Neural substrate of cognitive theory of mind impairment in amyotrophic lateral sclerosis

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Neural substrate of cognitive theory of mind impairment in amyotrophic lateral sclerosis Laurence Carluer a,b,c,d,*,1, Audrey Mondou a,b,c,d,1, Marie-Sonia Buhour a,b,c,e, Micka€el Laisney a,b,c,e, Alice Pelerin a,b,c,d, Francis Eustache a,b,c,e, Fausto Viader a,b,c,d and Beatrice Desgranges a,b,c,e a

Unit U1077, INSERM, Caen, France Joint Research Unit UMR-S1077, Caen University, Caen, France c Joint Research Unit UMR-S1077, Ecole Pratique des Hautes Etudes, Caen, France d Neurology Department, Caen University Hospital, Caen, France e Joint Research Unit UMR-S1077, Caen University Hospital, Caen, France b

article info

abstract

Article history:

We now know that amyotrophic lateral sclerosis (ALS) is not restricted to the motor system.

Received 7 April 2014

Indeed, a large proportion of patients with ALS exhibit cognitive impairment, especially ex-

Reviewed 19 June 2014

ecutive dysfunction or language impairment. Although researchers have recently turned their

Revised 29 September 2014

attention to theory of mind (ToM) in ALS, only five studies have been performed so far, and they

Accepted 12 December 2014

reported somewhat contradictory results. Moreover, the neural basis of the potential ToM

Action editor Stefano Cappa

deficit in ALS remains largely unknown. The present study was therefore designed to clarify

Published online 29 December 2014

whether a cognitive ToM deficit is indeed associated with ALS, specify the putative link between cognitive ToM deficits and executive dysfunction in ALS, and identify the dysfunctional

Keywords:

brain regions responsible for any social cognition deficits. We investigated cognitive ToM and

Amyotrophic lateral sclerosis

executive functions in a group of 23 patients with ALS and matched healthy controls, using an

Cognitive impairment

original false-belief task and a specially designed battery of executive tasks. We also performed

Theory of mind

an 18F-fluorodeoxyglucose positron emission tomography examination. Results confirmed the

Executive dysfunction

presence of cognitive ToM deficits in patients compared with controls, and revealed significant

FDG-PET

correlations between ToM and executive functions, although the cognitive ToM deficit persisted when a composite executive function score was entered as a covariate. Using statistical parametric mapping, we calculated positive correlations between tracer uptake and falsebelief scores on a voxel-by-voxel basis in the patient sample. Results showed that the cognitive ToM deficit correlated with the dorsomedial and dorsolateral prefrontal cortices, as well as the supplementary motor area. Our findings provide compelling clinical and imaging evidence for the presence of a genuine cognitive ToM deficit in patients with ALS. © 2014 Elsevier Ltd. All rights reserved.

Abbreviations: ALS, amyotrophic lateral sclerosis; 18FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; FTD, frontotemporal dementia; SMA, supplementary motor area; ToM, theory of mind; VBM, voxel-based morphometry. ^ te de Nacre, CS 14033, F-14000 Caen Cedex 9, France. * Corresponding author. U 1077 Inserm e EPHE e UCBN, CHU Co E-mail address: [email protected] (L. Carluer). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.cortex.2014.12.010 0010-9452/© 2014 Elsevier Ltd. All rights reserved.

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1.

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Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive paralysis, owing to loss of both upper and lower motor neurons. It causes weakness, muscular wasting, and spasticity, starting segmentally before becoming widespread and resulting in death from respiratory failure at a median of 3 years after onset.

1.1. Beyond the motor deficit: cognitive and behavioural impairment There is an acknowledged clinical, pathological and genetic link between ALS and frontotemporal dementia (FTD). A subgroup of patients with ALS (5e15%) meets the criteria for FTD, typically a frontal variant that predominantly causes executive dysfunction and a pattern of behavioural change (Lomen-Hoerth et al., 2003; Neary, Snowden, & Mann, 2000; Phukan et al., 2012; Ringholz et al., 2005). Previous studies suggested that 35e50% of patients with ALS without FTD exhibit mild cognitive and behavioural impairments. Despite some discrepant findings, probably due to the variety of neuropsychological tasks used, the most commonly reported deficits concern executive functions (Phukan et al., 2012; Ringholz et al., 2005) and language. Executive dysfunction in ALS patients affects mental set shifting, action planning and sequencing (Abrahams et al., 2000; Phukan, Pender, & Hardiman, 2007; Pinkhardt et al., 2008; Ringholz et al., 2005), resulting in reduced word fluency (Abrahams et al., 2000). Language impairments have also been reported in a significant percentage of ALS patients (35%), and these deficits may indeed be more common than executive dysfunction itself (Abrahams, Newton, Niven, Foley, & Bak, 2014). Impairments in memory and, less frequently, in visuoconstructional, visuoperceptual and visuospatial abilities, have also been found (Bak & Hodges, 2004; Flaherty-Craig, Eslinger, Stephens, & Simmons, 2006; Massman et al., 1996; Phukan et al., 2012; Raaphorst, de Visser, Linssen, de Haan, & Schmand, 2010; Ringholz et al., 2005; Strong et al., 1999; Taylor et al., 2013). Regardless of cognitive impairment, nondemented patients with ALS may exhibit behavioural changes characterized by irritability, disinhibition and apathy (Gibbons, Richardson, Neary, & Snowden, 2008; Grossman, WoolleyLevine, Bradley, & Miller, 2007; Lomen-Hoerth et al., 2003; Murphy, Henry, & Lomen-Hoerth, 2007; Phukan et al., 2007), the latter being regarded as the most common feature. All these findings reflect the heterogeneity of the cognitive and behavioural changes in ALS, probably due to a variable involvement of the temporal and frontal structures subserving executive functions, language and behaviour (Abrahams et al., 2014). The cognitive and behavioural changes described in patients with ALS are, to a great extent, also found in FTD, leading to the now largely acknowledged notion that the two diseases - ALS and FTD - lie at either end of a continuum (Goldstein & Abrahams, 2013; Murphy, Henry, Langmore, et al., 2007; Wilson, Grace, Munoz, He, & Strong, 2001).

1.2.

