Social cognition in Juvenile Myoclonic Epilepsy

Epilepsy Research 128 (2016) 61–67

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Social cognition in Juvenile Myoclonic Epilepsy Filippo S. Giorgi a,∗ , Melania Guida a , Lorenzo Caciagli b , Cristina Pagni a , Chiara Pizzanelli a , Enrica Bonanni a , Gloria Tognoni a , Ubaldo Bonuccelli a a b

Neurology Unit, Department of Clinical and Experimental Medicine and University Hospital, University of Pisa, Pisa, Italy Scuola Superiore di Studi Universitari e di Perfezionamento Sant’Anna, Pisa, Italy

a r t i c l e

i n f o

Article history: Received 15 September 2016 Accepted 24 October 2016 Available online 26 October 2016 Keywords: Juvenile Myoclonic Epilepsy Social cognition Theory of mind Psychosocial outcome Executive functions Genetic Generalized Epilepsy

a b s t r a c t Objective: Juvenile Myoclonic Epilepsy (JME) is a common genetic generalized epilepsy syndrome. Several studies have detailed cognitive and imaging abnormalities pointing to frontal lobe dysfunction, as well as disadvantageous behavioral traits and poor social outcome, challenging the commonly held view of JME being a benign disorder. Social cognition is the ability to elaborate mental representations of social interactions and to use them correctly in social contexts, and includes Theory of Mind (ToM), which pertains to the attribution of cognitive and affective mental states to self and others and seems to rely on complex fronto-temporal interactions. ToM has been recently assessed in focal epilepsy syndromes, but little is available for generalized epilepsies. We performed a cross-sectional study to assess social cognition, with an emphasis on ToM, as well as standard cognitive functions in patients with JME. Method: We recruited twenty JME patients and twenty matched controls. Tests used to assess social cognition and ToM included the Emotion Attribution Task, Strange Stories Task (SST), Faux Pas Task (FPT), Reading the Mind in the Eyes Task and Social Situation Task. Subjects were also assessed via an extensive neuropsychological battery. Results: Patients exhibited worse performance in the SST and in several scores of the FPT. They also showed widespread cognitive impairment, involving executive functions, psychomotor speed, verbal and visuo-spatial memory. Conclusions: In addition to cognitive impairment for fronto-temporal tasks, some features of social cognition are also altered in JME. The latter deficit may underlie the poor social outcome previously described for these patients, and might also relate to imaging findings of frontal lobe dysfunction. © 2016 Elsevier B.V. All rights reserved.

1. Introduction Juvenile Myoclonic Epilepsy (JME) is a common genetic generalized epilepsy syndrome (GGE), with onset during adolescence or early adulthood, characterized by myoclonic jerks occurring especially during sleep-wake transition, generalized tonic-clonic seizures and, less frequently, absence seizures (ILAE, 1989; Kasteleijn-Nolst Trenite et al., 2013). The interictal electroencephalogram typically shows bursts of fast generalized spike-wave or polyspike-wave discharges superimposed on a normal background. JME accounts for 5% to 10% of all epilepsies, and approximately 18% of all GGEs (Jallon and Latour, 2005).

∗ Corresponding author at: Neurology Unit, Pisa University Hospital, Via Roma, 67-56126 Pisa, Italy. E-mail addresses: [email protected], [email protected] (F.S. Giorgi). http://dx.doi.org/10.1016/j.eplepsyres.2016.10.017 0920-1211/© 2016 Elsevier B.V. All rights reserved.

Normal MRI brain and normal intelligence are considered hallmarks of JME. Subtle functional and structural alterations, however, have been recently shown in these patients by advanced neuroimaging studies (Koepp et al., 2013; Wolf et al., 2015). In addition, recent analyses have identified cognitive impairment, especially involving executive functions (Iqbal et al., 2015; Wandschneider et al., 2012). A psychological profile characterized by emotional instability, unreliability, risk-taking behaviors and, occasionally, personality and mood disorders has been described since the early reports by Janz and Christian, and later confirmed by other authors (Plattner et al., 2007; Wandschneider et al., 2013; Zamarian et al., 2013). Remarkably, a poor social outcome has also been reported for JME, with up to 70% of patients presenting at least one major unfavorable marker such as unplanned pregnancy, depression, unemployment, social isolation, or unstable affective relationships (Camfield and Camfield, 2009). Several authors hypothesized that the above described cognitive and neuropsychological profile might negatively impact social functioning (Baykan et al., 2013).

