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Affective brain regions are activated during the processing of pain-relatedwords in migraine patients

Judith Eck 1, Maria Richter ⇑,1, Thomas Straube, Wolfgang H.R. Miltner, Thomas WeissDepartment of Biological and Clinical Psychology, Institute of Psychology, Friedrich Schiller University of Jena, Jena, Germany

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 5 November 2010Received in revised form 7 January 2011Accepted 14 January 2011

Keywords:Pain-related wordsMigrainePain matrixAffectivefMRI

0304-3959/$36.00 � 2011 International Associationdoi:10.1016/j.pain.2011.01.026

⇑ Corresponding author. Tel.: +49 3641 935255.E-mail address: maria.richter@med.uni-jena.de (M

1 These author contributed equally to this work.

a b s t r a c t

Several brain areas that constitute the neural matrix of pain can be activated by noxious stimuli and bypain-relevant cues, such as pictures, facial expressions, and pain-related words. Although chronic painpatients are frequently exposed to pain-related words, it remains unclear whether their pain matrix isspecifically activated during the processing of such stimuli in comparison to healthy subjects. To answerthis question, we compared the neural activations induced by verbal pain descriptors in a sample ofmigraine patients with activations in healthy controls using functional magnetic resonance imaging. Par-ticipants viewed pain-related adjectives and negative, non-pain-related adjectives that were matched forvalence and arousal and were instructed to either generate mental images (imagination condition) or tocount the number of vowels (distraction condition). In migraine patients, pain-related adjectives as com-pared with negative adjectives elicited increased activations in the left orbitofrontal cortex and anteriorinsula during imagination and in the right secondary somatosensory cortex and posterior insula duringdistraction. More pronounced pain-related activation was observed in affective pain-related regions inthe patient as compared with the control group during imagination. During distraction, no differentialengagement of single brain structures in response to pain-related words could be observed betweengroups. Overall, our findings indicate that there is an involvement of brain regions associated with theaffective and sensory-discriminative dimension of pain in the processing of pain-related words inmigraine patients, and that the recruitment of those regions associated with pain-related affect isenhanced in patients with chronic pain experiences.

� 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

1. Introduction

Emotions, empathy, attention, learning, and expectations exerta strong impact on the processing and evaluation of noxious events[27,28,33,51,67,68] and its underlying neural substrates [16,24,26,36,57,60,66,70]. Furthermore, it was shown that non-noxious stim-uli can induce expectations [28,47,64], memories [25], imagina-tions [40], and empathy for pain [6,55,24,60] when these stimuliwere previously associated with a painful experience. Accordingto Hebb’s network concept of the organization of perception, learn-ing, and memory, it can be further postulated that whenever weexperience acute pain, its semantic and emotional representationsbecome simultaneously activated and associated with neuralstructures that process noxious events and constitute the experi-ence of pain [5,21]. Thus, we assume that verbal terms depictingpain-related experience activate brain areas that are engaged inthe processing of noxious stimuli. This assumption is in line with

for the Study of Pain. Published by

. Richter).

the finding that the processing of pain-related verbal material inhealthy subjects is specifically associated with enhanced activationwithin areas of the pain matrix such as the anterior cingulate cor-tex (ACC), the secondary somatosensory cortex (SII), the insularcortex, and the prefrontal and the parietal cortex [18,42,52]. Fur-thermore, if individuals vary in the amount of experienced pain,it is expected that those brain areas are particularly sensitive topain-associated semantics in individuals with chronic pain experi-ence. Indeed, it was shown that chronic pain patients recall morepain-related life events in response to ambiguous words thanhealthy individuals and exhibit larger event-related potentials[23,35]. In addition, pain patients show altered electroencephalog-raphy (EEG) responses when receiving a noxious stimulus after thepresentation of pain-related verbal stimuli [12,37].

Furthermore, pain-specific activation was also found whenattention was focused on pain-irrelevant aspects of the stimuli,such as the gender of faces expressing pain [58] or the numberof vowels of the pain-related words presented [52]. Studies usingthe Stroop paradigm showed slightly delayed responses to pain-related words during implicit processing [2,62]. In addition,enhanced left-hemispheric neural negativity was observed in

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Table 1Participant characteristics and performance data.

Migraine patients Healthy controls

NMale/female gender 1/9 1/9Age, mean (SE) 37.9 (4.7) 37.8 (4.8)BDI-2, mean (SE) 6.2 (1.6) 2.1 (0.5)

Migraine history2–5 years N = 1 —P6 years N = 9 —Migraine attack frequencySeveral times a month N = 2 —Once a week N = 1 —Several times a week N = 7 —

Average duration of a migraine attackSeveral hours N = 6 —63 days N = 2 —>3 days N = 2 —

Amount of pain-related impairmenta

During past 4 weeks, mean (SE) 3.3 (0.3) 1.1 (0.1)During past 6 months, mean (SE) 3.8 (0.3) 1.1 (0.1)During lifetime 3.4 (0.3) 1.2 (0.1)

Difficulty ratings (0–10 rating scale)Imagination task, mean (SE) 2.6 (0.7) 0.8 (0.3)Distraction task, mean (SE) 3.6 (0.8) 1.8 (0.6)

SE, standard error.a 1 = 0–5%, 2 = 5–10%, 3 = 10–20%, 4 = 20–50%, 5 = 50–80%, 6 = >80%.

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chronic pain patients while processing supra-threshold pain words[14]. Those results point out that the perception of pain-relatedwords provokes enhanced neuronal and behavioral responses evenif semantic aspects of the words are not processed explicitly.

Based on these observations, the present study aimed toinvestigate whether chronic pain patients show enhanced corticalactivations in response to pain-related words in comparison tonon-pain-related words with negative valence. We comparedpain-related and non-pain-related negative adjectives to distin-guish effects of valence, arousal, and pain-relevance of the stimuli.Furthermore, in migraine patients, we expected more pronouncedpain-specific activations within regions of the pain matrix than inhealthy control subjects. Based on previous results showingdifferent activations when subjects focus on a distraction task ascompared with explicit processing of the semantics, 2 differentattention manipulations (imagination and distraction) were usedto investigate whether the postulated differences are related tothe focus of attention.