Theory of mind (ToM), ALS and FTD

ToM is defined by the ability to infer and understand the mental states of self and others. This understanding refers not only to how other people are feeling emotionally, but also to the realization that they may have different beliefs in given situations and thus behave differently. A distinction has been made between so-called cognitive ToM (also known as mentalizing), which deals with the cognitive states, beliefs, thoughts or intentions of other people (Coricelli, 2005), and affective ToM, which concerns their affective states, emotions or feelings (Brothers & Ring, 1992). In day-to-day social interactions, ToM enables us to constantly consider perspectives distinct from our own, and to describe, explain and predict behaviour based on the mental states of others (Baron-Cohen, 1995). The neural network underlying successful ToM performance includes the temporoparietal junction (Saxe & Wexler, 2005), posterior superior temporal sulci, precuneus, anterior temporal lobes (Olson, Plotzker, & Ezzyat, 2007) and medial prefrontal cortices (Amodio & Frith, 2006). The importance of the prefrontal cortex for cognitive ToM is supported both by lesion studies, in which selective damage to this area impaired the capacity to understand and infer thoughts and beliefs of others (Lee et al., 2010; Roca et al., 2011; Stuss, Gallup, & Alexander, 2001), and then by functional neuroimaging studies in healthy individuals (Amodio & Frith, 2006; Gallagher & Frith, 2003). Recent neuroimaging studies have suggested that cognitive ToM mainly recruits the dorsomedial and dorsolateral prefrontal cortices, whereas affective ToM mainly depends on the ventromedial prefrontal, orbitofrontal and inferior frontal cortices (Abu-Akel & Shamay-Tsoory, 2011; Gallagher & Frith, 2003). Neuroimaging data highlight an extensive neural network, suggesting that ToM is not a single process, and that other cognitive functions are also involved when a person reasons about the mental states of others. Although the nature of the link between cognitive ToM and executive function is still a matter for debate, ToM and executive function have been shown to be closely related in developmental experiments both in children (Carlson & Moses, 2001) and in adults (Qureshi, Apperly, & Samson, 2010; Rakoczy, Harder-Kasten, & Sturm, 2012). Specifically, executive function has been found to be involved in ascribing beliefs that aim to represent the world truthfully, because ascribing such beliefs requires the inhibition of the default assumption that beliefs are true (Sabbagh, Moses, & Shiverick, 2006). According to recent models, belief reasoning can be subdivided into three distinct components: representation of reality, belief inference and self-perspective inhibition (Leslie, Friedman, & German, 2004; Samson, Apperly, & Humphreys, 2007; Van der Meer, Groenewold, Nolen, Pijnenborg, & Aleman, 2011). The first component corresponds to the representation of the true state of reality, that is, the individual's own belief, and involves general cognitive functions (attention, perception, and semantic and episodic memory). Belief inference, the second component, is thought to be specific to ToM and independent of executive function, whereas the third component (self-perspective inhibition) is thought to be

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executive function-dependent and thus domain-general (Qureshi et al., 2010; Samson, Apperly, Kathirgamanathan, & Humphreys, 2005). In false-belief situations, in order to work out the content of the protagonist's belief about something, individuals have to inhibit the response based on the real world. They therefore have to inhibit their own belief, and shift from their own belief to that of the protagonist. Several studies have highlighted ToM impairments in the behavioural variant of FTD, using false-belief tasks (Eslinger et al., 2007; Fernandez-Duque, Baird, & Black, 2009; Gregory et al., 2002; Le Bouc et al., 2012; Shany-Ur et al., 2012), simple cartoon tasks requiring social inference (Lough et al., 2006; Snowden et al., 2003), and tests of faux-pas recognition vy, & Dubois, 2012; (Funkiewiez, Bertoux, de Souza, Le Gleichgerrcht, Torralva, Roca, Pose, & Manes., 2011; Torralva et al., 2007; Torralva, Roca, Gleichgerrcht, Bekinschtein, & Manes, 2009). To our knowledge, only five studies have investigated ToM abilities in ALS so far, with somewhat contradictory results (Cavallo et al., 2011; Cerami et al., 2013; Gibbons et al., 2007; Girardi, Macpherson, & Abrahams, 2011; Meier, Charleston, & Tippett, 2010). Gibbons and colleagues studied cognitive ToM through cartoons and stories, some of which required participants to attribute mental states to others, while others described physical events. A group analysis failed to reveal any significant differences between patients and controls, but the individual patients' results were heterogeneous, ranging from normal to severely impaired. The ToM scores of patients correlated with measures of executive functioning, especially those executive tests that demand abstraction and mental set shifting (Wisconsin Card Sorting Test and verbal fluency). The authors concluded that the cognitive ToM deficits were probably linked to a more general executive dysfunction. Girardi et al. (2011) highlighted a ToM deficit in patients with ALS using a preference judgement task. Their findings not only revealed a ToM deficit in this executively undemanding task, but also showed that this deficit was unrelated to the presence of executive dysfunction. Cavallo et al. (2011) studied patients' ability to understand social and nonsocial situations by attributing intentions to others. The patients' performances only differed from those of controls in the first situation, indicating specific deficits in the domain of social understanding in patients with ALS. There were no significant correlations with executive functions (verbal fluency). When they administered a faux-pas task (detection of a social blunder or lack of tact in a scenario), Meier et al. (2010) found that patients with ALS identified significantly fewer faux-pas stories than controls did, but were just as accurate in identifying control stories. Although the faux-pas task involves not only representing the knowledge or beliefs (cognitive ToM) of others, but also appreciating their emotional state (affective ToM), the authors suggested that the deficit was more likely to lie primarily with the affective ToM component of the task. Moreover, when they repeated the analyses, co-varying out performance on oral letter fluency, the findings were unchanged, indicating that the ALS group had real difficulty with the faux-pas stories. Finally, Cerami et al. (2013) assessed both affective and cognitive ToM in patients with ALS, using a nonverbal task of attribution of mental states (emotional states or intentions) to other individuals, and only found

