Neuropsychologia 71 (2015) 1–10

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Neuropsychologia journal homepage: www.elsevier.com/locate/neuropsychologia

Social information processing following resection of the insular cortex Olivier Boucher a,b, Isabelle Rouleau c,d, Maryse Lassonde a,b, Franco Lepore a, Alain Bouthillier c, Dang K. Nguyen c,n a

Centre de recherche en neuropsychologie et cognition, Département de psychologie, Université de Montréal, Montréal, Que., Canada Centre de recherche du CHU Hôpital Sainte-Justine, Montréal, Que., Canada c Centre hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montréal, Que., Canada d Département de psychologie, Université du Québec à Montréal, Montréal, Que., Canada b

art ic l e i nf o

a b s t r a c t

Article history: Received 28 September 2014 Received in revised form 22 January 2015 Accepted 10 March 2015 Available online 11 March 2015

The insula has been implicated in social cognition and empathy in several neuroimaging paradigms. Impairments in social information processing, including specific deficits in disgust recognition, have been described following isolated insular damage, although the evidence remains limited to a few case studies. The present study examines social cognition and empathy in a group of fifteen patients for whom the insula was removed as part of their epilepsy surgery. These patients were compared to a lesion-control group of 15 epileptic patients who had a surgery in the anterior temporal lobe that spared the insula, and to 20 healthy volunteers matched on age, sex, and education. Participants were assessed on an Emotion Recognition Task (ERT), the Reading the Mind in the Eyes test, and a self-administered empathy questionnaire. Patients who underwent insular resection showed poorer ability to recognize facial expressions of emotions and had lower scores of perspective taking on the empathy questionnaire than healthy controls. Using results from healthy controls as normative data, emotion recognition deficits were more frequent in insular patients than in both other groups. Specific emotion analyses revealed impairments in fear recognition in both groups of patients, whereas happiness and surprise recognition was only impaired in patients with insular resection. There was no evidence for a deficit in disgust recognition. The findings suggest that unilateral damage to the operculo-insular region may be associated with subtle impairments in emotion recognition, and provide further clinical evidence of a role of the insula in empathic processes. However, the description of 15 consecutive cases of insula-damaged patients with no specific deficit in disgust recognition seriously challenges the assumptions, based on previous case reports, that the insula is specifically involved in disgust processing. & 2015 Elsevier Ltd. All rights reserved.

Keywords: Emotion recognition Empathy Epilepsy Insula Neuropsychology Neurosurgery

1. Introduction The insula is located deep in the Sylvian fissure, hidden behind the frontal, temporal, and parietal opercula, and is considered as the fifth lobe of the human brain. It has long been viewed roughly as part of the “visceral brain”, which was supported by direct electro-cortical stimulation of the insular cortex eliciting visceral sensory and motor responses in patients undergoing brain surgery (Penfield and Faulk, 1955; Pool, 1954). These findings have been replicated on several occasions since then (Isnard et al., 2004; Nguyen et al., 2009; Stephani et al., 2011), and the role of the insular cortex in viscero-sensory processing is now well-established (e.g., Craig, 2002). However, with the advent of functional n Correspondence to: Service de neurologie, Hôpital Notre-Dame du CHUM, 1560 rue Sherbrooke Est, Montréal, Que., Canada H2L 4M1. E-mail address: [email protected] (D.K. Nguyen).

http://dx.doi.org/10.1016/j.neuropsychologia.2015.03.008 0028-3932/& 2015 Elsevier Ltd. All rights reserved.

neuroimaging techniques, the insular cortex has been shown to be also involved in processing complex information, such as social and emotional stimuli (Damasio et al., 2000; Kurth et al., 2010; Phan et al., 2002). Although no global interpretation of insular function prevails, neuroimaging studies have contributed to the formulation of different hypotheses, including salience detection, subjective awareness, and neural representation of body states which are integrated in other cerebral structures for higher-order cognitive processes (Bechara and Damaio, 2005; Craig, 2002; 2009; Damasio, 1994; Menon and Uddin, 2010). Despite converging evidence from neuroimaging studies that the insula is activated during social information processing (e.g., Kurth et al., 2010; Melloni et al., 2014; Singer et al., 2004), what essential role it actually plays remains unclear. This is mostly attributable to the very low incidence of lesions restricted to this area (Cereda et al., 2002). In a pioneering case study, Calder et al. (2000) described the case of a patient who presented with a specific impairment in the experience and recognition of the

