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Research papers

Hypnotic susceptibility modulates brain activity related to experimentalplacebo analgesia

Alexa Huber ⇑, Fausta Lui, Carlo Adolfo PorroDepartment of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena I-41125, Italy

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

a r t i c l e i n f o

Article history:Received 17 September 2012Received in revised form 8 February 2013Accepted 22 March 2013

Keywords:HypnotisabilityPlacebofMRIPain anticipationPainHumans

0304-3959/$36.00 � 2013 International Associationhttp://dx.doi.org/10.1016/j.pain.2013.03.031

⇑ Corresponding author. Address: Dipartimento di Siche e Neuroscienze, Sezione Fisiologia e NeuroscieReggio Emilia, Via Campi, 287, I-41125 Modena, Italy.+39 059 205 5363.

E-mail address: alexa.huber@unimore.it (A. Huber

a b s t r a c t

Identifying personality traits and neural signatures that predict placebo responsiveness is important,both on theoretical and practical grounds. In the present functional magnetic resonance imaging (fMRI)study, we performed multiple-regression interaction analysis to investigate whether hypnotic suscepti-bility (HS), a cognitive trait referring to the responsiveness to suggestions, explains interindividual differ-ences in the neural mechanisms related to conditioned placebo analgesia in healthy volunteers. HS wasnot related to the overall strength of placebo analgesia. However, we found several HS-related differencesin the patterns of fMRI activity and seed-based functional connectivity that accompanied placebo anal-gesia. Specifically, in subjects with higher HS, the placebo response was related to increased anticipatoryactivity in a right dorsolateral prefrontal cortex focus, and to reduced functional connectivity of that focuswith brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex); an opposite pattern of fMRI activity and functional connectivity was foundin subjects with lower HS. During pain perception, activity in the regions reflecting attention/arousal(bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral poster-ior temporal foci) was negatively related to the strength of the analgesic placebo response in subjects withhigher HS, but not in subjects with lower HS. These findings highlight HS influences on brain circuitsrelated to the placebo analgesic effects. More generally, they demonstrate that different neural mecha-nisms can be involved in placebo responsiveness, depending on individual cognitive traits.

� 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

1. Introduction

Recently, there has been growing interest in identifying person-ality traits that predict good placebo responsiveness [11,16,21,22,27,48,65]. Hypnotic susceptibility (HS), or hypnotisability [25],is a cognitive trait that refers to the generalised tendency to re-spond to hypnotic suggestions [23], including those for analgesia[30,47]. HS also predicts the efficacy of suggestions administeredduring normal wakefulness – termed ‘‘imaginative suggestions’’[43], which might be relevant for the placebo effect. The HS traitis associated with attentional absorption [67,79], imagery vivid-ness [9,32], and fantasy-proneness [37]. It is in part heritable[63] and can be reliably measured with standardised scales [17,53].

It has been claimed that HS should predict good placeboresponsiveness (eg, by [31,63]), as both placebo effects [3,55,59]

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and analgesia related to hypnotic or imaginative suggestions areat least in part mediated by expectancy [20,28,31,44].

However, previous behavioural studies failed to demonstrate asignificant association between HS and placebo response [39,66].Therefore, the relationship between HS and placebo responsive-ness may be more complex than previously assumed. One possiblehypothesis is that different neurocognitive mechanisms underlieplacebo effects, depending on the individual level of HS, even ifthe overall magnitude of placebo response is not affected. Indeed,the placebo analgesic effect is not a unitary phenomenon. Rather,it has been demonstrated that placebo analgesia can be mediatedby different mechanisms related to conditioning, expectancy, re-duced anxiety, and reward anticipation [16].

The aim of the present study was to investigate, using func-tional magnetic resonance imaging (fMRI), whether HS is associ-ated with differences in the neural mechanisms underlying theplacebo analgesic response in healthy volunteers, in a conditionedplacebo protocol. Specifically, we investigated whether neuralactivity and functional connectivity can be explained in terms ofan interaction between HS and behavioural placebo effects.

Elsevier B.V. All rights reserved.

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Previous studies on HS have been criticised for including onlysubjects with high (‘‘Highs’’) or low (‘‘Lows’’) HS score, therebyignoring about one half of the population, which falls in the med-ium range of HS (‘‘Mediums’’) [46,58]. In the present study, we didnot preselect the subjects, and we did not divide them into sub-groups. Instead, we used the individual HS score as a linear regres-sor to assess relationships based on the whole naturally occurringdistribution of HS.

Findings obtained during the fMRI session of the study, but notrelated to HS, have been published in Lui et al. [36].

Fig. 1. Time course of events in a single trial during the functional magneticresonance imaging placebo experiment.

