain, or skin conductance response (p values ≥ .29)., Conclusions: In this study, dispositional mindfulness mitigated acute thermal pain only when pain was assessed using the MPQ. These findings may reflect differences in immediate versus retrospective judgments or the type of pain assessed by each measure. Future research should examine regulation processes that may explain these differential analgesic benefits, such as attention, rumination, or reappraisal., (Copyright © 2021 by the American Psychosomatic Society.)

Rationale: There is a robust link between patients' expectations and clinical outcomes, as evidenced by the placebo effect. Expectations depend in large part on the context surrounding treatment, including the patient-provider interaction. Prior work indicates that providers' behavior and characteristics, including warmth and competence, can shape patient outcomes. Yet humans rapidly form trait impressions of others before any in-person interaction. It is unknown whether these first impressions influence subsequent health care choices and expectations., Objective: Our goal was to test whether trait impressions of hypothetical medical providers, based exclusively on facial images, influence the choice of medical providers and expectations about pain and analgesia following hypothetical painful medical procedures., Method: Across five online experiments, participants (total N = 1108) viewed and made judgments about hypothetical healthcare providers. Experiments 1-4 included computer-generated faces that varied in features associated with competence, while experiment 5 included real faces. We measured how apparent competence affected expectations about pain and anticipated analgesic use in all studies. We also measured warmth and similarity., Results: Across five online studies, participants selected providers who appeared more competent, based on facial visual information alone. Further, providers' apparent competence predicted participants' expectations about post-procedural pain and medication use. Participants' perception of their similarity to providers also shaped expectations about pain and treatment outcomes., Conclusions: Results from our experimental simulations suggest that humans develop expectations about pain and health outcomes before even setting foot in the clinic, based exclusively on first impressions. These findings have strong implications for health care, as individuals increasingly rely on digital services to select healthcare providers and even receive treatment, a trend that is exacerbated as the world embraces telemedicine., (Published by Elsevier Ltd.)

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth., Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure., Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05)., Limitations: Limitations included the modest sample size and the cross-sectional design., Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry., Competing Interests: No competing interests declared., (© 2021 Joule Inc. or its licensors.)

Introduction: Clinical and laboratory studies demonstrate that placebo and nocebo effects influence various symptoms and conditions after the administration of both inert and active treatments., Objective: There is an increasing need for up-to-date recommendations on how to inform patients about placebo and nocebo effects in clinical practice and train clinicians how to disclose this information., Methods: Based on previous clinical recommendations concerning placebo and nocebo effects, a 3-step, invitation-only Delphi study was conducted among an interdisciplinary group of internationally recognized experts. The study consisted of open- and closed-ended survey questions followed by a final expert meeting. The surveys were subdivided into 3 parts: (1) informing patients about placebo effects, (2) informing patients about nocebo effects, and (3) training clinicians how to communicate this information to the patients., Results: There was consensus that communicating general information about placebo and nocebo effects to patients (e.g., explaining their role in treatment) could be beneficial, but that such information needs to be adjusted to match the specific clinical context (e.g., condition and treatment). Experts also agreed that training clinicians to communicate about placebo and nocebo effects should be a regular and integrated part of medical education that makes use of multiple formats, including face-to-face and online modalities., Conclusions: The current 3-step Delphi study provides consensus-based recommendations and practical considerations for disclosures about placebo and nocebo effects in clinical practice. Future research is needed on how to optimally tailor information to specific clinical conditions and patients' needs, and on developing standardized disclosure training modules for clinicians., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Self-report is the gold standard for measuring pain. However, decisions about pain can vary substantially within and between individuals. We measured whether self-reported pain is accompanied by metacognition and variations in confidence, similar to perceptual decision-making in other modalities. Eighty healthy volunteers underwent acute thermal pain and provided pain ratings followed by confidence judgments on continuous visual analogue scales. We investigated whether eye fixations and reaction time during pain rating might serve as implicit markers of confidence. Confidence varied across trials and increased confidence was associated with faster pain rating reaction times. The association between confidence and fixations varied across individuals as a function of the reliability of individuals' association between temperature and pain. Taken together, this work indicates that individuals can provide metacognitive judgments of pain and extends research on confidence in perceptual decision-making to pain.

