Social cognition in patients following surgery to the prefrontal cortex.

Psychiatry Research: Neuroimaging ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Social cognition in patients following surgery to the prefrontal cortex Lisanne Michelle Jenkins a,b,n, David Gordon Andrewes c, Christian Luke Nicholas a, Katharine Jann Drummond d, Bradford Armstrong Moffat e, Pramit Phal e, Patricia Desmond e, Roy Peter Caspar Kessels f,g a

Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Victoria, Australia Department of Psychiatry, The University of Illinois at Chicago, Chicago, IL, USA c Melbourne Neuropsychiatry Centre, Psychiatry Department, The University of Melbourne, Parkville, Victoria, Australia d Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, Victoria, Australia e Department of Radiology, The Royal Melbourne Hospital, Parkville, Victoria, Australia f Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, Nijmegen, The Netherlands g Department of Medical Psychology, Radboud University Medical Center, Nijmegen, The Netherlands b

art ic l e i nf o

a b s t r a c t

Article history: Received 5 March 2014 Received in revised form 4 July 2014 Accepted 7 August 2014

Impaired social cognition, including emotion recognition, may explain dysfunctional emotional and social behaviour in patients with lesions to the ventromedial prefrontal cortex (VMPFC). However, the VMPFC is a large, poorly defined area that can be sub-divided into orbital and medial sectors. We sought to investigate social cognition in patients with discrete, surgically circumscribed prefrontal lesions. Twenty-seven patients between 1 and 12 months post-neurosurgery were divided into groups based on Brodmann areas resected, determined by post-surgical magnetic resonance imaging. We hypothesised that patients with lesions to the VMPFC (n ¼5), anterior cingulate cortex (n ¼4), orbitofrontal cortex (n ¼7) and dorsolateral prefrontal cortex (DLPFC, n ¼ 11) would perform worse than a control group of 26 extra-cerebral neurosurgery patients on measures of dynamic facial emotion recognition, theory of mind (ToM) and empathy. Results indicated the VMPFC-lesioned group performed significantly worse than the control group on the facial emotion recognition task overall, and for fear specifically, and performed worse on the ToM measure. The DLPFC group also performed worse on the ToM and empathy measures, but DLPFC lesion location was not a predictor of performance in hierarchical multiple regressions that accounted for other variables, including the reduced estimated verbal IQ in this group. It was concluded that isolated orbital or medial prefrontal lesions are not sufficient to produce impairments in social cognition. This is the first study to demonstrate that it is the combination of lesions to both areas that affect social cognition, irrespective of lesion volume. While group sizes were similar to other comparable studies that included patients with discrete, surgically circumscribed lesions to the prefrontal cortex, future large, multi-site studies are needed to collect larger samples and confirm these results. Crown Copyright & 2014 Published by Elsevier Ireland Ltd. All rights reserved.

Keywords: Ventromedial Orbitofrontal Anterior cingulated Theory of mind

1. Introduction Patients with lesions to the ventromedial (VM) prefrontal cortex (PFC) display a specific syndrome of behavioural disturbances, including severe changes in emotional and social function that some researchers have suggested are related to poor recognition of emotion (Hornak et al., 2003; Mah et al., 2004). These patients often exhibit disinhibited behaviour, are socially inappropriate, are impulsive, have poor judgment and decision-making, have blunted emotional experience, have difficulty monitoring n Corresponding author at: The University of Illinois at Chicago, Psychiatric Institute, Department of Psychiatry, 1601 W Taylor St, M/C 912, Chicago, IL 60612, USA. Tel.: þ1 312 532 3317. E-mail address: [email protected] (L.M. Jenkins).

themselves, and lack awareness of their behaviour (Eslinger and Damasio, 1985; Barrash et al., 2000; Beer et al., 2006). Thus, patients with VMPFC lesions have been likened to sociopaths (Eslinger and Damasio, 1985; Blair and Cipolotti, 2000). Lesions to this area can lead to severely negative psychosocial consequences, including loss of employment, divorce and bankruptcy (Eslinger and Damasio, 1985). A difficulty with research in these patients is that organic lesions are not selective, and those affecting the VMPFC are often large and involve parts of the orbital (OFC) and medial (MPFC) PFC, both of which have been separately implicated in emotion recognition and social cognition. For example, OFC lesions result in impairments in recognition of facial and vocal emotional expressions (Hornak et al., 2003), and other nonverbal social and emotional cues such as body language (Mah et al., 2004). Lesions

http://dx.doi.org/10.1016/j.pscychresns.2014.08.007 0925-4927/Crown Copyright & 2014 Published by Elsevier Ireland Ltd. All rights reserved.

