Supplemental Tables
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Page 1 of 18 Contents Contents .............................................................................................................................................................................. 1 Supplemental Tables ........................................................................................................................................................... 2 eTable 1: Assessment of clinical diagnosis of patient group. ......................................................................................... 2 eTable 2: Group differences during Observation. ........................................................................................................... 3 eTable 3: Group differences during Empathy experiment. ............................................................................................. 4 eTable 4. Regions normalized after empathy instruction. ............................................................................................... 5 Supplemental Figures ......................................................................................................................................................... 6 eFigure 1: Movie rating questionnaire. ........................................................................................................................... 6 eFigure 2: PCL-R assessment in patient group. .............................................................................................................. 6 eFigure 3: Group difference per Experiment as a function of movie types included. ..................................................... 7 eFigure 4: Summary figure of interaction between Observation and Empathy .............................................................. 8 Supplemental text ............................................................................................................................................................... 9 eText 1: Education Level ................................................................................................................................................ 9 eText 2: Specific assessment of the psychopathy group ................................................................................................. 9 eText 3: Emotion specific activations and the main effect of stimulus type ................................................................... 9 eText 4: Interaction analysis with z-transform ............................................................................................................. 13 eText 5: Analysis of the eye tracker data ...................................................................................................................... 13 eText 6: Differences in baseline activation ................................................................................................................... 14 eText 7: Movie Rating Questionnaire ........................................................................................................................... 14 eText 8: Regressing out differences in Experience from differences in Observation ................................................... 14 Supplemental References .................................................................................................................................................. 18 Page 2 of 18 Supplemental Tables eTable 1: Assessment of clinical diagnosis of patient group. The table lists DSM-IV diagnosis and psychoactive medication per patient. Subjects were given arbitrary numbers to preserve their anonymity. PD = Personality Disorder. NOS = Not Otherwise Specified. Subject Axis I 1 305.20 Cannabis Abuse 301.7 Antisocial PD 305.10 Nicotine Dependance 301.81 Narcissistic PD 305.70 Amphetamine Abuse 304.20 Cocaine Dependence 305.50 Opioid Abuse 305.00 Alcohol Abuse 301.7 Antisocial PD 305.60 Cocaine Abuse 305.20 Cannabis Abuse 305.00 Alcohol Abuse 301.7 Antisocial PD 302.81 Fetishism 301.83 Borderline PD 302.84 Sexual Sadism 301.81 Narcissistic PD 4 312.31 Pathological Gambling 301.7 Antisocial PD 5 303.90 301.83 Borderline PD 301.7 Antisocial PD 301.9 PD NOS 301.9 PD NOS 2 3 Axis II Current Medication 6 304.80 Alcohol Dependence Attention-Deficit / Hyperactivity Disorder Polysubstance Dependence 7 302.2 Pedophilia 305.00 Alcohol Abuse 305.00 Alcohol Abuse 300.23 Social Phobia 305.00 Alcohol Abuse 301.81 Narcissistic PD 305.60 Cocaine Abuse 301.7 Antisocial PD 305.20 Cannabis Abuse 301.83 Borderline PD V71.09 No Diagnosis or 301.81 Narcissistic PD Condition on Axis I 301.7 Antisocial PD 301.9 PD NOS 301.7 Antisocial PD 301.7 Antisocial PD 314.01 8 9 10 11 304.30 12 V71.09 13 304.80 Cannabis Dependence No Diagnosis or Condition on Axis I Polysubstance Dependence 302.70 Sexual Dysfunction NOS 301.81 Narcissistic PD 305.60 Cocaine Abuse 301.9 PD NOS 305.50 Opioid Abuse V61.21 Sexual Abuse of Child 301.7 Antisocial PD 302.2 Pedophilia 303.90 Alcohol Abuse V61.1 Sexual Abuse of Adult 301.7 Antisocial PD V61.1 Physical Abuse of Adult 304.30 Cannabis Dependence 305.00 Alcohol Dependence 312.31 Compulsive Gambling 304.20 Cocaine Dependence 301.7 Antisocial PD 304.30 Cannabis Dependence 301.83 Borderline PD 302.2 Pedophilia 301.9 PD NOS V61.21 Sexual Abuse of Child 305.20 Cannabis Abuse 14 15 16 17 18 citalopram 20 mg per day amitriptyline 25 mg daily 7 tablets Page 3 of 18 eTable 2: Group differences during Observation. Differences in brain activity between the psychopathy and control group (p unc<0.001 and qfdr<0.05, gray matter mask). Rows filled with gray indicate clusters that do overlap