Placebo Effects in the Neuroendocrine System: Conditioning of the Oxytocin Responses

Objective There is evidence that placebo effects may influence hormone secretion. However, few studies have examined placebo effects in the endocrine system, including oxytocin placebo effects. We studied whether it is possible to trigger oxytocin placebo effects using a classical conditioning paradigm. Methods Ninety-nine women were assigned to a conditioned, control, or drug control group. In the two-phase conditioning paradigm, participants in the conditioned and drug control groups received an oxytocin nasal spray combined with a distinctive smell (conditioned stimulus [CS]) for three acquisition days, whereas the control group received placebo spray. Subsequently, the conditioned and control groups received placebo spray with the CS and the drug control group received oxytocin spray for three evocation days. Salivary oxytocin was measured several times during each day. Pain sensitivity and facial evaluation tests previously used in oxytocin research were also administered. Results On evocation day 1, in the conditioned group, oxytocin significantly increased from baseline to 5 minutes after CS (B[slope] = 19.55, SE = 5.88, p < .001) and remained increased from 5 to 20 (B = −10.42, SE = 5.81, p = .071) and 50 minutes (B = −0.70, SE = 3.37, p = .84). On evocation day 2, a trend for increase in oxytocin was found at 5 minutes (B = 15.22, SE = 8.14, p = .062). No placebo effect was found on evocation day 3 (B = 3.57, SE = 3.26, p = .28). Neither exogenous nor conditioned oxytocin affected pain or facial tasks. Conclusions Results indicate that oxytocin release can be conditioned and that this response extinguishes over time. Triggering hormonal release by placebo manipulation offers various clinical possibilities, such as enhancing effects of pharmacological treatments or reducing dosages of medications. Trial Registration: The study was registered as a clinical trial on www.trialregister.nl (number NTR5596).

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Mindfulness Training and Physical Health: Mechanisms and Outcomes

Objective There has been substantial research and public interest in mindfulness interventions, biological pathways, and health for the past two decades. This article reviews recent developments in understanding relationships between mindfulness interventions and physical health. Methods A selective review was conducted with the goal of synthesizing conceptual and empirical relationships between mindfulness interventions and physical health outcomes. Results Initial randomized controlled trials in this area suggest that mindfulness interventions can improve pain management outcomes among chronic pain populations, and there is preliminary evidence for mindfulness interventions improving specific stress-related disease outcomes in some patient populations (i.e., clinical colds, psoriasis, irritable bowel syndrome, posttraumatic stress disorder, diabetes, HIV). We offer a stress-buffering framework for the observed beneficial effects of mindfulness interventions and summarize supporting biobehavioral and neuroimaging studies that provide plausible mechanistic pathways linking mindfulness interventions with positive physical health outcomes. Conclusions We conclude with new opportunities for research and clinical implementations to consider in the next two decades.

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Major Depressive Disorder in Medical Illness: A Review of Assessment, Prevalence, and Treatment Options

Major depression, as well as other depressive disorders, is commonly comorbid with other medical illnesses, particularly chronic and systemic medical illnesses. The co-occurrence of the disorders is so common that it challenges our notions of the meaning of comorbidity and our desire to neatly separate psychiatric and medical illnesses. The overlap between symptoms of physical illness and the neurovegetative symptoms of major depression and the initial normative emotional response to physical illness add to the challenge of accurate diagnosis and timely treatment of depression in the medically ill. We review the literature on the comorbidity of depression and the various medical illnesses, including diagnostic and treatment approaches. The differential diagnosis for major depression among medically ill patients should include delirium and medication-induced symptoms. We suggest that major depression itself may be best conceptualized as a systemic illness whose pathophysiology overlaps with other systemic medical illnesses. The initial treatment strategies for major depression in medical illness are like those for the general population; however, the comorbid medical illnesses may interfere with remission. To illustrate these points, we describe a patient with clinical characteristics covered in this review who experienced major depression as well as several chronic illnesses, including hypersensitivity pneumonitis, multiple sclerosis, chronic pain due to degenerative joint disease, and diabetes mellitus.

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Brain Functional Connectivity in Patients With Somatic Symptom Disorder

