Dopamine has no direct causal role in the formation of treatment expectations and placebo analgesia in humans.

Dopamine-based reward and learning mechanisms have been suggested to contribute to placebo effects. However, the exact role of dopaminergic neurotransmission in their generation and maintenance is still unclear. This study aimed to shed light on the causal role of dopamine in establishing positive treatment expectations, as well as on the magnitude and duration of their effect on pain. To this end, we used an established placebo analgesia paradigm in combination with 2 opposing pharmacological modulations of dopaminergic tone, i.e., the dopamine antagonist sulpiride and the dopamine precursor L-dopa which were both applied in an experimental, double-blind, randomized, placebo-controlled trial with a between-subject design in N = 168 healthy volunteers. The study medication successfully altered dopaminergic tone during the conditioning procedure. Contrary to our hypotheses, the medication did not modulate the formation of positive treatment expectation and placebo analgesia tested 1 day later. Placebo analgesia was no longer detectable on day 8 after conditioning. Using a combined frequentist and Bayesian approach, our data provide strong evidence against a direct dopaminergic influence on the generation and maintenance of placebo effects. Further exploration of the neurochemical mechanisms underlying placebo analgesia remains paramount in the quest to exploit these effects for optimal treatment outcomes. Trial registration: ClinicalTrials.gov German Clinical Trials Register, ID: DRKS00029366, https://drks.de/search/en/trial/DRKS00029366.

An externally validated resting-state brain connectivity signature of pain-related learning.

Pain can be conceptualized as a precision signal for reinforcement learning in the brain and alterations in these processes are a hallmark of chronic pain conditions. Investigating individual differences in pain-related learning therefore holds important clinical and translational relevance. Here, we developed and externally validated a novel resting-state brain connectivity-based predictive model of pain-related learning. The pre-registered external validation indicates that the proposed model explains 8-12% of the inter-individual variance in pain-related learning. Model predictions are driven by connections of the amygdala, posterior insula, sensorimotor, frontoparietal, and cerebellar regions, outlining a network commonly described in aversive learning and pain. We propose the resulting model as a robust and highly accessible biomarker candidate for clinical and translational pain research, with promising implications for personalized treatment approaches and with a high potential to advance our understanding of the neural mechanisms of pain-related learning.

Reduction of Aversive Learning Rates in Pavlovian Conditioning by Angiotensin II Antagonist Losartan: A Randomized Controlled Trial.

BACKGROUND: Angiotensin receptor blockade has been linked to aspects of aversive learning and memory formation and to the prevention of posttraumatic stress disorder symptom development. METHODS: We investigated the influence of the angiotensin receptor blocker losartan on aversive Pavlovian conditioning using a probabilistic learning paradigm. In a double-blind, randomized, placebo-controlled design, we tested 45 (18 female) healthy volunteers during a baseline session, after application of losartan or placebo (drug session), and during a follow-up session. During each session, participants engaged in a task in which they had to predict the probability of an electrical stimulation on every trial while the true shock contingencies switched repeatedly between phases of high and low shock threat. Computational reinforcement learning models were used to investigate learning dynamics. RESULTS: Acute administration of losartan significantly reduced participants' adjustment during both low-to-high and high-to-low threat changes. This was driven by reduced aversive learning rates in the losartan group during the drug session compared with baseline. The 50-mg drug dose did not induce reduction of blood pressure or change in reaction times, ruling out a general reduction in attention and engagement. Decreased adjustment of aversive expectations was maintained at a follow-up session 24 hours later. CONCLUSIONS: This study shows that losartan acutely reduces Pavlovian learning in aversive environments, thereby highlighting a potential role of the renin-angiotensin system in anxiety development.

Hydrocortisone Differentially Affects Reinstatement of Pain-related Responses in Patients With Chronic Back Pain and Healthy Volunteers.

Despite the crucial role of effective and sustained extinction of conditioned pain-related fear in cognitive-behavioral treatment approaches for chronic pain, experimental research on extinction memory retrieval in chronic pain remains scarce. In healthy populations, extinction efficacy of fear memory is affected by stress. Therefore, we investigated the effects of oral hydrocortisone administration on the reinstatement of pain-related associations in 57 patients with non-specific chronic back pain (CBP) and 59 healthy control (HC) participants in a differential pain-related conditioning paradigm within a placebo-controlled, randomized, and double-blind design. Participants' skin conductance responses indicate hydrocortisone-induced reinstatement effects in HCs but no observable reinstatement in HCs receiving placebo treatment. Interestingly, these effects were reversed in patients with CBP, that is, reinstatement responses were only observed in the placebo and not in the hydrocortisone group. Our findings corroborate previous evidence of stress-induced effects on extinction efficacy and reinstatement of fear memory in HCs, extending them into the pain context, and call for more research to clarify the role of stress in fear extinction and return of fear phenomena possibly contributing to treatment failure in chronic pain treatment. PERSPECTIVE: Opposing effects in HCs and patients with non-specific CBP may be associated with changes in the patients' stress systems. These findings could be of relevance to optimizing psychological, extinction-based treatment approaches.