The brain transforms nociceptive input into a complex pain experience comprised of sensory, affective, motivational, and cognitive components. However, it is still unclear how pain arises from nociceptive input and which brain networks coordinate to generate pain experiences. We introduce a new high-dimensional mediation analysis technique to estimate distributed, network-level patterns that formally mediate the relationship between stimulus intensity and pain. We applied the model to a large-scale analysis of functional magnetic resonance imaging data (N = 284), focusing on brain mediators of the relationship between noxious stimulus intensity and trial-to-trial variation in pain reports. We identify mediators in both traditional nociceptive pathways and in prefrontal, midbrain, striatal, and default-mode regions unrelated to nociception in standard analyses. The whole-brain mediators are specific for pain versus aversive sounds and are organized into five functional networks. Brain mediators predicted pain ratings better than previous brain measures, including the neurologic pain signature (Wager et al. 2013). Our results provide a broader view of the networks underlying pain experience, as well as novel brain targets for interventions., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent studies indicate that a significant reorganization of cerebral networks may occur in patients with chronic pain, but how immediate pain experience influences the organization of large-scale functional networks is not yet well characterized. To investigate this question, we used functional magnetic resonance imaging in 106 participants experiencing both noxious and innocuous heat. Painful stimulation caused network-level reorganization of cerebral connectivity that differed substantially from organization during innocuous stimulation and standard resting-state networks. Noxious stimuli increased somatosensory network connectivity with (a) frontoparietal networks involved in context representation, (b) "ventral attention network" regions involved in motivated action selection, and (c) basal ganglia and brainstem regions. This resulted in reduced "small-worldness," modularity (fewer networks), and global network efficiency and in the emergence of an integrated "pain supersystem" (PS) whose activity predicted individual differences in pain sensitivity across 5 participant cohorts. Network hubs were reorganized ("hub disruption") so that more hubs were localized in PS, and there was a shift from "connector" hubs linking disparate networks to "provincial" hubs connecting regions within PS. Our findings suggest that pain reorganizes the network structure of large-scale brain systems. These changes may prioritize responses to painful events and provide nociceptive systems privileged access to central control of cognition and action during pain., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Understanding how people rate their confidence is critical for the characterization of a wide range of perceptual, memory, motor and cognitive processes. To enable the continued exploration of these processes, we created a large database of confidence studies spanning a broad set of paradigms, participant populations and fields of study. The data from each study are structured in a common, easy-to-use format that can be easily imported and analysed using multiple software packages. Each dataset is accompanied by an explanation regarding the nature of the collected data. At the time of publication, the Confidence Database (which is available at https://osf.io/s46pr/) contained 145 datasets with data from more than 8,700 participants and almost 4 million trials. The database will remain open for new submissions indefinitely and is expected to continue to grow. Here we show the usefulness of this large collection of datasets in four different analyses that provide precise estimations of several foundational confidence-related effects.

Pain is a subjective, multidimensional experience that is distinct from nociception. A large body of work has focused on whether pain processing is supported by specific, dedicated brain circuits. Despite advances in human neuroscience and neuroimaging analysis, dissociating acute pain from other sensations has been challenging since both pain and non-pain stimuli evoke salience and arousal responses throughout the body and in overlapping brain circuits. In this review, we discuss these challenges and propose that brain-body interactions in pain can be leveraged in order to improve tests for pain specificity. We review brain and bodily responses to pain and nociception and extant efforts toward identifying pain-specific brain networks. We propose that autonomic nervous system activity should be used as a surrogate measure of salience and arousal to improve these efforts and enable researchers to parse out pain-specific responses in the brain, and demonstrate the feasibility of this approach using example fMRI data from a thermal pain paradigm. This new approach will improve the accuracy and specificity of functional neuroimaging analyses and help to overcome current difficulties in assessing pain specific responses in the human brain., (Published by Elsevier Inc.)