Objective The aim of the study was to evaluate whether individuals with somatic symptom disorder (SSD) display increased resting-state functional connectivity (FC) within and between the sensorimotor network (SMN), default mode network (DMN), salience network, and dorsal attention network (DAN). Methods Eighteen patients with SSD and 20 age- and sex-matched healthy control participants underwent resting-state functional magnetic resonance imaging. We used a seed-based correlation approach for the four brain networks. Results Patients with SSD had higher scores on the Somato-Sensory Amplification Scale (z = 5.22, p < .001) and Symptom Checklist-90-Revised-Somatization (z = 4.94, p < .001) and greater FC within the SMN, DMN, and salience network than healthy control participants. Patients with SSD also had increased FC between the SMN and DMN, SMN and salience network, SMN and DAN, and salience network and DAN (t = 5.10–7.47, all false discovery rate q < .05). The Somato-Sensory Amplification Scale scores correlated with FC between the SMN and salience network and between the SMN and DAN (r = .61–.82, all p < .003). Conclusions Based on the results of the FC analysis between the SMN and salience network, we suggest that SSD may be associated with alterations of sensory-discriminative processing of pain and other somatic symptoms, which is influenced by affective processing. Based on the results of the FC analysis of the SMN and DAN, we suggest that patients with SSD have a deficit in attention, leading to misperception of external stimuli and failure to regulate bodily functions aimed at interactions with external stimuli.

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Psychological Therapy for Centralized Pain: An Integrative Assessment and Treatment Model

Objective Chronic pain is a significant health problem that is increasing in prevalence, and advances in treatment are needed. Methods We briefly review the leading evidence-based psychological therapies for chronic pain—cognitive-behavioral and acceptance/mindfulness-based therapies—and examine several limitations and missing perspectives of these approaches. We review six lesser-known interventions that address these limitations, and we describe our integrative model for psychological assessment and treatment of centralized pain. We present a typical patient and describe how we apply this approach, along with challenges to its implementation and possible solutions to these challenges. Results Greater pain treatment efficacy may be possible if clinicians: (a) distinguish patients with primarily centralized (i.e., somatoform or nociplastic) pain from those with primarily peripheral (nociceptive, inflammatory, or neuropathic) pain; (b) acknowledge the capacity of the brain not only to modulate pain but also generate as well as attenuate or eliminate centralized pain; (c) consider the powerful role that adverse life experiences and psychological conflicts play in centralized pain; and (d) integrate emotional processing and interpersonal changes into treatment. Our integrative treatment involves delivering a progression of interventions, as needed, to achieve pain reduction: tailored pain neuroscience education, cognitive and mindfulness skills to decrease the pain danger alarm mechanism, behavioral engagement in avoided painful and other feared activities, emotional awareness and expression to reverse emotional avoidance and overcome trauma or psychological conflict, and adaptive communication to decrease interpersonal stress. Conclusions This integrative assessment and treatment model has the potential to substantially reduce and sometimes eliminate centralized pain by changing the cognitive, behavioral, emotional, and interpersonal processes that trigger and maintain centralized pain.

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Altered Brain Structure and Functional Connectivity and Its Relation to Pain Perception in Girls With Irritable Bowel Syndrome

Objective Imaging studies in adults with irritable bowel syndrome (IBS) have shown both morphological and resting state (RS) functional connectivity (FC) alterations related to cortical modulation of sensory processing. Because analogous differences have not been adequately investigated in children, this study compared gray matter volume (GMV) and RS-FC between girls with IBS and healthy controls (HC) and tested the correlation between brain metrics and laboratory-based pain thresholds (Pth). Methods Girls with Rome III criteria IBS (n = 32) and matched HCs (n = 26) were recruited. In a subset of patients, Pth were determined using a thermode to the forearm. Structural and RS scans were acquired. A voxel-based general linear model, adjusting for age, was applied to compare differences between groups. Seeds were selected from regions with group GMV differences for a seed-to-voxel whole brain RS-FC analysis. Significance for analyses was considered at p < .05 after controlling for false discovery rate. Significant group differences were correlated with Pth. Results Girls with IBS had lower GMV in the thalamus, caudate nucleus, nucleus accumbens, anterior midcingulate (aMCC), and dorsolateral prefrontal cortex. They also exhibited lower RS-FC between the aMCC and the precuneus, but greater connectivity between the caudate nucleus and precentral gyrus. Girls with IBS had higher Pth with a moderate effect size (t(22.81) = 1.63, p = .12, d = 0.64) and lower thalamic GMV bilaterally was correlated with higher Pth (left: r = −.62, p(FDR) = .008; right: r = −.51, p(FDR) = .08). Conclusions Girls with IBS had lower GMV in the PFC, basal ganglia, and aMCC, as well as altered FC between multiple brain networks, suggesting that structural changes related to IBS occur early in brain development. Girls with IBS also showed altered relationships between pain sensitivity and brain structure.