Open-label placebo treatment does not enhance cognitive abilities in healthy volunteers.

The use of so-called 'smart drugs' such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have limited user enthusiasm. Open-label placebo (OLP) treatment, i.e., inert treatments that are openly disclosed to individuals as having no active pharmacological ingredient, has been shown to improve various medical symptoms and conditions, including those related to cognitive performance. OLP treatment could therefore be an exciting alternative to pharmacological cognitive enhancers. Here, we used a randomized-controlled design to investigate the effect of a 21-day OLP treatment on several sub-domains of cognitive performance in N = 78 healthy volunteers. Subjective and objective measures of cognitive performance as well as different measures of well-being were obtained before and after the treatment period. Using a combination of classic Frequentist and Bayesian analysis approaches showed no additional benefit from OLP treatment in any of the subjective or objective measures of cognitive performance. Our study thus highlights possible limitations of OLP treatment in boosting cognitive performance in healthy volunteers. These findings are discussed in the light of expectancy-value considerations that may determine OLP efficacy.

Trait anxiety is associated with hidden state inference during aversive reversal learning.

Updating beliefs in changing environments can be driven by gradually adapting expectations or by relying on inferred hidden states (i.e. contexts), and changes therein. Previous work suggests that increased reliance on context could underly fear relapse phenomena that hinder clinical treatment of anxiety disorders. We test whether trait anxiety variations in a healthy population influence how much individuals rely on hidden-state inference. In a Pavlovian learning task, participants observed cues that predicted an upcoming electrical shock with repeatedly changing probability, and were asked to provide expectancy ratings on every trial. We show that trait anxiety is associated with steeper expectation switches after contingency reversals and reduced oddball learning. Furthermore, trait anxiety is related to better fit of a state inference, compared to a gradual learning, model when contingency changes are large. Our findings support previous work suggesting hidden-state inference as a mechanism behind anxiety-related to fear relapse phenomena.

Neural underpinnings of preferential pain learning and the modulatory role of fear.

Due to its unique biological relevance, pain-related learning might differ from learning from other aversive experiences. This functional magnetic resonance imaging study compared neural mechanisms underlying the acquisition and extinction of different threats in healthy humans. We investigated whether cue-pain associations are acquired faster and extinguished slower than cue associations with an equally unpleasant tone. Additionally, we studied the modulatory role of stimulus-related fear. Therefore, we used a differential conditioning paradigm, in which somatic heat pain stimuli and unpleasantness-matched auditory stimuli served as US. Our results show stronger acquisition learning for pain- than tone-predicting cues, which was augmented in participants with relatively higher levels of fear of pain. These behavioral findings were paralleled by activation of brain regions implicated in threat processing (insula, amygdala) and personal significance (ventromedial prefrontal cortex). By contrast, extinction learning seemed to be less dependent on the threat value of the US, both on the behavioral and neural levels. Amygdala activity, however, scaled with pain-related fear during extinction learning. Our findings on faster and stronger (i.e. "preferential") pain learning and the role of fear of pain are consistent with the biological relevance of pain and may be relevant to the development or maintenance of chronic pain.

Same but different: how agency modulates pain perception.

Why is analgesic treatment more effective when it is self-administered? Strube et al. compare two possible accounts and show that the effect of agency on perception is linked to a shift in expectation (prior) rather than to reduced likelihood precision, highlighting that agency has a profound impact on the entire perceptual process.

Pain-related reorganization in the primary somatosensory cortex of patients with postherpetic neuralgia.