Since early work attempting to characterize the brain's role in pain, it has been clear that pain is not generated by a specific brain region, but rather by coordinated activity across a network of brain regions, the "neuromatrix." The advent of noninvasive whole-brain neuroimaging, including functional magnetic resonance imaging, has provided insight on coordinated activity in the pain neuromatrix and how correlations in activity between regions, referred to as "functional connectivity," contribute to pain and its modulation. Initial functional connectivity investigations assumed interregion connectivity remained stable over time, and measured variability across individuals. However, new dynamic functional connectivity (dFC) methods allow researchers to measure how connectivity changes over time within individuals, permitting insights on the dynamic reorganization of the pain neuromatrix in humans. We review how dFC methods have been applied to pain, and insights afforded on how brain connectivity varies across time, either spontaneously or as a function of psychological states, cognitive demands, or the external environment. Specifically, we review psychophysiological interaction, dynamic causal modeling, state-based dynamic community structure, and sliding-window analyses and their use in human functional neuroimaging of acute pain, chronic pain, and pain modulation. We also discuss promising uses of dFC analyses for the investigation of chronic pain conditions and predicting pain treatment efficacy and the relationship between state- and trait-based pain measures. Throughout this review, we provide information regarding the advantages and shortcomings of each approach, and highlight potential future applications of these methodologies for better understanding the brain processes associated with pain., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful, although this difference emerged late, in the 4-second period after thermal stimulation. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.

We explored the ongoing question of whether placebo analgesia alters afferent nociceptive processing in a novel paradigm designed to minimize the role of response bias in placebo measurement. First, healthy adult participants received a standard heat placebo induction and conditioning procedure using a topical "analgesic" cream applied to one arm. During a subsequent placebo testing procedure, participants rated stimuli on the placebo-treated arm and untreated arm, using a task that minimized subjects' ability to guess the expected response, thus reducing experimenter demand. Retrospectively participants reported moderate analgesia effectiveness (mean=5.3/10), but for individual temperature ratings, only 2 subjects exhibited a perceptual placebo response >5 points. Next, these subjects completed a novel, exploratory task designed to measure changes in inter-arm in discriminative accuracy that would be expected from changes in afferent nociception. Both placebo responders (but no non-responders) showed reduced discriminative ability when the hotter stimulus occurred on the placebo arm, an effect consistent with alterations in nociceptive afferent flow and unlikely to be caused by response bias.

Chronic pain is a major problem in clinical medicine and public health, affecting approximately one in five adults, and is associated with significant societal and familial burden. Early-life adversities, psychological, and biobehavioral factors are associated with an elevated risk of the subsequent development of chronic pain. In this special issue of Psychosomatic Medicine, articles address the neuroscientific, psychological, and biobehavioral processes involved in acute and chronic pain. We focus on the following themes that emerged in this special issue: (a) risk factors and early adversity as related to chronic pain; (b) the role of expectations in shaping pain perception; and (c) mechanisms of interventions targeting pain modulation. This article concludes by outlining important new targets for research, including the neurobiology of pain, important methodological challenges, and targets for personalized pain interventions.

Objective: Naturalistic studies suggest that expectation of adverse experiences such as pain exerts particularly strong effects on anxious youth. In healthy adults, expectation influences the experience of pain. The current study uses experimental methods to compare the effects of expectation on pain among adults, healthy youth, and youth with an anxiety disorder., Methods: Twenty-three healthy adults, 20 healthy youth, and 20 youth with an anxiety disorder underwent procedures in which auditory cues were paired with noxious thermal stimulation. Through instructed conditioning, one cue predicted low-pain stimulation and the other predicted high-pain stimulation. At test, each cue was additionally followed by a single temperature calibrated to elicit medium pain ratings. We compared cue-based expectancy effects on pain across the three groups, based on cue effects on pain elicited on medium heat trials., Results: Across all groups, as expected, participants reported greater pain with increasing heat intensity (β = 2.29, t(41) = 29.94, p < .001). Across all groups, the critical medium temperature trials were rated as more painful in the high- relative to low-expectancy condition (β = 1.72, t(41) = 10.48, p < .001). However, no evidence of between-group differences or continuous associations with age or anxiety was observed., Conclusions: All participants showed strong effects of expectancy on pain. No influences of development or anxiety arose. Complex factors may influence associations among anxiety, development, and pain reports in naturalistic studies. Such factors may be identified using experiments that employ more complex, yet controlled manipulations of expectancy or assess neural correlates of expectancy.