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emotion of disgust following left hemisphere infarction that involved the insula and the basal ganglia. This, combined with data from neuroimaging studies (e.g., Phillips et al., 1997; Wicker et al., 2003), lead to the proposal that the insula plays a major role in disgust processing. Impaired recognition of facial expressions of disgust, along with emotional disturbance, has also been later reported in another rare patient with an ischemic lesion involving the left posterior insula (Borg et al., 2013). However, others have reported no such impairment following isolated insular injury (Straube et al., 2010). Furthermore, the specificity of the insula for processing disgust has been questioned by several studies which suggested an involvement in processing other emotions as well (e.g., Britton et al., 2006; Dal Monte et al., 2013; Schienle et al., 2002). A recent case study reported impaired perception of pain in others in three patients with isolated anterior insular lesions, providing further support for a more global role of the insula in empathic processes rather than a specific role in disgust processing (Gu et al., 2012). Still, clinical evidence for a role of the insular cortex in socio-emotional processing relies mostly on exceptional, anecdotal reports of single or a few patients with heterogeneous clinical presentations, and larger studies with systematic assessments of patients with isolated insular damage are still lacking. The insula has been shown to be involved in the epileptogenic zone of a non-negligible proportion of drug-resistant epileptic patients (Isnard et al., 2004; Nguyen et al., 2009). With the recent advances in microsurgical techniques, an increasing number of insular resections have been reported for epilepsy control purposes (Kaido et al., 2006; Malak et al., 2009; von Lehe et al., 2009) which may, in the meantime, disrupt insular function by tissue removal or destruction. For instance, resection of the left insula may result in transient expressive language deficits (Boucher et al., 2015; Duffau et al., 2006; Sanai et al., 2010). However, whether insular resection for seizure control is associated with impairments in social processing remains undocumented. The assessment of social information processing and empathy in these patients may also uncover crucial information on the role of the insular cortex. The present study examines social information processing in a group of patients who had partial or complete removal of the insular cortex as part of their epilepsy surgery. Patients were compared to a group of healthy controls, and to a lesion-control group of patients who had epilepsy surgery that spared the insula. The latter group was recruited to exclude the possibility that social information processing deficits in insular patients are solely attributable to the effects of intractable epilepsy, or to non-anatomically-specific effects of brain tissue resection and surgery. Given the higher prevalence of temporal lobe epilepsy and in order to create a homogeneous group, patients who underwent anterior temporal lobe (including the medial structures) epilepsy surgery were recruited as lesion-controls, although specific fear recognition or more global social cognition impairments have previously been documented in this population (Adolphs et al., 2001; Ammerlaan et al., 2008; Cohn et al., In press; Dellacherie et al., 2011; Gosselin et al., 2011). We hypothesized that insular surgery would be associated with a global impairment in the ability to recognize emotions and mental states in others, whereas temporal lobe surgery would be specifically associated with impaired recognition of fearful expressions.

2. Material and methods 2.1. Participants and procedure All adult patients who underwent partial or complete insular resection for control of drug-resistant epilepsy in our epilepsy

service, during the period extending from November 2004 to July 2013, were invited to participate to this study, with the exception of one patient with an epileptic focus which involved the frontal lobe and the insula who presented with notable behavioral problems prior to his surgery. None of these patients had a major sensory, motor, or language impairment that could have affected their performance in the present study, as revealed by standard neuropsychological assessment (Boucher et al., 2015). All seventeen patients accepted our invitation but two were excluded after data collection because they had undergone an additional resection involving a large portion of the prefrontal cortex, which may have affected their results. The insular patients were matched with two control groups: a lesion-control group (n¼ 15) of patients who had epilepsy surgery in the anterior temporal lobe that spared the insula, and a healthy control group (n ¼20). Participants from both control groups were selected in order to be comparable to the insular group on age, sex, education, and for the lesion-control group, hemisphere of resection and time since surgery. The healthy control group was recruited using ads published on the hospital’s intranet page; criteria of selection were: age between 18 and 55 years, and no history of neurological problems. The final sample of insular patients (n¼ 15) along with information on their surgeries, are described in Table 1; Table 2 reports the same information for the lesion-control group. Fig. 1 depicts resection overlap among insular patients and representative cases of insular resections. Individual post-operative MRI scans from each patient from the insular group can also be found in Supplementary Fig. 1. The list of psychoactive drugs taken by each patient at time of assessment, including anticonvulsants, antidepressants, and anxiolytics, is reported in Supplemental Table S1. Assessments were conducted by a licensed neuropsychologist (O.B.), after obtaining informed written consent from the study participant. Patients were assessed at least four months after neurosurgery. Three patients (two in the insular group, one in the temporal group) were assessed in English because they were native English speakers; all the other participants were tested in French. A 50$ financial compensation was given to each participant at the end of the assessment. The study protocol was approved by our institutional Ethics committee. 2.2. Social processing assessment 2.2.1. Emotion Recognition Task We created an experimental task using the stimuli from the Directed Emotional Faces database (Goeleven et al., 2008; Lundqvist et al., 1998) to assess recognition of facial expressions of emotions. This Emotion Recognition Task (ERT) was implemented with E-Prime (Psychology Software Tools, Pittsburgh, PA). Stimuli were frontal pictures of 20 human faces (10 of each gender) each displaying the six basic emotions (anger, fear, disgust, happiness, surprise, and sadness). All pictures were gray-scaled, sized-adjusted, and cropped to exclude non-facial clues, and presented on a computer screen with black background. Stimuli were presented for 200 ms and were immediately followed by a white-noise mask lasting 250 ms. Then, the six-emotion response choice was presented on the screen, and remained until the participant gave his/ her answer using the computer keyboard. The following stimulus was preceded by a fixation cross (1500–2500 ms) at the center of the screen. Each picture was presented once in one of two blocks of 60 trials, each of which contained an equal number of pictures of each emotion. The first block was preceded by a practice trial, which included one picture of each emotion. The number of correct responses and reaction times for correct responses were collected for the complete experiment as well as for each emotion separately.