Please cite this article as: Jenkins, L.M., et al., Social cognition in patients following surgery to the prefrontal cortex. Psychiatry Research: Neuroimaging (2014), http://dx.doi.org/10.1016/j.pscychresns.2014.08.007i

L.M. Jenkins et al. / Psychiatry Research: Neuroimaging ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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to the MPFC also result in impaired recognition of facial and vocal emotion (Hornak et al., 2003; Baird et al., 2006). Neuroimaging studies have observed activation in a part of the MPFC known as the anterior cingulate cortex (ACC) in response to a range of emotional facial expressions (George et al., 1993; Dolan et al., 1996; Morris et al., 1998; Phillips et al., 1998; Blair et al., 1999; Wicker et al., 2003), particularly sadness (Phan et al., 2004). Another potential explanation for impaired social behaviour in patients with VMPFC lesions is that they have deficits in empathy, an ability to share the emotions of others (Singer, 2006), that is disrupted in patients with OFC lesions (Grattan et al., 1994; Eslinger, 1998; Shamay-Tsoory et al., 2003; Shamay-Tsoory et al., 2005; Hynes et al., 2006). Also a key factor for social interactions is the understanding of the thoughts and intentions of others, which includes theory of mind (ToM) (Premack and Woodruff, 1978) or mentalizing (Frith and Frith, 1999), functions that have been demonstrated in neuroimaging studies to involve the MPFC (Frith and Frith, 1999; Gallagher and Frith, 2003). Thus, subcomponents of the VMPFC may offer distinct contributions to social cognition. While many studies poorly define the VMPFC, a noteworthy exception is the study by Hornak et al. (2003) which investigated recognition of emotion in patients with surgically circumscribed lesions to the PFC. Such an approach had the advantage of determining more precisely the role of subcomponents of the PFC in emotion recognition. The present study adopted this approach and furthered the earlier work in a number of ways, including by dynamically varying the intensity of expression in the facial emotion recognition task and by measuring social cognition in the form of ToM and empathy. The present study also included more precise radiological analysis of post-surgical magnetic resonance imaging (MRI) scans to allow a finer classification of patients into groups based on Brodmann areas (BAs) resected. To reduce the potential influence of compensatory recovery mechanisms, we used strict inclusion criteria of patients between 1 and 12 months post-surgery. Finally, an additional improvement was the inclusion of a non-cerebral neurosurgical control group. Given that the OFC and MPFC have both been implicated in the recognition of facial emotion, it was hypothesised that these two groups and the VM group would be impaired on a test of dynamic facial emotion recognition compared with a control group of extra-cerebral neurosurgery patients. It was also hypothesised that patients with MFPC lesions would be impaired on a ToM measure, that patients with OFC lesions would be impaired on an empathy measure, and that patients with VMPFC lesions would be impaired on both measures. Finally, based on a study using a reward-related task (Hornak et al., 2004), it was hypothesised that any impairment in social cognition in a group with dorsolateral PFC (DLPFC) lesions would be related to impairments in attention.

lenses, and poor English comprehension and expression (score o 13) on the Frenchay Aphasia Screening Test (Enderby et al., 1987). 2.2. MRI analysis Lesion site and volume were ascertained from post-surgical structural MRI scans closest to the date of testing. The brain regions were segmented from these images using the Brain Extraction Tool (BET; Smith, 2002; Jenkinson et al., 2005) within the brain image analysis package FSL 4.1 (Smith et al., 2004; Woolrich et al., 2009). These brain-extracted images were then normalised by co-registration to the Montreal Neurological Institute (MNI) 2-mm standard brain using a 12-parameter affine algorithm (FLIRT; Jenkinson and Smith, 2001; Jenkinson et al., 2002) within FSL. The image analysis programme Analyse (version 9.0 Mayo Clinic Biomedical Imaging Resource, Rochester, MN) was used to manually correct for inaccuracies in this automatic segmentation and to segment the lesions. Regions of interest (ROIs) outlined the resection cavity on every slice. All ROIs were traced by the primary author (LMJ) and confirmed by a neuroradiologist (PP). 2.3. Group categorisation Participants were divided into groups according to BAs resected. A volumetric BA map (Drury et al., 1998) from MRIcro (Rorden and Brett, 2000) was co-registered to MNI space using FSL, and masks created for each BA. The number of voxels in each area of interest was calculated by adding the number of voxels in each BA, i.e., ACC ¼ BA24 þBA25þBA32; OFC ¼ medial BA10þ BA11þ BA47; DL¼ BA6þ BA8þ lateral BA9þBA44þ BA45þBA46 (no other BAs were resected in any patients). The number of voxels in the overlap of each patient's ROI with each area of interest was calculated as a percentage. Participants were assigned to the group for which they had the largest percentage of resection. Participants with more than 5% resection of the ACC plus more than 5% resection of the OFC were assigned to a VM group. Three of these VM patients also had more than 5% resection of the DL area, but no patients in the DL group had more than 5% resection of the ACC or orbital area. We chose 5% rather than ‘at least some part’ which was used by Hornak et al. (2003, p. 1693) due to potential registration or ROI-drawing error, and the relative inexactness of BA maps. Patients with BA25 lesions also had orbital lesions, so they were included in the VM group; therefore, the ACC group comprised patients with pregenual and dorsal ACC lesions. The lesion locations of individuals within each group are presented in Figs. 1–4. 2.4. Lesion characteristics Most brain surgery patients had primary tumours. Table 1 shows the frequencies of World Health Organisation (WHO) tumour type and grade, by group. Although the VM group contained all the patients with the highest WHO grade (IV) lesions, a Fisher's exact test found no significant between-group difference in WHO grade. A Kruskal–Wallis test found a significant difference between groups in lesion volume (cubic mm), H(3) ¼12.26, po 0.01 (ACC M ¼1234.50, S.D.¼ 253.58 cm3; Orbital M¼ 881.14, S.D. ¼861.48 cm3; VM M ¼5563.40, S.D.¼ 4828.69 cm3; DL M¼ 914.45, S.D. ¼736.73 cm3). The VM group had the largest lesions compared with all other groups. That was expected given that the VM area is a combination of the ACC and OFC areas. Point-biserial correlations between each group and lesion volume found a significant coefficient for the VM group, rpb ¼0.624 (p o 0.001), indicating that 38.93% of the variance in lesion volume was accounted for by VM location. Lesion volume therefore was a potential confounding factor. In order to determine whether group effects remained after controlling for lesion volume, hierarchical regression was favoured over a covariate approach due the sample size.