Studies on functional and structural changes in the primary somatosensory cortex (S1) have provided important insights into neural mechanisms underlying several chronic pain conditions. However, the role of S1 plasticity in postherpetic neuralgia (PHN) remains elusive. Combining psychophysics and magnetic resonance imaging (MRI), we investigated whether pain in PHN patients is linked to S1 reorganization as compared with healthy controls. Results from voxel-based morphometry showed no structural differences between groups. To characterize functional plasticity, we compared S1 responses to noxious laser stimuli of a fixed intensity between both groups and assessed the relationship between S1 activation and spontaneous pain in PHN patients. Although the intensity of evoked pain was comparable in both groups, PHN patients exhibited greater activation in S1 ipsilateral to the stimulated hand. Pain-related activity was identified in contralateral superior S1 (SS1) in controls as expected, but in bilateral inferior S1 (IS1) in PHN patients with no overlap between SS1 and IS1. Contralateral SS1 engaged during evoked pain in controls encoded spontaneous pain in patients, suggesting functional S1 reorganization in PHN. Resting-state fMRI data showed decreased functional connectivity between left and right SS1 in PHN patients, which scaled with the intensity of spontaneous pain. Finally, multivariate pattern analyses (MVPA) demonstrated that BOLD activity and resting-state functional connectivity of S1 predicted within-subject variations of evoked and spontaneous pain intensities across groups. In summary, functional reorganization in S1 might play a key role in chronic pain related to PHN and could be a potential treatment target in this patient group.

Hippocampus mediates nocebo impairment of opioid analgesia through changes in functional connectivity.

The neural mechanisms underlying placebo analgesia have attracted considerable attention over the recent years. In contrast, little is known about the neural underpinnings of a nocebo-induced increase in pain. We previously showed that nocebo-induced hyperalgesia is accompanied by increased activity in the hippocampus that scaled with the perceived level of anxiety. As a key node of the neural circuitry of perceived threat and fear, the hippocampus has recently been proposed to coordinate defensive behaviour in a context-dependent manner. Such a role requires close interactions with other regions involved in the detection of and responses to threat. Here, we investigated the functional connectivity of the hippocampus during nocebo-induced hyperalgesia. Our results show an increase in functional connectivity between hippocampus and brain regions implicated in the processing of sensory-discriminative aspects of pain (posterior insula and primary somatosensory/motor cortex) as well as the periaqueductal grey. This nocebo-induced increase in connectivity scaled with an individual's increase in anxiety. Moreover, hippocampus connectivity with the amygdala was negatively correlated with the pain intensity reported during nocebo hyperalgesia relative to the placebo condition. Our findings suggest that the hippocampus links nocebo-induced anxiety to a heightened responsiveness to nociceptive input through changes in its crosstalk with pain-modulatory brain areas.

Acquisition learning is stronger for aversive than appetitive events.

Appetitive and aversive learning are both key building blocks of adaptive behavior, yet knowledge regarding their differences is sparse. Using a capsaicin heat pain model in 36 healthy participants, this study directly compared the acquisition and extinction of conditioned stimuli (CS) predicting pain exacerbation and relief. Valence ratings show stronger acquisition during aversive compared to appetitive learning, but no differences in extinction. Skin conductance responses and contingency ratings confirmed these results. Findings were unrelated to individual differences in pain sensitivity or psychological factors. Our results support the notion of an evolutionarily hardwired preponderance to acquire aversive rather than appetitive cues as is protective for acute aversive states such as pain but may contribute to the development and maintenance of clinical conditions such as chronic pain, depression or anxiety disorders.

Impaired pain-related threat and safety learning in patients with chronic back pain.

ABSTRACT: Pain-related learning mechanisms likely play a key role in the development and maintenance of chronic pain. Previous smaller-scale studies have suggested impaired pain-related learning in patients with chronic pain, but results are mixed, and chronic back pain (CBP) particularly has been poorly studied. In a differential conditioning paradigm with painful heat as unconditioned stimuli, we examined pain-related acquisition and extinction learning in 62 patients with CBP and 61 pain-free healthy male and female volunteers using valence and contingency ratings and skin conductance responses. Valence ratings indicate significantly reduced threat and safety learning in patients with CBP, whereas no significant differences were observed in contingency awareness and physiological responding. Moreover, threat learning in this group was more impaired the longer patients had been in pain. State anxiety was linked to increased safety learning in healthy volunteers but enhanced threat learning in the patient group. Our findings corroborate previous evidence of altered pain-related threat and safety learning in patients with chronic pain. Longitudinal studies exploring pain-related learning in (sub)acute and chronic pain are needed to further unravel the role of aberrant pain-related learning in the development and maintenance of chronic pain.

When experience is not enough: learning-based cognitive pain modulation with or without instructions.

