The Cognitive Neuroscience of Placebo Effects: Concepts, Predictions, and Physiology.

Placebos have been used ubiquitously throughout the history of medicine. Expectations and associative learning processes are important psychological determinants of placebo effects, but their underlying brain mechanisms are only beginning to be understood. We examine the brain systems underlying placebo effects on pain, autonomic, and immune responses. The ventromedial prefrontal cortex (vmPFC), insula, amygdala, hypothalamus, and periaqueductal gray emerge as central brain structures underlying placebo effects. We argue that the vmPFC is a core element of a network that represents structured relationships among concepts, providing a substrate for expectations and a conception of the situation-the self in context-that is crucial for placebo effects. Such situational representations enable multidimensional predictions, or priors, that are combined with incoming sensory information to construct percepts and shape motivated behavior. They influence experience and physiology via descending pathways to physiological effector systems, including the spinal cord and other peripheral organs.

A multistudy analysis reveals that evoked pain intensity representation is distributed across brain systems.

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.

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.

Modular preprocessing pipelines can reintroduce artifacts into fMRI data.

The preprocessing pipelines typically used in both task and resting-state functional magnetic resonance imaging (rs-fMRI) analysis are modular in nature: They are composed of a number of separate filtering/regression steps, including removal of head motion covariates and band-pass filtering, performed sequentially and in a flexible order. In this article, we illustrate the shortcomings of this approach, as we show how later preprocessing steps can reintroduce artifacts previously removed from the data in prior preprocessing steps. We show that each regression step is a geometric projection of data onto a subspace, and that performing a sequence of projections can move the data into subspaces no longer orthogonal to those previously removed, reintroducing signal related to nuisance covariates. Thus, linear filtering operations are not commutative, and the order in which the preprocessing steps are performed is critical. These issues can arise in practice when any combination of standard preprocessing steps including motion regression, scrubbing, component-based correction, physiological correction, global signal regression, and temporal filtering are performed sequentially. In this work, we focus primarily on rs-fMRI. We illustrate the problem both theoretically and empirically through application to a test-retest rs-fMRI data set, and suggest remedies. These include (a) combining all steps into a single linear filter, or (b) sequential orthogonalization of covariates/linear filters performed in series.

Facilitation of pain in the human spinal cord by nocebo treatment.

Nocebo hyperalgesia is an increase in subjective pain perception after a patient or subject underwent an inert treatment without any active ingredient. For example, verbal suggestion of increased pain can enhance both pain experience and responses in pain-related cortical brain areas. However, changes in cortical pain responses may be secondary to earlier amplification of incoming pain signals within the spinal cord. To test for a potential early enhancement of pain signals in the dorsal horn of the spinal cord, we combined a nocebo heat pain paradigm with spinal functional magnetic resonance imaging in healthy volunteers. We found that local application of an inert nocebo cream on the forearm increased pain ratings compared with a control cream, and also reduced pain thresholds on the nocebo-treated skin patch. On the neurobiological level, pain stimulation induced a strong activation in the spinal cord at the level of the stimulated dermatomes C5/C6. Comparing pain stimulation under nocebo to a control pain stimulation of the same physical intensity revealed enhanced pain-related activity in the ipsilateral dorsal horn of the spinal cord. Importantly, the activation of the main effect of pain and the nocebo effect spatially overlapped. The current study thus provides direct evidence for a pain-facilitating mechanism in the human spinal cord before cortical processing, which can be activated by cognitive manipulations such as nocebo treatments.

Cortical and subcortical responses to high and low effective placebo treatments.

The effectiveness of placebo treatments depends on the recipient's expectations, which are at least in part shaped by previous experiences. Thus, positive past experience together with an accordant verbal instruction should enhance outcome expectations and subsequently lead to higher placebo efficacy. This should be reflected in subjective valuation reports and in activation of placebo-related brain structures. We tested this hypothesis in a functional magnetic resonance imaging study, where subjects experienced different levels of pain relief and conforming information about price levels for two placebo treatments during a manipulation phase, thereby establishing a weak and a strong placebo. As expected, both placebos led to a significant pain relief and the strong placebo induced better analgesic efficacy. Individual placebo value estimates reflected treatment efficacy, i.e. subjects were willing to pay more money for the strong placebo even though pain stimulation was completed at this time. On the neural level, placebo effects were associated with activation of the rostral anterior cingulate cortex, the anterior insula, and the ventral striatum and deactivations in the thalamus and secondary somatosensory cortex. However, only placebo-related responses in rostral anterior cingulate cortex were consistent across both the anticipation of painful stimuli and their actual administration. Most importantly, rostral anterior cingulate cortex responses were higher for the strong placebo, thus mirroring the behavioral effects. These results directly link placebo analgesia to anticipatory activity in the ventral striatum, a region involved in reward processing, and highlight the role of the rostral anterior cingulate cortex, as its activity consistently scaled with increasing analgesic efficacy.

