Social Determinants and Consequences of Pain: Toward Multilevel, Intersectional, and Life Course Perspectives.

Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain remain rarely addressed in the context of pain prevention and management. In this review, we aim to 1) examine the broad scope of social determinants and consequences of pain and their interactions across multiple levels of organization, and 2) provide a framework synthesizing existing concepts and potential areas for future work on social aspects of pain, drawing upon socioecological, intersectional, and life course approaches. Integrating interdisciplinary theory and evidence, we outline pathways through which multilevel social factors and pain may affect each other over time. We also provide a brief summary of intrapersonal aspects of pain, which are thought to operate at the interface between individuals and the social context. Progressing from micro- to macrolevel factors, we illustrate how social determinants of pain can directly or indirectly contribute to pain experiences, expression, risk, prognosis, and impact across populations. We consider 1) at the interpersonal level, the roles of social comparison, social relatedness, social support, social exclusion, empathy, and interpersonal conflict; 2) at the group or community level, the roles of intimacy groups, task groups, social categories, and loose associations; and 3) at the societal level, the roles of political, economic, and cultural systems, as well as their policies and practices. We present examples of multilevel consequences of pain across these levels and discuss opportunities to reduce the burden and inequities of pain by expanding multilevel social approaches in pain research and practice. PERSPECTIVE: Despite wide endorsement of a biopsychosocial framework for pain, social aspects of pain are often unclearly defined, hindering their use in pain prevention, management, and research. We summarize the scope of social aspects of pain and provide a framework synthesizing existing concepts and potential areas for future work.

Variation is the Norm: Brain State Dynamics Evoked By Emotional Video Clips.

For the last several decades, emotion research has attempted to identify a "biomarker" or consistent pattern of brain activity to characterize a single category of emotion (e.g., fear) that will remain consistent across all instances of that category, regardless of individual and context. In this study, we investigated variation rather than consistency during emotional experiences while people watched video clips chosen to evoke instances of specific emotion categories. Specifically, we developed a sequential probabilistic approach to model the temporal dynamics in a participant's brain activity during video viewing. We characterized brain states during these clips as distinct state occupancy periods between state transitions in blood oxygen level dependent (BOLD) signal patterns. We found substantial variation in the state occupancy probability distributions across individuals watching the same video, supporting the hypothesis that when it comes to the brain correlates of emotional experience, variation may indeed be the norm.

Expressive suppression to pain in others reduces negative emotion but not vicarious pain in the observer.

Although there are situations where it may be appropriate to reduce one's emotional response to the pain of others, the impact of an observer's emotional expressivity on their response to pain in others is still not well understood. In the present study, we examined how the emotion regulation strategy expressive suppression influences responses to pain in others. Based on prior research findings on expressive suppression and pain empathy, we hypothesized that expressive suppression to pain expression faces would reduce neural representations of negative emotion, vicarious pain, or both. To test this, we applied two multivariate pattern analysis (MVPA)-derived neural signatures to our data, the Picture Induced Negative Emotion Signature (PINES; Chang, Gianaros, Manuck, Krishnan, and Wager (2015)) and a neural signature of facial expression induced vicarious pain (Zhou et al., 2020). In a sample of 60 healthy individuals, we found that viewing pain expression faces increased neural representations of negative emotion and vicarious pain. However, expressive suppression to pain faces reduced neural representations of negative emotion only. Providing support for a connection between neural representations of negative emotion and pain empathy, PINES responses to pain faces were associated with participants' trait-level empathy and the perceived unpleasantness of pain faces. Findings suggest that a consequence of suppressing one's facial expressions in response to the pain of others may be a reduction in the affective aspect of empathy but not the experience of vicarious pain itself.

Modeling neural and self-reported factors of affective distress in the relationship between pain and working memory in healthy individuals.