2. Methods 2.1. Participants Participants were 27 patients post-neurosurgery to the PFC, with a single surgical resection cavity confirmed by MRI. Of these, 25 were recruited from a neurosurgical inpatient ward and outpatient neurosurgery clinic at the Royal Melbourne Hospital. Two patients were recruited from an inpatient ward of St Vincent's Hospital, Melbourne. Control participants were 26 patients post-spinal surgery at the Royal Melbourne Hospital, who had undergone cervical and lumbar laminectomy, discectomy or rhizolysis. Thus, this group had also experienced a serious neurosurgical operation, without cerebral involvement. All participants were aged over 18 years and within 1–12 months postneurosurgery. Consent was obtained according to the declaration of Helsinki and the Human Research Ethics committees of The University of Melbourne, The Royal Melbourne Hospital and St Vincent's Hospital, Melbourne. Exclusion criteria were nerve sheath tumour, neurological disease other than reason for surgery (e.g., cerebrovascular accident, dementia), history of heart disease or heart failure, documented cerebral trauma, vision or hearing problems other than corrective

2.5. Demographic characteristics Table 2 presents demographic results. Thirty participants identified themselves as Australian, three as English, two Italian, two Vietnamese and one each from the following countries: El Salvador, Cyprus, Uruguay, Poland, Iraq, Spain, USA, Hungary, Phillipines, South Africa, Finland, Turkey, Yugoslavia, Netherlands/China, Croatia and Papua New Guinea. Fisher's exact tests found no significant betweengroup differences (p 4.05) in the proportion of participants who spoke English as a second language (ESL). There were also no significant between-group differences in proportion of males and females, age, days since surgery, or years of education. 2.6. Screening measures Standard tests screened for language impairment, attention, estimated intelligence quotient (IQ), anxiety and depression. The Frenchay Aphasia Screening Test (FAST)- Comprehension and Expression subtests (Enderby et al., 1987) is a brief screening test for English comprehension and expression. The Test of Everyday



3

1

2

3

4

Fig. 1. Lesion locations of patients in the anterior cingulate group, n¼ 4, shown on MNI standard brain slices in radiological convention (i.e. left¼ right).

5

6

7

8

9

10

11 Fig. 2. Lesion locations of patients in the orbital group, n¼ 7, shown on MNI standard brain slices in radiological convention (i.e. left ¼ right).



4

12

13

14

15

16 Fig. 3. Lesion locations of patients in the ventromedial group, n¼ 5, shown on MNI standard brain slices in radiological convention (i.e. left ¼ right). Attention (TEA) Elevator counting subtest (Robertson et al., 1994) measures sustained attention. The Wechsler Adult Intelligence Scale-III Picture Completion subtest (Wechsler, 1997) measures estimated nonverbal IQ. The Wide-Range Achievement Test 3- Reading (WRAT-R) subtest (Wilkinson, 1993) estimates Full Scale IQ (using an age-corrected standard score). The Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith, 1983) is a measure of anxiety and depression designed for use with physically ill patients.

were found, to determine the proportion of unique variance for each variable. To obtain a single score to enter as a predictor in the ERT supplementary multiple regression, total accuracy overall was calculated by adding the correct responses to all ERT items (cf. Kessels et al., 2014). Lesion locations were entered as dummy variables in the first block, ahead of lesion volume, WRAT-R standard score and TEA score in the subsequent block. These analyses were conducted to ensure that group differences were due to lesion location rather than differences in lesion volume, WRAT-R or TEA score; therefore, no variables were removed.