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Nonetheless, dysfunctional social cognition in JME has not been formally demonstrated as yet. Social cognition is defined as the ability to elaborate mental representations of social interactions and to use them correctly in a social environment (Adolphs, 2001; Green et al., 2008). It is considered to encompass different domains: self-understanding, the understanding of others, and the interface between self and others (Blair and Cipolotti, 2000). According to this model, a relevant component of social cognition is represented by Theory of Mind (ToM), described as the ability to attribute beliefs and intentions (cognitive aspect) and emotions and feelings (affective aspect) to self and others, in order to interpret and predict one’s own and others’ behavior (Brune and Brune-Cohrs, 2006; Stone et al., 1998). A complex fronto-temporal interplay is supposed to account for both cognitive and affective ToM processing (Abu-Akel and Shamay-Tsoory, 2011). For this reason, ToM has thus far been assessed in patients with focal epilepsies affecting frontal and/or temporal lobes (Giovagnoli, 2014). Both cognitive and affective ToM impairment have been demonstrated in frontal lobe epilepsy (FLE) (Farrant et al., 2005; Giovagnoli et al., 2011; Giovagnoli et al., 2013), temporal lobe epilepsy (TLE) (Broicher et al., 2012; Giovagnoli et al., 2009; Giovagnoli et al., 2011; Giovagnoli et al., 2013; Hennion et al., 2015; Li et al., 2013b; Schacher et al., 2006; Shaw et al., 2007; Shaw et al., 2004), and benign childhood epilepsy with centro-temporal spikes (Genizi et al., 2012) [see (Giovagnoli, 2014) for a comprehensive review]. Studies addressing ToM reasoning in GGE are limited. Recently, impaired emotion recognition and empathic abilities, which can be compared to affective ToM, have been demonstrated in patients with mixed GGE (Jiang et al., 2014; Realmuto et al., 2015). To our knowledge, no studies specifically addressing social cognition have investigated patients with GGE, and especially JME. The nature of the relationship between social cognition/ToM and other neuropsychological domains still remains undefined. Several authors suggested the existence of a close connection between ToM and executive functions (EF), defined as high-level processes favoring flexible behaviors and adaptation to novel contexts (Gilbert and Burgess, 2008). However, it is not completely understood whether ToM and EF are distinct and functionally related abilities, or constitute a unitary process (Perner and Lang, 1999). Moreover, impairment in both domains was found in the majority of the studies addressing social cognition and EF in a variety of neurological disorders, including epilepsy [reviewed in (Aboulafia-Brakha et al., 2011)]. The present study set out to address two questions. The main aim was to evaluate social cognition, with an emphasis on ToM, in patients with JME. As the evidence discussed above clearly points to impaired frontal lobe functioning, altered decision-making and unfavorable social outcome in JME, we hypothesized that processes pertaining to social cognition may also be altered. In particular, we examined the following aspects: attribution of mental states to others; evaluation of behaviors as socially appropriate; recognition of others’ emotions and feelings. The second aim was to explore the relationship between performance in social cognition tasks and performance in neurocognitive tests addressing EF.

2. Material and methods 2.1. Subjects We selected patients attending our Epilepsy Center who had (a) a clinical and electroencephalographic diagnosis of JME according to ILAE criteria (ILAE, 1989); (b) brain MRI reported as normal; (c) normal premorbid intelligence quotient (IQ), as estimated through the Brief Intelligence Test (Sartori et al., 1997). Similarly to the

Table 1 Demographic and clinical features of patients and healthy controls.

Gender (M/F) Age (y)§ Schooling (y)§ Estimate of premorbid IQ (BIT)§ Age at onset (y)§ Disease duration (y)§ Seizure type% (M/GTCS/A) Seizure free (yes/no*) GTCS in the last 3 y (yes/no) IEDs in last-year EEG (yes/no)

JME Patients

Healthy controls

p

2/18 26.7 (6.6) 14.6 (2.5) 114.1 (3.9) 14.0 (3.8) 12.7 (8.4) 100/75/60 13/7 11/9 13/7

2/18 26.2 (5.8) 15.2 (2.5) 116.2 (2.5) – – – – – –

– 0.80 (n.s.) 0.49 (n.s.) 0.062 (n.s.) – – – – – –

§: mean (SD). *: patients classified as not seizure-free only reported isolated myoclonic jerks during the year before the investigation. Abbreviations: A: absence seizures; BIT: Brief Intelligence Test; EEG: electroencephalogram; GTCS: generalized tonic-clonic seizures; IEDs: interictal epileptiform discharges; IQ: intelligence quotient; M: myoclonic seizures; y: years.