with those reported in Table 2, and are thus partially within our ROI. Conventions as in Table 2. Cluster size T MNI coordinates x y Z Controls larger than patients 1561 7,70 -21 -33 6,87 -48 -48 6,50 -33 -54 2168 76 154 146 37 69 223 40 133 161 19 64 121 128 11 114 12 26 30 19 15 47 11 29 Hemisphere Macro anatomical location of peak voxel Overlap with cytoarchitectonic regions Hipp (CA, SUB, FD) BA2, BA3b, BA17, BA18 IPC (PFt, PGa, hIP1 hIP3, Amyg (LB) hIP2 IPC (PFm, PF, PFt, PGa, FFcm, PFop) BA2, BA3ab, BA44, BA45, BA4p Hipp (FD, CA, SUB) BA45 -3 15 -15 L L L Thalamus Middle Temporal Gyrus Fusiform Gyrus 7,47 6,99 48 48 -27 -42 -3 24 R R Middle Temporal Gyrus Supramarginal Gyrus 6,83 6,21 4,09 3,42 6,03 4,66 4,19 5,95 5,85 4,61 5,60 5,44 5,22 4,66 4,45 5,20 5,04 4,62 4,24 4,97 3,96 3,94 4,79 4,27 4,74 4,00 3,97 4,67 4,45 3,58 4,66 4,63 4,06 4,41 21 -42 -33 -48 -21 -9 -12 -3 6 3 30 -45 27 36 42 -15 -12 -3 -18 33 15 21 39 33 42 45 33 -9 -12 -6 -27 -27 -33 -24 -33 42 42 42 39 39 27 -39 -39 -33 -60 15 54 42 42 63 15 -3 12 15 12 18 -75 -78 -30 -24 -24 -18 -45 -30 -15 0 -6 -24 6 -12 6 3 30 33 30 -27 -24 -12 57 27 -3 6 -12 -3 -3 -3 -15 -15 6 -9 24 30 9 18 21 42 48 36 54 51 60 51 R L L L L L L L R R R L R R R L L L L R R R R R R R R L L L L L L L 4,38 4,08 3,49 4,28 4,25 4,24 3,28 4,04 4,02 3,98 3,57 3,97 3,34 3,86 3,32 3,24 -33 -27 -30 24 9 12 15 -36 -3 18 12 9 -3 -54 -63 -54 15 21 18 -36 -21 -48 -51 -78 30 -66 -54 -60 -60 -15 -9 -15 3 6 -9 -33 39 54 36 18 51 21 9 -36 -36 21 27 33 L L L R R R R L L R R R L L L L Hippocampus Inferior Frontal Gyrus (p. Orb.) Inferior Frontal Sulcus Inferior Frontal Gyrus (p. Tri.) Superior Frontal Sulcus / Gyrus Superior Medial Gyrus Midcingulate Gyrus Cerebellum Cerebellum Cerebellum Superior Parietal Lobe Inferior Frontal Gyrus (p. Tri.) Superior Orbital Middle Frontal Gyrus Middle Frontal Gyrus Mid Orbital Gyrus Caudate Caudate Caudate Insula/ Amygdala Caudate Putamen Middle Occipital Gyrus Middle Occipital Gyrus Superior Temporal Gyrus Rolandic operculum Insula Midcingulate Gyrus Precuneus Midcingulate Gyrus Precentral Gyrus Middle Frontal Gyrus Precentral Gyrus Anterior bank central sulcus / Precentral Gyrus Insula Insula Insula Cerebellum Midcingulate Gyrus Precuneus Precuneus Middle Occipital Gyrus Superior Medial Gyrus Cuneus Precuneus Cerebellum Cerebellum Postcentral Gyrus Postcentral Gyrus Postcentral gyrus bil. Lobules I-IV(Hem) SPL (7A) BA44 BA45 Amyg (LB) TE 1.1 OP1, OP2 BA6 SPL(5Ci, 5M) BA6 BA6 Lobule V SPL (5M) IPC(PGp) BA6 BA17 Lobule IX (Vermis) Lobule VIIIa (Vermis) OP1, OP4 Page 4 of 18 eTable 3: Group differences during Empathy experiment. Differences in brain activity between the psychopathy and control group (p unc<0.001 and qfdr<0.05, gray matter mask). Rows filled with gray indicate clusters that do overlap with those reported in Table 3. Conventions as in Table 2. Cluster size T MNI coordinates X Controls larger than patients 71 6,58 36 Y Z Hemisphere Macro anatomical location of peak voxel Overlap with cytoarchitectonic regions -33 51 R Postcentral gyrus BA2, BA3b, BA4p, BA3a 50 5,74 27 -57 57 R Superior parietal lobe SPL (7A, 7PC, 5L) 63 5,48 -39 -54 -21 L Fusiform gyrus Lobule VI (Hem) BA2, IPC (PFt) 88 54 115 39 4,94 -33 -36 45 L Postcentral gyrus 4,83 -30 -39 57 L Superior parietal lobe 4,31 -39 -30 42 L Postcentral gyrus 4,88 63 -39 21 R Superior temporal gyrus IPC (PF, PFm, PFcm) hOC5(V5) 4,82 -45 -75 6 L Middle occipital gyrus 4,71 -36 -78 18 L Middle occipital gyrus 4,57 -21 -78 30 L Superior occipital gyrus 4,66 51 -63 9 R Middle temporal gyrus hOC5(V5) 3,63 48 -72 0 R Middle temporal gyrus 40 4,61 -27 -72 -15 L Fusiform gyrus hOC4v(V4) 20 4,49 21 -9 54 R Precentral gyrus BA6 14 4,35 39 0 42 R Medial frontal gyrus 20 4,13 -48 -48 15 L Superior temporal gyrus 17 4,08 9 -39 -30 R Pons Lobules I-IV (Hem) 11 3,94 33 -75 -18 R Fusiform gyrus hOC4v(V4) Lobule VI (Hem), hOC3v(V3v) 21 12 3,91 21 3,87 39 3,38 33 Patients larger than controls 86 7,23 -54 247 5,57 -45 -60 -75 -78 -12 18 24 R R R Parahippocampal gyrus -57 -9 L Middle temporal gyrus -51 48 L Supramarginal gyrus Middle occipital gyrus Middle occipital gyrus 4,67 -33 -57 42 L Supramarginal gyrus 4,61 -39 -57 30 L Supramarginal gyrus 5,54 24 18 54 R Superior frontal gyrus 5,35 33 12 54 R Superior frontal gyrus 4,71 36 21 48 R Middle frontal gyrus 5,54 60 -3 33 R Precentral gyrus 3,21 54 -9 45 R Precentral gyrus 51 5,48 57 -48 -9 R Middle temporal gyrus 463 5,25 -3 57 12 L Superior frontal gyrus 5,17 9 48 6 R Anterior Cingulate Gyrus 5,12 6 39 30 R Superior frontal gyrus 4,99 30 -84 -9 R Lingual gyrus 173 64 30 76 4,96 3 -57 24 R Precuneus 93 4,92 45 -60 45 R Angular gyrus 76 96 24 4,71 51 -51 48 R Angular gyrus 3,76 27 -60 42 R Angular gyrus 4,69 42 -15 18 R Parietal operculum 4,06 60 -18 6 R Temporal operculum 3,49 51 -12 9 R Parietal operculum 4,59 -60 -6 18 L Postcentral gyrus 4,06 -54 -15 6 L Temporal operculum 3,90 -36 -27 18 L Parietal operculum 4,49 9 -69 45 R Precuneus hIP1, IPC (Pga, PFm), hIP3 BA6, BA3b, BA3a, BA4p hOC3v (V3v), hOC4v (V4) IPC (Pga, PFm) OP3, TE 1,0 OP4, OP2, OP1, BA3b, TE1.2 SPL (7A) Page 5 of 18 4,48 -15 18 60 L Superior frontal gyrus 4,39 -27 24 48 L Middle frontal gyrus 4,23 -36 24 36 L Middle frontal gyrus 36 4,14 27 -69 -30 R 10 3,97 21 -30 69 184 Cerebellum Lobule VI (Hem), Lobule VIIa Crus I (Hem) R Postcentral gyrus BA4a, BA6 16 3,66 -12 -72 -24 L Cerebellum 11 3,58 -24 12 -9 L Putamen 10 3,45 -48 3 -24 L Superior temporal gyrus eTable 4. Regions normalized after empathy instruction. Table represents results within the gray matter mask. Analysis is based on z-values. Marked with an asterisk the insula cluster, 31voxels are also significant when restricting