2.7. Experimental measures 2.7.1. Emotion recognition task (ERT) (Montagne et al., 2007; Kessels et al., 2014). A facial morphing task presented participants with video clips showing a neutral face change into an emotional face of differing intensities (20–100%). The emotions of anger, disgust, fear, happiness, sadness and surprise were each portrayed by four Caucasian actors (two males). After each morph, participants identified which emotion they perceived from a list of the five available emotions. To reduce testing time and burden, the 20% intensity and ‘surprise’ items and label were removed for the present study, as surprise was not an emotion of interest. This resulted in the presentation of a total of 160 film clips (five emotions by four actors by eight intensities) that varied in length from six frames (lasting approximately 1 s) to 20 frames (lasting approximately 3 s). 2.7.2. Perspective taking task (PTT) (Hynes et al., 2006). A series of vignettes required the reader to make inferences. Questions on the ToM scale required inferences concerning the thoughts of the character. The Empathy scale required inferences about the feelings of the character, and the Physical scale contained control questions requiring inferences regarding physical events. Five questions were selected from each scale. Participants were required to answer a multiple-choice question for each vignette. 2.8. Statistical analyses For analysis of the ERT, for each emotion and an overall measure that combined accuracy across all emotions, a 5 (group) 8 (intensity) mixed analysis of variance (ANOVA) was calculated. A priori contrasts compared each brain surgery group with the control group. For all ERT analyses, Box's M was non-significant (p 40.05) and Mauchly's test was significant for intensity (p o 0.05), so intensity effects were interpreted with Huynh–Feldt adjustments to the degrees of freedom. Repeated measures ANOVAs were also calculated for each discrete emotion, with intensity as the within-subjects factor. Group differences in lesion volume, WRAT-R standard score and TEA score (see Section 3.1) presented potential confounding influences. To determine the impact of such variables, Hornak et al. (2003) calculated correlations. Given the significant correlation between VM lesion location and lesion volume, however, supplementary hierarchical regressions were calculated when significant group differences

3. Results 3.1. Screening measures Table 3 shows no significant group differences on the FAST or Picture Completion test. There was, however, a significant effect of group for WRAT-R standard score. Post-hoc tests found the ACC and the DL groups had a significantly lower estimated IQ than the control group, po 0.05. A Kruskal–Wallis test found a significant difference between groups in TEA score. Follow-up Mann–Whitney tests found that both the ACC (p o0.05) and VM (p o0.001) groups scored significantly lower than the control group. A ceiling effect was observed for the orbital, DL and control groups. 3.2. Emotion recognition task For the overall accuracy measure, there was a significant effect of intensity, F(5.88, 282.45) ¼ 61.90, p o0.001, ηp² ¼0.56. As expected and shown in Fig. 5, the more intense the expression, the greater the accuracy. There was no significant intensity group interaction, F(23.54, 282.45) ¼ 1.55, p 40.05, ηp²¼ 0.11. While there was no significant main effect of group, F(4, 48) ¼2.00, p4 0.05, ηp²¼ 0.14, a planned contrast found that the VM group scored significantly lower than the control group F(1, 48) ¼ 7.07, po 0.05, ηp² ¼0.13, shown in Fig. 5. Table 4 shows the supplementary multiple regression model for ERT accuracy was not significant at step 1 when only the lesion locations were included. Nevertheless, the VM lesion location was a significant predictor of accuracy of identification of facial



5

17

18

19

20

21

22

23

24

25

26

27 Fig. 4. Lesion locations of patients in the dorsolateral group, n ¼11, shown on MNI standard brain slices in radiological convention (i.e. left ¼ right).

Table 1 WHO classification of tumours by group. Grade N/A I II III IV

a

Anterior cingulate

Orbital

Ventromedial

Dorsolateral

2 2 0 0 0

1 3 1 2 0

0 0 1 1 3

3 4 3 1 0

a Includes patients diagnosed with a single metastatic tumour (n¼ 2), angioma (n¼ 1), epidermoid cyst (n ¼1), abscess (n¼ 1) and bone fragment (n ¼1).

emotional expression overall. When lesion volume, WRAT-R and TEA score were added in step 2, the model became significant, and the change in R² value was significant, F(3, 45) ¼ 9.95, po 0.001. As shown in Table 4, at step 2, VM lesion location significantly predicted overall accuracy. Lesion volume and WRAT-R standard score were also significant predictors of overall accuracy. The positive standardised coefficients (β values) for these latter two variables indicated that as lesion volume and WRAT-R standard score increased, so did overall facial recognition accuracy. Orbital lesion location also approached significance at p ¼0.08. As explained in the supplementary material, larger lesions may have predicted better performance because lesion volume is likely due



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Table 2 Demographic differences between groups.

Gender M/F ESL Y/N Age (years) Days post-surgery Years education

ACC

Orbital

VM

DL

Control

Test

2/2 2/2 M ¼38.00, S.D. ¼11.58 M ¼142.25, S.D. ¼145.19 M ¼11.75, S.D. ¼0.50

3/4 2/5 M ¼53.43, S.D.¼ 8.00 M ¼125.71, S.D.¼ 105.71 M ¼ 12.57, S.D.¼ 3.91

3/2 1/4 M ¼51.80, S.D. ¼16.74 M ¼141.60, S.D. ¼125.11 M ¼ 12.20, S.D. ¼1.79

5/6 3/8 M ¼ 45.64, S.D. ¼ 17.52 M ¼ 149.91, S.D. ¼ 129.70 M ¼ 13.68, S.D. ¼ 3.51

12/14 7/19 M ¼ 45.69, S.D. ¼ 13.95 M ¼ 98.81, S.D. ¼ 77.15 M ¼ 12.69, S.D. ¼ 3.88

p 40.05 p 40.05 F(4, 48) ¼ 0.96, p 40.05, η2p ¼ 0.07 F(4, 48) ¼ 0.61, p 40.05, η2p ¼0.05 F(4, 48) ¼ 0.31, p 40.05, η2p ¼ 0.03

η2p ¼ partial eta squared. Table 3 Screening measures: Means (M), standard deviations (S.D.) and ANOVA statistics.