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impairments for affective ToM. Just four of their 20 patients displayed executive dysfunction, and no significant correlations were found between ToM task conditions and measures of executive functions. To sum up, most of these studies highlighted impairment of cognitive and/or affective ToM in patients with ALS. Nevertheless, it is still unclear whether any ToM deficit is associated with executive dysfunction, or whether ToM per se is disturbed. In the two studies that found no link between ToM and executive functions (Cavallo et al., 2011; Meier et al., 2010) the authors only tested verbal fluency, which does not represent a comprehensive measure of executive functioning. Some authors have speculated on the neural bases of ToM impairment in ALS, notably Meier et al. (2010), who postulated that the ToM deficit is associated with the orbitomedial prefrontal cortex. Cerami et al.'s (2013) study is the only one to have specifically explored the neural basis of the ToM deficit in ALS. These authors found a significant relationship between grey-matter density in the right fronto-insular and anterior cingulate cortices and the affective ToM deficit, but not with cognitive ToM (which was unimpaired). Thus, no study has so far provided data on the neural basis of any cognitive ToM deficit in ALS. Given that 1) cognitive ToM is known to be impaired in FTD, 2) ALS and FTD lie on the same pathological continuum, and 3) the status of cognitive ToM in ALS remains insufficiently known, we set out to investigate cognitive ToM in a group of non-demented ALS patients. We also planned to study the relationship between any possible cognitive ToM impairment and executive function scores. We were keen to assess cognitive ToM in the disease at an earlier stage than had been done in the previous studies, which investigated patients relatively late in the disease course: 38 months after clinical onset in Girardi et al. (2011), 24 months in Gibbons et al. (2007), 34.5 months in Meier et al. (2010), 30 months in Cavallo et al. (2011), and 23.9 months in Cerami et al. (2013). We chose to administer a novel false-belief task that is regarded as specifically assessing cognitive ToM and, moreover, has been designed to overcome patients' possible memory and comprehension difficulties (see Section 2. “Materials and Methods”). We also carried out a comprehensive executive function assessment. Finally, in order to identify the neural correlates of cognitive ToM, we assessed the correlations between scores on the false-belief task and brain metabolism values obtained with 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) imaging.

2.

Materials and methods

2.1.

Participants

Twenty-three patients with ALS were recruited for this study. Five patients presented with bulbar onset (22%) and 18 patients with limb onset (78%). Two different control groups were included in the study. The first group, composed of 23 healthy participants, was used to determine the presence of a cognitive ToM deficit in the patients with ALS. To compare the neuroimaging data, a second group of 22 healthy individuals was included. Both groups were matched for age, sex and

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years of education with the patients. All participants were native French speakers and had a minimum level of education equivalent to the now obsolete certificat d'etudes primaires”, a school-leaving certificate that was generally taken at ~14 years, following seven years of primary education. None of the participants had a history of alcoholism, head trauma, or neurological or psychiatric illness. Inclusion criteria also included a nonpathological score (at least 130/144) on the Mattis Dementia Rating Scale (Mattis, 1976), a scale widely used to assess general cognitive functioning and screen for dementia. All the patients met the modified El Escorial criteria for probable or definite ALS (Brooks, Miller, Swash, & Munsat, 2000). None of them fulfilled the criteria for a diagnosis of FTD according to the core and supportive diagnostic features of FTD detailed in the LundeManchester consensus statement (Neary et al., 1998). None of the ALS patients fulfilled the Rascovsky et al.'s (2011) criteria for possible and/or probable behavioural variant of FTD. Behavioural disorders were explored via the short form of the Neuropsychiatric Inventory (Cummings et al., 1994; Michel et al., 2005) in 21 patients. Ten of the patients had executive disorders that met the criteria for ALS with cognitive impairment (ALSci) (Strong et al., 2009), but none had behavioural disorders of the frontal type sufficiently severe to meet the criteria for ALS with behavioural impairment (ALSbi). All the patients underwent a neurological assessment that included the ALS Functional Rating Scale-revised form (ALSFRS-R; Cedarbaum et al., 1999), a functional scale that evaluates the presence of limb, bulbar and respiratory dysfunction, the Norris scale, which assesses the impact of bulbar involvement (Norris, U, Sachais, & Carey, 1979), and the Medical Research Council (MRC., 1976) Muscle Strength Scale. They were able either to speak or to write intelligibly, had a forced vital capacity above 50% (predicted value) and no clinical evidence of nocturnal hypoventilation. None of the patients had any additional severe or chronic illness, MRI contraindications, or communication difficulties severe enough to compromise the administration of cognitive tests. All the patients gave their written informed consent, and the study was approved by the regional independent ethics committee.

2.2.

Neuropsychological assessment

2.2.1.

Cognitive ToM assessment

Cognitive ToM abilities were assessed with the TOM-15 (Desgranges et al., 2012), a false-belief task based on original false-belief cartoons similar to those in the Sally-Anne task (Wimmer & Perner, 1983). While false-belief tests generally feature only a limited number of items, the TOM-15 comprises 15 short comic strips and was designed to be used with patients with dementia, such as those with semantic dementia (Duval et al., 2012) or Alzheimer's disease (Laisney et al., 2013). Each comic strip featured three pictures, together with a short written description indicating that one of the characters entertains a false belief about the true state of affairs (for an example, see Fig. 1). To reduce cognitive load, the pictures and written descriptions remained visible throughout. The stories were all based on the same principle: 1) they described a

situation involving a character who becomes aware of a certain piece of information; 2) unbeknownst to that character, the situation then changes. After studying each comic strip, participants were asked about the character's belief (i.e., a belief based on only partial knowledge of the facts). In order to answer the belief question correctly in a two-alternative forced choice, participants had to be able to understand that another person can hold a possibly mistaken belief. Five of the cartoons involved first-order representations (“X thinks that …”) and the remaining eight involved second-order representations (“X thinks that Y thinks that …”). Participants were not given any feedback about their choices. To assess the participants' story comprehension, once they had completed the false-belief task, they were presented with the same stories again, but this time had to answer a reality question about each one. Each correct answer was scored one point, and the maximum score for each condition was 15. Interference tasks were inserted between the ToM and comprehension conditions.

2.2.2.

Executive functions and working memory assessment

Patients and controls underwent a complementary neuropsychological assessment focused on executive functions and working memory. The ability to inhibit a dominant response was assessed by the number of correct responses to the second part of the French adaptation of the Hayling Sentence Completion Test (HSCT; Burgess & Shallice, 1997). Set-shifting abilities were assessed with the Trail Making Test (TMT; Godefroy & GREFEX, 2008) and letter verbal fluency task (Cardebat, Doyon, Puel, Goulet, & Joanette, 1990). The time taken to process Part A of the TMT yielded a measurement of processing speed, and that taken to process Part B minus the processing time for Part A measured the ability to flexibly shift the course of an ongoing activity. The score on the letter fluency task was the total number of words generated, excluding perseverative and intrusive errors. In order to take into account the effect of disease-induced motor impairment on oral production tasks, each participant's verbal fluency performance was expressed as an index based on the number of words produced in the verbal fluency task and the time it took him or her to read out the words in a subsequent reading task (Abrahams et al., 2000). Finally, the ability to manipulate items in working memory, which refers to the rearrangement and transformation of representations for goal-directed behaviour, was measured by the Letter Number Sequencing task (LN sequencing; Wechsler, 2000).

2.3.