Table 1 Characteristics of insular patients. Pt

Age at first seizures (yr)

Age at surgery (yr)

Time since surgery (yr)

Pre-surgery MRI

Resection

Post-operative outcomes

Side Insular area

31 5 18

47 23 25

1.1 0.6 0.6

Normal R insular tuber L temporal FCD

L R L

Posterior Complete Anterior-inferior

I4 I5 I6

5 21 25

38 36 52

0.5 0.4 2.4

Normal Normal R HS

L R R

Anterior 2/3rd Posterior Inferior

I7 I8

30 26

35 36

2.7 1.6

Normal Normal

L R

I9 I10 I11

9 33 7

27 39 22

1.6 4.0 9.0

Normal Normal R hemispheric atrophy, R HS

R L R

Anterior 2/3rd Anteriorsuperior Anterior Anterior 2/3rd Infero-posterior

I12

0

32

0.5

R

Posterior 1/3rd

I13

21

26

7.3

Normal (possible subtle R operculoinsular FCD) Normal

R

Inferior

I14 I15

31 4

34 38

8.8 6.7

Normal R insular FCD

L R

Posterior Complete

Subcortical ischemic infarcts

Engel et al.'s (1993) classification of outcome

Temporo-parietal opercula Fronto-parieto-temporal opercula Temporal lobe (T1, T2, T3, medial structures) Temporal operculum Parieto-temporal opercula Temporal lobe (T1, T2, T3, medial structures) Frontal opercula

No Yes Yes

Class I Class I Class I

Yes Yes Yes

Class I Class II Class I

No No

Class II Class I

Orbitofrontal operculum Temporal operculum Temporal lobe (T1, T2, T3, medial structures) Parietal operculum, inferior postcentral gyrus Temporal lobe (T1, T2, T3, medial structures) – Fronto-parietal opercula

Yes No No

Class I Class III Class I

Yes

Class I

No

Class I

No Yes

Class I Class I

O. Boucher et al. / Neuropsychologia 71 (2015) 1–10

I1 I2 I3

Other areas

Abbreviations: FCD, focal cortical dysplasia; HS, hippocampal sclerosis; L, left; R, right.

3

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Table 2 Characteristics of temporal patients. Pt

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 T13 T14 T15

Age at first seizures (yr)

Age at surgery (yr)

Time since surgery (yr)

Pre-surgery MRI

1 17 18 5 30 19 41 1 2 10 11 34 1 26 5

34 21 25 20 47 34 52 32 43 19 43 41 47 32 18

3.5 7.0 7.1 7.7 2.8 4.4 1.2 0.3 1.5 2.7 7.9 8.8 2.0 2.7 10.8

R HS R HS L HA L HS L HS Normal L HS R HA R HA R HS R HS B HS L HA, T1C R HS L HS

Resection Side Location R R R L L L L R R R R L L R L

ATL SAH SAH SAH SAH SAH ATL ATL SAH SAH SAH SAH ATL SAH SAH

Engel et al.'s (1993) classification of outcome

Class I Class I Class II Class I Class I Class I Class I Class I Class I Class I Class I Class I Class I Class I Class I

Abbreviations: ATL, anterior temporal lobectomy; B, bilateral; HA, hippocampal atrophy; HS, hippocampal sclerosis; L, left; R, right; SAH, selective amygdalo-hippocampectomy; T1C, Type 1 Chiari malformation.