2. Methods

2.1. Subjects

Ten patients with migraine (9 women; 22–65 years old, meanage = 37.9 years) and 10 healthy pain-free controls (9 women;23–63 years old, mean age = 37.8 years), matched for gender, age,and education, participated in this study as paid volunteers.Patients with migraine were chosen because these patients sufferfrom chronic pain and experience pain attacks repeatedly but canbe investigated during pain-free intervals, to ensure that no acutepain occurs during the experiment that might interfere with taskperformance and cortical activations. Migraine patients wererecruited via the Department of Neurology, Friedrich SchillerUniversity medical school, and were diagnosed according to thediagnostic criteria of the International Headache Society (IHS) bymedical headache specialists. Four patients were diagnosed asmigraine with aura and 6 patients as without aura.

All participants were native German speakers and right-handedas assessed by the Edinburgh Handedness Inventory (EHI) [41], andwere interviewed before the experiment to assess former pain epi-sodes or current pain disorders by clinical interview carried out bya trained clinical psychologist and screened with the SymptomChecklist-90-R (SCL-90-R) [15]. None of the healthy controls re-ported earlier pain episodes or any neurological disorder. It wasensured that migraine patients did not have from additional neuro-logical or chronic disorders. Because depression may alter the pro-cessing of pain-related words [38], depressive symptoms wereassessed with a German version of the Beck Depression Inven-tory-II (BDI-II) [20]. Patients were investigated during a mi-graine-free interval, ie, they reported no actual pain on the dayof the experiment. Personal and clinical characteristics of partici-pants are summarized in Table 1. In accordance with the Declara-tion of Helsinki, written informed consent was obtained from eachparticipant before the study, and the Ethics Committee of theFriedrich Schiller University approved the experiment.

2.2. Stimulus material

Verbal stimuli included pain-related, non-pain-related negative,neutral, and positive adjectives. A total of 40 words were selectedin a pilot study and rated for valence, arousal, and pain relevance.Pain-related adjectives, affectively negative but non-pain-relatedadjectives, and positive adjectives were matched for arousal, andpain-related and affectively negative but non-pain-related adjec-tives additionally were matched for valence. Furthermore, catego-ries of adjectives were also matched for the number of syllables

and the frequency in German language (COSMAS II database,http://www.ids-mannheim.de/cosmas2/). (For a more thoroughdescription of stimuli selection and a detailed list of these stimuli,see Richter et al. [52].) During an interview at the end of the exper-iments, participants were asked to name representative examplesof images that they created during the imagination condition foreach word category. Positive words were mostly associated withcosy, intimate, or relaxing situations, negative words with fearfulor violent images or with disgusting objects, neutral words withimages of shapes or buildings, and pain-related words with painsensations in different body parts. Five migraine patients and 1control subject named an imagination of headache as an examplefor the pain-related words.

The hypotheses of the present work focus on the differential ef-fects of pain-related in comparison to negative verbal stimuli with-in and between the 2 groups. Therefore, we do not reportobservations related to the processing of positive and neutral ver-bal stimuli, and we did not compare the different attention condi-tions directly.

2.3. Experimental procedure

Examples of each word category were presented while partici-pants were familiarized with the experimental procedure. Stimuliwere projected via a video beamer onto a screen mounted on thehead coil of the scanner. Each participant completed 2 runs of14-minutes’ duration in accordance with the study by Richteret al. [52]. The experimental design is displayed in Fig. 1. In run1, subjects were instructed to focus on the semantics of the wordsby generating a mental image of a situation associated with theadjective (imagination condition). To increase compliance, subjectswere told that after the experiment they would be asked to giveexamples of their imaginations. In run 2, participants were askedto count the number of vowels of the presented adjectives in orderto shift the attention away from the semantics to the perceptualfeatures of the words (distraction condition). The sequence of run1 and run 2 was counterbalanced across subjects. Word stimuliwere presented in 16 blocks per run (4 blocks of each word

Fig. 1. Schematic representation of the experimental paradigm exemplified on the imagination condition.

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category). The blocks consisted of 5 adjectives; each adjective wasdisplayed for 4.1 seconds, followed by a blank screen for 0.1 sec-ond. Each block was followed by a delay phase in which a fixationcross was presented for 11 seconds followed by a decision intervalof 7 seconds’ duration. After the decision task, a fixation cross waspresented as a baseline condition for 13 seconds. During the deci-sion interval at the end of the imagination blocks, subjects were re-quested to choose the correct word category from 2 categoriespresented (e.g., A = negative; B = pain-related). All participants cat-egorized the words properly. At the end of the distraction blocks, 2numbers were presented in the decision interval (e.g., A = 14;B = 12). Participants had to specify the number of counted vowelsfor the last word block presented by choosing 1 of the 2 numbers.Subjects responded via a magnetic resonance imaging (MRI)–com-patible button response box fixed under their right hand. Eachword was presented 4 times throughout the experiment, twice ineach run. The order of the words within the blocks and the orderof the blocks within each session were pseudo-randomized withthe restriction that the same word category was not presentedtwice in succession. After the scanning sessions, participants ratedthe mean valence and arousal of each word category on a 9-pointvisual rating scale, with low scores indicating low arousal and po-sitive valence, and high scores indicating high arousal and negativevalence. Finally, all subjects completed a questionnaire about theirpresent pain to ensure that all participants were free of pain duringthe fMRI experiment. Furthermore, a rating of task difficulty wasquoted for both tasks on a 0–10 visual rating scale.

2.4. Data acquisition

MRI data were acquired on a 1.5-Tesla whole-body scanner (Mag-netom Vision Plus, Siemens, Medical Systems, Erlangen, Germany).First, a T1 weighted high-resolution structural image was obtained(192 slices, TR = 15 ms, TE = 5 ms, flip angle = 30�, matrix = 256 �

256, slice thickness = 1 mm, no gap, voxel size = 1 � 1 � 1 mm).Afterward, 2 runs of 212 multislice volumes were acquired using aT2⁄ weighted echo-planar sequence (TR = 4000 ms, TE = 50 ms, flip

angle = 90�, matrix = 64 � 64, FoV = 192 mm), with each volumecomprising 40 axial slices covering the whole brain (no gap, voxel si-ze = 3 � 3 � 3 mm). Before imaging, a shimming procedure was per-formed to improve field homogeneity.