FAST comprehension FAST expression WRAT-R standard score Picture completion TEAǂ HADS Anxiety HADS Depression

ACC

Orbital

VM

DL

Control

Test

η2p

M ¼8.75, S.D.¼ 0.96 M ¼9.25, S.D.¼ 0.96 M ¼91.50, S.D.¼ 9.47 M ¼18.75, S.D.¼ 1.50 M ¼6.75, S.D.¼ 0.50 M ¼7.50, S.D.¼ 3.11 M ¼4.00, S.D.¼ 2.16

M ¼ 9.29, S.D. ¼ 1.25 M ¼ 9.43, S.D. ¼ 0.79 M ¼ 97.29, S.D. ¼ 12.85 M ¼ 18.14, S.D. ¼ 3.89 M ¼ 7.00, S.D. ¼ 0.00 M ¼ 9.29, S.D. ¼ 4.57 M ¼ 5.43, S.D. ¼ 3.91

M ¼9.00, S.D. ¼1.73 M ¼9.40, S.D. ¼0.89 M ¼102.80, S.D. ¼8.90 M ¼15.80, S.D. ¼3.03 M ¼6.20, S.D. ¼0.45 M ¼4.80, S.D. ¼3.27 M ¼3.60, S.D. ¼ 3.21

M ¼ 9.08, S.D. ¼ 0.90 M ¼ 9.25, S.D. ¼ 0.97 M ¼ 97.17, S.D. ¼ 11.63 M ¼ 18.00, S.D. ¼ 4.43 M ¼ 7.00, S.D. ¼ 0.00 M ¼ 6.09, S.D. ¼ 3.89 M ¼ 2.36, S.D. ¼ 1.75

M ¼9.31, S.D. ¼0.88 M ¼9.73, S.D. ¼0.60 M ¼103.77, S.D. ¼8.34 M ¼19.85, S.D. ¼3.78 M ¼7.00, S.D. ¼0.00 M ¼7.35, S.D. ¼2.860 M ¼4.31, S.D. ¼4.19

F(4, 48) ¼ 0.32

0.03

F(4, 48) ¼ 0.77

0.06

n

F(4, 48) ¼ 2.65

0.18

F(4, 48) ¼ 1.51

0.11

H(4) ¼ 34.20nn

0.66

F(4, 48) ¼ 1.59

0.12

F(4, 48) ¼ 0.91

0.07

η2p ¼ partial eta squared, ǂ Kruskal–Wallis test used with η2p ¼ χ 2 =N 1. n

po .05. p o.001.

nn

to a suppressor variable effect (Thompson and Levine, 1997), and thus should not be directly interpreted. However, we can be confident that VM lesion location predicted poor recognition accuracy even after controlling for lesion volume. Repeated measures ANOVAs for each discrete emotion found a significant effect of intensity for each emotion (p o0.001), with more intense expressions associated with greater identification accuracy. There was a significant main effect of group for fear, F(4, 48) ¼ 4.02, p o0.01, ηp² ¼0.25. The VM group performed significantly worse than the control group, F(1, 48) ¼14.35, p o0.001, ηp²¼ 0.23 (see Fig. 5). No other a priori tests were significant. A supplementary hierarchical regression was calculated with accuracy of fear identification collapsed over all intensities used as the dependent variable. There was a significant model at both steps 1 and 2, shown in Table 5. In step 1, VM lesion location was the only significant predictor of fear recognition accuracy. In step 2, the addition of lesion volume, WRAT-R standard score and TEA score led to a significant increase in the R² value, F(3, 45) ¼6.35, p o0.001. In step 2, VM lesion location, lesion volume and WRAT-R standard score were significant predictors of fear identification accuracy. As WRAT-R standard score increased, so did fear recognition accuracy. Finally, DL lesion location approached significance at steps 1 and 2. A repeated measures ANOVA also revealed a significant group intensity interaction for sadness items, F(26.11, 313.29) ¼ 1.68, p o0.05, ηp²¼ 0.12, so analyses of the simple effect of intensity were performed for each group. There was a significant effect of intensity at the p o0.001 level for the ACC, DL and control groups, and at the p o0.05 level for the orbital group, indicating that as intensity of the facial expression increased, so did accuracy for these groups. However, there was no significant effect of intensity for the VM group only, F(7, 28) ¼0.63, p 40.05, ηp² ¼0.14; thus, an