2.2.2. Reading the Mind in the Eyes Theory of mind was assessed using the revised version of the “Reading the Mind in the Eyes” test (Baron-Cohen et al., 2001). In this task, a series of 36 gray-scaled photographs depicting a pair of eyes are successively shown, together with a list of four words describing mental states. For each picture, the participant is asked to determine which word best characterizes the mental state of the person in the photograph. Participants were invited to consult the word definition handout when not sure about the meaning of a word. For participants assessed in French, we used the French version of the test which is freely available online on the Autism Research Center’s website (http://www.autismresearchcentre. com/arc_tests; however, four words from the French version were changed in order to better reflect the meaning of the words used in the original English version; Annoyed: “Gêné” was changed for “Irrité”; Desire: “Envieux” was changed for “Désireux”; Insisting: “Exigeant” was changed for “Insistant”; Excited: “Passionné” was changed for “Excité”). 2.2.3. Interpersonal Reactivity Index Empathy was assessed using the Interpersonal Reactivity Index (IRI; Davis, 1980). This self-administered questionnaire is composed of 28 items answered on a 5-point Likert scale ranging from “Does not describe me well” to “Describes me very well”. The questionnaire has four scales, each derived from seven different items: Perspective Taking, Fantasy, Empathic Concern, and Personal Distress (Davis, 1983).

2.3. Supplementary measures IQ was estimated using the average scaled scores obtained on the Matrix Reasoning and Similarities subtests from the Wechsler Adult Intelligence Scales – 3rd Edition (Wechsler, 1997). Processing Speed was estimated using the scaled score on the Coding subtest from the same battery. Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II; Beck et al., 1996), a selfreported instrument composed of 21 items representing a clinical symptom of depression, which must be answered on a scale ranging from “0” (no problem) to “3” (severe problem). Severity of anxiety was assessed using the Beck Anxiety Inventory (BAI; Beck et al., 1988). This questionnaire is composed of 21 items representing anxiety symptoms, and the participants are asked to

indicate the extent to which they were bothered by each item, during the preceding week, on a scale from “0” (not at all) to “3” (severely).

2.4. Statistical analyses Normality of distribution was inspected visually for each variable and checked for skewness (normality range:  2.0 to 2.0). Variables were also examined for potential outliers ( Z3.0 S.D. from the mean). Group comparisons for experimental tasks and for IRI subscales were performed using analyses of variance (ANOVAs). For each significant difference, post-hoc comparisons were conducted between each pair of groups using Tukey's HSD test. Comparisons for the accuracy of recognition of each specific emotion on the ERT were performed using non-parametric Kruskal–Wallis (three groups analyses) and Mann–Whitney tests (posthoc comparisons), since these variables were not normally distributed. For each main measure, the proportion of participants who obtained performance at a deficit level, using the healthy controls as a normative sample and a score4 2 SDs below the mean as a cut-off point, was also compared between groups using Chi-square tests. Supplementary analyses of covariance (ANCOVAs) were conducted with estimated IQ as a covariate, in order to exclude the possibility that an observed difference was attributable to differences in general cognitive abilities, since the groups were not all equivalent on estimated IQ. Because the speed of information processing may affect performance on the ERT due to the rapid presentation of the stimuli, additional ANCOVAs were also conducted with Processing Speed added to the model. The contribution of depression (BDI-II score413; yes/no) and anxiety (BAI score4 7; yes/no) to the obtained results was examined using the same procedure. Finally, exploratory ANOVAs were conducted in order to examine whether the laterality of the hemisphere where surgery occurred (left vs. right), the age of disease onset (o18 years vs. adult onset), and the presence subcortical ischemic infarcts following insular resection (yes vs. no), had an effect on social processing performance. Differences were considered significant at p o0.05. Statistical analyses were performed using SPSS 12.0.1 software (SPSS, Chicago, IL).

O. Boucher et al. / Neuropsychologia 71 (2015) 1–10

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Fig. 1. (A) Overlap of resections conducted within the insular group. The color bar indicates the number of overlapping cases at each voxel. Maximal lesion overlap is found in the right insular cortex. (B) Post-operative T1-weighted sagittal, coronal, and axial MRI scans from representative cases of the study sample. Pt. #2 (top) complete right insulectomy with fronto-parieto-temporal opercular resection; Pt #7 (middle): selective resection of the left anterior insula; Pt. #5 (bottom): resection of the right posterior insula and parieto-temporal opercula.

3. Results 3.1. Study population Comparisons between groups on socio-demographic variables, estimated IQ, Processing Speed, depressive symptoms, anxiety

symptoms, and epilepsy-related factors revealed a significant difference in estimated IQ and Processing Speed between groups (Table 3). Post-hoc comparisons revealed that patients who underwent temporal surgery had significantly lower estimated IQ (p ¼0.016) and Processing Speed (p ¼0.028) scores than healthy controls. Insular patients were not different from the healthy

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O. Boucher et al. / Neuropsychologia 71 (2015) 1–10

Table 3 Description of the study sample. Variable

Insular patients (n¼15)

Socio-demographics Age (yr) Education (yr) Sex (% women)

