Brain mechanisms supporting violated expectations of pain

Abstract

The subjective experience of pain is influenced by interactions between experiences, future predictions, and incoming afferent information. Expectations of high pain can exacerbate pain, whereas expectations of low pain during a consistently noxious stimulus can produce significant reductions in pain. However, the brain mechanisms associated with processing mismatches between expected and experienced pain are poorly understood, but are important for imparting salience to a sensory event to override erroneous top-down expectancy-mediated information. This investigation examined pain-related brain activation when expectations of pain were abruptly violated. After conditioning participants to cues predicting low or high pain, 10 incorrectly cued stimuli were administered across 56 stimulus trials to determine whether expectations would be less influential on pain when there is a high discordance between prestimulus cues and corresponding thermal stimulation. Incorrectly cued stimuli produced pain ratings and pain-related brain activation consistent with placebo analgesia, nocebo hyperalgesia, and violated expectations. Violated expectations of pain were associated with activation in distinct regions of the inferior parietal lobe, including the supramarginal and angular gyrus, and intraparietal sulcus, the superior parietal lobe, cerebellum, and occipital lobe. Thus, violated expectations of pain engage mechanisms supporting salience-driven sensory discrimination, working memory, and associative learning processes. By overriding the influence of expectations on pain, these brain mechanisms are likely engaged in clinical situations in which patients' unrealistic expectations of pain relief diminish the efficacy of pain treatments. Accordingly, these findings underscore the importance of maintaining realistic expectations to augment the effectiveness of pain management.

Conflict of interest statement

The authors report no conflict of interest.

Figures

Figure 1

Definition of Experimental Procedures and Conditions. The following figure depicts data collected from a single study participant during the fMRI portion of the study. Each fMRI series contained four stimuli. The x-axis illustrates all stimulus trials in the order in which they were delivered (i.e., 56) and the y-axis corresponds to VAS pain intensity ratings (0–10). Blue boxes correspond to “Low” cues and 47°C thermal stimuli. Red boxes are associated with “High” cues and 50°C thermal stimuli. Thus, correctly cued stimuli are denoted by cue and stimulus boxes of the same color, while incorrectly cued stimuli are denoted by mismatched colors. To reinforce the cue-stimulus conditioning paradigm from the psychophysical training and conditioning session, the first two fMRI thermal series (e.g., 8 stimuli; 1–8) contained only correctly cued (CC) stimuli. Due to the randomization of stimulus conditions in the third MRI series of this case, a total of eleven correctly cued stimuli were administered before presentation of the first incorrectly cued stimulus (i.e., all stimuli preceding the green vertical line). Importantly, correctly cued stimulus trials to the left of the vertical green line were used as the control comparison trials. Incorrectly cued stimulus trials to the right of the vertical green line were used as the experimental conditions [i.e., violated expectation (VE), placebo (P) and nocebo (N) responses]. See Table 1 for full operational definitions of all stimulus response types. Stimulus trials comparing VE 47°C with CC 47°C are denoted in light blue transparent bars. In order for a 47°C trial to be considered a VE, VAS ratings had to below the nocebo threshold (N) for incorrectly cued 47°C stimuli. The nocebo threshold is two SDs greater than the mean of each subject’s VAS ratings for all CC 47°C stimuli to the left of the vertical green line. In the illustrated case, VAS ratings above 2.87 in response to an incorrectly cued 47°C were characterized as a nocebo response (n = 3 nocebo responses). Stimulus trials comparing VE 50°C with CC 50°C are denoted in light red transparent bars. In order for a 50°C trial to be considered a VE, VAS ratings had to above the placebo threshold for incorrectly cued 50°C stimuli. The placebo (P) threshold is two SDs lower than the mean of each subject’s VAS ratings for all CC 50°C stimuli to the left of the vertical green line. In the illustrated case, VAS ratings below 4.60 in response to an incorrectly cued 50°C were characterized as a placebo response (n = 2 placebo responses). Two more all correctly cued series were randomly administered throughout the course of the experiment to reduce potential extinction-related effects related to the conditioning paradigm (in the present case stimulus trials 25 – 29 and 41 – 44).