National Adult Reading Test for English speaking people (Nelson and Willison, 1991), the Brief Intelligence Test is validated as a test for premorbid intellectual functioning in Italian-speaking people, and consists in reading aloud a list of words with atypical phonemic pronunciation. An IQ estimate is then obtained through regression equations taking into account age, gender and education. Patients with (a) history of psychiatric and/or neurologic comorbidity, (b) abnormal standard brain MRI and/or (c) seizures in the 24 h preceding the neuropsychological evaluation were excluded. We selected 20 consecutive patients fulfilling the above mentioned inclusion criteria. All of them were on antiepileptic drug therapy: 13 subjects were on monotherapy with valproic acid (n = 4), levetiracetam (n = 4), lamotrigine (n = 4) or clonazepam (n = 1); seven patients were on polytherapy with valproic acid/levetiracetam (n = 3), valproic acid/lamotrigine (n = 3) or levetiracetam/lamotrigine (n = 1). Clinical and demographic features are reported in Table 1. The control group included 20 volunteer healthy subjects. To more appropriately match controls with patients, which is critical in ToM studies (Cavallini et al., 2013; Li et al., 2013a; Thompson and Thornton, 2014), for each patient we selected a control subject of the same gender and with education and age ranging within ±1 y (Table 1). All subjects provided written informed consent to participate in the study, which was approved by our Institutional Review Board. All data included in this manuscript was obtained in compliance with the Declaration of Helsinki. 2.2. Assessment of social cognition Since the interest in social cognition and ToM in epilepsy cohorts is recent, there are no standardized test batteries to assess these domains in patients with epilepsy (Giovagnoli, 2014). According to the model proposed by Blair and Cipolotti (Blair and Cipolotti, 2000), we chose to test different aspects of social cognition: emotion perception (Emotion Attribution Task), ToM (Strange Stories Task, Faux Pas Task, Reading the Mind in the Eyes Task) and social perception (Social Situation Task). The Emotion Attribution Task addresses the ability to attribute emotions to others in appropriate contexts (Blair and Cipolotti, 2000). In the modified Italian version (Prior et al., 2003) of the Emotion Attribution Task proposed by Blair and colleagues (Blair et al., 1995), patients were administered nine stories addressing three primary emotions (happiness, anger and disgust; three stories for each emotion). Four scores were calculated: a total score (range 0–9) and one score for each emotion type (range 0–3). The Strange Stories Task evaluates both affective and cognitive ToM and investigates the ability to interpret non-literal statements in everyday life situations (Happe, 1994). We used the Italian

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version of the test with 13 short stories [(Prior et al., 2003), adapted from (Happe, 1994)], each accompanied by a comprehension question (“Was it true, what X said?”) and a justification question (“Why did X say that?”). The stories deal with pretense, joke, lie, white lie, misunderstanding, double bluff, sarcasm/irony and persuasion (two stories for most aspects, one for the latter three ones), and the score ranges from 0 to 13, one point for each correctly interpreted story. The Faux Pas Task is also considered to require both affective and cognitive ToM abilities. It tests the recognition of a social faux pas (FP), i.e. a “blunder”, in some short stories. Owing to time constraints, we had to impose limits on the duration of the ToM evaluation and selected 10 out of the original 20 short stories, five with and five without a FP [stories 1, 2, 4, 6, 10, 13, 14, 16, 17, 19 from (Stone et al., 1998)]. After reading each story, the patient was asked if a faux pas had occurred [question (Q)1, “Did someone say something they should not have said?”]. If he/she recognized a faux pas, five more questions were asked regarding the identification of the character making the faux pas (Q2, “Who said something they shouldn’t have said?”), the comprehension of behavioral adequacy (Q3, “Why shouldn’t he/she have said it?”), intentions [Q4-Q5, “Why do you think he/she have said it?”, “Did he/she know that Y had previously. . . (context-dependent question)”] and affective states of the involved characters (Q6, “How did Y feel about this?”). Two final control questions screened for obvious deficits in text comprehension. One point was assigned for each correct answer for Q1-6 in FP story, while two points were attributed for Q1 in non-FP stories and in control questions. Ten scores were calculated: one score for each question (range 0–5) and a cumulative score for faux pas recognition (FP/FP, range 0–30), a score for non-faux pas recognition (FP/N, range 0–10), and two control scores based on text comprehension (C/FP e C/N, range 0–10). The Reading the Mind in the Eyes Task assesses affective ToM, as it evaluates the ability to identify mental states from eye gaze (Baron-Cohen et al., 2001). The examiner showed the patient 36 different photographs displaying the eye region of the face of actors/actresses. The subject was asked to indicate the most appropriate one out of four adjectives to convey the best description of the person’s thoughts or feelings [(Vellante et al., 2013) from (Baron-Cohen et al., 2001)]. The score ranges from 0 to 36. The Social Situation Task examines social perception, and tests the ability to judge the appropriateness of behavior in specific social context by distinguishing ordinary conducts from violations (Dewey, 1991). The subjects read text passages pertaining to 25 situations encompassing ordinary and unusual behavior, and were asked to rate the social appropriateness of each behavior using an A-D scale, where (A) was attributed to fairly normal, (B) to rather strange, (C) to very eccentric and (D) to shocking behavior [(Prior et al., 2003) from (Dewey, 1991)]. Three scores were calculated: one for the correct identification of ordinary behaviors (range 0–15), one for the correct identification of violations (range 0–25) and one describing the weight assigned to each violation (range 0–75). 2.3. Assessment of other cognitive functions Patients and controls were administered a comprehensive battery of standardized neuropsychological tasks, including (a) Forward and backward Digit Span and Corsi Block Span (Orsini et al., 1987) for working memory as well as immediate recall of verbal and visuo-spatial stimuli; (b) Rey Auditory Verbal Learning Test (Carlesimo et al., 1996), for immediate and delayed recall of verbal stimuli; (c) Rey-Osterrieth Complex Figure Test (Carlesimo et al., 2002), for visuo-spatial abilities (copy), immediate and delayed recall of visuo-spatial stimuli; (d) Trail Making Test A and B (Giovagnoli et al., 1996), for psychomotor speed (Test A) and shifting abilities (Test B and Test B-A); (e) Stroop Color-Word

