The dominant theories of human placebo effects rely on a notion that consciously perceptible cues, such as verbal information or distinct stimuli in classical conditioning, provide signals that activate placebo effects. However, growing evidence suggest that behavior can be triggered by stimuli presented outside of conscious awareness. Here, we performed two experiments in which the responses to thermal pain stimuli were assessed. The first experiment assessed whether a conditioning paradigm, using clearly visible cues for high and low pain, could induce placebo and nocebo responses. The second experiment, in a separate group of subjects, assessed whether conditioned placebo and nocebo responses could be triggered in response to nonconscious (masked) exposures to the same cues. A total of 40 healthy volunteers (24 female, mean age 23 y) were investigated in a laboratory setting. Participants rated each pain stimulus on a numeric response scale, ranging from 0 = no pain to 100 = worst imaginable pain. Significant placebo and nocebo effects were found in both experiment 1 (using clearly visible stimuli) and experiment 2 (using nonconscious stimuli), indicating that the mechanisms responsible for placebo and nocebo effects can operate without conscious awareness of the triggering cues. This is a unique experimental verification of the influence of nonconscious conditioned stimuli on placebo/nocebo effects and the results challenge the exclusive role of awareness and conscious cognitions in placebo responses.analgesia | hyperalgesia | consciousness P lacebo and nocebo effects are critical components of medical practice and clinical research. Placebo analgesia and nocebo hyperalgesia are the most robust and well studied of these effects. Learning is known to play an important role in placebo and nocebo effects and the dominant theories invoke classical conditioning and expectancies as explanatory tools (1). Both rely on a notion that the conscious perception of sensory or social stimuli, such as the cue that triggers expectancy or the conditioned stimulus in classical conditioning, are needed to obtain placebo responses. In some circumstances, conditioning may be an automatic nonconscious process, but in most cases, it seems to involve the formation of expectations (2-4). However, it is not known whether conscious perception of a conditioned stimulus is needed to elicit a conditioned response.There is a large literature suggesting that behavior can be motivated by stimuli that are not consciously perceived, because they are presented at low intensities or masked from conscious awareness (5, 6), sometimes referred to as subliminal stimuli. Nonconscious operations are considered a fundamental feature of human cognition, for example in reward processing (7,8), fear learning (9, 10), and social behavior (11,12). Furthermore, evidence suggests that conditioned responses may be acquired outside of conscious awareness (13-15). Neuroimaging studies of the human brain suggest that certain structures, such as the striatum and ...

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Relief fits the definition of a reward. Unlike other reward types the pleasantness of relief depends on the violation of a negative expectation, yet this has not been investigated using neuroimaging approaches. We hypothesized that the degree of negative expectation depends on state (dread) and trait (pessimism) sensitivity. Of the brain regions that are involved in mediating pleasure, the nucleus accumbens also signals unexpected reward and positive prediction error. We hypothesized that accumbens activity reflects the level of negative expectation and subsequent pleasant relief. Using fMRI and two purpose-made tasks, we compared hedonic and BOLD responses to relief with responses during an appetitive reward task in 18 healthy volunteers. We expected some similarities in task responses, reflecting common neural substrates implicated across reward types. However, we also hypothesized that relief responses would differ from appetitive rewards in the nucleus accumbens, since only relief pleasantness depends on negative expectations. The results confirmed these hypotheses. Relief and appetitive reward task activity converged in the ventromedial prefrontal cortex, which also correlated with appetitive reward pleasantness ratings. In contrast, dread and pessimism scores correlated with relief but not with appetitive reward hedonics. Moreover, only relief pleasantness covaried with accumbens activation. Importantly, the accumbens signal appeared to specifically reflect individual differences in anticipation of the adverse event (dread, pessimism) but was uncorrelated to appetitive reward hedonics. In conclusion, relief differs from appetitive rewards due to its reliance on negative expectations, the violation of which is reflected in relief-related accumbens activation.

Objective While patients suffering from fibromyalgia (FM) are known to exhibit hyperalgesia, the central mechanisms contributing to this altered pain processing are not fully understood. In this study we investigate potential dysregulation of the neural circuitry underlying cognitive and hedonic aspects of the subjective experience of pain such as anticipation of pain and of pain relief. Methods FMRI was performed on 31 FM patients and 14 controls while they received cuff pressure pain stimuli on their leg, calibrated to elicit a pain rating of ∼50/100. During the scan, subjects also received visual cues informing them of impending pain onset (pain anticipation) and pain offset (relief anticipation). Results Patients exhibited less robust activations during both anticipation of pain and anticipation of relief within regions commonly thought to be involved in sensory, affective, cognitive and pain-modulatory processes. In healthy controls, direct searches and region-of-interest analyses in the ventral tegmental area (VTA) revealed a pattern of activity compatible with the encoding of punishment: activation during pain anticipation and pain stimulation, but deactivation during relief anticipation. In FM patients, however, VTA activity during pain and anticipation (of both pain and relief) periods was dramatically reduced or abolished. Conclusion FM patients exhibit disrupted brain responses to reward/punishment. The VTA is a source for reward-linked dopaminergic/GABAergic neurotransmission in the brain and our observations are compatible with reports of altered dopaminergic/GABAergic neurotransmission in FM. Reduced reward/punishment signaling in FM may relate to the augmented central processing of pain and reduced efficacy of opioid treatments in these patients.