2.5. Data analysis

Behavioral data were analyzed with SPSS 13.0 (SPSS Inc., Chi-cago, IL). The BDI-II scores of all subjects were included in an inde-pendent-samples t-test for a comparison of migraine patients andhealthy controls. The valence and arousal ratings of the presentedwords as well as the error rates of the vowel counting task weresubmitted as dependent variables to separate analyses of variance(ANOVAs) with repeated measures on word category (pain-relatedvs negative) as within subject factor and group (migraine patientsvs healthy controls) as between-subject factor. Because this reportfocuses on the evaluation of neural activations induced by theprocessing of pain-related as compared with non-pain-relatedaffective cues with equal valence and arousal, only negative andpain-related words were included in the ANOVAs.

The fMRI data were preprocessed with the Statistical ParametricMapping software (SPM2, Wellcome Trust Centre for Neuroimag-ing, London, UK). The first 4 scans of each run were discarded fromanalysis to eliminate nonequilibrium effects of magnetization. Pre-processing included slice scan time correction and motion correc-tion. Inspection of the movement parameters indicated nomovement larger than 3 mm or 3� in any direction. To accountfor any residual effects of movement, the estimated movementparameters were included in the statistical analysis. Furthermore,echo planar imaging (EPI) scans were normalized into the standardbrain atlas from the Montreal Neurological Institute (MNI) space

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using the EPI template of SPM2. The normalized images with a vox-el size of 2 � 2 � 2 mm were spatially smoothed with an 8-mmFWHM Gaussian kernel. Finally, a temporal high-pass filter of 1/128 Hz was applied to remove low-frequency drifts.

Afterward, a first-level analysis was computed subject-wisewith SPM2. Five regressors were modeled for each session, andthe resulting boxcar functions were convolved with a canonicalhemodynamic response function. The regressors represented the4 different word categories in the imagination and the distractioncondition and the delay combined with the decision interval inboth conditions (the last regressor mentioned was modeled to pre-vent that activity in this time period influences the baseline). Toaccount for serial autocorrelations in fMRI time series, the AR(1)algorithm was applied. Contrast images for negative words andpain-related words against baseline were computed separatelyfor the imagination and distraction condition, and for each subject.These first-level contrasts were entered in a full-brain, second-le-vel, random-effects analysis, which was computed using SPM5(Wellcome Trust Centre for Neuroimaging, London, UK). One anal-ysis of covariance with the factors word category (pain-related vsnegative), task (imagination vs distraction), group (patients vs con-trols), and 1 covariate of no interest (BDI-II scores) was calculated.A voxel threshold of P < .005 and a cluster threshold of P < .005,uncorrected for multiple comparisons, were used to identify clus-ters of activation [32]. This resulted in a minimal cluster extentof 304 contiguous voxels. Furthermore, to present the overall neu-ral network involved in the processing of pain-related words, weused a more conservative voxel threshold of P < .001 combinedwith a cluster threshold of P < .005, resulting in a minimal clustersize of 167 voxels, for the contrasts against baseline [13].

Although we do not refer to the comparisons against neutralwords in our hypotheses, we included the results of the ANOVAincluding 3 conditions for factor Word category (pain-related, neg-ative, and neutral) as Supplementary material to survey the activa-tion differences in comparison to affectively neutral stimuli(neutral vs pain-related, or neutral vs negative, respectively).

3. Results

In the present work, we focus on the results of migraine pa-tients and the comparison of patients vs gender- and age-matchedcontrols regarding pain-related and negative words. In addition,we also show the comparison of the pain descriptors with the fix-ation interval for healthy controls to demonstrate that both groupsof participants were properly engaged in the instructed task.

Table 2Mean ratings and standard errors of valence and arousal for all categories.

Migraine patients Healthy controls

Valence ratingsa, mean (SE)Pain-related words 8.7 (0.2) 8.3 (0.2)Negative words 8.3 (0.2) 8.3 (0.2)Neutral words 4.9 (0.1) 4.9 (0.1)Positive words 1.2 (0.2) 1.6 (0.1)

Arousal ratingsb, mean (SE)Pain-related words 7.3 (0.5) 6.5 (0.8)Negative words 6.4 (0.5) 5.9 (0.5)Neutral words 2.0 (0.5) 1.4 (0.2)Positive words 7.3 (0.4) 7.4 (0.3)

SE, standard error.a Valence was measures on a 9-point rating scale, with 1 indicating maximum

positive and 10 indicating maximum negative valence.b Arousal was measures on a 9-point rating scale, with 1 indicating minimum and

10 indicating maximum arousal.

3.1. Behavioral and performance data

Levene’s test for equality of variances of BDI-2 scores revealedsignificant differences. Therefore, we applied Welch’s t-test for un-equal variances [71]. The t-test showed significantly higher BDI-2scores for migraine patients as compared with healthy controls(T(10.86) = �2.50, P < .05). Hence, the BDI-2 scores of subjects wereincluded as a nuisance factor in the statistical analysis of the fMRIdata to account for differences between groups related to depres-sive symptoms.

ANOVAs of post-scanning arousal and valence ratings indicatedno significant effect of word category (valence: F(1) = 2.25, P =.151; arousal: F(1) = 3.53, P = .076), or group (valence: F(1) = 1,P = .331; arousal: F(1) = 0.87, P = .363), and no group by word cate-gory interaction (valence: F(1) = 2.25, P = .151; arousal: F(1) = 0.14,P = .711) (Table 2).

The error rates, defined as the percentage of trials in which thewrong number of vowels was counted, were independent of factorsWord category (F(1) = 0.05, P = .830) and Group (F(1) = 0.03,

P = .861). Furthermore, the ANOVA indicated no interaction be-tween factors Group and Category (F(1) = 0.05, P = .830).

The rating for task difficulty was marginally higher for the dis-traction (mean = 2.7 ± 0.52) as compared with the imaginationcondition (mean = 1.7 ± 0.42) within the whole group (T = 1.59,P = .13) similar to the results by Richter et al. [52]. Furthermore,we found higher difficulty rating for patients compared with con-trols, which were significant during the imagination condition(T = 2.37, P = .03), and indicated a trend during distraction(T = 1.82, P = .09) (Table 1).