Mean 7 SD

Range

37.6 7 8.6 12.8 7 2.7

23–54 8–18

Temporal patients (n¼ 15) %

Mean7 SD

Range

38.7 710.3 13.3 72.8

22–54 8–20

60

Control variables Estimated IQa Psychomotor speedb BDI-II (raw score) BAI (raw score)

Epilepsy-related factors Age at surgery (yr) Time since surgery (yr) Hemisphere (% left) Developmental onset (%o 18 yrs)

Healthy controls (n¼ 20) %

Mean 7 SD

Range

36.17 10.2 13.5 71.8

24–52 11–18

53

%

p-Value

50

0.739 0.695 0.840

98.9 7 11.2 97.7 7 12.7 9.7 7 7.0 6.5 7 6.3

83–120 75–110 2–27 0–26

94.0 713.0 95.0 711.6 9.5 711.2 8.0 79.4

70–113 80–125 0–36 0–29

104.5 77.9 107.0 7 13.9 5.2 7 5.9 3.6 7 3.5

88–120 80–130 0–19 0–12

0.021 0.022 0.064 0.190

34.0 7 8.5 3.2 7 3.2

22–52 0.4–9.0

33.9711.4 4.7 73.2

18–52 0.3–10.8

– –

– –

0.971 0.208 0.713 0.713

40 40

– –

47 47

Note. Statistical comparisons between the groups were conducted using non-parametric Chi square (sex and hemisphere) and Kruskal–Wallis (Beck Depression Inventory-II and Beck Anxiety Inventory) tests, and analysis of variance (ANOVA; all other variables). a b

Based on average performance on the Matrix Reasoning and Similarities subtests from the Wechsler Adult Intelligence Scales – 3rd Edition. Estimated using the Coding subtest from the Wechsler Adult Intelligence Scales – 3rd Edition.

controls or temporal patients on estimated IQ (p4 0.20), but showed a non-significant trend for poorer Processing Speed than healthy controls (p¼ 0.097). There was no significant difference between groups on any other variable. 3.2. Social information processing The results from each group on the experimental tasks are reported in Table 4, and individual scores from each single patient and on each measure are provided in Supplemental Table S2. There were significant group differences for three outcomes: ERT accuracy scores, Reading the Mind in the Eyes test performance, and the Perspective Taking scale of the empathy questionnaire. For each of these outcomes, post-hoc comparisons revealed that insular patients had significantly lower scores than the healthy controls (Cohen's d: ERT accuracy¼  1.04; Reading the Mind in the Eyes ¼  0.86; Perspective Taking scale ¼  0.95). Neither the insular group nor the healthy control participants differed

significantly from the temporal lobe group, for which scores tended to range between those of the two other groups. Analyses were then re-conducted after exclusion of the insular patients who also had a temporal lobe resection (n ¼4), in order to better delineate the specific effects of operculo-insular resection. Despite decrease in sample size which resulted in reduced statistical power, patients with resection limited to the operculo-insular cortex still showed significantly poorer recognition accuracy scores on the ERT (mean 7SD ¼73.7 79.6; p¼ 0.029; Cohen's d¼  0.94) and lower total IRI score (mean 7SD ¼53.2 712.2; p¼ 0.032; Cohen's d ¼  0.88) than healthy controls. However, the effect on the Reading the Mind in the Eyes test was no more present (mean 7SD ¼23.8 73.7; p¼ 0.186; Cohen's d ¼ 0.64). Fig. 2 illustrates mean ERT accuracy performance from each group according to each of the six emotions. Kruskal–Wallis nonparametric tests revealed significant group differences for fear (χ2(2) ¼8.5; p ¼0.014) and happiness (χ2(2) ¼13.1; p¼ 0.001), and there was also a trend for a difference in surprise recognition

Table 4 Socio-emotional assessments for each study group. Outcome

Insular patients (I) n

Emotion recognition task Percent correct (%) Mean RT (ms)

Mean

Temporal patients (T) SD

n

Mean

Healthy controls (C) SD

n

Mean

pValueb

Post-hoc comparisons

SD

15 15

71.9 2544

9.9 520

15 15

75.7 2822

7.8 1053

20 20

80.9 2389

5.0 747

0.004 0.291

C4 I –

Reading the Mind in the Eyes test: Raw score 14a

22.6

4.3

15

24.3

3.2

20

26.2

3.6

0.026

C4 I

Interpersonal Reactivity Index Perspective Taking scale Fantasy scale Empathic Concern scale Personal Distress scale Total score

15.3 11.5 19.2 9.1 55.1

4.4 5.3 4.6 5.7 11.0

15 15 15 15 15

17.5 11.5 20.1 10.5 59.7

6.1 3.8 3.1 6.5 10.5

20 20 20 20 20

19.6 13.6 20.0 10.9 64.1

3.8 5.9 4.4 5.7 10.9

0.039 0.378 0.798 0.671 0.063

C4 I – – – –

a b

15 15 15 15 15

One patient could not complete this task due to lack of time. Statistical comparisons were conducted using analysis of variance (ANOVA). Abbreviations: C, healthy controls; I, insular patients.