PET and MRI data acquisition

All the patients underwent a resting-state 18FDG-PET scan acquired with a Discovery RX VCT 64 PET-CT scanner (General Electric Healthcare, Milwaukee, WI, USA) with a resolution of 3.76
3.76
4.9 mm (field of view ¼ 157 mm). Forty-seven planes were obtained with a voxel size of 2.7
2.7
3.27 mm. A transmission scan was performed for attenuation correction before the PET acquisition. Participants fasted for at least 6 h before scanning. After a 30-min resting period in a quiet and dark environment, z150 MBq of 18FDG (100e200 MBq) were intravenously injected as a bolus. A 10-min PET acquisition scan began 50 min post-injection. Brain metabolic activity was

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Fig. 1 e Example of the stimuli and the questions used in the first- and second-order false belief task.

measured during quiet wakefulness with eyes closed and ears unplugged. The patients also underwent an MRI scan, which was used for coregistration and normalization, and to correct the 18FDGPET data for partial volume effects (PVEs). High-resolution T1-weighted anatomical images were acquired on an Achieva 3T scanner (Philips, Eindhoven, The Netherlands) using a 3D fast field echo sequence (3D-T1-FFE sagittal, repetition time ¼ 20 msec, echo time ¼ 4.6 msec, flip angle ¼ 20 , 170

slices, slice thickness ¼ 1 mm, field of view ¼ 256
256 mm2, matrix ¼ 256
256). One patient had to be excluded from the imaging analyses because his MRI data were unusable. The 18FDG-PET data were corrected for PVEs (PMOD Technologies, Adliswil, Switzerland), coregistered to their corresponding MRI and normalized using the deformation parameters obtained from the MRI. These normalized PVEcorrected data for the brain metabolic rate of glucose consumption are referred to as ncCMRglc hereafter. The resulting

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images underwent quantitative scaling to control for individual variations in overall FDG uptake. Each normalized PET image was divided by the values extracted from a region of interest (ROI) in the cerebellum. A Gaussian filter with 12-mm full width at half maximum was then applied to smooth each image in order to compensate for interparticipant differences and increase the signal-to-noise ratio. Finally, images were masked to exclude non-grey matter voxels from the analyses.

2.4.

Statistical analysis

Statistical analyses of the demographic and cognitive data were performed using Statistica 10.0 (StatSoft, Tulsa, OK, USA). The threshold of significance was set at p ¼ .05 (one-tailed). We ran a chi-square test to compare the sex ratios of the patient and control groups. We also compared them on age, number of years of education, HSCT score, TMT B-A reaction time difference, verbal letter fluency score and index, and LN Sequencing score, using unpaired Student's t tests. We summed the scores on the executive function tests (mean z score of the HSCT score, TMT B-A reaction time difference, verbal letter fluency index, and LN Sequencing score) to obtain a composite executive function score, in order to use it as a covariate in subsequent analyses. We began by running a Group (patients versus controls) * Condition (ToM versus comprehension) * Order (first versus second) analysis of variance (ANOVA) on the TOM-15 scores. We then ran an analysis of covariance (ANCOVA) on the TOM-15 scores with the composite executive function score as a covariate. Follow-up post hoc comparisons were conducted with Tukey's honestly significant difference (HSD) test. In the patient group, we calculated Pearson's correlation coefficient between the ToM score and executive function and working memory performances, in order to identify the executive functions that intervene in ToM functioning in patients with ALS. Correlations between the ToM score and whole-brain 18 FDG-uptake were performed using the “multiple regressions” routine of statistical parametric mapping (SPM5; Wellcome Trust Centre for Neuroimaging, London, UK) across 22 patients. Only correlations in the neurobiologically expected direction were conducted (i.e., positive correlations). Given the deleterious effect of age on glucose consumption, especially in frontal areas (Kalpouzos et al., 2009), the patients' age was entered as a confounding variable. To support the specificity of the observed correlations, the composite executive function scores and comprehension scores (comprehension condition of ToM-15) were also entered as confounding variables. We used a statistical threshold of p ¼ .005 (uncorrected for multiple tests) for the voxels and a cut-off of k (corresponding to the number of voxels in a particular cluster) > 50, to limit the attendant risk of false positives. Anatomical localization was based on Talairach's atlas and the Anatomical Automatic Labelling atlas (AAL; Tzourio-Mazoyer et al., 2002). Finally, the metabolism of the brain regions that significantly correlated with ToM scores in the patients was compared with that of a group of 22 healthy controls taken from our database. To this end, the mean metabolic values of each ROI, represented by the clusters of the peaks of

significant correlation coefficients in the analysis with confounding variables, were extracted for the patients using “Binary ROIs analysis” in SPM5, and compared with the data extracted for the controls, using t tests. Owing to scheduling difficulties, two patients did not perform the TMT, and two others did not perform the LN Sequencing task. The missing data were replaced by the mean value for the group when they were used as confounding variables in the ANCOVA and the cognitiveemetabolic correlation analysis.

3.

Results

3.1. General data, executive functions and working memory Both groups' demographic and medical data, as well as their executive function and working memory performances, are reported in Table 1. The patient and control groups were matched on sex, c2(1) ¼ .09, p ¼ .76, 4c ¼ .04, age t(44) ¼ .02, p ¼ .98, d ¼ .01, and years of education, t(44) ¼ 1.29, p ¼ .20, d ¼ .38. Regarding executive functions and working memory, patients scored more poorly than controls on the HSCT, t(44) ¼ 5.57, p < .001, d ¼ 1.64, TMT B-A, t(42) ¼ 2.10, p ¼ .05, d ¼ .63, and both letter verbal fluency, t(44) ¼ 5.33 p < .001, d ¼ 1.57, and index, t(44) ¼ 3.57 p < .001, d ¼ 1.05. There was no significant difference between the groups on LN Sequencing task performances, t(42) ¼ 1.63, p ¼ .11, d ¼ .49.

3.2.

Cognitive ToM

The ANOVA on the TOM-15 scores (Fig. 2) indicated a significant group effect, F(1, 44) ¼ 13.57, p < .001, h2 ¼ .23, a significant

Table 1 e Demographic and medical data, and executive function and working memory performances of controls and patients with ALS.