The relationship between pain and cognition has primarily been investigated in patients with chronic pain and healthy participants undergoing experimental pain. Recently, there has been interest in understanding the disruptive effects of non-experimental pain in otherwise healthy individuals. Recent studies suggest that healthy individuals reporting pain also demonstrate decrements in working memory (WM) performance, however factors contributing to this relationship remain poorly understood. The present study examined the association between pain and WM in a large community-based sample of healthy individuals and investigated whether self-reported affective distress and medial frontal cortex activity might help to explain this relationship. To address these research questions, a large publicly available dataset from the Human Connectome Project (N = 416) was sourced and structural equation modeling was utilized to examine relationships between pain intensity experienced over the past 7 days, self-reported affective distress, performance on a WM (n-back) task, and task-related activation in the medial frontal cortex. Examining participants who reported non-zero pain intensity in the past 7 days (n = 228), we found a direct negative association between pain intensity and performance on the WM n-back task, consistent with prior findings. Self-reported affective distress was not associated with WM performance. Additionally, pain intensity was indirectly associated with WM performance via WM task-related activity in the ventromedial prefrontal cortex (vmPFC). Our findings suggest that pain experienced in everyday life by otherwise healthy individuals may directly impact WM performance. Furthermore, WM task-related increases in vmPFC activity may be a factor contributing to this relationship.

Multiple Brain Networks Mediating Stimulus-Pain Relationships in Humans.

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.

Generalizable representations of pain, cognitive control, and negative emotion in medial frontal cortex.

The medial frontal cortex, including anterior midcingulate cortex, has been linked to multiple psychological domains, including cognitive control, pain, and emotion. However, it is unclear whether this region encodes representations of these domains that are generalizable across studies and subdomains. Additionally, if there are generalizable representations, do they reflect a single underlying process shared across domains or multiple domain-specific processes? We decomposed multivariate patterns of functional MRI activity from 270 participants across 18 studies into study-specific, subdomain-specific, and domain-specific components and identified latent multivariate representations that generalized across subdomains but were specific to each domain. Pain representations were localized to anterior midcingulate cortex, negative emotion representations to ventromedial prefrontal cortex, and cognitive control representations to portions of the dorsal midcingulate. These findings provide evidence for medial frontal cortex representations that generalize across studies and subdomains but are specific to distinct psychological domains rather than reducible to a single underlying process.

Group-regularized individual prediction: theory and application to pain.

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.

Controlling automatic imitative tendencies: interactions between mirror neuron and cognitive control systems.

Humans have an automatic tendency to imitate others. Although several regions commonly observed in social tasks have been shown to be involved in imitation control, there is little work exploring how these regions interact with one another. We used fMRI and dynamic causal modeling to identify imitation-specific control mechanisms and examine functional interactions between regions. Participants performed a pre-specified action (lifting their index or middle finger) in response to videos depicting the same two actions (biological cues) or dots moving with similar trajectories (non-biological cues). On congruent trials, the stimulus and response were similar (e.g. index finger response to index finger or left side dot stimulus), while on incongruent trials the stimulus and response were dissimilar (e.g. index finger response to middle finger or right side dot stimulus). Reaction times were slower on incongruent compared to congruent trials for both biological and non-biological stimuli, replicating previous findings that suggest the automatic imitative or spatially compatible (congruent) response must be controlled on incongruent trials. Neural correlates of the congruency effects were different depending on the cue type. The medial prefrontal cortex, anterior cingulate, inferior frontal gyrus pars opercularis (IFGpo) and the left anterior insula were involved specifically in controlling imitation. In addition, the IFGpo was also more active for biological compared to non-biological stimuli, suggesting that the region represents the frontal node of the human mirror neuron system (MNS). Effective connectivity analysis exploring the interactions between these regions, suggests a role for the mPFC and ACC in imitative conflict detection and the anterior insula in conflict resolution processes, which may occur through interactions with the frontal node of the MNS. We suggest an extension of the previous models of imitation control involving interactions between imitation-specific and general cognitive control mechanisms.