2. Materials and methods

2.1. Subjects

We investigated 36 healthy volunteers without any history ofneurological or psychiatric illness, who were not under medica-tions at the time of the study. Eight subjects were excluded fromthe analysis because of excessive head motion (n = 2) or technicalproblems during the MR session (n = 3), or because they did not re-turn for the HS session (n = 3). The remaining 28 subjects (11 male;mean age 22.4 years; 23 right-handed, 4 ambidextrous, and 1 left-handed) entered the final analysis. Handedness was assessed usingthe Edinburgh Inventory [51].

2.2. Experimental procedures

All experimental procedures were conducted in conformancewith the politics and principles contained in the Declaration of Hel-sinki, and all subjects gave their written informed consent to takepart in the study.

The study included 2 sessions – the first for the fMRI experi-ment and the second for the HS measurement. During the first ses-sion, subjects were told that the aim of the study was to evaluateboth the efficacy and the brain correlates of a new analgesic proce-dure; to this end, they would receive noxious cutaneous heat stim-uli on the top of one foot while in the MR scanner and, in sometrials, the painful stimulus would be accompanied by a sub-thresh-old electric stimulation at the ankle, which could induce analgesia.After the completion of the fMRI experiments, each subject was de-briefed, then was invited to a second session for the assessment ofsome personality characteristics, during which HS was assessedindividually by one of the authors (A.H.); HS assessment was dou-ble-blind for placebo response, and vice versa. Subjects received asmall remuneration for taking part in the study.

2.2.1. Session 1: placebo fMRI experimentFull details of the experimental protocol and of fMRI data acqui-

sition can be found in Lui et al. [36] and will only be summarisedhere.

Radiant heat pulses, generated by an infrared solid-state laserstimulator (Electronic Engineering, Florence, Italy) with a wave-length of 1.34 lm and a laser beam approximately 10 mm in diam-eter, were used as cutaneous stimuli. To avoid nociceptor fatigue orsensitisation, the laser beam was moved randomly after each stim-ulus over a 3 � 5 cm skin area.

During the fMRI experiment, stimulus intensity was set eitherat an individually defined level inducing a nonpainful (N) warmsensation, just below pain threshold, or at a level inducing pain(P) of moderate intensity. The side of stimulation was randomisedacross subjects (the right foot was always stimulated in 13, the leftfoot always stimulated in 15 subjects).The experiment was per-formed during a normal alert state.

Two conditioning runs and one test run, each including 12 trials,were carried out for each subject while fMRI images were acquired.

Each trial lasted 51 seconds (see Fig. 1). At time 0, subjects re-ceived a visual warning cue: the black screen they were lookingat turned either Red (‘‘Red’’ trials) or Green (‘‘Green’’ trials). Twelveseconds later the screen turned black again, and immediately after-wards the subject received a stimulation on the top of one foot. Thesubjects had been informed that the Red cue would be followed bya brief painful laser stimulus, whereas the Green cue would be fol-lowed by an identical painful stimulus associated with a sub-threshold electric shock, which could induce analgesia (the placebomanipulation). To this purpose, 2 electrodes were pasted above theankle; however, the electrodes were not connected to any pulsegenerator, and no electric shock was ever delivered. In the 2 condi-tioning runs, the laser stimulus intensity after the Green cue wasmilder (nonpainful stimulus, N) with respect to the stimulus inten-sity following the Red cue (painful stimulus, P). In contrast, in thetest run the stimulus following the Green cue had the same poweras the stimulus following the Red cue (painful stimulus, P). In eachrun, ‘‘Red’’ (n = 6) and ‘‘Green’’ (n = 6) trials were pseudo-randomlyalternated.

Seventeen seconds after the stimulus, subjects had to rate theperceived pain intensity by rotating a knob, which moved a cursoron a computerised visual analogue scale, anchored at 0 = no pain,and 100 = worst imaginable pain. The differences in pain ratingsbetween the ‘‘Red’’ and the ‘‘Green’’ trials in the test run, expressedas a t-score, were taken as a measure of the behavioural placebo re-sponse of the subject.

Functional images were acquired with a Philips Intera MR systemat 3T and a gradient-echo echo-planar sequence (repetition time[TR] = 3000 ms; echo time [TE] = 35 ms; field of view [FOV] =240 mm; acquisition matrix 80 � 80, reconstructed at 128 � 128;30 axial slices; voxel size 1.9 � 1.9 � 3.5 mm; 0.5-mm interslicegap). High-resolution T1-weighted anatomical images were ac-quired for each subject to allow anatomical localisation (TR =9.9 ms; TE = 4.6 ms; 170 sagittal slices; voxel size 1 � 1 � 1 mm).

2.2.2. Session 2: hypnotic susceptibility and self-report measuresFear of pain was assessed using an ad hoc Italian translation of

the Fear of Pain Questionnaire (FPQ-III) [40], which is specificallydesigned for healthy people. The FPQ-III consists of 30 items andhas shown good internal consistency and test-retest reliability.Subjects report how fearful they are about experiencing pain asso-ciated with various situations (eg, ‘‘Biting your tongue whileeating,’’ ‘‘Having a tooth pulled’’).