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Test (Caffarra et al., 2002), with evaluation of both time interference effect and error rate, for selective attention and inhibition; (f) Semantic (Novelli et al., 1986) and Phonemic Fluency Test (Carlesimo et al., 1996), for verbal fluency on semantic and phonemic clues, respectively. According to previous literature (Gilbert and Burgess, 2008; Sanchez-Cubillo et al., 2009; Wandschneider et al., 2012), tests selected to address the EF domain were the following: Digit Span, Corsi Block Span, Stroop Color-Word Test, Trail Making Test B-A, as well as Semantic and Phonemic Fluency Tests. 2.4. Statistical analysis Statistical analyses were conducted with SPSS vers.20 package software. The Kolmogorov-Smirnov test was used to verify the normal distribution of variances. Differences in demographical characteristics were analyzed using ANOVA and Pearson’s chi-square test for nominal variables. Mann-Whitney test was used for non-parametric data (social cognition and ToM tests) and ANOVA for parametric ones (neuropsychological tasks). As multiple domains were assessed, we corrected for multiple comparisons using Benjamini and Hochberg’s False Discovery Rate (FDR) procedure (Benjamini and Hochberg, 1995; Glickman et al., 2014), implemented within the p.adjust function in R (version 3.2.1), on social cognition and neuropsychological test scores considered altogether. Spearman rank correlations explored the relationship between three selected ToM tasks (Strange Stories Task, cumulative score – FP/FP – of the Faux Pas Task, and Reading the Mind in the Eyes Task), and tests addressing EF (Digit Span, Corsi Block Span, Stroop Color-Word Test, Trail Making Test B-A, Semantic and Phonemic Fluency Tests). To account for the multiple correlations examined, we applied the FDR procedure implemented within the p.adjust function in R. Unless otherwise specified, FDR-adjusted p values are reported in the results sections, with pFDR < 0.05 considered as statistically significant. 3. Results Detailed demographic features of patients and controls are summarized in Table 1. The two groups did not differ with respect to gender (␹2 = 0.000, p = 1.000), age (F1,38 = 0.650, p = 0.800), education (F1,38 = 0.488, p = 0.489) and estimated premorbid IQ (F1,38 = 3.701, p = 0.062). Both patients and controls were within normal IQ ranges. 3.1. Assessment of social cognition (Table 2) No statistically significant differences were identified between patients and controls for the overall score of the Emotion Attribution Task and for the recognition of each single emotion (anger, happiness and disgust). Patients performed significantly worse than controls on the Strange Stories Task. As for the Faux Pas Task, patients with JME scored significantly lower than controls on the identification of faux pas intentionality (Q4 and Q5, respectively) and affective states of the involved characters (Q6). The cumulative FP/FP score was also significantly lower in patients than controls. No significant differences were observed in faux pas detection (Q1), recognition of the character making the faux pas (Q2), comprehension of behavioral inadequacy (Q3), recognition of non-faux pas (FP/N) and in the scores of the control questions (C/FP and for C/N). No significant between-group differences were found for the Reading the Mind in the Eyes Task and the Social Situation Task (recognition of ordinary behavior, recognition of violations and violation weight). (see Table 2 for full statistical data).