3.2. Neuroimaging data

3.2.1. Neural activation for imagination of pain-related words againstbaseline

Both migraine patients and healthy controls showed a similarnetwork of activated brain regions in response to pain-relatedwords against baseline during the imagination task, including acti-vations in the striate and extrastriate cortex of the occipital lobeextending to the left fusiform gyrus and the cerebellum bilaterally,the left supplementary motor area (SMA), the left medial superiorfrontal gyrus (SFG), and the left insula. Furthermore, widely dis-tributed activations were found in the left lateral frontal lobe, com-prising dorsolateral prefrontal areas (DLPFC), the rostrolateralprefrontal cortex (RLPFC), the ventrolateral prefrontal cortex(VLPFC), the orbitofrontal cortex (OFC), and the premotor cortex(Table 3). In migraine patients, these frontal activations extendedalso to the temporal pole and the superior temporal gyrus (STG)and additional activations were detected in the right VLPFC andthe right OFC extending to the right insula, the right temporal poleand the putamen (Fig. 2A). Healthy controls showed additionalactivation in the right SMA and the right SFG (Fig. 2B). Baselinecompared with pain-related words revealed no significantly deac-tivated brain regions in the group of patients, but bilateral deacti-vations in the precuneus, in the right superior temporal andangular gyrus in the control subjects.

3.2.2. Effect of group and word category during imaginationIn the group of migraine patients, the direct comparison of pain-

related and negative words revealed that activation in the left OFCextending to the anterior insula was more pronounced in responseto pain-related than to negative words (Fig. 2C and Table 4).

The interaction contrast between word category and group re-vealed increased activations for migraine patients relative tohealthy controls in frontal and temporal cortices. A left lateralizedfrontal cluster included the OFC and the anterior insula. The tem-poral activations, by contrast, were right lateralized and comprised

Table 3Activations to pain-related words versus baseline during the imagination task.

Brain region Brodmann area t-Value Cluster size Stereotacticcoordinates

x y z

Patients: pain > baselineOccipital lobe, fusiform gyrus, cerebellum B 17, 18, 19, 37 8.99 89,136 16 �84 �16Lateral frontal lobe, temporal pole, STG, insula L 44, 45, 6, 10, 11, 47, 46, 9, 38, 22 7.47 32,736 �46 48 �8IFG, temporal pole, insula, putamen R 44, 45, 47, 38 5.77 5304 50 50 �6SFG, SMA L 6, 8 5.05 1672 �4 16 54Patients: baseline > painNo significant clusters of activation

Healthy controls: pain > baselineOccipital lobe, fusiform gyrus, cerebellum B 17, 18, 19, 37 8.42 50,880 �14 �88 �12Lateral frontal lobe, insula L 44, 45, 6, 9, 10, 46, 47 5.53 20,600 �40 26 10SFG, SMA B 6, 8 5.88 6496 �6 10 56Inferior and middle temporal gyrus L 37, 21 4.41 1880 �56 �54 �8

Healthy controls: baseline > painPrecuneus B 7 4.67 4608 8 �58 40STG, angular gyrus R 22, 39 5.45 2776 60 �62 16

Listed are clusters of activation with an uncorrected voxel threshold of P < .001 and an uncorrected cluster threshold of P < .005 correspondingto a cluster size of 1336 mm3. MNI coordinates (x, y, z) and t-values are provided for the local voxel maxima of the respective clusters.Corresponding neuroanatomical regions, Brodmann areas, laterality (L, left; R, right; B, bilateral), and cluster size (in mm3) are described.STG, superior temporal gyrus, IFG, inferior frontal gyrus, SFG, superior frontal gyrus, SMA, supplementary motor area.

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the right inferior temporal gyrus (ITG), the right fusiform gyrus, aswell as the hippocampus and parahippocampal areas (Fig. 2D andTable 4).

3.2.3. Neural activation for distraction from pain-related wordsagainst baseline

The cortical network activated during the distraction task bythe processing of pain-related words compared with baseline com-prised the striate and extrastriate cortex of the occipital lobeextending to the bilateral inferior and the left superior parietallobe, the left primary somatosensory cortex, the left inferior tem-poral gyrus, and the cerebellum (Table 5). Additional bilateral acti-vations were found in the frontal lobe, including the primary motorcortex, the premotor cortex, and the inferior and the middle frontalgyrus. For migraine patients, the left frontal activations extendedto the VLPFC and DLPFC. In healthy controls, bilateral frontal acti-vations extended slightly more to the SFG. Finally, both groupsshowed bilateral activation, more pronounced in the left hemi-sphere, in the SMA extending to the superior medial gyrus (SMG)and slightly to the dorsal part of the anterior cingulate cortex(dACC) (Fig. 3A and B). No deactivated clusters were found for mi-graine patients. Healthy controls, in contrast, showed a deactivatedcluster in the left angular gyrus extending to the middle temporalgyrus (MTG) as well as in the bilateral precuneus and the posteriorcingulate cortex (PCC) extending to the calcarine gyrus.

3.2.4. Effect of group and word category during distractionIn the patient group, we found 1 cluster extending from the pos-

terior insular cortex to secondary somatosensory cortex and supra-marginal cortex that was stronger activated for pain-related wordsas compared with negative words. In the converse contrast, theprecuneus showed increased activation. The interaction betweenfactors word category and group failed to reveal any significantclusters of activation during the distraction task (Fig. 3C andTable 6).

4. Discussion

In this fMRI study, we tested whether neural responses withinthe pain circuitry can be elicited by the processing of pain-relatedas compared with non-pain-related negative affective adjectives inmigraine patients in comparison to healthy controls.

4.1. Imagination condition

The neural network involved in the processing of pain descrip-tors during imagination comprised activations in the ventral visualpathway and within a left lateralized language network was iden-tified for both groups, including temporal and lateral frontal struc-tures, corresponding to activations found during language tasks[53]. The engagement of ventrolateral, dorsolateral, and rostrolat-eral prefrontal structures might be related to the demands of theimagination task, including working and long-term memory pro-cesses [4,9]. Importantly, activations were identified in the orbito-frontal cortex and the anterior insula. Both structures are involvedin pain processing, pain imagination [3,40,50,69], and in the pro-cessing of emotional stimuli [29,45].