Sex (M/F) Age (years) Education (years) Onset (bulbar/limb) Disease duration (months since clinical onset) ALSFRS-R score Norris score MRC score HSCT correct responses** TMT B-A (s)* Letter verbal fluency score** Letter verbal fluency index** LN sequencing score

Controls

Patients

15/8 59.74 (±10.48) 11.00 (±2.71) / /

14/9 59.65 (±13.02) 9.96 (±2.77) 5/18 18.78 (±8.56)

/ / / 9.13 (±2.42) 28.83 (±23.95) 23.78 (±5.13) 4.60 (±1.49) 10.48 (±2.11)

38.87 (±4.78) 36 (±4.81) 102.35 (±16.47) 5.09 (±2.50) 54.48 (±52.92) 16.10 (±4.65) 6.46 (±2.01) 9.00 (±3.74)

Note. Values are means ± SD. ALSFRS-R ¼ Amyotrophic Lateral Sclerosis Functional Rating Scale-revised form, MRC ¼ Muscle Strength Scale, HSCT ¼ Hayling Sentence Completion Test, TMT ¼ Trail Making Test. Significant differences (Student's t tests) between the performances of patients and controls are marked with * for p < .05 and ** for p < .001.

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Fig. 2 e Performances (mean and standard error of the mean) on the TOM-15 task in the first (/8) and second (/7) order ToM and comprehension conditions for controls and patients with ALS. Note. Significant differences (Tukey's HSD post hoc test) between the performances of the controls and patients are marked with ** for p < .001.

condition effect, F(1, 44) ¼ 32.04, p < .001, h2 ¼ .42, a significant Group
Condition interaction effect, F(1, 44) ¼ 10.16, p < .05, h2 ¼ .19, a nonsignificant order effect, F(1, 44) ¼ 1.05, p ¼ .31, h2 ¼ .02, a significant Group
Order interaction effect, F(1, 44) ¼ 9.03, p < .05, h2 ¼ .17, a significant Condition
Order interaction effect, F(1, 44) ¼ 16.50, p < .001, h2 ¼ .27, and a significant Group
Condition
Order interaction effect, F(1, 44) ¼ 5.50, p < .05, h2 ¼ .11. Post hoc analyses indicated that for the ToM condition, patients scored lower than controls in the second-order (p < .001), but not in the first-order (p ¼ .47). The patients' second-order ToM scores were lower than their firstorder ones (p < .001), but there was no difference between the two orders in controls (p ¼ 1). For the comprehension condition, there was a nonsignificant difference between the two groups in the first-order (p ¼ .92) and second-order (p ¼ .94) and between the two orders for both patients (p ¼ .68) and controls (p ¼ .75). In the first-order, there was a nonsignificant difference between ToM and comprehension conditions in both the patient group (p ¼ .63) and the control group (p ¼ .99). In the second-order, there was a significant difference between ToM and comprehension conditions in the patient group, with lower performances in the ToM condition (p < .001). There was no such difference in the control group (p ¼ .34). The ANCOVA on TOM-15 performances, with the composite executive score as a covariate, yielded identical results (data not shown). Correlation coefficients between the ToM score and executive function and working memory performances were significant and in the expected direction between the ToM score and the TMT B-A reaction time, r ¼ .50, p < .03, n ¼ 21, the letter verbal fluency score, r ¼ .38, p < .04, n ¼ 23, and index, r ¼ .44, p < .02, n ¼ 21, and the LN Sequencing score, r ¼ .49,

p < .02, n ¼ 21. The correlation coefficient between the ToM score and the HSCT score tended towards significance, r ¼ .33, p ¼ .06, n ¼ 23.

3.3. Correlations between the ToM score and uptake

18

FDG

The peaks of the significant positive correlations between the ToM score and ncCMRglc, with the composite executive function score, age and comprehension scores as confounding variables for 22 patients with ALS are listed in Table 2. Significant positive correlations concerned the medial prefrontal (bilateral superior frontal gyrus) and dorsolateral prefrontal cortices (bilateral middle frontal gyrus), and bilateral supplementary motor area (SMA) (Fig. 3). Finally, the ncCMRglc of the two main ROIs in which the ToM score significantly correlated with 18FDG uptake was lower in the patients than in controls: the right superior frontal gyrus [t(42) ¼ 2.43, p < .05, d ¼ .73], and the left superior frontal gyrus [t(42) ¼ 2.67, p < .05, d ¼ .80].

4.

Discussion

The aim of the present study was to explore cognitive ToM in patients with ALS using an original false-belief task, and to examine whether any ToM deficits could be related to, or even entirely explained by, executive dysfunction. We found a cognitive ToM deficit in our patient sample that was partly explained by deficient executive processes, especially shifting, inhibition and the ability to manipulate items in working memory, but which persisted when a composite executive function score was entered as a covariate. We also sought to

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Table 2 e Mean peaks of significant (p < .005, uncorrected) positive correlations between ncCMRglc and performances on the TOM-15 test in the ToM condition. k

Labels

MNI coordinates x

763

323

68

R Sup Frontal R Mid Frontal R Supplementary Motor Area L Sup Frontal L Supplementary Motor Area L Mid Frontal L Precentral

y

Z (voxel level)

z

24

8

62

4.01

4

30

44

3.73

30

4

56

3.20

Note. Results are listed in decreasing order of peak z score value adjusted to MNI space. k ¼ cluster size in terms of the number of significant voxels. Labels were obtained using the AAL toolbox (see Materials and Methods section). L ¼ left; R ¼ right; Sup ¼ superior; Mid ¼ middle. Only labels representing more than 15% of the cluster are reported.

identify the neural substrates of the cognitive ToM deficit e something that had never before been achieved in ALS e by calculating correlations between the false-belief scores and PET data. Our neuroimaging results indicated that the

cognitive ToM deficit in our patients correlated with a set of cortical areas (dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, SMA) that is known to be involved in social cognition and, more specifically, in cognitive ToM. We found that the patients performed more poorly than controls on the TOM-15 task. Their cognitive ToM deficit could not be explained by poor comprehension, as they achieved normal scores in the control condition (reality questions). More specifically, patients performed as well as controls in the first-order but more poorly than controls in the second order of the TOM-15 task. Using TMT, HSCT and verbal fluency (both score and index), we showed executive deficit in our group of patients which was not explained by their motor disability, as previously reported in ALS. In addition, we found significant correlations between the patients' ToM performances and their verbal fluency, TMT performance, HSCT performance (trend towards significance), and LN Sequencing score. These correlations suggest that the poor performances on the false-belief task could at least partially be explained by a deficit in shifting, inhibition, and the ability to manipulate items in working memory. In our study, patients and controls had similar results in the TOM-15 comprehension condition, suggesting that the first component of belief reasoning (the representation of reality) is not affected. Conversely, we found that inhibition and shifting were correlated with ToM performances, indicating that executive dysfunction contributes to

Fig. 3 e Positive correlations between ncCMRglc and performances in the ToM condition of the TOM-15 test as well as differences between patients' and controls' regional metabolism in the regions significantly correlated with ToM scores. Right is right; HS ¼ Healthy Subjects; ALS ¼ Amyotrophic Lateral Sclerosis patients.