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Fig. 2. Mean performance from each group on the Emotion Recognition Test according to each emotion. Error bars represent standard error of the mean. **p o 0.01; *p o0.05.

(χ2(2) ¼5.6; p ¼0.060). Compared to the healthy controls, insular patients identified fear (p ¼0.021), happiness (p o0.001), and surprise (p¼ 0.023) less accurately, whereas only fear recognition was poorer in temporal patients (p ¼0.009). Insular patients tended to identify happiness less accurately than temporal patients, although this did not reach statistical significance (p ¼0.089). Differences in fear and happiness recognition between insular patients and the healthy controls remained after the exclusion of insular patients who also had temporal lobe resection (p ¼0.044 and p ¼0.002, respectively), but the difference with surprise turned to a non-significant trend (p ¼0.079). Group comparisons for the proportions of participants who obtained performance at the deficit level (i.e., 2 SDs below the mean of the healthy control group) revealed a significant difference on the ERT accuracy (χ2(2) ¼ 12.6; p ¼0.002). Post-hoc comparisons between each pair of groups revealed that the proportion of deficit ERT performance was higher in the insular group (53%) than in both the temporal patients (13%; χ2(1) ¼5.4; p¼ 0.020) and the healthy controls (5%; χ2(1) ¼10.5; p ¼0.001). Because of previous reports suggesting a relation between insular damage and deficit in disgust processing, additional analyses were conducted specifically for disgust recognition. Only one (6.7%) patient with insular resection (Pt #I6 – who also had temporal lobe resection involving medial structures) had a deficit-level performance for disgust recognition (and for fear and anger recognition as well), compared to four (26.7%) among patients from the temporal group and one (5%) among healthy controls (difference not significant). There was no significant difference for the other tests. 3.3. Contribution of general cognitive abilities, processing speed, and mood In ANCOVA models adjusting for estimated IQ, group effects remained on the ERT accuracy scores (F(2,46) ¼4.83, p¼ 0.013), but fell short of significance on the Reading the Mind in the Eyes Test (F(2,45) ¼3.12, p ¼0.054) and the IRI Perspective Taking scale (F(2,46) ¼2.73, p ¼0.076). Post-hoc comparisons (uncorrected for multiple comparisons) between the groups revealed that IQ-adjusted ERT performance was significantly poorer in insular patients (estimated mean ¼72.1%, SE¼1.8) than in both the healthy controls (estimated mean ¼ 79.5%, SE¼1.9; p¼ 0.004) and the temporal lobe patients (estimated mean ¼77.3%, SE¼1.6; p ¼0.049). The same results were obtained when Processing Speed was added to the model (not shown), suggesting that performance of temporal patients on this task was more similar to the healthy controls than to the insular patients after adjusting for differences

in IQ and psychomotor speed. Separate ANCOVAs adjusting for either depression or anxiety showed that these variables had virtually no effect on the outcomes (not shown). 3.4. Effects of epilepsy-related factors ANOVAs conducted within all epileptic patients revealed that patients with epilepsy surgery in the left hemisphere (n ¼ 13) had poorer performance than those with right hemisphere resection (n ¼17) on ERT accuracy (F (1,28) ¼4,31, p ¼0.047) and ERT mean RT (F(1,28) ¼4.21, p ¼0.050). These differences did not reach statistical significance when examined for the insular and temporal groups separately (not shown), which is likely attributable to insufficient statistical power due to the small sample sizes. Analyses comparing patients with a developmental (o 18 years) onset of seizures and those with an adult onset did not reveal a significant difference on any outcome and the same was found when analyses were restricted to insular patients (not shown). Finally, comparisons between insular patients with and without subcortical ischemic infarcts as a complication of neurosurgery revealed no significant difference on measures of social processing.

4. Discussion This study examined social cognition and empathy in a group of epileptic patients who underwent partial or complete resection of the insular cortex for seizure control. Compared to a group of healthy control participants comparable on age, sex, and education, insular patients were significantly impaired in their ability to recognize emotions in others using facial cues. Insular patients were also more likely to display emotion recognition deficits than both the healthy controls and a lesion-control group of patients with anterior temporal lobe resection. Examining for specific emotion recognition impairments revealed that insular patients were impaired in fear, happiness, and surprise recognition, whereas temporal lobe patients were specifically impaired in fear recognition. We also found that patients who had resection of the insular cortex performed more poorly on a test of theory of mind, the Reading the Mind in the Eyes test. However, this effect did not remain significant when four patients who had additional resection of the temporal lobe were excluded from the analyses, suggesting that this task may be less sensitive to the effects of insular damage, maybe due to a greater involvement of semantic processes for this task. Finally, insular patients, but not temporal lobe patients, also reported themselves as less prone to take others’