Human pain neuroimaging has exploded in the past 2 decades. During this time, the broader neuroimaging community has continued to investigate and refine methods. Another key to progress is exchange with clinicians and pain scientists working with other model systems and approaches. These collaborative efforts require that non-imagers be able to evaluate and assess the evidence provided in these reports. Likewise, new trainees must design rigorous and reliable pain imaging experiments. In this article we provide a guideline for designing, reading, evaluating, analyzing, and reporting results of a pain neuroimaging experiment, with a focus on functional and structural magnetic resonance imaging. We focus in particular on considerations that are unique to neuroimaging studies of pain in humans, including study design and analysis, inferences that can be drawn from these studies, and the strengths and limitations of the approach., Perspective: This article provides an overview of the concepts and considerations of structural and functional magnetic resonance neuroimaging studies. The primer is written for those who are not familiar with brain imaging. We review key concepts related to recruitment and study sample, experimental design, data analysis and data interpretation., (Published by Elsevier Inc.)

Nociception reliably elicits an autonomic nervous system (ANS) response. Because pain and ANS circuitry interact on multiple spinal, subcortical, and cortical levels, it remains unclear whether autonomic responses are simply a reflexive product of noxious stimulation regardless of how stimulation is consciously perceived or whether the experience of pain mediates ANS responses to noxious stimulation. To test these alternative predictions, we examined the relative contribution of noxious stimulation and individual pain experience to ANS responses in healthy volunteers who underwent 1 or 2 pain assessment tasks. Participants received 8 seconds of thermal stimulation of varied temperatures and judged pain intensity on every trial. Skin conductance responses and pupil dilation responses to stimulation served as measures of the heat-evoked autonomic response. We used multilevel modelling to examine trial-by-trial relationships between heat, pain, and ANS response. Although both pain and noxious heat stimulation predicted skin conductance response and pupil dilation response in separate analyses, the individual pain experience statistically mediated effects of noxious heat on both outcomes. Furthermore, moderated mediation revealed that evidence for this process was stronger when stimulation was perceived as painful compared with when stimulation was perceived as nonpainful. These findings suggest that pain appraisal regulates the heat-evoked autonomic response to noxious stimulation, documenting the flexibility of the autonomic pain response to adjust to perceived or actual changes in environmental affordances above and beyond nociceptive input.

Fear-relevant stimuli such as snakes and spiders are thought to capture attention due to evolutionary significance. Classical conditioning experiments indicate that these stimuli accelerate learning, while instructed extinction experiments suggest they may be less responsive to instructions. We manipulated stimulus type during instructed aversive reversal learning and used quantitative modeling to simultaneously test both hypotheses. Skin conductance reversed immediately upon instruction in both groups. However, fear-relevant stimuli enhanced dynamic learning, as measured by higher learning rates in participants conditioned with images of snakes and spiders. Results are consistent with findings that dissociable neural pathways underlie feedback-driven and instructed aversive learning., (© 2018 Atlas and Phelps; Published by Cold Spring Harbor Laboratory Press.)

Background: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice., Methods: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated., Results: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects., Conclusions: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice., (© 2018 S. Karger AG, Basel.)

Placebo effects are beneficial clinical outcomes that emerge as a result of nonspecific contextual factors, transmitted primarily by the treating physician and the social, physical, and behavioral cues he or she displays. The patient-provider therapeutic alliance is critical for determining placebo effects and health outcomes. In this chapter, we review the recent literature, suggesting that provider social characteristics modulate placebo and clinical outcomes. We highlight the importance of studying not only the provider but also the patient's perception of the provider, which is subject to the influence of the patient's psychosocial orientation, such as their psychosocial motivations and perceptions of their interpersonal relationships broadly. We argue that psychosocial orientation can exaggerate the influence of the patient-provider relationship on placebo effects and can directly affect the likelihood of placebo effects emerging by modulating the underlying biological systems that support them. Here, we examine patient loneliness, or perceived social isolation, as a case example for understanding how patients' psychosocial orientation may affect placebo effects across diseases. We propose psychosocial mechanisms by which loneliness might modulate placebo effects across medical outcomes, and focus in particular on how loneliness might specifically alter behaviorally conditioned immune responses and placebo analgesia. Future studies should directly measure social factors to formally test the effects of social isolation on placebo effects and better elucidate the role of psychosocial and interpersonal factors in placebo effects and clinical outcomes., (© 2018 Elsevier Inc. All rights reserved.)