The Tellegen Absorption Scale (TAS) [67] consists of 34 itemsand assesses the tendency to be involved in one’s own mentalimages, a cognitive trait related to HS.

HS was assessed using the Italian version of the StanfordHypnotic Susceptibility Scale – Form A [76], which yields a totalHS score ranging between 0 and 12. Scores 0-3 are considered‘‘low,’’ scores 4-8 ‘‘medium,’’ and scores 9-12 ‘‘high.’’ The StanfordHypnotic Susceptibility Scale is the most widely used measure ofhypnotisability and yields reliable and stable results [10,53].

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2.3. Data analysis

2.3.1. Statistical analysis of behavioural resultsTo assess associations between HS and pain ratings in the fMRI

experiment, we performed an analysis of covariance including onecovariate (HS) and the following 3 repeated-measures factors: cue(Red vs Green), run (1-3), and trial (1-6). Pearson correlation coef-ficients were used to assess correlations between HS, behaviouralplacebo response, and questionnaire results. We also performed4 multiple regression analyses to assess whether HS and behav-ioural placebo response interacted in explaining 1) TAS score, 2)FPQ score, and pain ratings in the 3) ‘‘red’’ and 4) ‘‘green’’ trialsof the test run, respectively, using the interaction approach de-scribed in detail in the next session. All analyses were carried outusing the SPSS software package (SPSS Inc, Chicago, IL, USA) anda significance level set at P < 0.05.

2.3.2. fMRI data analysisData analysis was performed using the MATLAB 7.12 (The Math-

Works, Inc, Natick, MA, USA) and SPM5 (Wellcome Department ofImaging Neuroscience, London, UK) software packages. For eachsubject, all functional volumes were realigned to the first volumeacquired, slice time corrected, normalised to the MNI (MontrealNeurological Institute) template, and smoothed with a4 � 4 � 8 mm full width at half maximum (FWHM) Gaussian kernel.

The statistical analysis of fMRI data was performed under theframework of the generalised linear model (GLM), including sepa-rate regressors related to the anticipation phase (block of 4 TRs),the perception phase (modelled as a brief event starting at stimu-lus onset), and the rating phase – see [33]. Only results related tothe anticipation and perception phase for the test run are describedin the present study.

The 6 motion parameters obtained during image realignmentwere included as nuisance regressors to account for possible resid-ual movement-related signal changes. In each subject, condition-specific effects were compared using linear contrasts. The individ-ual contrast images were then submitted to a second-level ran-dom-effects regression analysis, which included either HS, orbehavioural placebo response (as revealed by t-scores obtainedby comparing pain ratings between ‘‘Red’’ and ‘‘Green’’ trials inthe test run), or both, as the main regressor(s). These analysesaimed to investigate, first, whether HS explains increases in fMRIblood oxygen level dependent (BOLD) signals in the ‘‘Green’’ com-pared to the ‘‘Red’’ trials, and whether it did so independently ofthe strength of the behavioural placebo response. Second, in orderto evaluate a possible link between HS and overall differences incortical activity not related to the specific cue, for example, dueto differences in attention or anxiety during the experiment, we as-sessed the correlation between HS and BOLD signals for ‘‘Red’’ and‘‘Green’’ trials taken together. Results associated with HS, but inde-pendent of the placebo effect, are not presented here because theywere outside the aim of the study.

Third, we used interaction analysis [8] to assess whether HS andplacebo responsiveness interacted in explaining BOLD signals inspecific brain areas. To this end, we created a new regressor, repre-senting the interaction between HS and the behavioural placeboresponse, by subtracting the mean from these 2 variables, and mul-tiplying them element by element with each other. As described inFriston et al. [19], this analysis looks for a difference between sub-jects with higher vs lower HS scores in the slope of regressiondescribing the relationship between the behavioural placebo re-sponse and BOLD signal in a specific brain region. A significantpositive correlation of this new HS-by-placebo interaction variablewith the BOLD signal indicates that the behavioural placeboresponse is more positively correlated with the BOLD signal in sub-jects with higher HS. Conversely, a negative correlation with the

interaction variable indicates that the behavioural placebo re-sponse is less positively (or more negatively) correlated with theBOLD signal in the more hypnotisable subjects. In summary, a sig-nificant interaction effect would confirm our hypothesis that spe-cific brain regions are more or less relevant for the placeboeffect, depending on the subjects’ level of HS.

Note that the division into low vs medium-high hypnotisablesubjects shown in the Figures in the Results section serves onlyto illustrate the interaction – all statistical analyses were actuallyperformed on the whole sample using multiple regression, withoutcreating any subgroups.

A double statistical threshold (voxel intensity and spatial ex-tent) was adopted to achieve a combined significance level, cor-rected for multiple comparisons, of a < 0.05, as assessed byAlphaSim (Alpha Simulation) with 1000 Monte Carlo simulations(http://afni.nimh.nih.gov/afni/doc/manual/AlphaSim).