Individual variability in brain representations of pain.

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.

Effect of Pain Reprocessing Therapy vs Placebo and Usual Care for Patients With Chronic Back Pain: A Randomized Clinical Trial.

Importance: Chronic back pain (CBP) is a leading cause of disability, and treatment is often ineffective. Approximately 85% of cases are primary CBP, for which peripheral etiology cannot be identified, and maintenance factors include fear, avoidance, and beliefs that pain indicates injury. Objective: To test whether a psychological treatment (pain reprocessing therapy [PRT]) aiming to shift patients' beliefs about the causes and threat value of pain provides substantial and durable pain relief from primary CBP and to investigate treatment mechanisms. Design, Setting, and Participants: This randomized clinical trial with longitudinal functional magnetic resonance imaging (fMRI) and 1-year follow-up assessment was conducted in a university research setting from November 2017 to August 2018, with 1-year follow-up completed by November 2019. Clinical and fMRI data were analyzed from January 2019 to August 2020. The study compared PRT with an open-label placebo treatment and with usual care in a community sample. Interventions: Participants randomized to PRT participated in 1 telehealth session with a physician and 8 psychological treatment sessions over 4 weeks. Treatment aimed to help patients reconceptualize their pain as due to nondangerous brain activity rather than peripheral tissue injury, using a combination of cognitive, somatic, and exposure-based techniques. Participants randomized to placebo received an open-label subcutaneous saline injection in the back; participants randomized to usual care continued their routine, ongoing care. Main Outcomes and Measures: One-week mean back pain intensity score (0 to 10) at posttreatment, pain beliefs, and fMRI measures of evoked pain and resting connectivity. Results: At baseline, 151 adults (54% female; mean [SD] age, 41.1 [15.6] years) reported mean (SD) pain of low to moderate severity (mean [SD] pain intensity, 4.10 [1.26] of 10; mean [SD] disability, 23.34 [10.12] of 100) and mean (SD) pain duration of 10.0 (8.9) years. Large group differences in pain were observed at posttreatment, with a mean (SD) pain score of 1.18 (1.24) in the PRT group, 2.84 (1.64) in the placebo group, and 3.13 (1.45) in the usual care group. Hedges g was -1.14 for PRT vs placebo and -1.74 for PRT vs usual care (P < .001). Of 151 total participants, 33 of 50 participants (66%) randomized to PRT were pain-free or nearly pain-free at posttreatment (reporting a pain intensity score of 0 or 1 of 10), compared with 10 of 51 participants (20%) randomized to placebo and 5 of 50 participants (10%) randomized to usual care. Treatment effects were maintained at 1-year follow-up, with a mean (SD) pain score of 1.51 (1.59) in the PRT group, 2.79 (1.78) in the placebo group, and 3.00 (1.77) in the usual care group. Hedges g was -0.70 for PRT vs placebo (P = .001) and -1.05 for PRT vs usual care (P < .001) at 1-year follow-up. Longitudinal fMRI showed (1) reduced responses to evoked back pain in the anterior midcingulate and the anterior prefrontal cortex for PRT vs placebo; (2) reduced responses in the anterior insula for PRT vs usual care; (3) increased resting connectivity from the anterior prefrontal cortex and the anterior insula to the primary somatosensory cortex for PRT vs both control groups; and (4) increased connectivity from the anterior midcingulate to the precuneus for PRT vs usual care. Conclusions and Relevance: Psychological treatment centered on changing patients' beliefs about the causes and threat value of pain may provide substantial and durable pain relief for people with CBP. Trial Registration: ClinicalTrials.gov Identifier: NCT03294148.

Brain mechanisms of social touch-induced analgesia in females.

Supportive touch has remarkable benefits in childbirth and during painful medical procedures. But does social touch influence pain neurophysiology, ie, the brain processes linked to nociception and primary pain experience? What other brain processes beyond primary pain systems mediate their analgesic effects? In this study, women (N = 30) experienced thermal pain while holding their romantic partner's hand or an inert device. Social touch reduced pain and attenuated functional magnetic resonance imaging activity in the Neurologic Pain Signature (NPS)-a multivariate brain pattern sensitive and specific to somatic pain-and increased connectivity between the NPS and both somatosensory and "default mode" regions. Brain correlates of touch-induced analgesia included reduced pain-related activation in (1) regions targeted by primary nociceptive afferents (eg, posterior insula, and anterior cingulate cortex); and (b) regions associated with affective value (orbitofrontal cortex), meaning (ventromedial prefrontal cortex [PFC]), and attentional regulation (dorsolateral PFC). Activation reductions during handholding (vs holding a rubber device) significantly mediated reductions in pain intensity and unpleasantness; greater pain reductions during handholding correlated with greater increases in emotional comfort, which correlated with higher perceived relationship quality and (a trend toward) greater perceived closeness with the romantic partner. The strongest mediators of analgesia were activity reductions in a brain circuit traditionally associated with stress and defensive behavior in mammals, including ventromedial and dorsomedial PFC, rostral anterior cingulate cortex, amygdala/hippocampus, hypothalamus, and periaqueductal gray matter. Social touch affects core brain processes that contribute to pain and pain-related affective distress in females, and should be considered alongside other treatments in medical and caregiving contexts.