Catastrophizing is widely recognized as an important risk factor for adverse pain-related outcomes. However, questions remain surrounding the details of its assessment. In particular, recent laboratory studies suggest that evaluation of "situational" catastrophizing (i.e., catastrophizing measured during or directly after the administration of noxious stimulation) may provide information distinct from that obtained by standard, or "dispositional" measures which assess individuals' recall of catastrophizing in daily life. However, comparatively little research has systematically investigated the inter-relationships and properties of these two different forms of pain-related catastrophizing. The current study evaluated both situational and dispositional catastrophizing measures within multiple samples: healthy individuals (N=84), patients with painful temporomandibular joint disorders (TMD; N=48), and patients with painful arthritis (N=43). All participants first completed the Pain Catastrophizing Scale (PCS) 49 , and then underwent psychophysical pain testing, which included heat, cold, and pressure pain. Participants then completed a situational catastrophizing measure with reference to the laboratory pain he/she had just undergone. Situational catastrophizing scores were not significantly correlated with dispositional PCS scores in the healthy participants and arthritis patients, though they were associated in TMD patients. Situational catastrophizing was more strongly associated with experimental pain responses than dispositional PCS scores for the healthy subjects and arthritis patients. In general, higher levels of situational catastrophizing were associated with lower pain thresholds and higher pain ratings across all 3 samples. The findings highlight the importance of multi-dimensional assessment of pain-related catastrophizing, and suggests a role for measuring catastrophizing related to specific, definable events. PerspectiveThis study adds to a growing literature examining catastrophizing. Our findings highlight the potential importance of the multidimensional assessment of pain-related catastrophizing, and suggest a role for measuring catastrophizing related to specific, definable events.

SummaryWhen moderate pain was presented in a context of intense pain, it induced a relief and ‘hedonic flip’ such that pain was reported as pleasant.

Objective(s) Fibromyalgia (FM) is a chronic, common pain disorder characterized by hyperalgesia. A key mechanism by which Cognitive Behavioral Therapy (CBT) fosters improvement in pain outcomes is via reductions in hyperalgesia and pain-related catastrophizing, a dysfunctional set of cognitive-emotional processes. However, the neural underpinnings of these CBT effects are unclear. Our aim was to assess CBT’s effects on the brain circuitry underlying hyperalgesia in FM patients, and to explore the role of treatment-associated reduction in catastrophizing as a contributor to normalization of pain-relevant brain circuitry and clinical improvement. Methods Sixteen high-catastrophizing FM patients were enrolled in the study and randomized to 4 weeks of individual treatment with either CBT or a Fibromyalgia Education (control) condition. Resting state fMRI (rs-fMRI) scans evaluated functional connectivity between key pain-processing brain regions at baseline and post-treatment. Clinical outcomes were assessed at baseline, post-treatment and 6-month follow-up. Results Catastrophizing correlated with increased resting state functional connectivity between S1 and anterior insula. The CBT group showed larger reductions (compared to the Education group) in catastrophizing at post-treatment (p<0.05), and CBT produced significant reductions in both pain and catastrophizing at the 6-month follow-up (p<0.05). Patients in the CBT group also showed reduced resting state connectivity between S1 and anterior/medial insula at post-treatment; these reductions in resting state connectivity were associated with concurrent treatment-related reductions in catastrophizing. Discussion These results add to the growing support for the clinically important associations between S1-insula connectivity, clinical pain, and catastrophizing, and suggest that cognitive-behavioral therapy may, in part via reductions in catastrophizing, help to normalize pain-related brain responses in FM.

The tendency to interpret ambiguous everyday situations in a relatively negative manner (negative interpretation bias) is central to cognitive models of depression. Limited tools are available to measure this bias, either experimentally or in the clinic. This study aimed to develop a pragmatic interpretation bias measure using an ambiguous scenarios test relevant to depressed mood (the AST-D).1 In Study 1, after a pilot phase (N = 53), the AST-D was presented via a web-based survey (N = 208). Participants imagined and rated each AST-D ambiguous scenario. As predicted, higher dysphoric mood was associated with lower pleasantness ratings (more negative bias), independent of mental imagery measures. In Study 2, self-report ratings were compared with objective ratings of participants’ imagined outcomes of the ambiguous scenarios (N = 41). Data were collected in the experimental context of a functional Magnetic Resonance Imaging scanner. Consistent with subjective bias scores, independent judges rated more sentences as negatively valenced for the high versus low dysphoric group. Overall, results suggest the potential utility of the AST-D in assessing interpretation bias associated with depressed mood.