2.3.3. Seed-based functional connectivity analysisAs described in the Results section, we found a significant HS-

by-placebo interaction in the right dorsolateral prefrontal cortex(DLPFC). To better understand the meaning of this interaction,we performed seed-based functional connectivity (FC) analysisusing the AFNI software package (http://afni.nimh.nih.gov/afni).Seed-based FC analysis examines the correlations in BOLD signalfluctuations over time between a region of interest (‘‘seed’’) andall other brain voxels, thus providing information on the coherenceof fMRI activity between different brain regions [18].

Only the test run was included in the FC analysis. For each sub-ject, all functional volumes were slice time corrected, realigned tothe last volume acquired, globally scaled by dividing the BOLD sig-nal in each voxel by the total mean to make the data more compa-rable between subjects, normalised to the Talairach template, andsmoothed with a 6-mm FWHM Gaussian kernel.

The seed signal was obtained by averaging the BOLD signalwithin a sphere of 5-mm radius around the Talairach coordinatesx = 37, y = 17, z = 28, referring to the peak voxel of the interactioncluster in the right DLPFC obtained by repeating the GLM analysis(described in the previous section) in AFNI.

Following [64], no global signal regressor was included in theanalysis to avoid biasing of the correlation results. Several differentGLMs were constructed for each subject to explore the FC with theseed in various phases of the test run, namely: 1) during the entirerun; 2) only during the 12-second anticipation phase of each trial(including both ‘‘Red’’ and ‘‘Green’’ trials); and 3) only during theperception phase of each trial, defined for the purpose of the FCanalysis as the 12-second period starting with the laser stimulation(including both ‘‘Red’’ and ‘‘Green’’ trials). Two additional GLMswere constructed following a psychophysiological interactionmodel approach as described in [19] to assess the change in FCwith the seed: 4) during the ‘‘Green’’ compared to the ‘‘Red’’ antic-ipation phases, and 5) during the ‘‘Green’’ compared to the ‘‘Red’’perception phases. Average white matter signal, average lateralventricle signal, the 6 motion parameters obtained during imagerealignment, and the various task-related regressors (‘‘Red’’/‘‘Green’’ anticipation, stimulation and motor response – see previ-ous section) were included as nuisance regressors in all models. Asthe final output of these models for each subject, the FC of eachvoxel with the seed region was expressed as a Pearson correlationcoefficient, transformed to a z-score using Fisher’s transformation.These individual z-score maps were then submitted to a second-le-vel random-effects regression analysis, which included HS, thebehavioural placebo response (t-score), and the HS-by-placebointeraction variable as regressors of interest.

As for the original GLM analysis, a double statistical thresholdwas adopted to achieve a combined corrected significance levelof a < 0.05 as tested using AlphaSim.

Fig. 2. Relationship of pain intensity ratings (within-run average of 6 trials) withbehavioural placebo response (t-score; panel A) and hypnotic susceptibility (HS)score (panel B) in the test run. Separate regression lines and Pearson correlationcoefficients (r) are shown for each cue (red/green). VAS, visual analogue scale.⁄P < 0.05.

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3. Results

3.1. Behavioural results

A significant placebo response (as revealed by a t-test comparingpain ratings between ‘‘Red’’ and ‘‘Green’’ trials in the test run) wasfound in 43% of participants. HS scores ranged from 0 to 11(mean ± SD, 3.4 ± 3.3). Seventeen subjects had a low (7 of themwere placebo responders), 9 a medium (4 of them placebo respond-ers), and 2 a high HS score (one of them a placebo responder).

There was no significant correlation between HS score andplacebo response t-score (Pearson r = 0.03, P = 0.897).

Fig. 2 shows the relationship of pain ratings in the test run withplacebo response (top panel) and with HS (bottom panel). The re-sults of the analysis of covariance assessing the impact of HS onpain ratings over the 3 runs are reported in the Supplementary

Table 1BOLD signal changes related to the HS-by-placebo interaction in the test run.

Regions BA Clust

P (co

A. Anticipation phase: Regions showing a positive correlation between behavioural plataken together), but only in subjects with higher HS:

R supramarginal/angular gyrus, inferior parietal lobule 40 0.010R middle frontal gyrus 0.039

B. Perception phase: Regions showing a negative correlation between behavioural placetaken together), but only in subjects with higher HS:

L middle/inferior temporal gyrus 37, 19 0.004R middle temporal gyrus 21 0.002R middle/inferior temporal gyrus, R middle occipital gyrus 39, 37, 19 0.001L/R thalamus, L caudate 0.009L precuneus, L superior parietal lobule 7 0.009

BOLD, blood oxygen level dependent; HS, hypnotic susceptibility; BA, Brodmann area; k

Material. The main result was that HS was negatively correlatedwith overall pain intensity in the test run, but independently ofthe cue and, thus, of the placebo effect (see Fig. 2).

