Wael El-Deredy

Placebo conditioning and placebo analgesia modulate a common brain network during pain anticipation and perception

ABSTRACT The neural mechanisms whereby placebo conditioning leads to placebo analgesia remain unclear. In this study we aimed to identify the brain structures activated during placebo conditioning and subsequent placebo analgesia. We induced placebo analgesia by associating a sham treatment with pain reduction and used fMRI to measure brain activity associated with three stages of the placebo response: before, during and after the sham treatment, while participants anticipated and experienced brief laser pain. In the control session participants were explicitly told that the treatment was inactive. The sham treatment group reported a significant reduction in pain rating (p = 0.012). Anticipatory brain activity was modulated during placebo conditioning in a fronto‐cingulate network involving the left dorsolateral prefrontal cortex (DLPFC), medial frontal cortex and the anterior mid‐cingulate cortex (aMCC). Identical areas were modulated during anticipation in the placebo analgesia phase with the addition of the orbitofrontal cortex (OFC). However, during altered pain experience only aMCC, post‐central gyrus and posterior cingulate demonstrated altered activity. The common frontal cortical areas modulated during anticipation in both the placebo conditioning and placebo analgesia phases have previously been implicated in placebo analgesia. Our results suggest that the main effect of placebo arises from the reduction of anticipation of pain during placebo conditioning that is subsequently maintained during placebo analgesia.

Modulation of pain ratings by expectation and uncertainty: Behavioral characteristics and anticipatory neural correlates.

&NA; Expectations about the magnitude of impending pain exert a substantial effect on subsequent perception. However, the neural mechanisms that underlie the predictive processes that modulate pain are poorly understood. In a combined behavioral and high‐density electrophysiological study we measured anticipatory neural responses to heat stimuli to determine how predictions of pain intensity, and certainty about those predictions, modulate brain activity and subjective pain ratings. Prior to receiving randomized laser heat stimuli at different intensities (low, medium or high) subjects (n = 15) viewed cues that either accurately informed them of forthcoming intensity (certain expectation) or not (uncertain expectation). Pain ratings were biased towards prior expectations of either high or low intensity. Anticipatory neural responses increased with expectations of painful vs. non‐painful heat intensity, suggesting the presence of neural responses that represent predicted heat stimulus intensity. These anticipatory responses also correlated with the amplitude of the Laser‐Evoked Potential (LEP) response to painful stimuli when the intensity was predictable. Source analysis (LORETA) revealed that uncertainty about expected heat intensity involves an anticipatory cortical network commonly associated with attention (left dorsolateral prefrontal, posterior cingulate and bilateral inferior parietal cortices). Relative certainty, however, involves cortical areas previously associated with semantic and prospective memory (left inferior frontal and inferior temporal cortex, and right anterior prefrontal cortex). This suggests that biasing of pain reports and LEPs by expectation involves temporally precise activity in specific cortical networks.

Reproducibility of placebo analgesia: Effect of dispositional optimism

ABSTRACT Placebo has been shown to be a powerful analgesic with corresponding reduction in the activation of the pain matrix in the brain. However it is not clear whether the placebo response is reproducible within individuals and what role personality traits might play in predicting it. We induced placebo analgesia by conditioning subjects to expect pain reduction following a sham‐treatment in the guise of a local anaesthetic cream applied to one arm. Pain ratings were assessed before, during and after treatment. The procedure was repeated in a second session to assess the degree of reproducibility of the response. A high degree of correlation was found between the two sessions for the sham‐treatment group (R2 = 0.55; p < 0.001). Personality questionnaires were given during both experimental sessions to assess key traits such as optimism and state and trait anxiety. A regression model was used to statistically define a placebo responder in terms of personality scores. High dispositional optimism and low state anxiety were found to be significant predictors of placebo response. We suggest that repeated placebo responders are high in dispositional optimism and having a placebo response in the first session causes a drop in state anxiety at the beginning of the repeat session.

