Saturday, November 10, 2018

The Neuroscience of Pain: Biobehavioral, Developmental, and Psychosocial Mechanisms Relevant to Intervention Targets

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.

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Unique Autonomic Responses to Pain in Yoga Practitioners

imageObjective Autonomic nervous system activity is associated with neurobehavioral aspects of pain. Yogis use breathing, relaxation, and mindfulness to tolerate pain, which could influence autonomic responses. To evaluate how the link between autonomic responses and pain is altered by other factors, we compared perceptual and autonomic responses to pain between yogis and controls. Methods Nineteen yogis and 15 controls rated warm and painfully hot stimuli (1-cm2 thermode on calf), with visual anticipatory cues indicating certainly painful, certainly nonpainful, or uncertainly either painful or nonpainful. Heart rate, skin conductance, respiration, and blood pressure were measured. Results At baseline, yogis breathed slower and deeper than did controls, with no differences in other autonomic measures. During the task, perceptual ratings did not differ between groups in either the certain or uncertain conditions. Nevertheless, yogis had higher phasic skin conductance responses in anticipation of and response to all stimuli, but particularly during painful heat in uncertain contexts (uncertain: 0.46 [0.34] μS; certain: 0.37 [0.28] μS; t(18) = 3.962, p = .001). Furthermore, controls showed a decrease in heart rate to warm (−2.51 [2.17] beats/min) versus painful stimuli (0.83 [1.63] beats/min; t(13) = 5.212, p < .001) and lower respiratory sinus arrhythmia during pain compared with warm trials, whereas yogis had similar reactions to painful and nonpainful stimuli. Conclusions Autonomic responses to pain differed in yogis and healthy volunteers, despite similar pain ratings. Thus, autonomic reactivity to pain may be altered by environmental and psychological factors throughout an individual's life.

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Reduced Fear-Conditioned Pain Modulation in Experienced Meditators: A Preliminary Study

imageObjective Mindfulness-based practice is a form of cognitive/affective training that may help reduce suffering by attenuating maladaptive anticipatory processes. This study's objective was to examine the pain modulating impact of classical fear learning in meditation practitioners. Methods The hyperalgesic effects of pain expectation and uncertainty were assessed outside formal meditation in 11 experienced meditators (>1000 hours) compared with meditation-naive controls during a Pavlovian classical fear-conditioning paradigm involving two visual stimuli (CS+/CS−), one of which (CS+) co-terminated with a noxious electrical stimulus (unconditioned stimulus) on 50% of trials. A Rescorla-Wagner/Pearce-Hall hybrid model was fitted onto the conditioned skin conductance responses using computational modeling to estimate two learning parameters: expected shock probability and associability (i.e., uncertainty). Results Using a scale ranging between 0 (no pain) and 100 (extremely painful), meditators reported less pain (M = 19.9, SE = 5.1 for meditators, M = 32.4, SE = 2.4 for controls) but had comparable spinal motor responses (nociceptive flexion reflex) to the unconditioned stimulus. Multilevel mediation analyses revealed that meditators also exhibited reduced hyperalgesic effects of fear learning on higher-order pain responses but comparable effects on the nociceptive flexion reflex. These results suggest that mindfulness affects higher-order perceptual processes to a greater extent than from descending inhibitory controls. Furthermore, meditators showed reduced hyperalgesic effects of fear conditioning with no significant group difference in conditioned learning as evidenced by discriminative anticipatory skin conductance responses and learning parameters derived from computational modeling. Conclusions These results highlight potential mechanisms underlying mindfulness-related hypoalgesia, relevant to clinical conditions in which repeated pain exposure might reinforce hyperalgesic processes through fear conditioning.

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Enhancement of Meditation Analgesia by Opioid Antagonist in Experienced Meditators

imageObjective Studies have consistently shown that long-term meditation practice is associated with reduced pain, but the neural mechanisms by which long-term meditation practice reduces pain remain unclear. This study tested endogenous opioid involvement in meditation analgesia associated with long-term meditation practice. Methods Electrical pain was induced with randomized, double-blind, cross-over administration of the opioid antagonist naloxone (0.15-mg/kg bolus dose, then 0.2-mg/kg per hour infusion dose) with 32 healthy, experienced meditation practitioners and a standardized open monitoring meditation. Results Under saline, pain ratings were significantly lower during meditation (pain intensity: 6.41 ± 1.32; pain unpleasantness: 3.98 ± 2.17) than at baseline (pain intensity: 6.86 ±1.04, t(31) = 2.476, p = .019, Cohen's d = 0.46; pain unpleasantness: 4.96 ±1.75, t(31) = 3.746, p = .001, Cohen's d = 0.68), confirming the presence of meditation analgesia. Comparing saline and naloxone revealed significantly lower pain intensity (t(31) = 3.12, p = .004, d = 0.56), and pain unpleasantness (t(31) = 3.47, p = .002, d = 0.62), during meditation under naloxone (pain intensity: 5.53 ± 1.54; pain unpleasantness: 2.95 ± 1.88) than under saline (pain intensity: 6.41 ± 1.32; pain unpleasantness: 3.98 ± 2.17). Naloxone not only failed to eliminate meditation analgesia but also made meditation analgesia stronger. Conclusions Long-term meditation practice does not rely on endogenous opioids to reduce pain. Naloxone's blockade of opioid receptors enhanced meditation analgesia; pain ratings during meditation were significantly lower under naloxone than under saline. Possible biological mechanisms by which naloxone-induced opioid receptor blockade enhances meditation analgesia are discussed.