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the ToM deficit by affecting the third component of belief reasoning, self perspective inhibition, in accordance with the study by Gibbons et al. (2007). We also found a correlation between ToM performance and the ability to manipulate items in working memory, suggesting that ToM also requires this particular ability, as already suggested by Phillips et al. (2011). We can therefore infer from our results that the patients' poor performance on the false-belief task stemmed, at least in part, from the impairment of shifting, inhibition, and the ability to manipulate items in working memory. Nevertheless, the involvement of these functions only partially explained the cognitive ToM deficit in our patients with ALS, for when we ran an ANCOVA on ToM performances, with a composite executive function score as a covariate, the cognitive ToM impairment remained significant. This suggests that the second component of belief reasoning (i.e., belief inference), which is thought to be independent of executive function and specific to cognitive ToM, was also impaired in our patients. Assuming, therefore, that belief reasoning does indeed have three components, our results show that the patients failed on the falsebelief task because of impairment in both their belief inference and their self-perspective inhibition. This is the first study in ALS to have highlighted a cognitive ToM deficit after controlling for executive dysfunction. Of the eight ALS patients with the most severe cognitive profile (both ALSci and cognitive TOM impairment) in this sample, only two had a bulbar onset. While no definite conclusion can be drawn from such a small sample, this result does not suggest that ALS patients with bulbar onset are more prone to cognitive impairment than those with a predominantly spinal form of the disease. Six of our 23 ALS patients had impaired ToM but spared executive functions, which further supports the idea that ToM may be specifically impaired in ALS. The specificities of the study were 1) an earlier disease duration compared to previous studies; 2) the use of a ToM task that better controls for subtle memory and comprehension difficulties; and 3) the use of different neuropsychological tasks assessing executive functions. It might therefore be worthwhile conducting a longitudinal study to determine whether and to what extent the influence of executive functions on the cognitive ToM deficit changes as the disease progresses. The correlations between the patients' scores on the falsebelief test and their PET data implicated the dorsomedial and dorsolateral prefrontal cortices, and the SMA. Given that we entered the patients' age (which could potentially influence FDG uptake), as well as a composite executive function score (combining the HSCT, TMT, letter verbal fluency index and LN Sequencing) and the comprehension scores as nuisance variables, these correlations probably reflect the specific neural substrates of the ToM deficit in our patient group. It has been suggested that the high-level ability to simultaneously maintain different representations of one's own and others' intentions or beliefs is mediated by the prefrontal cortex (Frith & Frith, 1999; Gallagher & Frith, 2003; Leslie et al., 2004). Recent neuroimaging studies have shown that cognitive ToM mainly recruits the dorsomedial and dorsolateral prefrontal cortices, whereas affective ToM mainly depends on the ventromedial prefrontal, orbitofrontal and inferior frontal cortices (Abu-Akel & Shamay-Tsoory, 2011; Gallagher & Frith, 2003).

27

False-belief reasoning, which is a core component of cognitive ToM, has been investigated in several imaging studies in healthy people (Rothmayr et al., 2011; Saxe & Powell, 2006; Sommer et al., 2007). The medial prefrontal cortex appears to be involved in decoupling other people's perspectives from one's own (e.g., decoupling the story protagonist's belief about an object's location from one's own € hnel et al., 2012; Gallagher & Frith, knowledge about it) (Do 2003; Leslie 1987). Once they have decoupled these perspectives, individuals need to inhibit their prepotent tendency to respond according to their own true belief equalling the true state of reality. Converging evidence suggests that the dorsolateral prefrontal cortex (more specifically, the middle frontal gyrus) is associated first with self-perspective inhibition, through its executive functions of inhibition, planning and coordination, and second with storage processes in working memory (e.g., short-term storage of information about the location of the object in the story, as well as maintaining the representation of a protagonist's false belief) (Rothmayr et al., 2011). Accordingly the dorsolateral cortex may underpin the third component of belief reasoning, namely self-perspective inhibition, as suggested by Le Bouc et al. (2012) in a study of cognitive ToM in patients with FTD. In their study, the patients' cognitive ToM deficit stemmed from a self-perspective inhibition deficit that correlated with the right middle frontal gyrus. In our study, although we added a composite executive function score as a covariate, it may not have sufficed to erase the contribution of certain brain regions to the executive functions involved in resolving cognitive ToM items such as those contained in the TOM-15. Our study also highlighted the involvement of the SMA, which is directly connected to the corticospinal tract and motor neurons. The pre-SMA (anterior part of the SMA) also has reciprocal connections with the dorsolateral prefrontal cortex (Koenigs, Barbey, Postle, & Grafman, 2009), and functional connectivity studies have indicated that it is involved in cognitive functioning (Kim et al., 2010). Although the SMA involvement we observed could have been linked to the process of motor neuron degeneration, when motor scores were entered as an additional covariate, results remained unchanged (data not shown). We therefore suggest that the SMA contributes to cognitive ToM, and thus to the deficit in ALS, through its involvement in the mirror system (Filimon, Nelson, Hagler, & Sereno, 2007). This system is commonly assumed to be engaged when an individual perceives physical motion, irrespective of its sensory or verbal format, as well as when the perceiver executes that motion. The mirror system allows us to recognize the goal of a perceived action by matching it with a representation in our memory of our own actions, and by affording us the vicarious experience of others' emotional states in our own mind (Decety & Jackson, 2004). Van Overwalle and Baetens (2009) have suggested that the mirror system informs and supports ToM. By identifying the goals of an observed action and simulating the emotional states of others, the mirror neuron system may bring about the first step in a more complex process of inferring other people's intentions, giving us a more direct access to their inner world without any metarepresentation.