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Table 2 Assessment of Social Cognition. JME patients

Controls

Test

Median (IQR)

Range

Median (IQR)

Range

U

z value

p (FDR-adjusted)

Emotion Attribution Task Overall score Happiness Anger Disgust

8.5 (2.0) 3.0 (0) 3.0 (1) 3.0 (0.25)

7–9 2–3 1–3 1–3

9.0 (0) 3.0 (0) 3.0 (0) 3.0 (0)

6–9 2–3 2–3 1–3

141.00 200.00 138.00 179.50

−1.885 0.000 −2.221 −0.795

0.108 1.0 0.066 0.586

Strange Stories Task

13.0 (1.0)

10–13

13.0 (0)

13−13

130.00

−2.870

0.022

Faux Pas Task FP/FP Q1 Q2 Q3 Q4 Q5 Q6 FP/N C/FP C/N

28.5 (3.75) 5.0 (0) 5.0 (0) 5.0 (0) 5.0 (1.0) 5.0 (1.0) 4.5 (1.25) 10.0 (0) 10.0 (0) 10.0 (0)

16–30 3–5 3–5 3–5 2–5 3–5 2–5 8–10 10−10 9–10

30.0 (0) 5.0 (0.0) 5.0 (0.0) 5.0 (0.0) 5.0 (0.0) 5.0 (0.0) 5.0 (0.0) 10.0 (0) 10.0 (0) 10.0 (0)

29–30 5−5 5−5 5−5 4–5 4–5 4–5 10−10 10−10 10−10

105.00 160.00 160.00 160.00 128.50 139.00 107.50 180.00 200.00 190.00

−3.020 −2.080 −2.080 −2.080 −2.653 −2.370 −3.191 −1.433 0.000 −1.000

0.022 0.076 0.076 0.076 0.033 0.0495 0.017 0.251 1.0 0.476

Reading the Mind in the Eyes Task

26 (2.5)

14–32

28 (5.0)

17–35

155.00

−0.748

0.620

Social Situation Task Ordinary behavior Violations Violation weight

14.0 (2.0) 24.0 (2.0) 53.0 (13.5)

10–14 20–25 32–69

14.0 (2.0) 24.0 (2.0) 53.0 (14.5)

12–15 20–25 41–66

165.50 163.00 193.50

−0.458 −0.531 −0.380

0.779 0.779 0.779

All the above-reported p values are FDR-adjusted, and values <0.05 are highlighted in bold. Abbreviations: C/FP = score for control question for faux pas recognition; C/N = score for control question for non-faux pas recognition; FDR = p value corrected for multiple comparison using the False Discovery Rate procedure; FP = Faux Pas Task; FP/FP = score for faux pas recognition; FP/N = score for non-faux pas recognition; IQR = interquartile range; Q1-Q6 = Questions 1–6 of the Faux Pas Task.

Table 3 Neuropsychological evaluation. Test

JME Patients mean (SD)

Controls mean (SD)

F value

p (FDR-adjusted)

Digit Span Corsi Span Rey Auditory Verbal Learning Test – immediate recall Rey Auditory Verbal Learning Test – delayed recall Rey-Osterrieth Complex Figure Test – copy Rey-Osterrieth Complex Figure Test – immediate recall Rey-Osterrieth Complex Figure Test – delayed recall Stroop Color-Word Test – time interference effect Stroop Color-Word Test – error rate Trail Making Test A Trail Making Test B Trail Making Test B-A Semantic Fluency Test Phonemic Fluency Test

7.0 (1.5) 4.9 (0.8) 46.8 (6.5) 9.3 (1.9) 32.1 (1.5) 16.3 (5.8) 15.3 (6.5) 24.3 (4.9) 0.1 (0.5) 50.6 (12.4) 118.0 (30.6) 67.2 (24.4) 38.8 (8.7) 42.7 (7.4)

8.4 (1.7) 5.8 (1.0) 50.6 (6.7) 10.9 (1.3) 32.3 (1.8) 20.6 (5.1) 21.0 (5.0) 23.5 (7.0) 0 (0) 41.4 (9.4) 106.1 (33.2) 64.3 (22.9) 45.7 (11.3) 52.0 (8.7)