ABSTRACT: The effects of expectations on pain perception are often studied using large differences in pain probabilities between experimental conditions, although they may be far more subtle in clinical contexts and, therefore, more difficult to detect. The current study aimed to investigate at which point subtle differences in pain probabilities can be detected and lead to differentiable expectations and perceptions. Furthermore, we investigated whether instructions can aid learning from experience and enhance subsequent pain modulatory effects. During a predictive learning task, participants were presented with 5 different cues, followed by either a high and low noxious stimulus. They learned about the different cue-stimulus contingencies either solely through experience (LEARN, N = 40) or a combination of experience and explicit information about the cue-stimulus contingencies (INSTRUCT, N = 40). We found that without explicit information, picking up the different pain probabilities was challenging, while explicit instruction significantly improved their detection. As revealed by drift diffusion modeling, learning from experience was insufficient for the development of a bias towards low pain even when it was highly likely. By contrast, when explicit information was provided, perception became more nuanced with the direction and extent of bias, capturing the subtle differences in pain probabilities. These findings highlight that the use of instructions to foster the detection of subtle pain improvements during pain treatment to enhance their cognitive pain modulatory effects warrant further investigation.

Cortico-Brainstem Mechanisms of Biased Perceptual Decision-Making in the Context of Pain.

Prior expectations can bias how we perceive pain. Using a drift diffusion model, we recently showed that this influence is primarily based on changes in perceptual decision-making (indexed as shift in starting point). Only during unexpected application of high-intensity noxious stimuli, altered information processing (indexed as increase in drift rate) explained the expectancy effect on pain processing. Here, we employed functional magnetic resonance imaging to investigate the neural basis of both these processes in healthy volunteers. On each trial, visual cues induced the expectation of high- or low-intensity noxious stimulation or signaled equal probability for both intensities. Participants categorized a subsequently applied electrical stimulus as either low- or high-intensity pain. A shift in starting point towards high pain correlated negatively with right dorsolateral prefrontal cortex activity during cue presentation underscoring its proposed role of "keeping pain out of mind". This anticipatory right dorsolateral prefrontal cortex signal increase was positively correlated with periaqueductal gray (PAG) activity when the expected high-intensity stimulation was applied. A drift rate increase during unexpected high-intensity pain was reflected in amygdala engagement and increased functional connectivity between amygdala and PAG. Our findings suggest involvement of the PAG in both decision-making bias and altered information processing to implement expectancy effects on pain. PERSPECTIVE: Modulation of pain through expectations has been linked to changes in perceptual decision-making and altered processing of afferent information. Our results suggest involvement of the dorsolateral prefrontal cortex, amygdala, and periaqueductal gray in these processes.

Direct Verbal Suggestibility as a Predictor of Placebo Hypoalgesia Responsiveness.

OBJECTIVE: Reliably identifying good placebo responders has pronounced implications for basic research on, and clinical applications of, the placebo response. Multiple studies point to direct verbal suggestibility as a potentially valuable predictor of individual differences in placebo responsiveness, but previous research has produced conflicting results on this association. METHODS: In two double-blind studies, we examined whether behavioral direct verbal suggestibility measures involving a correction for compliance would be associated with individual differences in responsiveness to conditioned and unconditioned placebo hypoalgesia using an established placebo analgesia paradigm. In study 1 (n = 57; mean [standard deviation] age = 23.7 [8.1] years; 77% women), we used behavioral hypnotic suggestibility as a predictor of placebo hypoalgesia induced through conditioning and verbal suggestion, whereas in study 2 (n = 78; mean [standard deviation] = 26.1 [7.4] years; 65% women), we measured nonhypnotic suggestibility and placebo hypoalgesia induced through verbal suggestion without conditioning. RESULTS: In study 1, the placebo hypoalgesia procedure yielded a moderate placebo response (g = 0.63 [95% confidence interval = 0.32 to 0.97]), but the response magnitude did not significantly correlate with hypnotic suggestibility (rs = 0.11 [-0.17 to 0.37]). In study 2, the placebo procedure did not yield a significant placebo response across the full sample (g = 0.11 [-0.11 to 0.33]), but the magnitude of individual placebo responsiveness significantly correlated with nonhypnotic suggestibility (rs = 0.27 [0.03 to 0.48]). CONCLUSIONS: These results suggest that the extent to which direct verbal suggestibility captures variability in placebo responsiveness depends on the use of conditioning and highlights the utility of suggestibility as a potential contributing factor to placebo responding when placebo hypoalgesia is induced through verbal suggestions.