28

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Overall, our imaging results suggest that the cognitive ToM deficit observed in our patients with ALS implicates various brain regions involved in true- and false-belief reasoning. The fact that the main areas involved (i.e., bilateral superior frontal gyri, right middle frontal gyrus and bilateral SMA) were hypometabolic in our patients, compared with healthy controls, confirms that we not only found a neural network that is involved in social cognition and, more specifically, in cognitive ToM, in healthy people, but also that this neural network is directly impacted by ALS. It is worth noting that, compared to controls, other brain regions are also hypometabolic in ALS, particularly in the prefrontal cortex (data not shown), in accordance with the literature (Pagani et al., 2014). When Cerami et al. (2013) investigated an affective ToM deficit in a group of patients with ALS, they found that it correlated with grey-matter density in the right inferior frontal cortex (inferior frontal gyrus, insular lobe) and anterior cingulate cortex. We have now identified a clear cognitive ToM deficit in patients with ALS, along with its neural substrate. Cerami et al.'s study and ours show that both the cognitive and affective forms of ToM are impaired in ALS, at least in a subset of patients, and that they depend on distinct neural networks. One limitation of the present study is that we did not screen our patients for the C9ORF72 mutation, which is a major cause of familial FTD, ALS-FTD and both familial and apparently sporadic ALS (Sabatelli et al., 2012). Further studies are therefore needed to look for possible correlations between the presence of this mutation and ToM impairments in patients with ALS. Another limitation is that we cannot completely exclude the possibility that we failed to pick up a subtle comprehension impairment in the comprehension condition (performances on the comprehension task were near to ceiling levels for both patients and controls). This seems unlikely, however, as none of the patients exhibited comprehension difficulties in any other test, including the most complex ones, such as the HSCT, in which no patient made errors in Part A.

5.

Conclusion

This study once again demonstrates that the effects of ALS are not necessary restricted to motor functions, and that it can also be a cognitive disease. The possibility that patients' ability to make judgements, take decisions and infer others' mental states could be compromised may have practical implications for their management, as this disorder sometimes requires critical life choices to be made, such as the use of artificial feeding and respiration techniques. A possible cognitive ToM deficit should be envisaged insofar as it could compromise a patient's ability to engage competently in end-of-life decisions. The nonmotor TOM-15 test could be used in clinical practice to detect cognitive ToM deficits.

Funding This work was supported by the French Ministry of Health (PHRCI, 2008, n ID-RCB A01150-55) and Fondation pour la dicale (FRM). Recherche Me

references

Abrahams, S., Leigh, P. N., Harvey, A., Vythelingum, G. N., , D., & Goldstein, L. H. (2000). Verbal fluency and Grise executive dysfunction in amyotrophic lateral sclerosis (ALS). Neuropsychologia, 38, 734e747. Abrahams, S., Newton, J., Niven, E., Foley, J., & Bak, T. H. (2014). Screening for cognition and behaviour changes in ALS. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration, 15, 9e14. Abu-Akel, A., & Shamay-Tsoory, S. (2011). Neuroanatomical and neurochemical bases of theory of mind. Neuropsychologia, 49(11), 2971e2984. Amodio, D. M., & Frith, C. D. (2006). Meeting of minds: the medial frontal cortex and social cognition. Nature Reviews. Neuroscience, 7, 268e277. Bak, T. H., & Hodges, J. R. (2004). The effects of motor neurone disease on language: further evidence. Brain and Language, 89, 354e361. Baron-Cohen, S. (1995). Mindblindness: An essay on autism and theory of mind. Cambridge, MA: Bradford Books/MIT Press. Brooks, B. R., Miller, R. G., Swash, M., Munsat, T. L., &, World Federation of Neurology Research Group on Motor Neuron Diseases. (2000). El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 1, 293e299. Brothers, L., & Ring, B. (1992). A neuroethological framework for the representation of minds. Journal of Cognitive Neuroscience, 4(2), 107e118. Burgess, P. W., & Shallice, T. (1997). The Hayling and Brixton tests. Bury St. Edmunds: Thames Valley Test Company. Cardebat, D., Doyon, B., Puel, M., Goulet, P., & Joanette, Y. (1990). Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level. Acta Neurologica Belgica, 90, 207e217. Carlson, S., & Moses, L. (2001). Individual differences in inhibitory control and children's theory of mind. Child Development, 72, 1032e1053. Cavallo, M., Adenzato, M., MacPherson, S. E., Karwig, G., Enrici, I., & Abrahams, S. (2011). Evidence of social understanding impairment in patients with amyotrophic lateral sclerosis. PLoS One, 6. Cedarbaum, J. M., Stambler, N., Malta, E., Fuller, C., Hilt, D., Thurmond, B., et al. (1999). The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. Journal of the Neurological Sciences, 169, 13e21. Cerami, C., Dodich, A., Canessa, N., Crespi, C., Iannaccone, S., Corbo, M., et al. (2013). Emotional empathy in amyotrophic lateral sclerosis: a behavioural and voxel-based morphometry study. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration, 15, 21e29. Coricelli, G. (2005). Two-levels of mental states attribution: from automaticity to voluntariness. Neuropsychologia, 43, 294e300. Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A., & Gornbein, J. (1994). The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology, 44, 2308e2314. Decety, J., & Jackson, P. L. (2004). The functional architecture of human empathy. Behavioral and Cognitive Neuroscience Reviews, 3, 71e100. Desgranges, B., Laisney, M., Bon, L., Duval, C., Mondou, A., preuve de fausses Bejanin, A., et al. (2012). TOM-15: Une e valuer la the orie de l'esprit cognitive. Revue de croyances pour e Neuropsychologie, 4, 216e220. € hnel, K., Schuwerk, T., Meinhardt, J., Sodian, B., Hajak, G., & Do Sommer, M. (2012). Functional activity of the right temporoparietal junction and of the medial prefrontal cortex