F1,38 = 8.17 F1,38 = 6.68 F1,38 = 3.68 F1,38 = 9.61 F1,38 = 0.07 F1,38 = 6.12 F1,38 = 9.30 F1,38 = 0.17 F1,38 = 1.00 F1,38 = 6.94 F1,38 = 1.38 F1,38 = 0.15 F1,38 = 12.95 F1,38 = 4.59

0.033 0.0495 0.108 0.022 0.853 0.0495 0.022 0.779 0.496 0.044 0.390 0.779 0.017 0.076

All score variables are reported as corrected for age and educational attainment. All the above-reported p values are FDR-adjusted, and values <0.05 are highlighted in bold. Abbreviations: FDR = p value corrected for multiple comparison using the False Discovery Rate procedure; SD = Standard deviation.

3.2. Assessment of other cognitive functions (Table 3) JME patients achieved scores significantly lower than controls for Digit Span, Corsi Span, Rey Auditory Verbal Learning Test – delayed recall, Rey-Osterrieth Complex Figure – immediate recall and delayed recall, Trail Making Test A and Semantic Fluency Test (see Table 3 for full statistical data).

(␳ = 0.784, p = 0.001 uncorrected), but not in patients with JME (␳ = 0.278, p = 0.28 uncorrected). No other significant correlations were identified between EF tests and the Strange Stories, Faux Pas (FP/FP score) and Reading the Mind in the Eyes Tasks, neither in the whole sample of tested subjects nor in subgroups. 4. Discussion

3.3. Correlations between ToM and neuropsychological tasks addressing EF Considering patients and controls altogether, the score of the Reading the Mind in the Eyes task was positively correlated with performance on the Corsi-Block Span test (␳ = 0.678, p < 0.001). As documented by an exploratory sub-group analysis, this correlation reached statistical significance in the healthy control subgroup

JME is a common epilepsy syndrome, is classified as GGE and has long been considered as benign. Recent evidence, however, showed altered social outcome in patients with JME, along with cognitive impairment and morpho-functional MRI abnormalities. In this study, we assessed social cognition, which is likely to play a crucial role in determining behavior in social contexts. Altered social cognition was first identified in autism spectrum disorders, schizophrenia (Brune and Brune-Cohrs, 2006) and

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diseases affecting frontal and temporal lobes (Aboulafia-Brakha et al., 2011). More recently, ToM deficits have been detailed for focal epilepsy (Giovagnoli, 2014). Here, we found that some features of social cognition differ significantly between patients with JME and controls matched for age, gender and education. To our knowledge, this is the first available data on ToM reasoning in GGE syndromes. In detail, performances during the Strange Stories Task and Faux Pas Task were significantly worse in our patients, suggesting a concomitant impairment of both affective and cognitive ToM. In other epilepsy syndromes, impaired performance on the Strange Stories Task was found in patients with early-onset amygdala damage (Shaw et al., 2004) but not in FLE (Farrant et al., 2005). With respect to the Faux Pas Task, our JME patients failed to recognize intentions and affective mental states, but answered the control questions appropriately, confirming a correct comprehension of the stories. Lower scores in the Faux Pas Task, similarly to what we described for our patients, were documented for FLE (Giovagnoli et al., 2011; Giovagnoli et al., 2013) and TLE (Broicher et al., 2012; Giovagnoli et al., 2009; Giovagnoli et al., 2011; Giovagnoli et al., 2013; Hennion et al., 2015; Li et al., 2013b; Schacher et al., 2006). Initial reports detected impairment on both Strange Stories Task and Faux Pas Task in subjects with bilateral medial prefrontal (Lee et al., 2010) and orbitofrontal (Stone et al., 1998) cortical damage, supporting a prominent role of these areas in ToM reasoning. Subsequent investigations, integrating findings from lesion studies as well as functional imaging on healthy subjects, point to the distinct role of the temporo-parietal junction in enabling the representation of mental states (Saxe, 2006; Scholz et al., 2009). Recent unifying attempts have led to conceptualize the so-called “ToM network”, which would rely on dynamic interactions among (a) posterior areas, such as the temporo-parietal junction, (b) limbic/paralimbic structures and basal ganglia, crucial for emotional input and integration with concomitant sensory information, as well as with (c) pre-frontal areas, including medial prefrontal and dorso-lateral prefrontal cortices, which might act as ‘executive centers’ and direct behavior (Abu-Akel and Shamay-Tsoory, 2011). There is also support to the view that cognitive and affective aspects of ToM are behaviorally distinguishable, and may be mediated by the interaction of temporo-parietal areas with distinct fronto-striatal subdivisions, such as dorsal prefrontal cortex and dorsal striatum for cognitive ToM, and prefrontal/orbitofrontal areas and ventral striatum for affective ToM, respectively (Abu-Akel and Shamay-Tsoory, 2011). In our subjects, we detected suboptimal performance in both ToM aspects, which might indicate a diffuse underlying fronto-temporal dysfunction in JME, with no clear-cut specificity for a subcomponent of the wider “ToM network”. Our patients only showed a trend towards an impaired recognition of anger in the Emotion Attribution Task. Interestingly, altered emotion recognition during the administration of eye or facial emotion recognition tasks has been already described for mixed GGE cohorts (Jiang et al., 2014; Realmuto et al., 2015). Disrupted emotion recognition has also been described in FLE (Farrant et al., 2005) and, more extensively, in TLE (Broicher et al., 2012; Li et al., 2013b; Shaw et al., 2007; Shaw et al., 2004), in which it pertained to the recognition of negative emotions such as anger, sadness and fear. Perception and recognition of emotions are likely produced by the activation of diffuse fronto-temporal networks, with anger perception particularly relying on prefrontal cortical areas (Lindquist et al., 2012). Our finding of a statistical trend for impaired recognition of anger is in line with previous evidence in GGE, and warrants further exploration in larger samples of subjects with JME. The neuropsychological evaluation of our JME group showed deficits of executive functions (verbal and visuo-spatial working memory and verbal fluency), psychomotor speed, as well as verbal (delayed recall) and visuo-spatial memory (immediate and delayed