The comparison of pain-related and negative adjectives inmigraine patients revealed enhanced activation in the left anteriorinsula, which has been previously associated with the processingof selective C-fiber input [69], the affective component of pain pro-cessing [3,56], and the processing of pain-related information[40,46]. In addition, Roy et al. found that activation of the rightanterior insula co-varied with pain perception modulated byaffective pictures [54]. This higher-order mechanism of pain mod-ulation was interpreted as the integration of interoceptive infor-mation with ongoing emotional states. Thus, we hypothesize thatour semantic pain-related stimuli induced imaginations thatevoked an enhanced threat to the bodily integrity of migrainepatients and consequently activated the anterior insula, as shownin previous studies [11,40]. Furthermore, migraine patients alsoshowed stronger activation of the left OFC in response to painwords compared with negative words. This cortical structure isthought to be involved in higher cognitive functions includingthe representation of the reward value of primary reinforcingpositive and negative stimuli such as taste, touch and pain[29,30,34,72], and also in assigning reinforcement value to previ-ously neutral stimuli. Thus, we suggest that the OFC is activatedby visual pain-related information when both pain as the primaryaversive reinforcer as well as pain descriptors were previously pro-cessed simultaneously. It was also shown that the OFC showsstronger activations by negative than by positive emotional pic-tures [54]. Therefore, the stronger activation might be due to en-hanced affective involvement in migraine patients while viewingpain-related verbal cues compared with negative cues. In

Fig. 2. Activation maps of the imagination condition illustrating the contrast of pain-related words vs baseline for migraine patients (A) and healthy controls (B), thecomparison of pain-related and negative words for migraine patients (C), as well as the interaction between group of subjects (migraine patients vs healthy controls) andword category (pain-related words vs negative words) (D). Activations are superimposed on a single-subject MNI (Montreal Neurological Institute standard brain) template,displayed in neurological convention.

Table 4Activations to pain-related words versus negative words in migraine patients, and interaction between group and word category during theimagination task.

Brain region Brodmann areas t-Value Cluster size Stereotactic coordinates

x y z

Patients: pain > negativeLateral and mid-orbitofrontal cortex, anterior insula L 10/11/47 4.57 2864 �24 36 �16

Patients: negative > painNo significant clusters of activation

Pain – negativePatients > pain – negativeHealthy controls

Lateral and mid-orbitofrontal cortex, IFG, anterior insula L 10/11/47 4.58 3696 �26 30 �14Fusiform gyrus, hippocampus, para-hippocampal gyrus, ITG R 20,37,36 4.34 4960 38 �36 �18

Pain – negativeHealthy Controls > pain – negativePatients

No significant clusters of activation

Listed are clusters of activation with an uncorrected voxel threshold of P < .005 and an uncorrected cluster threshold of P < .005 correspondingto a cluster size of 2432 mm3. MNI coordinates (x, y, z) and t-values are provided for the local voxel maxima of the respective clusters.Corresponding neuroanatomical regions, Brodmann areas, laterality (L, left; R, right; B, bilateral), and cluster size (in mm3) are described.IFG, inferior frontal gyrus, ITG, inferior temporal gyrus.

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Table 5Activations to pain-related words versus baseline during the distraction task.

Brain region Brodmann area t-Value Cluster size Stereotactic coordinates

x y z

Patients: pain > baselineOccipital lobe, inferior and superior parietal lobe,

S1, ITG, cerebellumB 17, 18, 19, 7, 2, 39, 40, 37 8.14 109,000 �34 �80 �20

Inferior and middle frontal gyrus, PMC, M1, VLPFC, DLPFC L 44/45, 6, 4, 9, 46 6.90 14,736 �44 6 30Inferior and middle frontal gyrus, PMC, M1 R 44, 9, 6, 8, 4 5.33 5920 50 10 30Superior medial gyrus, SMA, ACC B 6, 8/32 4.88 2280 �6 14 50

Patients: baseline > painNo significant clusters of activation

Healthy controls: pain > baselineOccipital lobe, inferior and superior parietal lobe,

S1, ITG, cerebellumB 17, 18, 19, 7, 2, 39, 40, 37 9.14 12,4552 �34 �88 �8

Inferior, middle and superior frontal gyrus, PMC, M1 L 44, 6, 4, 9 7.24 13,904 �44 6 30Inferior, middle and superior frontal gyrus, PMC, M1 R 44, 6, 8, 9, 4 5.51 11,712 52 4 46Superior medial gyrus, SMA/ ACC B 6, 8/32 7.59 9640 �4 8 56

Healthy controls: baseline > painMiddle temporal gyrus, angular gyrus L 39 5.72 6832 �48 �66 20Posterior cingulate gyrus, precuneus, calcarine gyrus B 30/23/31, 17, 18 5.58 6360 �6 �56 16

Listed are clusters of activation with an uncorrected voxel threshold of P < .001 and an uncorrected cluster threshold of P < .005 correspondingto a cluster size of 1336 mm3. MNI coordinates (x, y, z) and t-values are provided for the local voxel maxima of the respective clusters. Thecorresponding neuroanatomical regions, the Brodmann areas, the laterality (L, left; R, right; B, bilateral), and the cluster size (in mm3) aredescribed.ITG, inferior temporal gyrus, M1, primary motor cortex, S1, primary somatosensory cortex, PMC, premotor cortex, DLPFC, dorsolateral pre-frontal cortex, VLPFC, ventrolateral prefrontal cortex, SMA, supplementary motor area, ACC, anterior cingulate cortex.

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summary, our results indicate that the processing of pain-relatedverbal material is specifically accompanied by increased activa-tions of regions related to the affective experience of pain in sub-jects characterized by frequent pain.

The direct comparison of migraine patients and healthy controlsduring imagination revealed enhanced activations in the patientgroup in right medial temporal lobe structures when controllingfor task demands and the emotionality of the words. Because med-ial temporal lobe structures are crucial for declarative and associa-tive memory processes and for the detailed construction of mentalimages [19,39,65], we assume that pain patients, because of theirgreater amount of pain experience, generated more detailed andvivid mental scenes for pain descriptors in relation to negativewords. In addition, patients showed increased responses to paindescriptors within the left anterior insula and the left OFC, suggest-ing that they process pain-related information in a manner differ-ent from that in controls [35,61]. This increased activation is inaccordance with the assumption that migraine patients establishan associative memory network for pain with more widespreadand sensitive connections to pain-related information because oftheir distinct pain-related experiences. Therefore, the memory net-work of patients might be more easily activated in top–downdirection by several kinds of information associated with pain.