TAS score (mental absorption) was significantly correlated withHS score, as expected (Pearson r = 0.41, P = 0.029). FPQ score (fearof pain) showed no significant correlation with HS or placebo re-sponse score. Multiple regression interaction analysis showed thatHS and behavioural placebo responsiveness did not interact inexplaining either TAS score, FPQ score, or pain ratings in the‘‘Red’’ or ‘‘Green’’ trials of the test run.

3.2. fMRI results, anticipation phase

The placebo-related brain activity changes, without consideringHS, have been described in Lui et al. [36]. A large focus in the rightDLPFC (Brodmann area [BA] 46) showed signal increases in the testrun during ‘‘Green’’ vs ‘‘Red’’ anticipation that were significantlycorrelated with the strength of the behavioural placebo response(DLPFC ‘‘placebo’’ focus). This focus remained significant whenfear-of-pain (FPQ score) was included in the regression model.Activity changes in this region were not correlated with HS. In fact,HS showed no significant correlations with BOLD signal changes inany region in the anticipation or perception phase.

The results regarding the interaction between HS and placeboresponsiveness in the anticipation phase are shown in Table 1A.Two foci, in the right DLPFC and parietal regions, showed a signif-icant positive interaction effect (considering ‘‘Green’’ and ‘‘Red’’ tri-als together). Fig. 3 illustrates this interaction effect for the DLPFCfocus. The behavioural placebo response was associated with in-creased BOLD signal in the more hypnotisable subjects (orangelines in Fig. 3, panel B), but with decreased BOLD signal in the lesshypnotisable subjects (black lines). Within the DLPFC focus, theinteraction effect reached the cluster-wise significance thresholdalso in the ‘‘Green’’ trials alone.

This DLPFC ‘‘interaction’’ focus is adjacent to, and partly over-laps, the DLPFC ‘‘placebo’’ focus, as shown in Fig. 3, panel C.

In summary, a strong behavioural placebo response wasassociated with 1) higher activity in the right DLPFC during‘‘Green’’ compared to ‘‘Red’’ anticipation, in the whole experimen-tal population; and 2) higher total activity in this region in sub-jects with higher HS as compared to less hypnotisable subjects(see Fig. 3, panel C).

3.3. fMRI results, perception phase

Overall signal changes (‘‘Green’’ and ‘‘Red’’ trials taken together)were significantly negatively correlated with the HS-by-placebo

er level Voxel level MNI coordinates(peak)

Talairach coordinates(peak)

rr) k t Z x y z z y z

cebo response and signal changes during anticipation (‘‘Red’’ and ‘‘Green’’ trials

160 5.32 4.28 34 �54 30 34 �51 30129 5.02 4.11 36 24 22 36 24 19

bo response and signal changes during pain perception (‘‘Red’’ and ‘‘Green’’ trials

167 6.94 5.09 �56 �66 �6 �55 �64 �2214 6.33 4.81 52 �36 �10 51 �35 �7265 6.11 4.70 52 �72 �8 51 �70 �3154 4.65 3.89 �2 �8 14 �2 �7 13156 4.21 3.61 �26 �68 46 �26 �64 46

, number of voxels; MNI, Montreal Neurological Institute; R, right; L, left.

Fig. 3. Blood oxygen level dependent (BOLD) signal changes in the dorsolateralprefrontal cortex (DLPFC) related to the hypnotic susceptibility (HS)-by-placebointeraction variable during the anticipation phase of the test run. A right DLPFCcluster (panel A) showed a positive correlation between the HS-by-placebointeraction variable and BOLD signal changes, when ‘‘Red’’ and ‘‘Green’’ trials wereconsidered together. We refer to this focus as the DLPFC ‘‘interaction’’ focus.Regression lines and Pearson correlation coefficients (r) (panel B) depict thecorrelation of the behavioural placebo response t-score with cluster-averagedsignal strength (beta values) during the anticipation phase (average across both‘‘Red’’ and ‘‘Green’’ trials), separately for subjects with low (black) or medium-highHS score (dashed orange). Note that this division into subgroups serves only toillustrate the interaction – all interaction results are based on a statistical analysisperformed on the whole sample using multiple regression, without creating anysubgroups – see Methods. The interaction between placebo response and HS scoreis indicated by the difference in slope between the black and orange regressionlines. Panel C: The DLPFC ‘‘interaction’’ focus (yellow) partially overlapped withanother focus located in the right DLPFC (red), already described in [36],whichshowed a BOLD signal increase positively correlated with the behavioural placeboresponse during ‘‘Green’’ vs ‘‘Red’’ anticipation. ⁄P < 0.05; ⁄⁄P < 0.01; L = left hemi-sphere. y values represent anteroposterior coordinates (expressed in mm) in theMontreal Neurological Institute (MNI) space.