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recall). In the last decade, several studies revealed impaired frontal lobe function, especially involving executive functions, prospective memory, attention and psychomotor speed, in patients with JME as well as in their unaffected siblings (Iqbal et al., 2015; Iqbal et al., 2009; Moschetta and Valente, 2012; Pascalicchio et al., 2007; Wandschneider et al., 2010). The results from our JME cohort are broadly in line with the above-detailed literature. Some authors have found deficits in verbal memory in JME (Iqbal et al., 2015; Iqbal et al., 2009; Pascalicchio et al., 2007), while visuospatial memory is less often reported as impaired (Pascalicchio et al., 2007; Sonmez et al., 2004). In our cohort, both verbal and visuo-spatial memory were found to be worse than in controls. Concomitant executive and memory dysfunction, as seen in our cohort, may be ascribed to the presence of suboptimal strategies for information coding, learning and retrieval (Baddeley and Wilson, 1988). The precise nature of the relationship between social cognition/ToM and executive functions still remains undefined. Some authors consider them as forming a unitary process, in light of the common neuroanatomical basis and the presence of executive components in social cognition/ToM tasks (Perner and Lang, 1999). Alternatively, it is maintained that social cognition/ToM and executive functions may be functionally related yet distinct abilities, with the integrity of one being a prerequisite for the optimal functioning of the other (Perner and Lang, 1999). In patients with acquired neurological disorders, concomitant impairment of both domains was found in the majority of the reports, when both were contextually tested [reviewed in (Aboulafia-Brakha et al., 2011)]. The results obtained in patients with epilepsy are more variable. Simultaneous impairment of ToM and executive functions was found in FLE (Farrant et al., 2005), although no correlations between the two domains were detected. Giovagnoli and colleagues identified a relationship between performance in the Faux Pas Task and tests addressing executive functions in TLE, but not in FLE (Giovagnoli et al., 2011). Conversely, other studies showed a dissociation between ToM and executive functions in TLE (Li et al., 2013b; Schacher et al., 2006). In patients with GGE, measures of executive functioning and cognitive empathy, which can be considered similar to affective ToM, were shown to be correlated (Jiang et al., 2014). In our subjects, performance during the Reading the Mind in The Eyes Task and the Corsi Block-Span test, both relying on visuospatial processing abilities, exhibited a strong positive correlation. The latter, however, was obtained when investigating the whole subject sample, and appeared to be driven mainly by the control cohort, without surviving statistical significance in the JME subgroup alone. Successful identification of mental states during the Reading the Mind in the Eyes Task may rely on the transitory manipulation of visuo-spatial cues within working-memory networks. This may occur more consistently in healthy individuals with intact short-term memory functions, while being less prominent in the JME patient subgroup, possibly due to the existence of alternative compensatory strategies. No further correlations between social cognition/ToM tasks and EF tests were obtained. On balance, our analysis indicates concomitant impairment in social cognition and EF domains in JME, but largely fails to detect a consistent relationship between the two domains, both in the whole-sample and separately in each subgroup. Subtle structural alterations in frontal gray and white matters were shown in JME by neuropathology studies in the 1980s (Meencke and Janz, 1984), and have been subsequently paralleled by findings of advanced neuroimaging investigations (Wandschneider et al., 2012; Wolf et al., 2015). Recent MRI analyses detected aberrant cortical metrics in mesial frontal areas (Alhusaini et al., 2013; Kim et al., 2007; O’Muircheartaigh et al., 2011; Woermann et al., 1999), posterior cingulate, lateral