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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

Objective 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

Objective 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

Objective 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

Objective 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

Objective 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

Objective 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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Brain–Heart Pathways to Blood Pressure-Related Hypoalgesia

Objective High blood pressure (BP) is associated with reduced pain sensitivity, known as BP-related hypoalgesia. The underlying neural mechanisms remain uncertain, yet arterial baroreceptor signaling, occurring at cardiac systole, is implicated. We examined normotensives using functional neuroimaging and pain stimulation during distinct phases of the cardiac cycle to test the hypothesized neural mediation of baroreceptor-induced attenuation of pain. Methods Eighteen participants (10 women; 32.7 (6.5) years) underwent BP monitoring for 1 week at home, and individual pain thresholds were determined in the laboratory. Subsequently, participants were administered unpredictable painful and nonpainful electrocutaneous shocks (stimulus type), timed to occur either at systole or at diastole (cardiac phase) in an event-related design. After each trial, participants evaluated their subjective experience. Results Subjective pain was lower for painful stimuli administered at systole compared with diastole, F(1, 2283) = 4.82, p = 0.03. Individuals with higher baseline BP demonstrated overall lower pain perception, F(1, 2164) = 10.47, p < .0001. Within the brain, painful stimulation activated somatosensory areas, prefrontal cortex, cingulate cortex, posterior insula, amygdala, and the thalamus. Stimuli delivered during systole (concurrent with baroreceptor discharge) activated areas associated with heightened parasympathetic drive. No stimulus type by cardiac phase interaction emerged except for a small cluster located in the right parietal cortex. Conclusions We confirm the negative associations between BP and pain, highlighting the antinociceptive impact of baroreceptor discharge. Neural substrates associated with baroreceptor/BP-related hypoalgesia include superior parietal lobule, precentral, and lingual gyrus, regions typically involved in the cognitive aspects of pain experience.

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Anticipatory Effects on Perceived Pain: Associations With Development and Anxiety

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.

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Emotional Modulation of Pain and Spinal Nociception in Sexual Assault Survivors

Objective Sexual assault (SA) is associated with an increased risk for chronic pain and affective distress. Given that emotional processes modulate pain (e.g., negative emotions enhance pain, positive emotions inhibit pain), increased pain risk in SA survivors could stem from a disruption of emotional modulation processes. Methods A well-validated affective picture-viewing paradigm was used to study emotional modulation of pain in 33 healthy, pain-free SA survivors and a control group of 33 healthy, pain-free individuals with no reported history of SA (matched on age, sex, race, and number of non-SA traumas). Unpleasant (mutilation), neutral, and pleasant (erotic) pictures were presented, while painful electrocutaneous stimulations were delivered at the ankle. Pain intensity ratings and nociceptive flexion reflex (NFR) magnitudes (a physiologic measure of spinal nociception) were recorded in response to electric stimuli. Multilevel models were used to analyze the data with group (SA versus non-SA) and content (mutilation, neutral, erotic) as independent variables. Results Both groups demonstrated similar emotional modulation of pain (FGroupbyContent(2,646.52) = 0.44, p = .65), but a main effect of group (FGroup(1,65.42) = 4.24, p = .043) indicated the SA group experienced more overall pain from electric stimuli (hyperalgesia). A significant group by content interaction for NFR (p = .035) indicated that emotional modulation of NFR was present for the non-SA group (FContentSimpleEffect(2,684.55) = 12.43, p < .001), but not the SA group (FContentSimpleEffect(2,683.38) = 1.71, p = .18). Conclusions These findings suggest that SA survivors have difficulty emotionally engaging brain-to-spinal cord mechanisms to modulate spinal nociception. A disruption of descending inhibition plus hyperalgesia could contribute to comorbidity between sexual trauma and chronic pain.

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Childhood Adversity and Pain Facilitation

Objective This study investigated whether childhood adversity would be associated with hypersensitivity on two measures of central pain facilitation: area of secondary allodynia and temporal summation of second pain (TSSP), and whether pain facilitation would be explained by adult posttraumatic stress disorder (PTSD) symptoms. Method Participants endorsing high (n = 31) and low (n = 31) childhood adversity underwent capsaicin-induced secondary allodynia and TSSP testing. The tests were conducted a week apart with test order counterbalanced. Results Larger areas of secondary allodynia were observed in the high adversity group compared with the low adversity group (F(1,60) = 4.81, p = .032). This group difference was largely (62%) explained by greater PTSD symptoms in the high adversity group. Although no overall difference was found in TSSP slopes (p = .886), this was attributed to an order by group interaction (F(1,58) = 5.07, p = .028) and low power. Subsequent analyses revealed positive TSSP slopes in the high adversity group when TSSP testing was performed first, and this order effect was associated with blunted sympathetic responses to TSSP on the first visit. The two facilitation measures were unrelated (p = .631). Conclusions Larger areas of secondary allodynia were observed in the high adversity group, which was explained largely by PTSD symptoms. This suggests that adversity-related changes in pain facilitation may underlie the association between childhood adversity and generalized widespread pain. Although TSSP was affected by previous testing, adversity-related pain facilitation was observed when TSSP testing occurred first. Finally, adversity was not associated with a consistent pattern of hypersensitivity across the two measures of central pain facilitation.