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perspective than healthy controls on a self-reported empathy questionnaire. Our results with the ERT suggest that insular damage is associated with an impaired ability to recognize emotions in others, and that this impairment is not specific to the emotion of disgust, as widelycited clinical reports and functional imaging studies had previously suggested (Adolphs et al., 2003; Borg et al., 2013; Calder et al., 2000; Jehna et al., 2011; Phillips et al., 1997). Conversely, when analyses were conducted separately for each emotion, insular patients were significantly impaired in fear, happiness, and surprise recognition. Disgust was even the only emotion for which insular patients performed better, on average, than the control groups. Furthermore, the prevalence of deficit-level performance in disgust recognition was not higher in insular patients than in temporal patients or healthy controls. These results are congruent with an increasing body of evidence linking the insula to the ability to recognize emotions in others, and that this does not apply exclusively to the emotion of disgust (Britton et al., 2006; Dal Monte et al., 2013). There is increasing evidence from neuroimaging and lesionmapping studies that the insula, and especially its anterior portion, is a key structure within the ‘empathic network’ (Driscoll et al., 2012; Fan et al., 2011; Leigh et al., 2013; Morelli and Liberman, 2013; Singer et al., 2004). Empathy, however, is not a unitary construct. At least two dissociated empathy systems have been identified which depend on distinct brain networks, namely the ‘affective empathy’ system, a basic emotional contagion system involving the inferior frontal gyrus in the mirror neuron system, and the ‘cognitive empathy’ system, which allows more advanced cognitive perspectivetaking processes and involves the ventromedial prefrontal cortex (Shamay-Tsoory et al., 2009). In accordance with its presumed role in subjective feelings (Craig, 2009) and with neuroimaging studies reporting insular activations during the observation and experience of an emotion (Jabbi et al., 2008; Singer et al., 2004; Wicker et al., 2003), the insula is typically related to the affective component of empathy (e.g., Nummenmaa et al., 2008; Preston et al., 2007). It is thus somewhat surprising that the only IRI scale that was scored lower among insular patients from our study was the Perspective Taking scale, which is composed of items more associated with the advanced cognitive aspects of empathy. Nevertheless, a meta-analysis of recent fMRI studies on empathy found that the left insula shows activations in response to tasks of both affective and cognitive empathy (Fan et al., 2011). Further studies involving patients with insular lesions will be necessary to understand the relative contribution of the insula from each cerebral hemisphere to the affective and cognitive components of empathy. The lesion-control participants – all of whom had medial temporal resection involving the amygdala – displayed a specific impairment in fear recognition on the ERT. Impairments in the ability to recognize fearful (and other negative) expressions had previously been reported after resection of the anteromedial temporal lobe including the amygdala (Adolphs et al., 2001; Ammerlaan et al., 2008; Dellacherie et al., 2011; Gosselin et al., 2011). By contrast, evidence for theory of mind and empathic deficits after amygdala resection remains scarce in the literature, and our results offer no further support for this hypothesis. Although bilateral amygdala lesions have been associated with impaired performance on the Reading the Mind in the Eyes and Recognition of Faux-Pas tests in a two-case study (Stone et al., 2003), a study including 19 patients with unilateral amygdala resection found no difference with healthy controls on the Faux-Pas and Happé's Strange Stories tests, two other well-validated theory of mind measures (Shaw et al., 2007), and one study even reported a unique case of hyper-empathy following right amygdalo-hippocampectomy (Richard-Mornas et al., 2014). Our study thus suggests that the insular cortex and anteromedial temporal structures contribute differently to social processing.