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interaction variable in 5 regions, listed in Table 1B. These included 3temporal foci: 2 symmetrically located near the occipital-temporal-parietal junction and the third, more anterior, in the right middle

temporal gyrus. The other 2 foci were in the left precuneus/superiorparietal lobule, and in a subcortical region including the thalamusand left caudate nucleus (Fig. 4A). The details of these interactionsare illustrated by the scatter plots in Fig. 4, panel B. Among the morehypnotisable subjects, the behavioural placebo response was asso-ciated with lower signal in these regions during the perceptionphase; in contrast, in subjects with lower HS, the association waseither positive (in the case of thalamus and of right posterior middletemporal gyrus) or nonsignificant. The same pattern of correlationswas present when either ‘‘Green’’ or ‘‘Red’’ trials were consideredseparately (not shown). In addition to the interaction effect, all fociexcept for the precuneus also showed a main effect of increasedactivity during the perception phase (not shown).

3.4. Functional connectivity of the right DLPFC ‘‘interaction’’ focus

To further explore the functional significance of the right DLPFC‘‘interaction’’ focus described in Section 3.2, we assessed its FCduring the test run, and explored its relationship with the HS-by-placebo interaction variable. The regions showing the strongest FCwith the right DLPFC across all subjects (irrespective of HS andplacebo) are illustrated in Fig. 5. The results regarding differencesin FC related to the HS-by-placebo interaction are summarised inTable 2 and in Fig. 6.

During the entire test run, HS and behavioural placebo responsenegatively interacted in explaining DLPFC connectivity with a largefocus comprising left anterior cingulate cortex (ACC; BA 32) and leftmedial and superior frontal gyrus (BA 8, 9, 10) (Table 2A and Fig. 6,panel B). During the perception phase only, HS and placebo re-sponse negatively interacted in predicting DLPFC connectivity with2 foci located in the right cerebellum and in the left inferior frontalgyrus (BA 47), as shown in Table 2B and Fig. 6, panel C. This meansthat among the more hypnotisable subjects, the placebo responsewas associated with reduced FC of these regions with the DLPFC,whereas subjects with lower HS showed the opposite pattern.

4. Discussion

This study aimed at exploring HS-related differences in the neuralmechanisms mediating placebo analgesia. The results can be sum-marised as follows. First, HS was not related to the overall strengthof placebo analgesia. Second, HS and placebo responsiveness inter-acted in explaining activity in a right DLPFC focus, and its functionalconnectivity pattern both during the anticipation and the perceptionphase. Third, HS and placebo responsiveness also interacted inexplaining activity in several brain regions during the perceptionphase. The present results confirm our hypothesis that differencesin HS are associated with different placebo effects, that is, similarbehavioural responses mediated by different neural mechanisms;to our knowledge, these findings also provide the first demonstra-tion that different neurocognitive mechanisms can underlie placeboresponses, depending on individual cognitive traits.

4.1. Hypnotic susceptibility is not related to the overall strength of theplacebo analgesic effect

We found no significant correlation between HS and the behav-ioural placebo response. It has been demonstrated that both scoreson HS scales [20,77] and responses to suggestions of analgesia[31,44,45] are, in part, mediated by the subject’s expectancies; thiswould appear to imply a relationship between HS and the placeboeffect [31,63]. However, our behavioural results are in line withthose of the few previous studies investigating the association be-tween HS and placebo analgesia, which failed to demonstrate it[39,66].

Fig. 4. Blood oxygen level dependent (BOLD) signal changes related to the hypnotic susceptibility (HS)-by-placebo interaction variable during the perception phase of the testrun. Five brain regions (panel A) showed a negative correlation between the HS-by-placebo interaction variable and BOLD signal changes (‘‘Red’’ and ‘‘Green’’ trials takentogether). Regression lines and Pearson correlation coefficients (r) depict the correlation of behavioural placebo response (t-score) with cluster-averaged signal strength (betavalues) during the perception phase (panel B), separately for subjects with low (black) or medium-to-high HS score (dashed orange). Note that this division into subgroupsserves only to illustrate the interaction – all interaction results are based on a statistical analysis performed on the whole sample using multiple regression, without creatingany subgroups. The interaction between placebo response and HS score is indicated by the difference in slope between the black and orange regression lines. Post. MTG,posterior middle temporal gyrus; PRECUN, precuneus; THAL, thalamus; L, left side; R, right side. Coordinates (mm) are in the Montreal Neurological Institute (MNI) space.⁄P < 0.05; ⁄⁄P < 0.01; ⁄⁄⁄P < 0.001.

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4.2. Hypnotic susceptibility and placebo responsiveness interact inexplaining activity and functional connectivity of the right DLPFC

The behavioural placebo response was associated with higheranticipatory activity in more hypnotisable subjects, as opposed toless hypnotisable subjects, in the right DLPFC and in a right inferiorparietal lobule focus.