increase in intensity of facial expression shown did not aid correct identification of facial emotion for the VM group (see Fig. 5). 3.3. Perspective taking task Scores for the Physical, ToM and Empathy sub-scales are presented in Fig. 6. Mann–Whitney tests found no significant differences between any of the brain surgery groups and the control group on the Physical scale. Both the VM group (U¼115.00, po 0.01, r ¼0.52) and the DL group (U ¼190.00, p o0.05, r ¼0.28) performed significantly worse than the control group on the ToM scale. The DL group also scored significantly lower than the control group on the Empathy scale (U¼176.50, p o0.05, r ¼0.34). Table 6 shows the results of the hierarchical regression for ToM scale score. The overall model was significant at both steps 1 and 2, and adding lesion volume, WRAT-R standard score and TEA score significantly increased the explained variance, F(3, 45) ¼ 7.31, p o0.001. At step 1, VM lesion location was a significant predictor of ToM score. The negative standardised coefficient indicates that patients with VM lesions performed more poorly on this scale. VM lesion location remained significant at step 2, with WRAT-R score also being significant. As WRAT-R standard score increased, accuracy on the ToM items increased. Lesion volume was also significant at step 2, and again appeared to be a suppressor variable. TEA score approached significance, and had a positive standardised coefficient, suggesting that patients with better sustained attention performed better on the ToM scale. Table 7 shows the results of the hierarchical regression of the Empathy scale of the PTT. The model was not significant at step 1, but became significant at step 2, and this increase in R² was significant, F(3, 45)¼4.05, po0.05. While there were no significant



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Fig. 5. Mean number of items correct on the Emotion recognition task, by emotion.

predictors at step 1, at step 2, WRAT-R score was significant. The positive standardised coefficient indicated that when all other variables were held constant, higher WRAT-R scores predicted better performance on the Empathy scale. This finding suggests that the poor performance of the DL group on the empathy scale was due to the group's significantly lower scores on the WRAT-R.

4. Discussion We investigated social cognition in patients with discrete surgical lesions to the prefrontal cortex including the ACC, OFC, VMPFC and DLPFC. This study is noteworthy for its attempted methodological improvements upon previous research. Our



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Table 4 Hierarchical regression for overall accuracy on the Emotion Recognition Task. B Step 1 R²¼ 0.14 Constant ACC lesion Orbital lesion VM lesion DL lesion Step 2 R²¼ 0.49nnn Constant ACC lesion Orbital lesion VM lesion DL lesion Lesion volume WRAT R TEA

SE B

β

t

p

Zero-order

Semi-partial

120.15 9.15 10.58 24.15 4.34

3.65 9.99 7.92 9.09 6.69

0.13 0.19 0.37 0.09

32.93 0.92 1.34 2.66 0.65

0.00nnn 0.36 0.19 0.02n 0.52

0.06 0.11 0.32 0.03

0.12 0.18 0.36 0.09

36.42 6.16 12.21 48.01 5.06 0.01 0.61 13.37

91.48 9.32 6.73 13.88 5.96 0.00 0.23 12.29

0.09 0.22 0.73 0.11 0.69 0.32 0.20

0.40 0.66 1.82 3.46 0.85 4.11 2.62 1.09

0.69 0.51 0.08 0.01nn 0.40 0.00nnn 0.02n 0.28

0.06 0.11 0.32 0.03 0.07 0.39 0.26

0.07 0.19 0.37 0.09 0.44 0.28 0.12

p

Zero-order

Semi-partial

n

po 0.05. p o0.01. nnn p o0.001. nn

Table 5 Hierarchical regression for accuracy of fear identification on the Emotion Recognition Task. B Step 1 R²¼ 0.25nn Constant ACC lesion Orbital lesion VM lesion DL lesion Step 2 R²¼ 0.47nnn Constant ACC lesion Orbital lesion VM lesion DL lesion Lesion volume WRAT-R TEA n

SE B

β

t

25.54 4.79 3.11 10.74 3.72

1.14 3.12 2.47 2.84 2.09

0.20 0.17 0.49 0.24

22.43 1.54 1.26 3.79 1.78

0.00nnn 0.13 0.21 0.00nnn 0.08

0.10 0.03 0.41 0.09

0.19 0.16 0.47 0.22

33.75 3.31 3.50 15.09 3.87 0.01 0.17 6.00

30.85 3.14 2.27 4.68 2.01 0.01 0.08 4.15

0.14 0.19 0.69 0.25 0.55 0.26 0.28

1.09 1.05 1.55 3.22 1.92 3.23 2.13 1.45

0.28 0.30 0.13 0.01nn 0.06 0.01nn 0.04n 0.16

0.10 0.03 0.41 0.09 0.10 0.36 0.38

0.11 0.17 0.35 0.21 0.35 0.23 0.16

po 0.05. p o0.01. p o 0.001.

nn

nnn

radiological measurement using post-surgical structural MRI sets the present study apart from existing lesion work in this area, allowing more confident inferences regarding specific functional roles of these sectors. Limiting the inclusion criteria from up to 22 years (Hornak et al., 2003) to between 1 and 12 months postneurosurgery reduced the potential influence of compensatory recovery mechanisms. Including a non-cerebral neurosurgical control group was a further improvement upon previous work that used a DLPFC control group (Hornak et al., 2003), given findings of impaired performance in DLPFC patients on a reward learning task (Hornak et al., 2004). 4.1. Impaired social cognition following ventromedial lesions The VM group was significantly impaired at identifying dynamic facial expressions of emotion overall, and fear specifically. In the hierarchical regression, VM lesion location predicted poor emotion recognition even when all other variables including lesion volume were held constant. Therefore, this result could not be

explained by lesion volume. The finding that VM lesion location significantly predicted poor performance on the ToM scale, holding constant all other variables, also supported the hypothesis. This is the first study to find that a combined orbital and medial lesion is related to poor recognition of dynamic facial emotion and poor ToM.