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Biased Competition Favoring Physical Over Emotional Pain: A Possible Explanation for the Link Between Early Adversity and Chronic Pain

Background Early adversity predisposes to chronic pain, but a mechanistic explanation is lacking. Survivors of early adversity with chronic pain often seem impaired in their ability to be aware of, understand, and express distressing emotions such as anger and fear in social contexts. In this context, it has been proposed that pain may at times serve as a “psychic regulator” by preventing awareness of more intolerable emotions. Method This narrative review builds on the premise that physical pain and emotional pain are conscious experiences that can compete for selective attention. We highlight mechanisms whereby the consequences of early adversity may put emotional pain at a competitive disadvantage. A case history, supportive research findings, and an evidence-based neurobiological model are presented. Results Arising from abuse or neglect in childhood, impairments in the adult capacity to attend to and/or conceptualize the emotional meaning of felt distress may be associated with impaired engagement of the default network and impaired top-down modulation of affective response generation processes. Persistent and poorly conceptualized affective distress may be associated with reduced emotion regulation ability, reduced vagal tone, increased inflammation, and amplified nociceptive signals. Attention to physical pain may be reinforced by the temporary reduction in negative emotions that it causes. Conclusions These processes jointly promote biased competition favoring attention to physical pain and away from one's own emotions. They may constitute an unintentional analog of the phenomenon of self-injury in patients with borderline personality disorder in whom the intentional infliction of physical pain serves to downregulate intense emotional distress. Attending to, expressing, and understanding previously unacknowledged psychological distress unrelated to pain may facilitate recovery from chronic pain after early adversity. Mechanistic studies that can validate this clinically derived neurobiological hypothesis are urgently needed.

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Cortical Thickness Alterations in Chronic Pain Disorder: An Exploratory MRI Study

Objective Chronic pain disorder (CPD) has been associated with brain changes, especially in limbic circuits. However, in most patients with chronic pain, depression or anxiety is a common comorbidity. In this exploratory and naturalistic study, we investigated brain cortical thickness (CTh) differences between patients with CPD and healthy controls, with consideration of concurrent psychiatric symptoms. Methods Twenty-three patients with CPD and 23 age- and sex-matched healthy volunteers were included in this study. CTh was estimated using Freesurfer on high-resolution three-dimensional T1-weighted images acquired with a 3T scanner. Group differences were investigated using an analysis of covariance model that included age, sex, and Beck Depression Inventory I and Trait Anxiety Inventory scores as covariates. The relationship between CTh and Toronto Alexithymia Scale (TAS-20) scores was also investigated in patients. Data were corrected for multiplicity using the False Discovery Rate approach (q < .05). Results The comparison between groups using demographics and Beck Depression Inventory I scores as covariates showed thinner cortex in patients compared with controls, after correction for multiplicity in the left precentral (F(1,42) = 21.9, p < .05) and postcentral gyri (F(1,42) = 26.9, p < .05) and in the left inferior temporal sulcus (F(1,42) = 19.6, p < .05). Moreover, using the Trait Anxiety Inventory as covariate, a trend toward significance (p < .001 uncorrected) was seen for the left precentral gyrus (F(1,42) = 13.8), right middle frontal (F(1,42) = 14.3) and inferior parietal gyri (F(1,42) = 13.4), and right anterior temporal pole (F(1,42) = 15.9). Conclusions The results indicate that brain morphological differences between patients with chronic pain disorder and healthy controls are localized to regions that correspond to sensory as well as affective dimensions of pain processing.

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Using Different Expectation Mechanisms to Optimize Treatment of Patients With Medical Conditions: A Systematic Review

Objective Patients' expectations have been shown to predict the course and treatment success of a variety of medical conditions. Therefore, expectation-focused psychological interventions (EFPIs) have been developed to use these expectation effects clinically. Importantly, EFPI differ with regard to the particular expectation mechanism being addressed, i.e., expectation optimization or expectation violation. The aims of this systematic review were to give an overview of the application of these expectation interventions and to evaluate their effectiveness. Methods Several databases were searched to identify clinical trials or experimental studies that conducted EFPI among participants with various medical conditions. Risk of bias was evaluated using the Cochrane Risk of Bias tool. Results Eleven studies (N = 944) investigating different medical conditions (coronary heart disease, cancer, chronic pain) were included. Qualitative synthesis revealed positive effects of EFPI on clinical outcome variables in all studies. Expectation optimization approaches yielded particularly promising results. Because of the large heterogeneity of outcome measures, quantitative synthesis was not possible. Conclusion This review highlights the potential of EFPI for optimizing treatment of patients with medical conditions. However, it seems that different expectation mechanisms might have different application possibilities. Therefore, we provide suggestions for further developing EFPI to tailor treatment and develop personalized psychological interventions. We argue that for this purpose, it is important to consider both disease-specific aspects and patients' personality traits. In addition, we discuss future challenges such as implementing EFPI into routine medical care.

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