Pain-related nucleus accumbens function: modulation by reward and sleep disruption.

The nucleus accumbens (NAc) has been implicated in sleep, reward, and pain modulation, but the relationship between these functional roles is unclear. This study aimed to determine whether NAc function at the onset and offset of a noxious thermal stimulus is enhanced by rewarding music, and whether that effect is reversed by experimental sleep disruption. Twenty-one healthy subjects underwent functional magnetic resonance imaging scans on 2 separate days after both uninterrupted sleep and experimental sleep disruption. During functional magnetic resonance imaging scans, participants experienced noxious stimulation while listening to individualized rewarding or neutral music. Behavioral results revealed that rewarding music significantly reduced pain intensity compared with neutral music, and disrupted sleep was associated with decreased pain intensity in the context of listening to music. In whole-brain family-wise error cluster-corrected analysis, the NAc was activated at pain onset, but not during tonic pain or at pain offset. Sleep disruption attenuated NAc activation at pain onset and during tonic pain. Rewarding music altered NAc connectivity with key nodes of the corticostriatal circuits during pain onset. Sleep disruption increased reward-related connectivity between the NAc and the anterior midcingulate cortex at pain onset. This study thus indicates that experimental sleep disruption modulates NAc function during the onset of pain in a manner that may be conditional on the presence of competing reward-related stimuli. These findings point to potential mechanisms for the interaction between sleep, reward, and pain, and suggest that sleep disruption affects both the detection and processing of aversive stimuli that may have important implications for chronic pain.

Mechanisms of placebo analgesia: A dual-process model informed by insights from cross-species comparisons.

Placebo treatments are pharmacologically inert, but are known to alleviate symptoms across a variety of clinical conditions. Associative learning and cognitive expectations both play important roles in placebo responses, however we are just beginning to understand how interactions between these processes lead to powerful effects. Here, we review the psychological principles underlying placebo effects and our current understanding of their brain bases, focusing on studies demonstrating both the importance of cognitive expectations and those that demonstrate expectancy-independent associative learning. To account for both forms of placebo analgesia, we propose a dual-process model in which flexible, contextually driven cognitive schemas and attributions guide associative learning processes that produce stable, long-term placebo effects. According to this model, the placebo-induction paradigms with the most powerful effects are those that combine reinforcement (e.g., the experience of reduced pain after placebo treatment) with suggestions and context cues that disambiguate learning by attributing perceived benefit to the placebo. Using this model as a conceptual scaffold, we review and compare neurobiological systems identified in both human studies of placebo analgesia and behavioral pain modulation in rodents. We identify substantial overlap between the circuits involved in human placebo analgesia and those that mediate multiple forms of context-based modulation of pain behavior in rodents, including forebrain-brainstem pathways and opioid and cannabinoid systems in particular. This overlap suggests that placebo effects are part of a set of adaptive mechanisms for shaping nociceptive signaling based on its information value and anticipated optimal response in a given behavioral context.

What's in a word? How instructions, suggestions, and social information change pain and emotion.

Instructions, suggestions, and other types of social information can have powerful effects on pain and emotion. Prominent examples include observational learning, social influence, placebo, and hypnosis. These different phenomena and their underlying brain mechanisms have been studied in partially separate literatures, which we discuss, compare, and integrate in this review. Converging findings from these literatures suggest that (1) instructions and social information affect brain systems associated with the generation of pain and emotion, and with reinforcement learning, and that (2) these changes are mediated by alterations in prefrontal systems responsible for top-down control and the generation of affective meaning. We argue that changes in expectation and appraisal, a process of assessing personal meaning and implications for wellbeing, are two potential key mediators of the effects of instructions and social information on affective experience. Finally, we propose a tentative model of how prefrontal regions, especially dorsolateral and ventromedial prefrontal cortex may regulate affective processing based on instructions and socially transmitted expectations more broadly.

Functional dissociation of stimulus intensity encoding and predictive coding of pain in the insula.