There are some further aspects that might, at least in part, ac-count for these differences between migraine patients and con-trols. A tendency towards higher arousal for pain-related wordswas inspected in our patient group, ie, a confounding effect ofarousal cannot completely be excluded. Furthermore, enhancedarousal and activation in various brain areas in migraine patientscompared with controls might be due to a migraine-specific deficitin neuronal habituation, more specifically, an increased respon-siveness to repeated external stimuli [8,10,63]. Regarding the factthat the same word stimulus was repeated 4 times throughoutour experiment, these migraine-specific mechanisms might haveaffected the comparison between groups. Nevertheless, we donot assume that those habituation deficits are more pronouncedfor the processing of pain-related words compared with otherword categories. Furthermore, we cannot exclude that differences

might partially be related to perceived task difficulty betweengroups. Although we did not measure the vividness of images gen-erated by our participants, there might be group-specific differ-ences regarding those imagery abilities that might additionallyaccount for the activation differences we found.

4.2. Distraction condition

The cortical network activated by pain descriptors during thevowel-counting task can be clearly associated with the task de-mands of this condition and points out participants’ adequate per-formance. Both groups of participants showed stronger activationin the dorsal than in the ventral visual stream, including the striateand extrastriate cortex extending to the posterior parietal lobe andthe inferior temporal gyrus. This finding is in line with the resultsobtained by Price et al., using a feature detection task [48]. Visualsearch and working memory components related to the task mighthave contributed to the activations in a bilateral fronto-parietalnetwork [1,17,31]. Further activations were found in structures in-volved in pain processing for both groups, including the left poster-ior parietal cortex, the ACC, the left primary somatosensory cortex,and, for migraine patients, also the left dorsolateral prefrontalcortex. Because those activations might be a result of the taskdemands of the visual stimuli presented [7,22,43,59], pain descrip-tors were also compared with non-pain-related negative adjectivesduring the distraction condition.

The direct comparison in the group of patients revealed en-hanced activations within the right posterior insula and S2, sug-gesting that the processing of pain descriptors during distractionis characterized by a specific recruitment of regions related to sen-sory-discriminative aspects and to the integration of sensation andaffect in migraine patients [44,49]. Previously, 2 other studies re-vealed specific pain-relevant activations in the affective subdivi-sion of the ACC while attention was distracted from pain-relatedinformation [52,58]. It was shown that self-referred pain imagina-tions enlarge activation of S2 and the insula compared with imag-ing other’s pain [11,24,40]. Accordingly, migraine patients mightautomatically activate self-referred pain-related images when

Fig. 3. Activation maps of the distraction condition illustrating the contrast of pain-related words vs baseline for migraine patients (A) and healthy controls (B), as well as thecomparison of pain-related and negative words for migraine patients (C). Activations are superimposed on a single-subject MNI (Montreal Neurological Institute standardbrain) template, displayed in neurological convention.

Table 6Activations to pain-related words versus negative words in migraine patients, and interaction between group and word category during thedistraction task.

Brain region BA t-Value Cluster size Stereotactic coordinates

x y z

Patients: pain > negativePosterior insula, supramarginal gyrus, secondary somatosensory cortex R 40 4.15 497 40 �22 30

Patients: negative > painPrecuneus B 7 3.84 2752 �8 �60 56Pain – negativePatients > pain – negativeHealthy controls

No significant clusters of activationPain – negativeHealthy controls > pain – negativePatients

No significant clusters of activation

Listed are clusters of activation with an uncorrected voxel threshold of P < .005 and an uncorrected cluster threshold of P < .005 correspondingto a cluster size of 2432 mm3. MNI coordinates (x, y, z) and t-values are provided for the local voxel maxima of the respective clusters.Corresponding neuroanatomical regions, Brodmann areas (BA), laterality (L, left; R, right; B, bilateral), and the cluster size (in mm3) aredescribed.

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exposed to pain words, even though attention is distracted fromthe semantics. Furthermore, it was reported that the implicit pro-cessing of pain faces in comparison to anger faces resulted in acti-vation of S2 and insular cortex. This effect was interpreted in termsof enhanced arousal or aversive conditioning induced by thosekinds of stimuli [58]. The activations that we found might thereforebe related to the process of aversive conditioning, which is morepronounce for pain-related cues compared with negative affectivebut non-pain-related cues in migraine patients.

When the processing of pain-related adjectives was comparedbetween the patient group and healthy controls while controllingfor effects of valence and arousal in the interaction contrast, nosignificant differences were found. This finding might lead to theassumption that the amount of pain experience is irrelevantfor the neural processing of verbal pain-related information whenthe focus of attention is not directed to the semantics. However,the higher amount of pain-associated experiences in migrainepatients might enhance the affective valence or the psychophysio-logical arousal induced by pain-related stimuli. Consequently, thedifferences of the above-mentioned contrast might be understateddue to the procedure of controlling for valence and arousal.

4.3. Study limitations

A general limitation of the study is the low number of partici-pants because of the stringent inclusion criteria and several drop-outs, which forced us to adopt less stringent P values in theanalyses of the fMRI data. Furthermore, arousal ratings seemedto be comparable between pain-related and negative words forhealthy controls, but not in the patient group, indicating that thestimulus material that we used might be balanced for healthy con-trols, but not for subjects characterized by frequent pain events.These differences should be considered in further studies onpain-related cues.

5. Conclusion

The present study demonstrated that migraine patients specifi-cally engage cortical structures related to the affective and sen-sory-discriminative dimension of pain during the processing ofpain-related verbal cues compared with non-pain-related negativecues. Most importantly, when attention was focused on the seman-tics of the words, migraine patients were characterized by en-hanced responses within the pain processing network comparedwith healthy subjects. Further studies may attend to the questionsof whether the obtained results can be generalized to other painconditions and whether the activations elicited by pain-relatedwords are associated with altered responses to acute and chronicpain, which would be expected according to the associative net-work theory.

Conflict of interest statement

There are no conflict of interest regarding this manuscript.

Acknowledgements

Research was partly funded by the BMBF (German FederalMinistry of Research and Technology, Bernstein Group01GQ0703 and 01EC1003B) and the IZKF (Interdisciplinary Centerfor Clinical Research) of the Friedrich Schiller University Jena. Wethank O. Witte and P. Storch for the cooperation during patientrecruitment, and also H. Hecht and H.P. Burmeister for their assis-tance during the scanning sessions and during the analysis ofimaging data.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at doi:10.1016/j.pain.2011.01.026.

References

[1] Anderson EJ, Mannan SK, Husain M, Rees G, Sumner P, Mort DJ, McRobbie D,Kennard C. Involvement of prefrontal cortex in visual search. Exp Brain Res2007;180:289–302.

[2] Andersson G, Haldrup D. Personalized pain words and Stroop interference inchronic pain patients. Eur J Pain 2003;7:431–8.