the analysis to the ROI (small volume correction, q fdr<0.05 for the entire ROI). Conventions as in Table 2. Cluster size T 43 5.44 MNI coordinates X Y Z -21 -33 -3 L Macro anatomical location of peak voxel Thalamus, Hippocampus 37 5.07 -42 39 -12 L Inferior Frontal Gyrus (p. Orb.) 203 4.75 -48 -57 39 L 13 4.68 36 39 -12 R 308 4.66 9 30 45 R 58 4.65 -48 3 -24 R 74 4.41 -9 39 33 L 99 4.38 -30 24 45 L Middle Temporal Gyrus, Temporal Pole Superior medial gyrus, Anterior Cingulate Cortex Middle frontal gyrus, Inferior Frontal Gyrus (p. Tri.) 14 4.31 -21 57 -3 L Superior Orbital Gyrus 55* 4.11 -36 3 -6 L Insula Lobe 14 3.97 -15 15 0 L Caudate 12 3.77 -18 39 33 R Superior Frontal Gyrus 30 3.73 60 -3 30 L Postcentral Gyrus BA3b, Ba4p, BA6 12 3.70 42 -63 39 R Angular Gyrus IPC (PGa, PGp) IPC (PGa, PFm) Hemisphere Angular Gyrus, Superior Parietal Lobe, Inferior Parietal Lobe Inferior Frontal Gyrus, Middle orbital gyrus Middle frontal gyrus, Superior Frontal Overlap with cytoarchitectonic regions Hipp (FD, SUB, CA) hIPC1,hIPC2, IPC (PGa, PFm), SPL (7A) Gyrus, Superior Medial Gyrus, Anterior Cingulate Cortex 31 3.69 48 -45 30 R Angular Gyrus 24 3.58 12 45 3 R Anterior Cingulate Cortex BA44, BA45 Page 6 of 18 Supplemental Figures eFigure 1: Movie rating questionnaire. This questionnaire was used to rate an instance of every movie shown to the subjects during the Observation. The original was in Dutch, but we translated it into English for the purpose of publication. eFigure 2: PCL-R assessment in patient group. A histogram of the PCL-R scores of all analysed patients. Page 7 of 18 eFigure 3: Group difference per Experiment as a function of included movie types. During Observation, controls activated their premotor, somatosensory and insular cortices more than patients (A1, with premotor and somatosensory cortices outlined in white). Except for parts of SI, these hypo-activations disappeared during Empathy (B). To explore if this Experiment effect could be due to Empathy only testing two (Love and Pain, albeit with instructions to empathize with the receiving or approaching hand separately) of the four movie types used during Observation (Love, Pain, Exclusion, Neutral), we re-calculated the group difference during Observation, only considering Love and Pain (A2). The premotor and insular hypo-activations, which are absent during Empathy (Panel B), are still present when analysing group differences during Observation for Love and Pain only (A2). This suggests that the Experiment effect was not a result of the reduction in the number of conditions during Empathy (i.e. using only Love and Pain). Because (A1) and (B) average 4 conditions, while A2 only averages 2, the statistical power of A2 is reduced. A3 therefore shows the same analysis as A2 at a more lenient p value (p<0.005), and the similarity with A1 becomes even clearer. This is consistent with our lack of finding a Group x Condition effect during Observation. Note that B also includes numerous hyper-activations in the patients (blue), none of which reach significance in any of the Observation analyses. Only results also surviving q<0.05 are shown in each panel to control the overall false positive rate. Page 8 of 18 eFigure 4: Summary figure of interaction between Observation and Empathy To illustrate how brain activation changed across experiments in the clusters that showed a Group difference during Observation, we extracted the mean parameter estimates within each of the 25 clusters that showed group differences in Figure 3A (i.e. during Observation) and averaged the parameter estimates for Pain and Love separately for Observation and Empathy. An ANOVA with 2 Groups x 2 Experiments x 25 Clusters showed that the Group x Experiment x Cluster was not significant (p>0.97), and we therefore generated a single plot summarizing the effect of Experiment on Group differences after averaging over all 25 Clusters. Inspecting the figure below suggests that the reduction of group difference during Empathy in clusters that displayed group differences during Observation was mainly due to an increase in activation in the patients when instructed to empathize with the hands. This particular analysis should however be interpreted with care for two reasons. First, the clusters were selected based on group differences during Observation (Fig. 3A), thereby inflating the Group x Experiment interaction. This is why we do not report a p-value for this interaction, but only for the interaction with Cluster. Second, differences in the timing of the two experiments might complicate the comparison of absolute values of parameter estimates across experiments. The whole brain interaction analysis presented in the main text, and the one computed on z-transformed values (see eText 4) do not suffer from these limitations. Page 9 of 18 Supplemental text eText 1: Education Level Subjects’ reported education was rated as suggested by the Central Bureau of Statistics in the Netherlands by a number ranging from 0 to 9, were 1 stands for primary school and 9 for a university master degree. Years of education is the summation of years attending school, not including short courses. eText 2: Specific assessment of the psychopathy group The DSM-IV diagnosis of each patient was established prior to arrival at the clinic, but adjusted based on additional or extended psycho-diagnostic and psychiatric investigation at the clinic itself. The golden standard for establishing psychopathy is the PCL-R (Hare et al., 2001, Hare, 2003), consisting of 20 items, which are scored 0 (no indication), 1 (some indication) or 2 (indication) and can lead to a maximum sum score of 40. The items are completed using