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temporal and high-order fronto-temporo-parietal association cortices (Alhusaini et al., 2013; Lin et al., 2014; O’Muircheartaigh et al., 2011), as well as in subcortical structures including thalamus and putamen (Keller et al., 2011; Kim et al., 2007). Functional MRI studies revealed abnormal activation patterns during working memory tasks (Vollmar et al., 2011) while diffusion imaging analyses suggest widespread connectivity changes involving frontal lobes as well as frontocortical-thalamic circuits (O’Muircheartaigh et al., 2012; Vollmar et al., 2012), which seem to correlate with cognitive dysfunction (O’Muircheartaigh et al., 2011; Pulsipher et al., 2009). No imaging analyses were included in our study. However, in light of the anatomo-functional correlates described in the literature for the tasks we utilized, our findings would add support to the view that dysfunctional frontal/fronto-temporal networks are present in JME. 5. Conclusions In summary, this is the first study to reveal impairment of social cognition in patients with JME. Altered social cognition could explain, at least in part, the poor social outcome described for JME in the literature. Our findings may also provide more evidence in favor of the involvement of frontal/fronto-temporal dysfunction in the physiopathology of JME, in line with previous imaging data and neuropsychological studies. Our results should be interpreted with caution, due to the relatively small sample size and to the absence of formal correlation testing between neuropsychological scores and neuroimaging metrics. Nonetheless, strengths of our study include the homogeneity of our patient sample, the presence of a wellmatched control group as well as the use of a comprehensive test battery to probe different aspects of social cognition. Future studies on larger samples may help further clarify the relationship between social cognition and executive functions, psychosocial outcome, clinical features and neuroimaging abnormalities in JME. Acknowledgement U.B. has received speaking fees from UCB Pharma. The remaining authors declare no conflict of interest. References Aboulafia-Brakha, T., Christe, B., Martory, M.D., Annoni, J.M., 2011. Theory of mind tasks and executive functions: a systematic review of group studies in neurology. J. Neuropsychol. 5, 39–55. Abu-Akel, A., Shamay-Tsoory, S., 2011. Neuroanatomical and neurochemical bases of theory of mind. Neuropsychologia 49, 2971–2984. Adolphs, R., 2001. The neurobiology of social cognition. Curr. Opin. Neurobiol. 11, 231–239. Alhusaini, S., Ronan, L., Scanlon, C., Whelan, C.D., Doherty, C.P., Delanty, N., Fitzsimons, M., 2013. Regional increase of cerebral cortex thickness in juvenile myoclonic epilepsy. Epilepsia 54, e138–141. Baddeley, A., Wilson, B., 1988. Frontal amnesia and the dysexecutive syndrome. Brain Cogn. 7, 212–230. Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Y., Plumb, I., 2001. The Reading the Mind in the Eyes Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J. Child Psychol. Psychiatry 42, 241–251. Baykan, B., Martinez-Juarez, I.E., Altindag, E.A., Camfield, C.S., Camfield, P.R., 2013. Lifetime prognosis of juvenile myoclonic epilepsy. Epilepsy Behav. 28 (Suppl. 1), S18–24. Benjamini, Y., Hochberg, Y., 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. Ser. B (Methodological), 289–300. Blair, R., Sellars, C., Strickland, I., Clark, F., Williams, A., Smith, M., Jones, L., 1995. Emotion attributions in the psychopath. Personal. Individ. Diff. 19, 431–437. Blair, R.J., Cipolotti, L., 2000. Impaired social response reversal: a case of ‘acquired sociopathy’. Brain 123 (Pt 6), 1122–1141. Broicher, S.D., Kuchukhidze, G., Grunwald, T., Kramer, G., Kurthen, M., Jokeit, H., 2012. Tell me how do I feel–emotion recognition and theory of mind in symptomatic mesial temporal lobe epilepsy. Neuropsychologia 50, 118–128. Brune, M., Brune-Cohrs, U., 2006. Theory of mind-evolution, ontogeny, brain mechanisms and psychopathology. Neurosci. Biobehav. Rev. 30, 437–455.

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