[3] Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms ofpain perception and regulation in health and disease. Eur J Pain2005;9:463–84.

[4] Badre D. Cognitive control, hierarchy, and the rostro-caudal organization of thefrontal lobes. Trends Cogn Sci 2008;12:193–200.

[5] Bower GH. Mood and memory. Am Psychologist 1981;36:129–48.[6] Bufalari I, Aprile T, Avenanti A, Di Russo F, Aglioti SM. Empathy for pain and

touch in the human somatosensory cortex. Cereb Cortex 2007;17:2553–61.[7] Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior

cingulate cortex. Trends Cogn Sci 2000;4:215–22.[8] Coppola G, Pierelli F, Schoenen J. Habituation and migraine. Neurobiol Learn

Mem 2009;92:249–59.[9] De Pisapia N, Slomski JA, Braver TS. Functional specializations in lateral

prefrontal cortex associated with the integration and segregation ofinformation in working memory. Cereb Cortex 2007;17:993–1006.

[10] de Tommaso M, Libro G, Guido M, Losito L, Lamberti P, Livrea P. Habituation ofsingle CO2 laser-evoked responses during interictal phase of migraine. JHeadache Pain 2005;6:195–8.

[11] Derbyshire SWG, Whalley MG, Stenger VA, Oakley DA. Cerebral activationduring hypnotically induced and imagined pain. NeuroImage 2004;23:392–401.

[12] Dillmann J, Miltner WHR, Weiss T. The influence of semantic priming onevent-related potentials to painful laser-heat stimuli in humans. Neurosci Lett2000;284:53–6.

[13] Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K. Anew SPM toolbox for combining probabilistic cytoarchitectonic maps andfunctional imaging data. Neuroimage 2005;25:1325–35.

[14] Flor H, Knost B, Birbaumer N. Processing of pain- and body-related verbalmaterial in chronic pain patients: central and peripheral correlates. Pain1997;73:413–21.

[15] Franke GH. SCL-90-R. Die Symptom-Checkliste von Derogatis—DeutscheVersion—Manual. Göttingen: Beltz Test Gesellschaft; 1995.

[16] Godinho F, Magnin M, Frot M, Perchet C, Garcia-Larrea L. Emotionalmodulation of pain: is it the sensation or what we recall? J Neurosci2006;26:11454–61.

[17] Gruber O, Goschke T. Executive control emerging from dynamic interactionsbetween brain systems mediating language, working memory and attentionalprocesses. Acta Psychol 2004;115:105–21.

[18] Gu XS, Han SH. Neural substrates underlying evaluation of pain in actionsdepicted in words. Behav Brain Res 2007;181:218–23.

[19] Hassabis D, Kumaran D, Maguire EA. Using imagination to understand theneural basis of episodic memory. J Neurosci 2007;27:14365–74.

[20] Hautzinger M, Kühner C, Keller F. BDI-II Beck-Depressions-Inventar. Frankfurtam Main: Harcourt Test Services; 2006.

[21] Hebb DO. The organization of behaviour: a neuropsychological theory. NewYork: Wiley; 1949.

[22] Hietanen JK, Nummenmaa L, Nyman MJ, Parkkola R, Hamalainen H. Automaticattention orienting by social and symbolic cues activates different neuralnetworks: an fMRI study. Neuroimage 2006;33:406–13.

[23] Huse E, Knost B, Flor H. Autobiographisches Gedächtnis bei Patienten mitchronischen Schmerzen. Zeitschrift für Klinische Psychologie undPsychotherapie 1999;28:199–204.

[24] Jackson PL, Brunet E, Meltzoff AN, Decety J. Empathy examined through theneural mechanisms involved in imagining how I feel versus how you feel pain.Neuropsychologia 2006;44:752–61.

[25] Kelly S, Lloyd D, Nurmikko T, Roberts N. Retrieving autobiographical memoriesof painful events activates the anterior cingulate cortex and inferior frontalgyrus. J Pain 2007;8:307–14.

[26] Kenntner-Mabiala R, Pauli P. Affective modulation of brain potentials topainful and nonpainful stimuli. Psychophysiology 2005;42:559–67.

[27] Kenntner-Mabiala R, Weyers P, Pauli P. Independent effects of emotion andattention on sensory and affective pain perception. Cognit Emot2007;21:1615–29.

[28] Koyama T, McHaffie JG, Laurienti PJ, Coghill RC. The subjective experience ofpain: where expectations become reality. Proc Natl Acad Sci USA2005;102:12950–5.

[29] Kringelbach ML, Rolls ET. The functional neuroanatomy of the humanorbitofrontal cortex: evidence from neuroimaging and neuropsychology.Prog Neurobiol 2004;72:341–72.

[30] Kulkarni B, Bentley DE, Elliott R, Youell P, Watson A, Derbyshire SWG,Frackowiak RSJ, Friston KJ, Jones AKP. Attention to pain localization andunpleasantness discriminates the functions of the medial and lateral painsystems. Eur J Neurosci 2005;21:3133–42.

J. Eck et al. / PAIN�

152 (2011) 1104–1113 1113

[31] Leonards U, Sunaert S, Van Hecke P, Orban GA. Attention mechanisms in visualsearch—an fMRI study. J Cogn Neurosci 2000;12:61–75.

[32] Lieberman MD, Cunningham WA. Type I and type II error concerns in fMRIresearch: re-balancing the scale. Soc Cognit Affect Neurosci 2009;4:423–8.

[33] Loggia ML, Mogil JS, Bushnell MC. Empathy hurts: compassion for anotherincreases both sensory and affective components of pain perception. Pain2008;136:168–76.

[34] Lorenz J, Cross DJ, Minoshima S, Morrow TJ, Paulson PE, Casey KL. A uniquerepresentation of heat allodynia in the human brain. Neuron 2002;35:383–93.

[35] Lutzenberger W, Flor H, Birbaumer N. Enhanced dimensional complexity of theEEG during memory for personal pain in chronic pain patients. Neurosci Lett1997;226:167–70.

[36] Miltner WHR, Braun C, Arnold M, Witte H, Taub E. Coherence of gamma-bandEEG activity as a basis for associative learning. Nature 1999;397:434–6.

[37] Montoya P, Pauli P, Batra A, Wiedemann G. Altered processing of pain-relatedinformation in patients with fibromyalgia. Eur J Pain 2005;9:293–303.