The DLPFC and the parietal cortex are part of the frontoparietalcontrol network, which may integrate information from the exter-nal environment with stored internal representations [42] to guidedecisions and performance adjustments [70]; this is relevant forcue modulatory effects on pain. Increased anticipatory activity inthe frontoparietal network (albeit in the left hemisphere in thatstudy) was shown to predict placebo analgesia [73]. The DLPFC(especially in the right hemisphere) may exert active control onpain perception by initiating top-down pain inhibitory mecha-nisms [35,78]; its role in placebo-induced pain modulation hasbeen repeatedly demonstrated [14,36,73–75] (see, for review,[4,41]). Moreover, activity in the right DLPFC is related to the per-ceived intensity of suggestion-induced pain under hypnosis [60].

Our results point to different DLPFC-related mechanisms under-lying the placebo response, depending on the subjects’ level of HS.This hypothesis is strengthened by the results regarding the FC ofthe right DLPFC. We found that, among subjects with higher HS,the behavioural placebo response was associated with reducedDLPFC connectivity with 1) a large focus encompassing right ante-rior mid-cingulate cortex (aMCC)/perigenual ACC/medial PFC (BA32 and 8-10) during the entire test run, and 2) with 2 foci in the leftinferior frontal gyrus (IFG; BA 47) and the right cerebellum duringthe perception phase only. Subjects with lower HS showed the

opposite pattern. The aMCC/perigenual ACC region is involved inpain anticipation [56,57], mediates the emotion and fear-avoid-ance aspects of pain, and can trigger descending antinociceptivecircuits [71]. The medial PFC shows increased activity duringself-related tasks, and more generally during evaluative processing[34].

The left IFG plays a role in evaluative judgment [68,80] andhas been shown to increase activity during pain anticipation[54] and noxious stimulation [2,36,50]. The cerebellum is activeduring noxious heat pain [12], possibly in relation to motoraspects [52].

On the basis of these findings, we suggest that, only in the morehypnotisable subjects, the placebo response may involve a decou-pling, or dissociation, of (increased) DLPFC activity from that offrontal/limbic midline structures and the left lateral frontal cortex.In contrast, among the less hypnotisable subjects, the placebo re-sponse is associated with increased connectivity of the DLPFC withthese areas, possibly reflecting increased top-down modulation[5,14,15]. The present results are in line with a study demonstrat-ing reduced FC among cognitive control-related brain regions inhighly hypnotisable subjects in the hypnotic state [13], and withstudies proposing a higher neurocognitive flexibility for these indi-viduals [24–26].

4.3. The placebo response is associated with a deactivation in severalbrain regions during pain perception, but only in subjects with higher HS

Only in subjects with higher HS, the behavioural placebo re-sponse was associated with a significant decrease in activity inthe thalamus/basal ganglia, left precuneus, and bilateral temporal

Fig. 5. Regions showing strong functional connectivity (FC) with the seed region located in the right dorsolateral prefrontal cortex (indicated by the green circle) throughoutthe test run, irrespective of hypnotic susceptibility (HS) and placebo response. Clusters containing at least 50 voxels satisfying a voxel-wise significance threshold ofP < 1.9 � 10�7 are shown. Red colours indicate positive FC, blue colours negative FC. Coordinates (mm) are in the Montreal Neurological Institute (MNI) space.

Table 2Differences in functional connectivity of the right DLPFC during the test run related to the HS-by-placebo interaction.

Regions BA Clusterlevel

MNIcoordinates(peak)

Talairachcoordinates(peak)

P(corr)

k x y z x y z

A. Region whose FC with the right DLPFC during the entire test run correlates negatively with thebehavioural placebo response, but only in subjects with higher HS (subjects with lower HS showthe opposite pattern):

L medial/superior frontal gyrus, L anterior cingulate, L cingulate gyrus 9, 32,10, 8

<0.01 427 �3 40 46 �3 41 40

B. Regions whose FC with the right DLPFC during pain perception (‘‘Red’’ and ‘‘Green’’ trials takentogether) correlates negatively with the behavioural placebo response, but only in subjects withhigher HS (subjects with lower HS show the opposite pattern):

R cerebellum <0.01 212 17 �72 �38 17 �71 �28L inferior frontal gyrus 47 <0.01 211 �41 22 �6 �41 21 �6

DLPFC, dorsolateral prefrontal cortex; HS, hypnotic susceptibility; BA, Brodmann area; MNI, Montreal Neurological Institute; FC, functional connectivity; R, right; L, lefthemisphere; k, number of voxels. All coordinates are expressed in mm.

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cortex during pain perception. Interestingly, in a recent study theprecuneus and thalamus/basal ganglia showed greater fMRI signaldecreases during peak pain processing in individuals who experi-enced greater placebo analgesia [73].