file information extended with, if necessary, a semi-structured interview. The diagnosis of psychopathy was established by two trained diagnosticians of the clinic, who independently scored the PCL-R for every patient and reached consensus about each item through discussion. Although psychopathy is considered to be dimensional, the manual recommends using a cut-off of 30, based on the results of studies in North America. However, in Europe a more lenient cut-off (PCL-R≥26) is often used (Grann et al., 1999, Rasmussen et al., 1999, Sjöstedt and Långström, 2002), which seems consistent with a lower mean PCL-R score recently found in a large Dutch forensic sample across three institutions (Spreen et al., 2008). We used this European cut-off. eText 3: Emotion specific activations and the main effect of stimulus type Background and hypotheses: Behavioural studies suggest that psychopathic/antisocial individuals show stronger deficits while recognizing facial expressions that normally act to limit aggression such as fear, pain and sadness, compared to other emotions (e.g. happiness, Keysers, 2011). Whether this emotion specific deficit generalizes to nonfacial stimuli, such as emotional hand interactions, is unclear. Accordingly, we included a range of emotions in our paradigm, some for which one might expect stronger group differences (distress, either triggered by somatic Pain, or by social Exclusion) and some for which one might expect smaller differences (Neutral and Love). However, in spite of the results obtained with facial expressions, our results indicated that the stimulus type did not interact with Group during the two perception experiments (Observation and Empathy) and during the Experience experiment only in one region outside our ROI. Therefore, we chose not to discuss the effects of stimulus type per se in the main paper. However, the main effect of stimulus type sheds light on the findings reported in the main text in two ways that merits its inclusion in the online material. First, there have been few experiments that included pleasant as well as unpleasant tactile experiences during Experience and Observation, and presenting the main effect of stimulus type (particularly Love vs Pain) will therefore add to our basic understanding of the vicarious representation of emotional touch. Second, such an analysis is necessary to understand the lack of interaction between stimulus type and group in the main text. The lack of interaction can have two underlying reasons: (a) Our stimuli were too similar to tap into emotion specific processes and will therefore not be able to trigger differences between the groups in emotion processing or (b) our stimuli were different enough, but affected our groups similarly. The significant main effects of stimulus type we present here excludes alternative (a) in favour of (b). Presenting all pair wise comparisons for all four conditions (4!/2!=12 pairwise comparisons per experiment) would take up too much space, even for online material. Accordingly, we will present, for Observation and Experience, the main effect of stimulus type (as an F-test in the repeated measures ANOVA), to summarize all voxels that contain significant information about which of the stimulus types was presented. Then we will present the post-hoc results for Pain vs. Love (i.e. two contrasts, Pain-Love and Love-Pain), to provide further details of the directionality of stimulus specific activations. We picked this particular comparison from the 12 possible for 4 reasons: (1) Pain vs. Love is the only pair of stimulus types used in all three experiments described in the main paper; (2) Pain and Love differed most in valence and their comparison should thus best capture effects driven by valence; (3) the literature allows strong hypotheses for this comparison and (4) this comparison is most relevant to the distinction between the perception of distress and pleasure hypothesized to be differentially impaired in antisocial personality disorder / psychopathy (Keysers, 2011). For the comparison of Love vs. Pain, the literature suggests that the dorsal anterior cingulate cortex (dACC), extending dorsally into the supplementary motor areas (SMA/pre-SMA), and the anterior Insula should be more strongly activated during the perception of Pain, as these regions have been consistently associated with experience of and empathy for pain in the first systematic meta-analysis of the literature by Lamm and colleagues (2011). In contrast, the ventromedial prefrontal cortex (vmPFC, ventral to the genu of the corpus calosum) should be more activated by the Love condition, because this region has been associated with the experience of pleasure and the observation of other people’s pleasures (Kringelbach, 2005, Mobbs et al., 2009). A caveat to keep in mind is that the stimuli were designed to look natural, and were therefore not completely matched on somatosensory and motor parameters. Accordingly, regions showing a main effect of movie type, or appearing in the contrasts Pain-Love or Love-Pain might be sensitive to differences in valence, but they may also have been sensitive to somatosensory or motor differences between the stimuli. Hence, we expect somatosensory (Keysers et al., 2010) or motor regions to appear in the main effect of emotion, but these differences should not and cannot be interpreted as suggesting valence representation in these regions. Page 10 of 18 Methods: For Experience and Observation separately, we created an ANOVA with Group and stimulus type as factors. The factor stimulus type included Pain and Love and the levels were considered dependent to account for the repeated measurement