Cerebral processes contribute to pain beyond the level of nociceptive input and mediate psychological and behavioural influences. However, cerebral contributions beyond nociception are not yet well characterized, leading to a predominant focus on nociception when studying pain and developing interventions. Here we use functional magnetic resonance imaging combined with machine learning to develop a multivariate pattern signature-termed the stimulus intensity independent pain signature-1 (SIIPS1)-that predicts pain above and beyond nociceptive input in four training data sets (Studies 1-4, N=137). The SIIPS1 includes patterns of activity in nucleus accumbens, lateral prefrontal and parahippocampal cortices, and other regions. In cross-validated analyses of Studies 1-4 and in two independent test data sets (Studies 5-6, N=46), SIIPS1 responses explain variation in trial-by-trial pain ratings not captured by a previous fMRI-based marker for nociceptive pain. In addition, SIIPS1 responses mediate the pain-modulating effects of three psychological manipulations of expectations and perceived control. The SIIPS1 provides an extensible characterization of cerebral contributions to pain and specific brain targets for interventions.

Multivariate pattern analysis (MVPA) has become an important tool for identifying brain representations of psychological processes and clinical outcomes using fMRI and related methods. Such methods can be used to predict or 'decode' psychological states in individual subjects. Single-subject MVPA approaches, however, are limited by the amount and quality of individual-subject data. In spite of higher spatial resolution, predictive accuracy from single-subject data often does not exceed what can be accomplished using coarser, group-level maps, because single-subject patterns are trained on limited amounts of often-noisy data. Here, we present a method that combines population-level priors, in the form of biomarker patterns developed on prior samples, with single-subject MVPA maps to improve single-subject prediction. Theoretical results and simulations motivate a weighting based on the relative variances of biomarker-based prediction-based on population-level predictive maps from prior groups-and individual-subject, cross-validated prediction. Empirical results predicting pain using brain activity on a trial-by-trial basis (single-trial prediction) across 6 studies (N=180 participants) confirm the theoretical predictions. Regularization based on a population-level biomarker-in this case, the Neurologic Pain Signature (NPS)-improved single-subject prediction accuracy compared with idiographic maps based on the individuals' data alone. The regularization scheme that we propose, which we term group-regularized individual prediction (GRIP), can be applied broadly to within-person MVPA-based prediction. We also show how GRIP can be used to evaluate data quality and provide benchmarks for the appropriateness of population-level maps like the NPS for a given individual or study., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Socially-conveyed rules and instructions strongly shape expectations and emotions. Yet most neuroscientific studies of learning consider reinforcement history alone, irrespective of knowledge acquired through other means. We examined fear conditioning and reversal in humans to test whether instructed knowledge modulates the neural mechanisms of feedback-driven learning. One group was informed about contingencies and reversals. A second group learned only from reinforcement. We combined quantitative models with functional magnetic resonance imaging and found that instructions induced dissociations in the neural systems of aversive learning. Responses in striatum and orbitofrontal cortex updated with instructions and correlated with prefrontal responses to instructions. Amygdala responses were influenced by reinforcement similarly in both groups and did not update with instructions. Results extend work on instructed reward learning and reveal novel dissociations that have not been observed with punishments or rewards. Findings support theories of specialized threat-detection and may have implications for fear maintenance in anxiety.

Placebo effects are beneficial effects that are attributable to the brain-mind responses to the context in which a treatment is delivered rather than to the specific actions of the drug. They are mediated by diverse processes--including learning, expectations and social cognition--and can influence various clinical and physiological outcomes related to health. Emerging neuroscience evidence implicates multiple brain systems and neurochemical mediators, including opioids and dopamine. We present an empirical review of the brain systems that are involved in placebo effects, focusing on placebo analgesia, and a conceptual framework linking these findings to the mind-brain processes that mediate them. This framework suggests that the neuropsychological processes that mediate placebo effects may be crucial for a wide array of therapeutic approaches, including many drugs.