The computational principles by which the brain creates a painful experience from nociception are still unknown. Classic theories suggest that cortical regions either reflect stimulus intensity or additive effects of intensity and expectations, respectively. By contrast, predictive coding theories provide a unified framework explaining how perception is shaped by the integration of beliefs about the world with mismatches resulting from the comparison of these beliefs against sensory input. Using functional magnetic resonance imaging during a probabilistic heat pain paradigm, we investigated which computations underlie pain perception. Skin conductance, pupil dilation, and anterior insula responses to cued pain stimuli strictly followed the response patterns hypothesized by the predictive coding model, whereas posterior insula encoded stimulus intensity. This novel functional dissociation of pain processing within the insula together with previously observed alterations in chronic pain offer a novel interpretation of aberrant pain processing as disturbed weighting of predictions and prediction errors.

Parametric trial-by-trial prediction of pain by easily available physiological measures.

Pain is commonly assessed by subjective reports on rating scales. However, in many experimental and clinical settings, an additional, objective indicator of pain is desirable. In order to identify an objective, parametric signature of pain intensity that is predictive at the individual stimulus level across subjects, we recorded skin conductance and pupil diameter responses to heat pain stimuli of different durations and temperatures in 34 healthy subjects. The temporal profiles of trial-wise physiological responses were characterized by component scores obtained from principal component analysis. These component scores were then used as predictors in a linear regression analysis, resulting in accurate pain predictions for individual trials. Using the temporal information encoded in the principal component scores explained the data better than prediction by a single summary statistic (i.e., maximum amplitude). These results indicate that perceived pain is best reflected by the temporal dynamics of autonomic responses. Application of the regression model to an independent data set of 20 subjects resulted in a very good prediction of the pain ratings demonstrating the generalizability of the identified temporal pattern. Utilizing the readily available temporal information from skin conductance and pupil diameter responses thus allows parametric prediction of pain in human subjects.

Placebo analgesia: a predictive coding perspective.

This Perspective reviews recent findings in placebo hypoalgesia and provides a conceptual account of how expectations and experience can lead to placebo hypoalgesia. In particular, we put forward the idea that the ascending and the descending pain system resembles a recurrent system that allows for the implementation of predictive coding-meaning that the brain is not passively waiting for nociceptive stimuli to impinge on it but is actively making inferences based on prior experience and expectations. The Bayesian formulation within the predictive coding framework can directly account for differences in the magnitude but also the precision of expectations that are known to influence the strength of placebo hypoalgesia. We discuss how modulatory neurotransmitters such as opioids might be related to the characterization of expectations with an emphasis on the precision of these expectations. Finally, we develop experimental strategies that are suited to test this framework at the behavioral and neuronal level.

Expectation requires treatment to boost pain relief: an fMRI study.

We investigated the effect of a possible interaction between topical analgesic treatment and treatment expectation on pain at the behavioral and neuronal level by combining topical lidocaine/prilocaine treatment with an expectancy manipulation in a 2 by 2 within-subject design (open treatment, hidden treatment, placebo, control). Thirty-two healthy subjects received heat pain stimuli on capsaicin-pretreated skin and rated their experienced pain during functional magnetic resonance imaging. This allowed us to separate drug- and expectancy-related effects at the behavioral and neuronal levels and to test whether they interact during the processing of painful stimuli. Pain ratings were reduced during active treatment and were associated with reduced activity in the anterior insular cortex. Pain ratings were lower in open treatment compared with hidden treatment and were related to reduced activity in the anterior insular cortex, the anterior cingulate cortex, the secondary somatosensory cortex, and the thalamus. Testing for an interaction revealed that the expectation effect was significantly larger in the active treatment conditions compared with the no-treatment conditions and was associated with signal changes in the anterior insular cortex, the anterior cingulate cortex, and the ventral striatum. In conclusion, this study shows that even in the case of a topical analgesic, expectation interacts with treatment at the level of pain ratings and neuronal responses in placebo-related brain regions. Our results are highly relevant in the clinical context as they show (i) that expectation can boost treatment and (ii) that expectation and treatment are not necessarily additive as assumed in placebo-controlled clinical trials.

Overt visual attention as a causal factor of perceptual awareness.

Our everyday conscious experience of the visual world is fundamentally shaped by the interaction of overt visual attention and object awareness. Although the principal impact of both components is undisputed, it is still unclear how they interact. Here we recorded eye-movements preceding and following conscious object recognition, collected during the free inspection of ambiguous and corresponding unambiguous stimuli. Using this paradigm, we demonstrate that fixations recorded prior to object awareness predict the later recognized object identity, and that subjects accumulate more evidence that is consistent with their later percept than for the alternative. The timing of reached awareness was verified by a reaction-time based correction method and also based on changes in pupil dilation. Control experiments, in which we manipulated the initial locus of visual attention, confirm a causal influence of overt attention on the subsequent result of object perception. The current study thus demonstrates that distinct patterns of overt attentional selection precede object awareness and thereby directly builds on recent electrophysiological findings suggesting two distinct neuronal mechanisms underlying the two phenomena. Our results emphasize the crucial importance of overt visual attention in the formation of our conscious experience of the visual world.