The precuneus plays an important role in visuospatial imagery,episodic memory retrieval, self-processing, and consciousness [7].It is probably involved in supporting the mental representationof the self, including a general body awareness, and shows reduced

Fig. 6. Differences in seed-based functional connectivity (FC) of the right dorsolateral prefrontal cortex (DLPFC) related to the hypnotic susceptibility (HS)-by-placebointeraction variable. The seed region in the right DLPFC is indicated by the green sphere in panel A. During the entire test run, the HS-by-placebo interaction variable wasnegatively related to the seed FC with a large focus including left anterior mid-cingulate cortex (aMCC) and medial prefrontal cortex (mPFC; panel B). During the perceptionphase only, the HS-by-placebo interaction variable was negatively related to the seed FC with a focus in the left inferior frontal gyrus (IFG; panel C). Regression lines andPearson correlation coefficients (r) depict the correlation of behavioural placebo response (t-score) with cluster-averaged FC (z-transformed Pearson correlation coefficients),separately for subjects with low (black) or medium-to-high HS score (dashed orange). Note that this division into subgroups serves only to illustrate the interaction – allinteraction results are based on a statistical analysis performed on the whole sample using multiple regression, without creating any subgroups. The interaction betweenplacebo response and HS score is indicated by the difference in slope between the black and orange regression lines. Coordinates (mm) are in the Montreal NeurologicalInstitute (MNI) space. L = left side. ⁄⁄P < 0.01.

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activity during altered states of consciousness, including the hyp-notic state [38,61,62].

Interestingly, the precuneus has reciprocal connections withother areas, including mid-DLPFC, thalamus/basal ganglia, andtemporoparietal junction, which are part of a network involvedin self-relatedness evaluation [34].

Activity in the posterior aspect of the temporal lobe and occip-ital-temporal-parietal junction is also part of a common networkinvolved in basic emotional reactions to visual stimuli, such ashappiness and sadness [1]; see review in [72].

Increased thalamic activity (as found in our less hypnotisableplacebo responders) is often observed in neuroimaging studies onpain [52] and may at least in part reflect increased attention or arou-sal [49]. Reduced thalamic activity has been shown to correlate withthe magnitude of placebo analgesia in previous studies [74], which,however, did not assess HS. The basal ganglia are thought to support

a basic attentional mechanism [6]. Reduced activity in the thalamusand basal ganglia has been observed in the hypnotic state [69].

This study has some limitations. First, given the positivelyskewed HS distribution and the low number of highly hypnotisablesubjects included in our sample, our findings apply mainly to thelow-to-medium range of HS; it should be noted, however, that85% of the population fall within this range [10]; also, in a recentsurvey involving a large sample of over 1000 Italian students, Lowswere the majority, as in our sample (E. Santarcangelo, personalcommunication). Future studies including a higher percentage ofmedium-to-high hypnotisable subjects are needed in order to con-firm and extend our findings across the full range of HS.

Second, our placebo experimental protocol included both a con-ditioning procedure and verbal suggestions aimed at creatingexpectancy of pain relief; it remains to be assessed whether HS-related neural differences are related to expectancy alone [16,31].

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For instance, see a recent study, which demonstrated conditionedplacebo analgesia using nonconsciously presented (masked) condi-tioning cues [29].

Third, we did not obtain direct physiological/behavioural mea-sures of arousal and attention, and therefore could not testwhether the reductions in brain activity in the thalamus and otherareas, which accompanied placebo analgesia in the more hypnoti-sable subjects, are related to modulation of these factors.

Fourth, we cannot exclude the possibility that activity in theidentified brain areas merely correlates with the behavioural pla-cebo response, without being causally involved in generating theplacebo effect. However, this interpretation seems unlikely, be-cause several of these regions, including the DLPFC, ACC, and thal-amus, have been demonstrated to show changes in activity inresponse to placebo manipulations [4,36].

Fifth, it seems reasonable to assume that placebo responsesbased on different neural mechanisms should also be experienceddifferently by the subject; this was not assessed in the presentstudy. Future investigations should use postexperimental inter-views or questionnaires to assess aspects of the subject’s experi-ence during the experiment, including, for example, thoughtsabout the validity of the cues, attention paid to the cues and painstimuli, distraction, levels of fear, relaxation, and consciousness,and possible dissociative phenomena.

4.4. Conclusion

On the basis of our findings, it can be hypothesised that differ-ent brain mechanisms may be involved in placebo analgesia,depending on the subjects’ level of HS. Our results therefore pointto multiple neurocognitive targets for modulating the placebo ef-fect, whose importance in the clinical setting awaits furtherinvestigation.

Conflict of interest statement

The authors declare no conflict of interest.

Acknowledgements

The authors thank Dr. Luana Colloca, Dr. Davide Anchisi, and Dr.Davide Duzzi for taking part in the fMRI experimental session; Dr.Giuseppe Pagnoni for advice in the functional connectivity analy-sis; Dr. Marco Serafini, Dr. Luca Nocetti, and Dr. Matteo Corradinifor their excellent technical help; and the Fondazione Cassa diRisparmio di Modena for its financial support to the Modena MRcenter. Funded by grants from the Fondazione Cassa di RisparmioModena and from M.I.U.R., Italy to C.A.P.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.pain.2013.03.031.

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