nature of the data. The factor Group was considered independent. For both Observation and Experience, we first calculated the main effect of stimulus type. All analyses were reported using a false-discovery correction at qfdr<0.05 or a threshold of p<0.001 uncorrected, whichever was more stringent (i.e. higher T values; > 10 voxels). Then, we performed two post-hoc t-tests to directly compare Pain-Love and Love-Pain for voxels that had shown a main effect of stimulus type. The threshold for these post-hoc comparisons was set at punc<0.001, because for these voxels the main effect had already survived an fdr correction q<0.05. Results of the Experience experiment: Many brain regions showed a main effect of experience type across both groups (punc<0.001 at F(3,168)=5.68, also survives qfdr<0.05, see next table and figure). These regions included regions associated with motor programming (BA6, BA44, BA4 and cerebellum), somatosensation (BA3, BA1, BA2), and regions sensitive to affect (caudate, putamen, insula, vmPFC). Notably, post-hoc testing confirmed our prediction that the vmPFC was more active during Love than Pain, and the anterior insula during Pain than Love. Main effect of hand interaction type during Experience, and the direct comparison of Pain and Love. Cl. size T MNI x y z Macro anatomical location of peak voxel Main Effect of Emotion Postcentral gyrus 1744 47,23 -45 -21 51 1624 52,46 51 -18 48 450 22,06 -3 57 -3 170 14,85 -6 6 48 155 20,58 -21 -51 -27 127 24,21 24 -51 -30 95 9,83 3 -51 21 83 15,88 -33 -69 42 68 11,64 -3 -33 57 64 9,73 -24 -3 3 57 9,96 24 3 0 53 11,29 -39 48 -3 50 41 31 29 27 25 18 18 12 10 10 8,93 7,93 16,25 10,28 10,36 10,28 10,35 8,84 8,48 8,52 7,36 51 -36 18 -3 51 57 6 51 6 33 -24 -51 -9 27 39 -27 57 -39 -12 12 -24 9 30 6 -3 36 9 33 39 24 48 0 -15 Love > Pain 539 870 117 123 10,93 10,82 8,46 7,46 -45 51 24 -21 -21 -18 -51 -51 161 284 24 39 13 47 55 17 6,33 6,28 4,98 4,89 4,87 4,81 4,76 4,05 -6 -9 57 24 -30 51 -18 3 6 48 45 -3 9 30 3 0 42 27 -60 0 9 3 6 -3 Pain > Love 847 7,16 -60 -36 Postcentral gyrus 51 48 -30 -27 9 Overlap with cytoarchitectonic regions Area 2, 3b, 6, 4p, 4a, OP1, OP4, IPC (PFt, Pfop, PF), TE 1.0, TE 1.1, Insula (Ig2) Area 2,3b, 1, 4a, 4p, 6, OP1, IPC (PF, PFm, PFcm, PGa, PFt) vmPFC, Anterior cingulate gyrus Supplementary motor area and mid cingulate gyrus Cerebellum Area 6 Cerebellum Lobule VI (Hem), Lobule V Posterior cingulate gyrus Area 17 and 18 Superior parietal lobe hIP1, hIP3, IPC (PFm, PGa) Paracentral lobule Area 4a, 4p, SPL (5M) Lobule VI (Hem), Lobule V Putamen Putamen Amyg (SF) Medial frontal gyrus Posterior inferior temporal gyrus hOC5 (V5) Middle frontal gyrus Central sulcus Midbrain Temporal pole Precentral gyrus Caudate Middle frontal gryus Medial frontal gyrus Superior frontal gyrus Parahippocampal gyrus Area 44, 45 Postcentral gyrus Postcentral gyrus Cerebellum Cerebellum Supplementary motor area and mid cingulate gyrus vmPFC, Anterior cingulate gyrus Precentral gyrus Putamen Middle frontal gyrus Posterior inferior temporal gyrus Putamen Caudate SII, posterior Insula Area 6, 4a, 4p Bilateral Lobules I-IV (Hem) Area 44 Area 45 Amyg (SF) Page 11 of 18 150 7,08 66 -24 3 150 6,28 54 -51 42 46 5,29 -48 -51 45 12 4,92 6 33 39 Superior temporal gyrus Superior parietal lobule Superior parietal lobule Medial frontal gyrus Main effect of hand interaction type during Experience experiment. Results of the Observation experiment: The main effect of movie type (see next table and figure, p<0.001, F(3,168)=4.85, survives qfdr<0.05) included a wide range of regions. These included regions associated with vision (V1, V2, V3, V4, V5, lingual gyrus), that are sensitive to low-level visual differences that existed between our stimulus types because of the differences in the speed and complexity of movement. The main effect also included regions associated with vicarious responses that are known to be sensitive to differences in motor actions (PF, PFG, BA6, BA44). The main effect of movie type also included regions associated with the somatosensory system (BA3, 1 and 2, OP1, OP4), that are known to be sensitive to the sight of other people’s tactile experiences. Finally, they also included regions associated with negative (dACC, Insula) and positive (subgenual vmPFC) affect. The direct post-hoc comparison of Love and Pain revealed that, in accord with our expectations, the subgenual vmPFC responded more to Love than Pain and the dACC and the insula responded more to Pain than Love (see next table). Page 12 of 18 Main effect of movie type during Observation, and the direct comparison of Pain and Love. Main Effect of Emotion HemiMacro anatomical location sphere of peak voxel R Postcentral Gyrus, Supramarginal Gyrus, Inferior Parietal Lobe L Superior Temporal Gyrus, Middle Temporal Gyrus, Temporo-Parietal juntion L Inferior Temporal Gyrus, Inferior occipital gyrus R Inferior Frontal Gyrus (p. Tri.), Medial Frontal Gyrus, Superior Frontal Gyrus, L Postcentral gyrus, Supramarginal gyrus, Inferior Parietal Lobe, Superior Parietal Lobe L Superior Frontal Gyrus Cl. size F-value 1223 28.36 MNI X 42 333 16.74 -57 -48 18 148 16.06 45 -66 -9 525 15.71 30 3 57 253 13.49 -33 -39 57 119 11.98 -24 -12 60 52 11.84 18 -90 0 L Calcarine gyrus, Linual gyrus BA17, BA18, V3v 203 11.48 -45 21 21 R BA44, BA45 12 9.98 -6 30 54 R Inferior Frontal Gyrus (p. Tri. And p. Oper.), Precentral Gyrus Superior Medial Gyrus Y -33 Z 57 70 9.90 -6 57 12 R vmPFC 169 9.85 3 -75 -3 L 46 9.44 -21 -90 -3 L 31 8.88 12 -27 42 L Linual gyrus, Cuneus, Cerebellum Inferior Occipital Gyrus, Middle Occipital Gyrus Middle Cingulate Cortex 11 7.99 -3 54 30 R Superior Medial Gyrus 16 7.83 27 -84 6 L Superior