The Feedback-Related Negativity Signals Salience Prediction Errors, Not Reward Prediction Errors

Modulations of the feedback-related negativity (FRN) event-related potential (ERP) have been suggested as a potential biomarker in psychopathology. A dominant theory about this signal contends that it reflects the operation of the neural system underlying reinforcement learning in humans. The theory suggests that this frontocentral negative deflection in the ERP 230–270 ms after the delivery of a probabilistic reward expresses a prediction error signal derived from midbrain dopaminergic projections to the anterior cingulate cortex. We tested this theory by investigating whether FRN will also be observed for an inherently aversive outcome: physical pain. In another session, the outcome was monetary reward instead of pain. As predicted, unexpected reward omissions (a negative reward prediction error) yielded a more negative deflection relative to unexpected reward delivery. Surprisingly, unexpected pain omission (a positive reward prediction error) also yielded a negative deflection relative to unexpected pain delivery. Our data challenge the theory by showing that the FRN expresses aversive prediction errors with the same sign as reward prediction errors. Both FRNs were spatiotemporally and functionally equivalent. We suggest that FRN expresses salience prediction errors rather than reward prediction errors.

Placebo analgesia is not due to compliance or habituation: EEG and behavioural evidence

This study was designed to resolve whether experimental placebo responses are due to either increased compliance or habituation. We stimulated both forearms and recorded laser-evoked potentials from 18 healthy volunteers treated on one arm with a sham analgesic cream and an inactive cream on the other (treatment group), and 13 volunteers with an inactive cream on both arms (controls). The treatment group showed a significant reduction in the pain ratings and laser-evoked potentials with both the sham and inactive creams. The control group showed no evidence of habituation to the laser stimulus. The results indicate that the reduction in pain during experimental placebo response is unlikely to be due to sensory habituation or compliance with the experimental instructions.

The value of personalised recommender systems to e-business: a case study

Recommender systems have recently grown in popularity both in e-commerce and in research. However, there is little, if any, direct evidence in the literature of the value of recommender systems to e-Businesses, especially relating to consumer packaged goods (CPG) sold in a supermarket setting. We have been working in collaboration with LeShop (www.LeShop.ch), to gather real evidence of the added business value of a personalised recommender system. In this paper, we present our initial evaluation of the performance of our model-based personalised recommender systems over the 21-month period from May 2006 to January 2008, with particular focus on the added-value to the business. Our analysis covers shopper penetration, as well as the direct and indirect extra revenue generated by our recommender systems. One of the key lessons we have learnt during this case study is that the effect of a recommender system extends far beyond the direct extra revenue generated from the purchase of recommended items. The importance of maintaining updated model files was also found to be key to maintaining the performance of such model-based systems.

Bayesian modelling of Jumping-to-Conclusions bias in delusional patients

Introduction. When deciding about the cause underlying serially presented events, patients with delusions utilise fewer events than controls, showing a “Jumping-to-Conclusions” bias. This has been widely hypothesised to be because patients expect to incur higher costs if they sample more information. This hypothesis is, however, unconfirmed. Methods. The hypothesis was tested by analysing patient and control data using two models. The models provided explicit, quantitative variables characterising decision making. One model was based on calculating the potential costs of making a decision; the other compared a measure of certainty to a fixed threshold. Results. Differences between paranoid participants and controls were found, but not in the way that was previously hypothesised. A greater “noise” in decision making (relative to the effective motivation to get the task right), rather than greater perceived costs, best accounted for group differences. Paranoid participants also deviated from ideal Bayesian reasoning more than healthy controls. Conclusions. The Jumping-to-Conclusions Bias is unlikely to be due to an overestimation of the cost of gathering more information. The analytic approach we used, involving a Bayesian model to estimate the parameters characterising different participant populations, is well suited to testing hypotheses regarding “hidden” variables underpinning observed behaviours.

Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula.