[38] Nikendei C, Dengler W, Wiedemann G, Pauli P. Selective processing of pain-related word stimuli in subclinical depression as indicated by event-relatedbrain potentials. Biol Psychol 2005;70:52–60.

[39] O’Craven KM, Kanwisher N. Mental imagery of faces and places activatescorresponding stimulus-specific brain regions. J Cogn Neurosci2000;12:1013–23.

[40] Ogino Y, Nemoto H, Inui K, Saito S, Kakigi R, Goto F. Inner experience of pain:imagination of pain while viewing images showing painful events formssubjective pain representation in human brain. Cereb Cortex 2007;17:1139–46.

[41] Oldfield RC. The assessment and analysis of handedness: the Edinburghinventory. Neuropsychologia 1971;9:97–113.

[42] Osaka N, Osaka M, Morishita M, Kondo H, Fukuyama H. A word expressingaffective pain activates the anterior cingulate cortex in the human brain: anfMRI study. Behav Brain Res 2004;153:123–7.

[43] Petrides M. The role of the mid-dorsolateral prefrontal cortex in workingmemory. Exp Brain Res 2000;133:44–54.

[44] Peyron R, Laurent B, García-Larrea L. Functional imaging of brain responses topain. A review and meta-analysis. Neurophysiol Clin/Clin Neurophysiol2000;30:263–88.

[45] Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotionperception I: the neural basis of normal emotion perception. Biol Psychiatry2003;54:504–14.

[46] Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, Rawlins JNP.Dissociating pain from its anticipation in the human brain. Science1999;284:1979–81.

[47] Porro CA, Baraldi P, Pagnoni G, Serafini M, Facchin P, Maieron M, Nichelli P.Does anticipation of pain affect cortical nociceptive systems? J Neurosci2002;22:3206–14.

[48] Price CJ, Wise RJS, Frackowiak RSJ. Demonstrating the implicit processing ofvisually presented words and pseudowords. Cereb Cortex 1996;6:62–70.

[49] Price DD. Neuroscience – psychological and neural mechanisms of theaffective dimension of pain. Science 2000;288:1769–72.

[50] Price DD, Verne GN, Schwartz JM. Plasticity in brain processing andmodulation of pain. Prog Brain Res 2006;157:333–52.

[51] Rainville P, Bao QV, Chretien P. Pain-related emotions modulate experimentalpain perception and autonomic responses. Pain 2005;118:306–18.

[52] Richter M, Eck J, Straube T, Miltner WHR, Weiss T. Do words hurt? Brainactivation during the processing of pain-related words. Pain 2010;148:198–205.

[53] Richter M, Miltner WHR, Straube T. Association between therapy outcome andright-hemispheric activation in chronic aphasia. Brain 2008;131:1391–401.

[54] Roy M, Piche M, Chen JI, Peretz I, Rainville P. Cerebral and spinal modulation ofpain by emotions. Proc Natl Acad Sci USA 2009;106:20900–5.

[55] Saarela MV, Hlushchuk Y, Williams AC, Schurmann M, Kalso E, Hari R. Thecompassionate brain: humans detect intensity of pain from another’s face.Cereb Cortex 2007;17:230–7.

[56] Schreckenberger M, Siessmeier T, Viertmann A, Landvogt C, Buchholz HG,Rolke R, Treede RD, Bartenstein P, Birklein F. The unpleasantness of tonic painis encoded by the insular cortex. Neurology 2005;64:1175–83.

[57] Seminowicz DA, Davis KD. Interactions of pain intensity and cognitive load:the brain stays on task. Cereb Cortex 2007;17:1412–22.

[58] Simon D, Craig KD, Miltner WH, Rainville P. Brain responses to dynamic facialexpressions of pain. Pain 2006;126:309–18.

[59] Simon O, Mangin JF, Cohen L, Le Bihan D, Dehaene S. Topographical layout ofhand, eye, calculation, and language-related areas in the human parietal lobe.Neuron 2002;33:475–87.

[60] Singer T, Seymour B, O’Doherty J, Kaube H, Dolan RJ, Frith CD. Empathy for paininvolves the affective but not sensory components of pain. Science2004;303:1157–62.

[61] Sitges C, Garcia-Herrera M, Pericas M, Collado D, Truyols M, Montoya P.Abnormal brain processing of affective and sensory pain descriptors in chronicpain patients. J Affect Disord 2007;104:73–82.

[62] Snider BS, Asmundson GJG, Wiese KC. Automatic and strategic processing ofthreat cues in patients with chronic pain: a modified Stroop evaluation. Clin JPain 2000;16:144–54.

[63] Stankewitz A, May A. Cortical excitability and migraine. Cephalalgia2007;27:1454–6.

[64] Straube T, Schmidt S, Weiss T, Mentzel HJ, Miltner WHR. Sex differences inbrain activation to anticipated and experienced pain in the medial prefrontalcortex. Hum Brain Mapp 2009;30:689–98.

[65] Suzuki WA. Associative learning signals in the brain. Prog Brain Res2008;169:305–20.

[66] Valet M, Sprenger T, Boecker H, Willoch F, Rummeny E, Conrad B, ErhardP, Tolle TR. Distraction modulates connectivity of the cingulo-frontalcortex and the midbrain during pain—an fMR1 analysis. Pain 2004;109:399–408.

[67] Villemure C, Slotnick BM, Bushnell MC. Effects of odors on pain perception:deciphering the roles of emotion and attention. Pain 2003;106:101–8.

[68] Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM,Rose RM, Cohen JD. Placebo-induced changes in fMRI in the anticipation andexperience of pain. Science 2004;303:1162–7.

[69] Weiss T, Hesse W, Ungureanu M, Hecht H, Leistritz L, Witte H, Miltner WHR.How do brain areas communicate during the processing of noxious stimuli?An analysis of laser-evoked event-related potentials using the GrangerCausality Index. J Neurophysiol 2008;99:2220–31.

[70] Weiss T, Miltner WHR, Dillmann J. The influence of semantic priming onevent-related potentials to painful laser-heat stimuli in migraine patients.Neurosci Lett 2003;340:135–8.

[71] Welch BL. The generalization of students problem when several differentpopulation variances are involved. Biometrika 1947;34:28–35.

[72] Wiech K, Seymour B, Kalisch R, Stephan KE, Koltzenburg M, Driver J, Dolan RJ.Modulation of pain processing in hyperalgesia by cognitive demand.Neuroimage 2005;27:59–69.