We present a new method, State-based Dynamic Community Structure, that detects time-dependent community structure in networks of brain regions. Most analyses of functional connectivity assume that network behavior is static in time, or differs between task conditions with known timing. Our goal is to determine whether brain network topology remains stationary over time, or if changes in network organization occur at unknown time points. Changes in network organization may be related to shifts in neurological state, such as those associated with learning, drug uptake or experimental conditions. Using a hidden Markov stochastic blockmodel, we define a time-dependent community structure. We apply this approach to data from a functional magnetic resonance imaging experiment examining how contextual factors influence drug-induced analgesia. Results reveal that networks involved in pain, working memory, and emotion show distinct profiles of time-varying connectivity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Recent human neuroimaging studies have investigated the neural correlates of either noxious stimulus intensity or reported pain. Although useful, analyzing brain relationships with stimulus intensity and behavior separately does not address how sensation and pain are linked in the central nervous system. In this study, we used multi-level mediation analysis to identify brain mediators of pain--regions in which trial-by-trial responses to heat explained variability in the relationship between noxious stimulus intensity (across 4 levels) and pain. This approach has the potential to identify multiple circuits with complementary roles in pain genesis. Brain mediators of noxious heat effects on pain included targets of ascending nociceptive pathways (anterior cingulate, insula, SII, and medial thalamus) and also prefrontal and subcortical regions not associated with nociceptive pathways per se. Cluster analysis revealed that mediators were grouped into several distinct functional networks, including the following: somatosensory, paralimbic, and striatal-cerebellar networks that increased with stimulus intensity; and 2 networks co-localized with "default mode" regions in which stimulus intensity-related decreases mediated increased pain. We also identified "thermosensory" regions that responded to increasing noxious heat but did not predict pain reports. Finally, several regions did not respond to noxious input, but their activity predicted pain; these included ventromedial prefrontal cortex, dorsolateral prefrontal cortex, cerebellar regions, and supplementary motor cortices. These regions likely underlie both nociceptive and non-nociceptive processes that contribute to pain, such as attention and decision-making processes. Overall, these results elucidate how multiple distinct brain systems jointly contribute to the central generation of pain., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objective: We examined the complex relationship between depression, anxiety, and seizure control and quality of life (QOL) outcomes after epilepsy surgery., Methods: Seven epilepsy centers enrolled 373 patients and completed a comprehensive diagnostic workup and psychiatric and follow-up QOL evaluation. Subjects were evaluated before surgery and then at 3, 6, 12, 24, 48, and 60 months after surgery. Standardized assessments included the Quality of Life in Epilepsy Inventory-89, Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). A mixed-model repeated-measures analysis was used to analyze associations of depression, anxiety, seizure outcome, and seizure history with overall QOL score and QOL subscores (cognitive distress, physical health, mental health, epilepsy-targeted) prospectively., Results: The groups with excellent and good seizure control showed a significant positive effect on the overall QOL compared to the groups with fair and poor seizure control. The BDI and BAI scores were both highly and negatively associated with overall QOL; increases in BDI and BAI scores were associated with decreased overall QOL score., Conclusions: Depression and anxiety are strongly and independently associated with worse QOL after epilepsy surgery. Interestingly, even partial seizure control, controlling for depression and anxiety levels, improved QOL. Management of mood and anxiety is a critical component to postsurgical care.

Rationale: Psychological processes such as expectancy, attention, and affect directly influence clinical outcomes. These factors are grouped together as "nonspecific" factors, or placebo effects, in the medical literature, and their individual contributions are rarely considered. The pain-reducing effects of analgesic treatments may reflect changes in these psychological factors, rather than pure drug effects on pain. Furthermore, drug effects may not be isolated by drug vs. placebo comparisons if drugs interact with relevant psychological processes., Objectives: We sought to determine whether the analgesic effects of opioid and placebo treatment are mediated by changes in attention, expectancy, or affect., Methods: We crossed intravenous administration of a potent opioid analgesic, remifentanil, with information about drug delivery (treatment expectancy or placebo) using a balanced placebo design. We measured drug and treatment expectancy effects on pain, attention, and responses to emotional images. We also examined interactions with cue-based expectations about noxious stimulation or stimulus expectancy., Results: Pain was additively influenced by treatment expectancy, stimulus expectancy, and drug concentration. Attention performance showed a small but significant interaction between drug and treatment expectancy. Finally, remifentanil enhanced responses to both positive and negative emotional images., Conclusions: The pain-relieving effects of opioid drugs are unlikely to be mediated by changes in threat or affective processing. Standard open-label opioid administration influences multiple clinically relevant cognitive and emotional processes. Psychological factors can combine with drug effects to influence multiple outcomes in distinct ways. The influence of specific psychological factors should be considered when developing and testing pharmacological treatments.