Abstract Psychological factors play a major role in exacerbating chronic pain. Effective self‐management of pain is often hindered by inaccurate beliefs about the nature of pain which lead to a high degree of emotional reactivity. Probabilistic models of perception state that greater confidence (certainty) in beliefs increases their influence on perception and behavior. In this study, we treat confidence as a metacognitive process dissociable from the content of belief. We hypothesized that confidence is associated with anticipatory activation of areas of the pain matrix involved with top‐down modulation of pain. Healthy volunteers rated their beliefs about the emotional distress that experimental pain would cause, and separately rated their level of confidence in this belief. Confidence predicted the influence of anticipation cues on experienced pain. We measured brain activity during anticipation of pain using high‐density EEG and used electromagnetic tomography to determine neural substrates of this effect. Confidence correlated with activity in right anterior insula, posterior midcingulate and inferior parietal cortices during the anticipation of pain. Activity in the right anterior insula predicted a greater influence of anticipation cues on pain perception, whereas activity in right inferior parietal cortex predicted a decreased influence of anticipatory cues. The results support probabilistic models of pain perception and suggest that confidence in beliefs is an important determinant of expectancy effects on pain perception.

I Want It Now! Neural Correlates of Hypersensitivity to Immediate Reward in Hypomania

BACKGROUND Hypomania is associated with impulsive decision making and risk taking, characteristics that may arise from hypersensitivity to reward. To date, the neural dynamics underlying intertemporal reward processing have neither been characterized clinically nor in the general population. Taking vulnerability to hypomania as a surrogate model of impulsivity, we utilized event-related potentials to study the neural mechanisms of delay discounting. METHODS In the first experiment, 32 participants completed an established Two Choice Impulsivity Paradigm in which free choice between immediate and delayed rewards was used to quantify impulsivity behaviorally. In the second experiment, electroencephalography was recorded while 32 separately recruited participants completed a speeded response task involving gains and losses of monetary incentives to be paid at three different delays after the experiment. RESULTS In the first experiment, the hypomania-prone group made significantly more immediate choices than the control group. In the second experiment, the hypomania-prone group evidenced greater differentiation between delayed and immediate outcomes in early attention-sensitive (N1) and later reward-sensitive (feedback-related negativity) components. Proneness to hypomania was also associated with greater N1 amplitude to rewards per se. CONCLUSIONS These results indicate steeper delay discounting in hypomania at multiple stages of information processing. The N1 modulation by valence and delay suggests an attentional bias to immediate rewards, which may drive subsequent cognitive appraisal of outcomes (feedback-related negativity). These results highlight the early influence of attention on reward processing and provide support for reward dysregulation accounts of bipolar disorder. Potential implications for mindfulness training and other therapeutic interventions are highlighted.

Visual information processing deficits as biomarkers of vulnerability to schizophrenia: an event-related potential study in schizotypy.

We aimed to clarify the importance of early visual processing deficits for the formation of cognitive deficits in the schizophrenia spectrum. We carried out an event-related potential (ERP) study using a computerised delayed matching to sample working memory (WM) task on a sample of volunteers with high and low scores on the Schizotypal Personality Questionnaire (SPQ). The amplitudes of the visual ERPs to the encoding and retrieval stimuli in the task were measured using the BESA software. The hypothesis was that the high schizotypes would have deficits in early visual processing (reduced P1 amplitude) and working memory similar to those observed in schizophrenia. The high schizotypy group identified fewer previously encoded target cues than the low schizotypy group in the WM task and their mean cue-evoked P1 amplitudes were significantly reduced, both in the encoding and the retrieval phases of the task. Accuracy on the WM task correlated with the P1 amplitude. None of the later components (N1 and P2) were significantly different between the groups, nor were there differences in performance on the CANTAB tests. The results are compatible with the hypothesis that trait vulnerability to schizophrenia is associated with impaired early visual processing which may contribute to impaired cognitive memory performance. However, the high schizotypes are apparently able to compensate for the visual processing deficits and perform normally when stimuli are presented for longer as in the CANTAB tasks. This study adds to growing evidence that the schizophrenia spectrum is characterized by early sensory abnormalities.