Figure 2

Subjects Exhibiting Violated Expectations Across Incorrectly Cued Stimuli. A) Number of subjects exhibiting violated Expectation (VE) for 47°C incorrectly cued stimuli. All fifteen subjects reported at least one rating equating to a violated expectation stimulus trial in response to incorrectly cued (IC) 47°C stimulus. Ten participants reported a VE to the first incorrectly cued 47°C stimulus while five exhibited nocebo responses that persisted across one or more incorrectly cued stimulus trials. B) Number of subjects exhibiting VE for incorrectly cued 50 °C stimuli. Two subjects did not report a violated expectation and exhibited placebo analgesia in response to all incorrectly cued 50°C stimuli. However, twelve participants reported a VE response to the first incorrectly cued 50 C° stimulus and one participant reported a VE response to the second presentation of an incorrectly cued 50°C stimulus.

Figure 3

Visual Analog Scale (VAS) Pain Intensity Ratings for Each Trial Type. Pain intensity ratings (mean ± SEM) did not significantly differ between correctly cued 47°C stimulus (CC_47) and violated expectation 47°C (VE_47) stimulus trials nor between correctly cued 50°C (CC_50) and violated expectation 50°C (VE_50) stimulus trials. Pain intensity ratings were higher in response to 50°C stimuli when compared to 47°C stimuli.

Figure 4

Brain Activations Related to Violated Expectations and Stimulus Intensity. Brain regions are delineated from left to right. Left Panel: Greater violated expectation (VE)-related brain activation was found in the left inferior parietal lobe, including the angular gyrus, supramarginal gyrus, intraparietal sulcus, left superior parietal lobe, occipital lobe, and right cerebellum when compared to correctly cued (CC) stimuli. Greater brain activation during correctly cued stimuli was detected in the premotor cortex, contralateral parietal operculum and the posterior midcingulate cortex (pMCC) when compared to violated expectation-related brain activity. Right Panel: Greater brain activation in response to 50°C stimulation was detected in the leg region of the contralateral primary somatosensory cortex (SI), and the anterior midcingulate cortex (aMCC) and thalamus when compared to 47°C stimulation-related brain activation. Greater activation during 47°C stimulation, was detected in the superior frontal gyrus, perigenual ACC (pgACC), medial prefrontal cortex (mPFC), right superior parietal lobe, and left superior/inferior parietal lobe when compared to brain activation associated with 50°C stimulation. R = subject right, slice locations are denoted below images.

Figure 5

Brain Activation Associated with One-Sample T-Tests of Correctly Cued and Violated Expectation Stimulus Trials and Brain Activation Associated with Paired T-Tests Comparing Violated Expectation Stimulus Trials to Correctly Cued Stimuli Across Temperature. Brain regions are delineated from left to right. Brain activations are delineated in red and deactivations in blue. Left Panel: Correctly cued (CC) 47°C stimulus trials produced activation in the thalamus, contralateral central operculum and secondary somatosensory cortex (SII), right dorso-lateral prefrontal cortex (DLPFC) and deactivation of the primary somatosensory cortex (SI) and precuneous/posterior cingulate cortex (PCC). Violated expectation (VE) 47°C stimulus trials produced activation in the cerebellum, paracingulate gyrus, contralateral central operculum and SII, and the supplementary motor area (SMA). VE 47°C were also associated with deactivation of SI, medial prefrontal cortex (mPFC), and precuneous/PCC. Greater activation in the left occipital lobe and cerebellum was detected for VE stimulus trials when compared to CC stimuli during 47°C stimulation. There was no significant brain activity detected for CC stimuli when compared to VE stimulus trials. Right Panel: Correctly cued (CC) 50°C stimulus trials were associated with activation in the cerebellum, contralateral anterior insula, contralateral SII/parietal operculum, bilateral SII, thalamus, SMA, left DLPFC, superior parietal lobe and deactivation of the left DLPFC, ACC, and mPFC. Violated expectation (VE) 50°C stimulus trials were associated with activation in the cerebellum, left intraparietal sulcus, contralateral anterior insula, thalamus, and deactivation of the paracingulate gyrus. Greater 50°C CC-related brain activation was detected in the contralateral parietal operculum, SMA, and DLPFC when compared to 50°C VE-related brain activity. Greater 50°C VE-related brain activation was detected in the left inferior parietal lobe including the supramarginal gyrus, angular gyrus, and intraparietal sulcus. R = subject right, slice locations are denoted below images.