4.2. Other discrete cortical lesions Our results did not support previous research indicating patients with OFC lesions have deficits in empathy (Grattan et al., 1994; Eslinger, 1998). This difference may have been due to a ceiling effect on the Empathy scale. There was no evidence that patients with OFC lesions had impairments in facial emotion recognition, contradicting previous findings (Mah et al., 2004; Goodkind et al., 2012). For example, Hornak et al. (2003) found patients with bilateral OFC lesions were impaired at perceiving facial emotion, whereas patients with unilateral OFC lesions were



9

Fig. 6. Mean Perspective Taking Task scale scores by group.

Table 6 Hierarchical regression for Theory of Mind Scale score. SE B

β

t

p

Zero-order

Semi-partial

4.42 0.67 0.57 1.82 0.61

0.20 0.55 0.44 0.50 0.37

0.16 0.17 0.48 0.22

21.93 1.22 1.29 3.63 1.64

0.00nnn 0.23 0.20 0.00nnn 0.11

0.06 0.05 0.41 0.08

0.15 0.16 0.46 0.21

10.25 0.03 0.46 1.81 0.43 0.00 0.05 1.43

5.35 0.55 0.39 0.81 0.35 0.00 0.01 0.72

0.01 0.14 0.47 0.15 0.40 0.41 0.38

1.92 0.05 1.17 2.23 1.22 2.35 3.31 1.99

0.06 0.96 0.25 0.03n 0.23 0.03n 0.01nn 0.06

0.06 0.05 0.41 0.08 0.14 0.43 0.41

0.01 0.13 0.24 0.13 0.25 0.36 0.21

B Step 1 R²¼ 0.23n Constant ACC lesion Orbital lesion VM lesion DL lesion Step 2 R²¼ 0.48nnn Constant ACC lesion Orbital lesion VM lesion DL lesion Lesion volume WRAT-R TEA n

p o0.05. p o 0.01. nnn p o 0.001. nn

not. Importantly, two of the six patients in the bilateral OFC lesioned group studied by Hornak et al. additionally had bilateral ACC lesions, which in the present study would have been classified as having VMPFC lesions. We are able to make more specific claims regarding the effect of VMPFC lesions as we had a specific VMPFC lesioned group. The lack of significant impairment in emotion recognition by the orbital group in the present study, combined with the results of the Hornak study, suggests that isolated unilateral damage to the OFC may not be sufficient to produce impairments in facial emotion recognition. There was a lack of significant findings for the DL group. While the DLPFC is not generally considered part of the emotion network,

patients with DLPFC lesions have been found to perform poorly on a reward-related task (Hornak et al., 2004); however, the researchers argued that this was due to impaired attentional mechanisms. In the present study, the ceiling effect shown by this group on the TEA suggests that attention was not deficient in the DL group. The lack of significant results for the ACC group was not expected given previous research indicating patients with ACC lesions are impaired at perceiving emotion (Hornak et al., 2003; Baird et al., 2006). Instead of being directly involved in the recognition of facial emotion, the MPFC may be important for recognition of emotional salience (e.g., Drevets et al., 2008) and directing attention toward salient stimuli (Drevets and Raichle,



10

Table 7 Hierarchical Regression for Empathy Scale Score.

Step 1 R²¼ 0.08 Constant ACC lesion Orbital lesion VM lesion DL lesion Step 2 R²¼ 0.28n Constant ACC lesion Orbital lesion VM lesion DL lesion Lesion volume WRAT-R TEA n n

po .05,

nn

p o .01,

nnn

B

SE B

β

t

p

Zero-order

Semi-partial

4.96 0.21 0.25 0.36 0.23

0.09 0.25 0.20 0.23 0.17

0.12 0.18 0.23 0.20

54.04 0.84 1.24 1.58 1.39

0.00nnn 0.40 0.22 0.12 0.17

0.05 0.10 0.16 0.11

0.12 0.17 0.22 0.19

0.70 0.01 0.20 0.47 0.16 0.00 0.02 0.35

2.64 0.27 0.19 0.40 0.17 0.00 0.01 0.35

0.01 0.15 0.30 0.14 0.34 0.38 0.22

0.27 0.01 1.03 1.19 0.92 1.68 2.61 0.99

0.79 0.99 0.31 0.24 0.36 0.10 0.02n 0.33

0.05 0.10 0.16 0.11 0.02 0.42 0.16

0.01 0.13 0.15 0.12 0.21 0.33 0.13

p o .001.