Exploration of laterality effects among our two patient groups revealed that patients who underwent left hemisphere surgery had significantly poorer and slower performance on the ERT compared to those with right hemisphere resection. Out of six patients who had left insular resection, five (83%) displayed a deficit in emotion recognition, compared to three out of nine (33%) in patients with right insular resection. A larger sample would be necessary to test for laterality effects in patients with insular damage more specifically, but these data suggest that the left insular injury may be associated with more severe impairments in social information processing. These results are discordant with the right-hemisphere hypothesis of emotion processing (Sedda et al., 2013; Yuvaraj et al., 2013), and with the results from a lesionmapping study involving over 100 patients, which showed that lesions in the right somatosensory-related cortices, including the insula, were associated with impaired recognition of emotions from human facial expressions (Adolphs et al., 2000). Nevertheless, a more recent, large voxel-based lesion-symptom mapping found that only the left insula was significantly involved in facial emotion recognition impairment following penetrating brain injury (Dal Monte et al., 2013). A left insular role in emotion recognition may account for the divergent results provided by two case reports of similar insular damage, one finding impaired disgust recognition after left hemisphere stroke (Calder et al., 2000), and the other one finding no emotion recognition impairment following right hemisphere stroke (Straube et al., 2010). Cohn et al. (2014) recently reported poorer social inference abilities after left vs. right anterior temporal lobectomy, suggesting that this lateralizing effect, if present, may also apply to other structures involved in emotion recognition as well. Although impaired social cognition and empathy were found in insular-lesioned patients at the group level, there was considerable heterogeneity in performance across patients, with some showing clear deficits and others, good performance. Similar findings are typically obtained for memory performance in epileptic patients undergoing selective amygdalo-hippocampectomy (e.g., von Rhein et al., 2012). It is plausible that compensatory mechanisms account for the intact social cognition performance and empathy scores following unilateral insular resection in some patients. Examination of the impact of age at seizure onset suggested no influence of this variable on the results. Interestingly, Couto et al. (2013) compared two patients who suffered from right-hemispheric focal strokes, one in the insular cortex, and the other with a subcortical stroke damaging the connections of the insula with frontotemporal areas and preserving the insular cortex. In comparison to a matched sample of 10 healthy participants, the patient with subcortical damage, but not the one with isolated insular injury, showed deficits in negative emotion processing and empathy. The authors suggested that frontotemporal connections of the insular cortex, and not the insula per se, are critical for social cognition and empathy. Although our supplemental analyses according to the presence or absence of subcortical infarct following insular surgery do not support the view that subcortical lesions account for the observed deficits in our patients, it is possible that the long-term effects of insular epilepsy on these connections have at least reduced the compensatory capacity of the connected structures, if not responsible for the observed effects. It is uncertain whether the relatively subtle impairments in social information processing found in patients with unilateral insular resection extend to the real world, as there was no corroboration from family members or other peers interacting with these patients on a daily basis. Previous studies have reported difficulties in understanding and considering the feelings of others, as reported by a family member, in a patient who presented with impaired disgust processing and personality changes following a left posterior insular stroke (Borg et al., 2013). In another rare patient with brain damage

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affecting the insula as well as other limbic and paralimbic structures bilaterally (including the amygdala), impaired recognition of anger expressions co-occurred with marked alterations in social relationships, the patient approaching strangers without regard for social signals (Adolphs et al., 1999; Feinstein et al., 2010). This patient was described as expressing little, if any, negative emotions, although a recent report demonstrated that he could still feel and express pain (Feinstein et al., 2015). By contrast, another very rare patient with extensive brain damage affecting the insula bilaterally and showing emotion recognition deficits (Adolphs et al., 2003) was reported to display adequate social interactions and showed reactions of empathy and sympathy with others (despite severe memory problems), suggesting that the insula may not be necessary for empathic processes and for experiencing emotions (Damasio et al., 2013). Among the limitations of our study is the fact that patients were not assessed prior to their surgery with the experimental tasks under study. Thus, we cannot exclude the possibility that performance on these tasks was already impaired prior to surgery, as a result of the long-term effect of epilepsy on brain function. Impaired emotion recognition may even be part of the neuropsychological profile associated with insular epilepsy, to a similar extent that executive deficits characterise frontal lobe epilepsy and memory deficits, temporal lobe epilepsy (Hernandez et al., 2002; Lippé and Lassonde, 2004). However, even in these cases, resection of the epileptic focus has been associated with deterioration of the function (Baxendale et al., 2006; Helmstaedter et al., 1998). Another limitation to our study is that most resections were operculo-insular rather than purely insular. Damage to the opercula might have affected performance in some patients. Finally, a larger sample size would have allowed comparisons according to the specific location of insular resection (e.g., left vs. right hemisphere; anterior vs. posterior insular cortex), which could be of special interest given the functional segregation within the insular cortex suggested by functional imaging and electrocortical stimulation studies (Afif et al., 2010; Kurth et al., 2010).

5. Conclusions This study examined, for the first time, social information processing in a series of patients who underwent insular resection for clinical management of their drug-resistant epileptic seizures. Our findings suggest that partial or complete resection of the insula is associated with subtle impairments in emotion recognition which are not specific to the emotion of disgust, as previously suggested. These findings underline the need for prospective studies aimed at assessing the consequences of insular resection on social cognition and affective processes.

Acknowledgments We are grateful to the participants involved in this study. We also want to thank Fabien d’Hondt, Micheline Gravel, Luc Keita, Manon Robert, and Alan Tucholka. This research was funded by the Fondation du CHUM Neurologie-épilepsie 93512 (D.K. Nguyen) and by a Grant from the Canadian Institutes of Health Research MFE-115520 (O. Boucher).

Appendix A. Supplementary material Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.neuropsychologia. 2015.03.008.

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