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Transforming Pain With Prosocial Meaning: A Functional Magnetic Resonance Imaging Study

imageObjective Contextual factors can transform how we experience pain, particularly if pain is associated with other positive outcomes. Here, we test a novel meaning-based intervention. Participants were given the opportunity to choose to receive pain on behalf of their romantic partners, situating pain experience in a positive, prosocial meaning context. We predicted that the ventromedial prefrontal cortex (vmPFC), a key structure for pain regulation and generation of affective meaning, would mediate the transformation of pain experience by this prosocial interpersonal context. Methods We studied fMRI activity and behavioral responses in 29 heterosexual female participants during (1) a baseline pain challenge and (2) a task in which participants decided to accept a self-selected number of additional pain trials to reduce pain in their male romantic partners (“accept-partner-pain” condition). Results Enduring extra pain for the benefit of the romantic partner reduced pain-related unpleasantness (t = −2.54, p = .016) but not intensity, and increased positive thoughts (t = 3.60, p = .001) and pleasant feelings (t = 5.39, p < .0005). Greater willingness to accept the pain of one's partner predicted greater unpleasantness reductions (t = 3.94, p = .001) and increases in positive thoughts (r = .457, p = .013). The vmPFC showed significant increases (q < .05 FDR-corrected) in activation during accept-partner-pain, especially for women with greater willingness to relieve their partner's pain (t = 2.63, p = .014). Reductions in brain regions processing pain and aversive emotion significantly mediated reductions in pain unpleasantness (q < .05 FDR-corrected). Conclusions The vmPFC has a key role in transforming the meaning of pain, which is associated with a cascade of positive psychological and brain effects, including changes in affective meaning, value, and pain-specific neural circuits.

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From Anticipation to the Experience of Pain: The Importance of Visceral Versus Somatic Pain Modality in Neural and Behavioral Responses to Pain-Predictive Cues

imageObjective The aim of this study was to compare behavioral and neural anticipatory responses to cues predicting either somatic or visceral pain in an associative learning paradigm. Methods Healthy women (N = 22) underwent functional magnetic resonance imaging. During an acquisition phase, two different visual cues repeatedly signalled either experimental visceral or somatic pain. In a subsequent extinction phase, identical cues were presented without pain. Before and after each phase, cue valence and contingency awareness were assessed on visual analog scales. Results Visceral compared to somatic pain–predictive cues were rated as more unpleasant after acquisition (visceral, 32.18 ± 13.03 mm; somatic, −18.36 ± 10.36 mm; p = .021) with similarly accurate cue-pain contingencies. After extinction, cue valence returned to baseline for both modalities (visceral, 1.55 ± 9.81 mm; somatic, −18.45 ± 7.12; p = .41). During acquisition, analyses of cue-induced neural responses revealed joint neural activation engaging areas associated with attention processing and cognitive control. Enhanced deactivation of posterior insula to visceral cues was observed, which correlated with enhanced responses within the salience network (anterior cingulate cortex, anterior insula) during visceral compared to somatic pain stimulation. During extinction, both pain modalities induced anticipatory neural activation in the extinction and salience network (all pFWE values < .05). Conclusions Conditioned emotional responses to pain-predictive cues are modality specific and enhanced for the visceral modality, suggesting that pain anticipation is shaped by the salience of painful stimuli. Common but also modality-specific neural mechanisms are involved during cue-pain learning, whereas extinction of cued responses seems unaffected by modality. Future research should examine potential implications for the pathophysiology of chronic pain conditions, especially chronic visceral pain.

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The Influence of Pain-Related Expectations on Intensity Perception of Nonpainful Somatosensory Stimuli

imageObjective The extent to which pain-related expectations, known to affect pain perception, also affect perception of nonpainful sensations remains unclear, as well as the potential role of unpredictability in this context. Methods In a proprioceptive fear conditioning paradigm, various arm extension movements were associated with predictable and unpredictable electrocutaneous pain or its absence. During a subsequent test phase, nonpainful electrocutaneous stimuli with a high or low intensity were presented during movement execution. We used hierarchical drift diffusion modeling to examine the influence of expecting pain on the perceptual decision-making process underlying intensity perception of nonpainful sensations. In the first experiment (n = 36), the pain stimulus was never presented during the test phase after conditioning. In the second experiment (n = 39), partial reinforcement was adopted to prevent extinction of pain expectations. Results In both experiments, movements that were associated with (un)predictable pain led to higher pain expectancy, self-reported fear, unpleasantness, and arousal as compared with movements that were never paired with pain (effect sizes η2p ranging from 0.119 to 0.557; all p values < .05). Only in the second experiment—when the threat of pain remained present—we found that the expectation of pain affected decision making. Compared with the no pain condition, an a priori decision-making bias toward the high-intensity decision threshold was found with the strongest bias during unpredictable pain (effect sizes η2p ranging from 0.469 to 0.504; all p-values < .001). Conclusions Thus, the expectation of pain affects inferential processes not only for subsequent painful but also for nonpainful bodily stimuli, with unpredictability moderating these effects, and only when the threat of pain remains present due to partial reinforcement.

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