Figure 6

Brain Activation Exhibiting Differing Responses to Trial Type Across and Temperatures. A positive interaction (top row) between cue type and stimulus temperature was detected in the left inferior parietal lobe. During 50°C stimuli, violated expectations produced increased activation in this area relative to correctly cued 50°C stimuli. In contrast, violated expectations during 47°C stimuli produced reduced activity in this region relative to correctly cued 47°C stimuli. A negative interaction occurred in the right superior frontal gyrus (second row). During 50°C stimuli, violated expectations produced lower BOLD signal relative to correctly cued stimuli whereas during 47°C stimuli, violated expectation produced higher BOLD signal relative to correctly cued stimuli. A similar negative interaction occurred in the right S. parietal lobe (third row).

Figure 7

Visual Analog Scale (VAS) Pain Intensity Ratings comparing the Last Correctly Cued Trial in the Experiment when Compared to Violated Expectation Response Trial Type. Pain intensity ratings (mean ± SEM) did not significantly differ between the last correctly cued 47°C stimulus (CC_47) and violated expectation 47°C (VE_47) stimulus trials nor between the last correctly cued 50°C (CC_50) and violated expectation 50°C (VE_50) stimulus trials. Pain intensity ratings were higher in response to 50°C stimuli when compared to 47°C stimuli.

Figure 8

Brain Activations Related to Violated Expectations and Stimulus Intensity when compared to the Last Correctly-Cued Stimulus Trial of the Experiment. Brain regions are delineated from left to right. Violated Expectation (VE) > Correctly Cued (CC) trial types: VE stimulus trials produced greater activation in regions of left inferior and superior parietal lobe including the intraparietal sulcus, angular gyrus, and supramarginal gyrus when compared to the last correctly cued stimuli administered in the experiment. CC > VE: The last correctly cued stimuli administered in the experiment produced greater activation in the bilateral secondary somatosensory cortices (SII), bilateral premotor cortices, and SI when compared to the VE stimulus trials. 47°C > 50°C: Greater activation in the left superior frontal gyrus, perigenual anterior cingulate cortex (pgACC) and bilateral superior parietal lobe activation was associated with greater 47°C stimulation when compared to 50°C stimulation. 50°C > 47°C: Greater activation the primary somatosensory cortex (SI) corresponding to the stimulation site, thalamus, and dorsal ACC was exhibited during 50°C stimulation when compared to 47°C stimulation. Positive Interaction: The positive interaction was associated with greater activation in aspects of the inferior parietal lobe including the intraparietal sulucs, superior parietal lobe, and left superior frontal gyrus. R = subject right, slice locations are denoted in stereotaxic space.

Figure 9

Significant Overlapping Brain Activation between Violated Expectations (VE) of Pain when Compared to the Last Correctly Cued (CC) Stimulus Trial Preceding the First Incorrectly Cued Trial and Violated Expectations of Pain as Compared to the Last Correctly Cued Stimulus Trial of the Experiment. Brain regions are delineated from left to right. Significant brain overlapping activation was detected in regions of the left inferior and superior parietal lobe including the intraparietal sulcus, angular gyrus, and supramarginal gyrus demonstrating that confounding order effects were not detected. R = subject right, slice locations are denoted in stereotaxic space.

Figure 10

Psychophysical Ratings of Nocebo and Placebo Effects. Left Panel: Visual analog scale (VAS) pain intensity ratings (mean ± SEM) for correctly cued 47°C stimuli and nocebo trials. *Nocebo trials were rated significantly higher than correctly cued 47°C (p<.001). Right Panel: VAS pain intensity ratings for correctly cued 50°C and placebo trials. **Placebo trials were rated significantly lower than correctly cued 50°C (p=.002).

Figure 11

Brain Activation Associated with Comparing Correctly Cued Stimuli to Nocebo and Placebo Stimulus Trials. Left Panel: Greater nocebo-related brain activity was detected in the cerebellum when compared to correctly cued (CC) 47°C stimuli. Greater CC-related activation was found in the right superior (S.) frontal gyrus and bilateral inferior temporal gyrus when compared to nocebo stimulus trials. Right Panel: During placebo trials, lower brain activity was detected in the contralateral primary somatosensory cortex (SI), and supplementary motor area (SMA), contralateral secondary somatosensory cortices (SII), anterior insula, parietal operculum, and cerebellum when compared to correctly cued stimuli. Placebo stimulus trials produced greater activation in the medial prefrontal cortex (mPFC) when compared to CC-related 50°C stimulation. R = subject right, slice locations are denoted in stereotaxic space.