1998; Pessoa et al., 2002), thereby exerting top-down control to regulate behaviour (Paus, 2001). The present study also failed to support findings highlighting the importance of the MPFC for ToM (Frith and Frith, 1999; Gallagher and Frith, 2003). However, it should be noted that although many functional neuroimaging studies highlight the importance of the MPFC for ToM (Frith and Frith, 1999), the results of the present study are consistent with lesion studies that have failed to find evidence implicating the MPFC in ToM (Rowe et al., 2001; Bird et al., 2004). Our finding that patients with VMPFC lesions demonstrate impairments in social cognition not seen in patients with isolated OFC or MPFC lesions is consistent with the known neurocircuitry of the VMPFC, discussed in Section 4.3. 4.3. Neurocircuitry of the ventromedial PFC in relation to emotion Extensive interconnectivity exists between the OFC and the anterior MPFC (van Hoesen et al., 1993; Carmichael and Price, 1996; Öngür and Price, 2000). There are, however, independent connections between these two areas and other areas serving emotional systems. For example, the OFC has direct, reciprocal connections with the amygdala (Carmichael and Price, 1995a), insula/operculum (Mesulam and Mufson, 1982), DLPFC (Barbas and Pandya, 1989; Carmichael and Price, 1995b), hypothalamus (Öngür et al., 1998; Rempel-Clower and Barbas, 1998; Cavada et al., 2000), and brainstem and spinal autonomic areas (Devito and Smith, 1964; Neafsey, 1990) including the periaqueductal grey (An et al., 1998; Rempel-Clower and Barbas, 1998). In combination with the inputs it receives from all five sensory modalities (Carmichael and Price, 1995b; Rolls, 2004), these connections make the OFC ideally situated to integrate sensory and visceral information and to modulate motor and visceral behaviour. In contrast, the major sensory inputs to the MPFC are primarily visceral, arising from the nucleus of the solitary tract and the parabrachial nucleus. Nociceptive inputs also arrive via the spinothalamic tract (Neafsey et al., 1993). Like the OFC, the MPFC also has major cortical efferents to autonomic structures in the hypothalamus and brainstem (Öngür and Price, 2000). Other autonomic outputs of the ventral ACC exist via the amygdala, insular cortex and mammillary bodies (Saper, 1982; van der Kooy et al., 1984; Allen and Hopkins, 1989; Hurley et al., 1991). Thus the MFC and OFC are densely interconnected but also have independent connections with areas important for emotion

that would allow for compensation should either the OFC or MPFC become damaged in isolation. We propose that when both the OFC and MPFC (i.e. the VMPFC) are damaged, there is a double disconnection with other areas of the emotional system, such as the amygdala. However, when either the OFC or MPFC is damaged in isolation, the other area may compensate, due to their overlap in function. 4.4. Limitations and conclusions Compared to controls, patients with lesions to the VMPFC demonstrated impairments in social cognition that patients with lesions restricted to the OFC or MPFC did not. Whilst the lack of findings for the ACC is potentially due to sample size, patients with discrete, surgically circumscribed lesions to this area are rare, evidenced by previous studies which have reported similar sample sizes (Hornak et al., 2003). Nevertheless, given the small group sizes, cautious interpretation of the results is warranted. Thus, while we found significant group differences, these results should be interpreted in the context of other lesion and neuroanatomical studies. We have attempted to do so by including a discussion of the neurocircuitry of the VMPFC in relation to emotion, and future studies should expand our attempt to recruit participants from multiple sites so that larger subgroups of patients with these uncommon, surgically circumscribed lesions may be included. The inclusion of only one test for emotional recognition and only one test for ToM and empathy is a limitation. Inclusion of additional established measures of social cognition, for instance, ecologically valid tests for social inference (e.g. the Awareness of Social Inference Test; McDonald et al., 2003) would have been informative. However, the testing burden of these participants had to be limited, given that all participants also participated in a mood-induction study with psychophysiological measures (the results of which will be published separately). Despite the restricted number of measures, the results of this study add to the existing knowledge in the field, and are strengthened by the precise radiological analysis, strict inclusion criteria, and noncerebral neurosurgical control group. The impairments in the VMPFC group were independent of lesion volume, suggesting that it is the combination of orbital and medial lesions that is responsible for the impairments in social cognition in these patients. Evidence from previous studies concerning the mechanisms of emotion processing suggests that both



areas are involved in the recognition of salient emotional stimuli; however, the MPFC is specialised for cognitive aspects such as selfawareness, ToM, and therefore social behaviour. Alternatively, the OFC is important for signalling current reward value of stimuli, which is important for appropriate social behaviour and subjective emotional experience (Hornak et al., 1996, 2003). Our results, despite small subgroup sizes, add to those of previous studies as well as neuroanatomical evidence, which supports a suggestion that the impaired recognition of emotional and social stimuli in patients with VMPFC lesions is possibly the result of a double disconnection between OFC and MPFC and other areas important for emotion, such as the amygdala. Future research should investigate the hypothesis that patients with isolated MPFC or OFC lesions have preserved social cognition due to compensation by the intact area. Functional neuroimaging could also be used to test the hypothesis that both the OFC and the MPFC are involved in social cognition.

Acknowledgements The authors thank the participants of this study and also Scott Langenecker and Jon-Kar Zubieta for their comments on an earlier draft.

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