Medial Gyrus 11 7.71 -33 24 -18 R 17 7.40 60 -48 -12 L 11 7.31 9 -30 -3 L Inferior Frontal Gyrus (p. Orb.) Inferior Temporal Gyrus, Middle Temporal Gyrus Hippocampus 12 7.09 18 -57 21 L Cuneus 10 6.97 3 60 -3 R Mid Orbital Gyrus 21 6.75 -36 -78 -6 L Inferior Occipital Gyrus Postcentral gyrus 192 5.66 -33 Love > Pain -39 54 L 66 5.38 -24 -12 60 L Precentral gyrus 341 5.30 21 -60 60 R Superior parietal lobule 174 4.67 24 18 51 R Superior frontal gyrus 16 3.83 -3 57 -6 L Subgenual vmPFC 169 5.35 3 -78 95 4.62 -57 -48 27 L Supramarginal gyrus 90 4.15 -51 18 0 L 11 4.12 3 -33 -6 R Inferior frontal gyrus (p. Tri, p. Orb) Brainstem 10 4.00 -33 24 -18 L Inferior frontal gyrus, Insula Pain > Love 0 R Linual gyrus, Cuneus Overlap with cytoarchitectonic regions BA1, BA2, BA 3b, IPC (PFt, PFop), SPL (7PC, 7A), OP1, OP4 IPC (PF, PFcm, PGa, PFm) V4, V5 BA44, BA45, BA6 BA1, BA2, BA 3b, IPC (PFt, PFop), SPL (7PC, 7A) BA6 BA17, BA18, Vermis V3v, V4, BA18 SPL (5Ci), BA6 V5 Page 13 of 18 Main effect of movie type during Observation experiment eText 4: Interaction analysis with z-transform Some differences in y between the two experiments might be due to differences in experimental design and attention. To explore whether the interaction persists if we scale the y values to account for changes in average and standard deviation between the experiments in the controls, we repeated the same ANOVA after z-transforming values separately for the two experiments using the mean (mobs, memp) and standard deviation (sdobs, sdemp) of y for the controls: zi,obs=(yi,obs-mobs)/sdobs; zi,emp=(yi,emp-memp)/sdemp. The z-transformed summary parameter estimates were then entered into the same ANOVA used for the untransformed y. eText 5: Analysis of the eye tracker data Because of technical challenges, stable eye gaze data was obtained for 13 patients and 19 control subjects. Differences during Observation between the two groups could also be driven by differences in gaze location (where) and gaze duration (how long) during the observation of the videos. We therefore examined the eye tracking data during Observation. We first removed artefacts, then blinks (i.e. values were the x and y coordinates were zero) and saccades (i.e. samples between which the eye gaze velocity relative to the last sample changed by more than 30 deg/s). Before each run the eye tracker was calibrated using 9 points on the screen where movies later appeared. To remove slow frequency drift away from this initial calibration due to head movements, the data was de-trended using a third-degree polynomial. To do this, we reasoned that while a fixation cross was presented in the middle of the screen, the average gaze position of the participant should be constant over time. Accordingly, we calculated the mean eye gaze position for each period of fixation cross, to then fit a third order polynomial as a function of time (one for the x-axis and one for the y-axis), separately for each functional run, to these average fixation periods. These regressions were used to detrend all eye gaze measurements by subtracting the expected (x,y) coordinates over time from all (x,y) measurements. To check if patients and controls looked at different regions of the screen while watching the movies, we pooled the data from all movie types and generated eye gaze density plots (for an example see next figure) for each subject, representing the relative time a subject spent looking at each possible coordinate. Example eye gaze density plot. A frame from a loving movie is displayed in the background. The white dots on top of the movie frame represent the relative amount of time this subject spent looking at that particular location. The whiter a dot, the more time that location was looked at. Page 14 of 18 This was done by counting how often each pixel of the screen had been a point of fixation (i.e. the number of 50Hz frames during which the point of regard was in this position after exclusions of saccades and blinks) while participants looked at the movies, and dividing this by the total amount of fixations measured during the movies. We then applied an 8x8 pixel FWHM Gaussian kernel smoothing. The eye gaze density pattern of the two groups was then compared pixelby-pixel with a 2-sample t-test at pFDR<0.05. This was done by transforming the matrix into a single slice Nifti Volume, and analysing it using SPM as if it were fMRI data. Because there was no Group x Movie Type interaction during Observation, we tested for differences in average eye gaze patterns towards all the movies. No significant differences were found between the two groups in spatial eye gaze pattern (q fdr >0.05, F(1,30)<15.22). To assess for group differences in the amount of time subjects spend looking at the movies, we calculated the ratio of samples per movie that fell inside the part of the screen where the movie was displayed during each event. We then calculated the average ratio across the movies for each subject and performed a 2-sample t-test (qfdr<0.05) to assess for differences between the groups and this indicated no differences in the amount of time spend looking at the movies. eText 6: Differences in baseline activation Differences between the groups might have been caused by differences in baseline activation. We therefore additionally examined whether there were group differences on the global parameters of the GLM during Observation, Empathy or Experience. We found no differences in baseline activation between the groups using a 2-sample t-test on the global parameters of the GLM during Observation, Empathy or Experience (all q fdr >0.05; F(1,42)<12,52)). We also did not find an interaction effect of the global parameters between Group and Experiment (Observation, Empathy, p unc>0.01, F<6.95) eText 7: Movie Rating Questionnaire To build the questionnaire (eFigure 1), 60 healthy Dutch volunteers, not participating in the MR study, watched all the movies used in this experiment with the aim to find the word that would best describe the emotion behind the interacting hands. The most frequently used words were then chosen as emotion descriptors for the questionnaire probing three aspects: (i) separately for the two hands in each movie, how strongly each emotion descriptor was perceived (0=no to 3=strong), (ii) the hand with which subjects spontaneously empathized most (Q2, neither, left, right or both) and (iii) how good or bad the movie made them feel (Q3). We had no movie rating scores from one control subject and one patient due to technical difficulties. Statistical testing was performed separately for the three questions, using an level of 0.01 in each of the analysis to control for false positives (resulting in =0.03 after Bonferoni correction for 3 separate analyses). Q1 was analysed by averaging the intensity reported separately for each emotion descriptor, participant, movie type, and hand (recoding the left and right hand for each movie as approaching or receiving, see Figure 1A). Results were then entered into a MANOVA with 2 Groups x 4 Movie Types x 2 Hands (approaching vs. receiving) and considering the average intensity rating for each emotion descriptor as the 3 dependent variables. The main effect of Groups and the interactions Groups x Movie Types, Groups x Hands and Groups x Movie Types x Hands were all non-significant at =0.01. The main effects of Movie Types, of Hands and the Movie Types x Hands interaction were all significant (all p<0.001). Accordingly, the different movie types were perceived as depicting different emotions, and the two hands Page 15 of 18 were perceived as reflecting different emotions. However, the two groups perceived the same emotions and emotional intensities behind the hands. A test of normality (Lilliefors), run on the 24 ratings however revealed that the ratings were not normally distributed (p<0.01). However, non-parametric testing (Mann-Whitney-U), comparing the two groups on each of the 24 ratings (4 Movie Types x 2 Hands x 3 Emotions) using a Bonferroni correction of 24, confirmed that for none of these 24 variables, the two groups significantly differed (all p>0.12). See table below for average ratings. Approaching Hand Q1(±sem) Receiving Hand Movie Type Group Mean/Aggressive Rejecting/Irritated Love/Affection Mean/Aggressive Rejecting/Irritated Love/Affection Love Patient 0.00(±0.00) 0.02(±0.02) 2.31(±0.10) 0.00(±0.00) 0.03(±0.02) 2.17(±0.09) Control 0.02(±0.02) 0.05(±0.03) 2.03(±0.10) 0.01(±0.01) 0.05(±0.03) 1.93(±0.10) Patient 0.03(±0.01) 0.17(±0.06) 0.80(±0.11) 0.01(±0.01) 0.35(±0.08) 0.59(±0.09) Control 0.21(±0.05) 0.13(±0.04) 0.55(±0.11) 0.03(±0.02) 0.40(±0.08) 0.43(±0.11) Patient 0.02(±0.02) 0.13(±0.05) 1.88(±0.11) 0.15(±0.06) 1.98(±0.08) 0.11(±0.03) Control 0.05(±0.03) 0.09(±0.04) 1.83(±0.12) 0.21(±0.07) 1.96(±0.10) 0.15(±0.06) Patient 1.99(±0.15) 0.25(±0.11) 0.06(±0.02) 0.39(±0.14) 1.26(±0.18) 0.16(±0.05) Control 2.50(±0.11) 0.07(±0.03) 0.10(±0.06) 0.11(±0.05) 1.54(±0.12) 0.16(±0.08) Neutral Exclusion Pain Q2 was analysed by calculating the percentage of movies of each Movie Type that lead to empathy with the approaching and/or the receiving hand, separately for each participant (ranging from (0%,0%) when none of the movies lead to empathy with either of the hands, to (100%,100%) if all movies lead to empathy with both hands). A MANOVA with 2 Groups x 4 Movie Types and 2 dependent variables (empathy with approaching, empathy with receiving hand) revealed a significant effect of Movie Type (p<0.001) but no main effect of Group or interaction Group x Movie Type Group (all p>0.123). This indicates that the Movie Type influenced which hand was empathised with, but groups did not differ in this pattern. Because a test of normality revealed that Q2 was not normally distributed (Lilliefors p<0.01), the ratings on the 4 Movie Types x 2 Hands were compared across groups using 8 non-parametric analyses (MannWhitney-U), but no significant differences were detected (all p>0.15). Average ratings (±sem) are shown in the figure below. Q3, “How do you yourself feel while watching the movie?” was of particular interest when it comes to empathy. A test of normality showed that Q3 was normally distributed (Lilliefors). An ANOVA on these ratings with 2 Groups x 4 Movie Types (see Figure below) showed that although the patients generally reported feeling slightly better than the controls (main effect of Group, p<0.001), there was no Group x Movie Type interaction (p>0.95). Page 16 of 18 The main effect of Group is difficult to interpret, as it could reflect properties of the participants rather than of the movies: the patients may have had a more positive emotional baseline, for instance because they might simply have felt particularly excited on a day out of the forensic institution. It should be noted, that this potential difference in baseline does not affect the main effect of Group in the fMRI experiments, because there, brain activation during the movies is always contrasted against the baseline activation during the interval between movies. On the other hand, the effect of Movie Type on the questionnaire ratings is a direct index of how the movies change how people feel. The ANOVA revealed a significant main effect of Movie Type (p<0.001), with all four Movie Types leading to significantly different ratings (all p<0.001). This effect of Movie Type was congruent with the concept of empathy: movies that depicted positive feelings (Love) induced both groups to report positive feelings (i.e. higher scores than the neutral movie, p<0.001), and movies depicting negative feelings (Pain, Exclusion) induced both groups to report negative feelings (i.e. lower scores than the neutral movie, p<0.001). The utter lack of significant Group x Movie Type interaction (p>0.95) thus suggests that what movie was shown changed how patients felt just as much as it changed how controls felt, and hence, that empathy was largely normal in the psychopathy group, based on these self-reports. Conclusions: The questionnaires were collected after the end of the fMRI experiment, and thus after the instructions to empathize. These instructions lead to relatively normal brain activation within regions associated with vicarious activations. Accordingly, one would expect the emotional ratings of the movies to show little difference between the groups. The results of the movie ratings are in accord with this prediction. Individuals with psychopathy reported similar emotions behind the hands and empathised with the same hands in the movies as the controls. Both groups also reported feeling better while viewing movies in which actors had positive experiences and worse while viewing movies in which actors had negative experiences; and this effect of movie type did not differ across groups. The only group difference that was statistically robust was a difference in how the patients reported feeling independently of movie type shown, but this difference could be due to differences in baseline emotional state or reporting style and is therefore not a direct measure of how they reacted to the movies. eText 8: Regressing out differences in Experience from differences in Observation The lack of sensitivity to other people’s experiences in psychopathic individuals might be due to a reduced intensity with which they experience similar situations. We therefore tested whether differences between the groups during Observation could be explained by differences in brain activity during Experience. Because group differences did not significantly depend on movie type for Observation, we first calculated a summary contrast image per subject by adding the beta values for the four movie types. The same was done for the four types of interactions during Experience. We then fitted a linear regression, voxel-by-voxel observation(i)=a*experience(i)+b+residual(i) where observation(i) and experience(i) represent the summed parameter estimates for all Observation and Experience conditions, respectively, for participant i in the voxel under analysis. We then compared the residual(i) across the two groups in each voxel to test for a group difference during Observation after removing the variance that can be accounted for by differences in Experience. Page 17 of 18 We then repeated the initial ANOVA on the residual, unexplained variance in Observation within those regions that were hypo-activated for the patient group during Observation. Some of the brain regions that demonstrated group differences in our initial analysis still showed significant group differences (see next table). Results of regression analysis. Differences (punc<0.001, qfdr<0.05) in average brain activity while viewing movies after variance related to experiencing similar interactions has been regressed out. Analysis is restricted using a regions of interest approach using the areas that were found to be differentially activated for the groups during Observation (based on the F-test). No areas were hyperactive for the patients compared to the control group (not even at p unc = 0.05). Conventions as in Table 2. Cluster size T MNI xcoordinates y z Hemisphere Macro anatomical location of peak voxel Overlap with cytoarchitectonic regions L R R R R L L Thalamus Superior temporal gyrus Supramarginal gyrus Superior frontal gyrus Thalamus Superior temporal gyrus Supramarginal gyrus Hippocampus (SUB, FD) Controls larger patients 21 27 10 12 12 10 12 4,44 4,30 3,95 3,82 3,76 3,74 3,60 -18 48 48 6 21 -48 -33 -33 -27 -42 27 -33 -48 -36 0 -3 24 48 3 15 42 IPC (PFm) BA6 Hippocampus (FD, CA, SUB) BA2 Page 18 of 18 Supplemental References Grann M, Långström N, Tengström A, Kullgren G. Psychopathy (PCL-R) Predicts Violent Recidivism among Criminal Offenders with Personality Disorders in Sweden. Law and Human Behavior. 1999;23(2):205-17. Hare RD. Manual for the Revised Psychopathy Checklist (2nd ed.). Toronto: Multi-Health Systems; 2003. Hare RD, Vertommen H, Brink Wvd, Ruiter Cd. De Psychopathie Checklist revised. Handleiding. Lisse: Swets & Zeitlinger; 2001. Keysers C. The Empathic Brain: Social Brain Press, Amsterdam; 2011. Keysers C, Kaas JH, Gazzola V. Somatosensation in social perception. Nature Reviews Neuroscience. 2010;11(6):417-28. Kringelbach ML. The human orbitofrontal cortex: linking reward to hedonic experience. Nat Rev Neurosci. 2005;6(9):691-702. Lamm C, Decety J, Singer T. Meta-analytic evidence for common and distinct neural networks associated with directly experienced pain and empathy for pain. NeuroImage. 2011;54(3):2492-502. Mobbs D, Yu R, Meyer M, Passamonti L, Seymour B, Calder AJ, et al. A key role for similarity in vicarious reward. Science. 2009;324(5929):900. Rasmussen K, Storsæter O, Levander S. Personality disorders, psychopathy, and crime in a Norwegian prison population. International Journal of Law and Psychiatry. 1999;22(1):91-7. Sjöstedt G, Långström N. Assessment of risk for criminal recidivism among rapists: A Comparison of four different measures. Psychology, Crime & Law. 2002;8(1):25. 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