c o r t e x 6 5 ( 2 0 1 5 ) 1 9 e3 0

associated with true and false belief reasoning. NeuroImage, 60, 1652e1661. Duval, C., Bejanin, A., Piolino, P., Laisney, M., De La Sayette, V., Belliard, S., et al. (2012). Theory of mind impairments in patients with semantic dementia. Brain, 135, 228e241. Eslinger, P. J., Moore, P., Troiani, V., Antani, S., Cross, K., Kwok, S., et al. (2007). Oops! Resolving social dilemmas in frontotemporal dementia. Journal of Neurology, Neurosurgery, and Psychiatry, 78, 457e460. Fernandez-Duque, D., Baird, J. A., & Black, S. E. (2009). False-belief understanding in frontotemporal dementia and Alzheimer's disease. Journal of Clinical and Experimental Neuropsychology, 31, 489e497. Filimon, F., Nelson, J. D., Hagler, D. J., & Sereno, M. I. (2007). Human cortical representations for reaching: mirror neurons for execution, observation, and imagery. NeuroImage, 37, 1315e1328. Flaherty-Craig, C., Eslinger, P., Stephens, B., & Simmons, Z. (2006). A rapid screening battery to identify frontal dysfunction in patients with ALS. Neurology, 67, 2070e2072. Frith, C. D., & Frith, U. (1999). Interacting mindsea biological basis. Science, 286, 1692e1695. vy, R., & Dubois, B. Funkiewiez, A., Bertoux, M., de Souza, L. C., Le (2012). The SEA (Social Cognition and Emotional Assessment): a clinical neuropsychological tool for early diagnosis of frontal variant of frontotemporal lobar degeneration. Neuropsychology, 26(1), 81e90. Gallagher, H. L., & Frith, C. D. (2003). Functional imaging of “theory of mind”. Trends in Cognitive Sciences, 7(2), 77e83. Gibbons, Z. C., Richardson, A., Neary, D., & Snowden, J. S. (2008). Behaviour in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 9, 67e74. , F., Gibbons, Z. C., Snowden, J. S., Thompson, J. C., Happe Richardson, A., & Neary, D. (2007). Inferring thought and action in motor neurone disease. Neuropsychologia, 45, 1196e1207. Girardi, A., Macpherson, S. E., & Abrahams, S. (2011). Deficits in emotional and social cognition in amyotrophic lateral sclerosis. Neuropsychology, 25, 53e65. Gleichgerrcht, E., Torralva, T., Roca, M., Pose, M., & Manes, F. (2011). The role of social cognition in moral judgment in frontotemporal dementia. Social Neuroscience, 6, 113e122. Godefroy, O., & GREFEX. (2008). Fonctions executives et pathologies neurologiques et psychiatriques: Evaluation en pratique clinique. Marseille: Solal. Goldstein, L. H., & Abrahams, S. (2013). Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. The Lancet Neurology, 12(4), 368e380. Gregory, C., Lough, S., Stone, V., Erzinclioglu, S., Martin, L., Baron-Cohen, S., et al. (2002). Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications. Brain, 125, 752e764. Grossman, A. B., Woolley-Levine, S., Bradley, W. G., & Miller, R. G. (2007). Detecting neurobehavioral changes in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 8, 56e61. telat, G., Baron, J. C., Landeau, B., Mevel, K., Kalpouzos, G., Che Godeau, C., et al. (2009). Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging. Neurobiology of Aging, 30, 112e124. Kim, J.-H., Lee, J.-M., Jo, H. J., Kim, S. H., Lee, J. H., Kim, S. T., et al. (2010). Defining functional SMA and pre-SMA subregions in human MFC using resting state fMRI: functional connectivitybased parcellation method. NeuroImage, 49(3), 2375e2386. Koenigs, M., Barbey, A. K., Postle, B. R., & Grafman, J. (2009). Superior parietal cortex is critical for the manipulation of information in working memory. Journal of Neuroscience, 29(47), 14980e14986.

29

Laisney, M., Bon, L., Guiziou, C., Daluzeau, N., Eustache, F., & Desgranges, B. (2013). Cognitive and affective theory of mind in mild to moderate Alzheimer's disease. Journal of Neuropsychology, 7, 107e120. Le Bouc, R., Lenfant, P., Delbeuck, X., Ravasi, L., Lebert, F., Semah, F., et al. (2012). My belief or yours? Differential theory of mind deficits in frontotemporal dementia and Alzheimer's disease. Brain, 135, 3026e3038. Lee, T. M. C., Ip, A. K. Y., Wang, K., Xi, C. H., Hu, P. P., Mak, H. K. F., et al. (2010). Faux pas deficits in people with medial frontal lesions as related to impaired understanding of a speaker's mental state. Neuropsychologia, 48, 1670e1676. Leslie, A. M. (1987). Pretense and representation: the origins of “theory of mind”. Psychological Review, 94(4), 412e426. Leslie, A. M., Friedman, O., & German, T. P. (2004). Core mechanisms in “theory of mind”. Trends in Cognitive Sciences, 8(12), 528e533. Lomen-Hoerth, C., Murphy, J., Langmore, S., Kramer, J. H., Olney, R. K., & Miller, B. (2003). Are amyotrophic lateral sclerosis patients cognitively normal? Neurology, 60, 1094e1097. Lough, S., Kipps, C. M., Treise, C., Watson, P., Blair, J. R., & Hodges, J. R. (2006). Social reasoning, emotion and empathy in frontotemporal dementia. Neuropsychologia, 44, 950e958. Massman, P. J., Sims, J., Cooke, N., Haverkamp, L. J., Appel, V., & Appel, S. H. (1996). Prevalence and correlates of neuropsychological deficits in amyotrophic lateral sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry, 61, 450e455. Mattis, S. (1976). Mental status examination for organic mental syndrome in the elderly patient. Geriatric psychiatry, 11, 77e121. Meier, S. L., Charleston, A. J., & Tippett, L. J. (2010). Cognitive and behavioural deficits associated with the orbitomedial prefrontal cortex in amyotrophic lateral sclerosis. Brain, 133, 3444e3457. Michel, E., Robert, P., Boulhassass, R., Lafont, V., Baudu, C., duite de Bertogliati, C., et al. (2005). Validation de la version re l'inventaire Neuropsychiatrique (NPI-R). Revue de Geriatrie, 30, 385e390. Murphy, J. M., Henry, R. G., Langmore, S., Kramer, J. H., Miller, B. L., & Lomen-Hoerth, C. (2007). Continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Archives of Neurology, 64, 530e534. Murphy, J., Henry, R., & Lomen-Hoerth, C. (2007). Establishing subtypes of the continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Archives of Neurology, 64, 330e334. Neary, D., Snowden, J. S., Gustafson, L., Passant, U., Stuss, D., Black, S., et al. (1998). Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria.In. Neurology, 51, 1546e1554. Neary, D., Snowden, J. S., & Mann, D. M. A. (2000). Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS). Journal of the Neurological Sciences, 180(1e2), 15e20. Norris, F. H., Jr., U, K. S., Sachais, B., & Carey, M. (1979). Trial of baclofen in amyotrophic lateral sclerosis. Archives of Neurology, 36(11), 715e716. Olson, I. R., Plotzker, A., & Ezzyat, Y. (2007). The enigmatic temporal pole: a review of findings on social and emotional processing. Brain, 130(7), 1718e1731. €  , A., Valentini, M. C., Oberg, Pagani, M., Chio J., Nobili, F., Calvo, A., et al. (2014). Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis. Neurology, 83(12), 1067e1074. Phillips, L. H., Bull, R., Allen, R., Insch, P., Burr, K., & Ogg, W. (2011). Lifespan aging and belief reasoning: Influences of executive function and social cue decoding. Cognition, 120, 236e247.

30

c o r t e x 6 5 ( 2 0 1 5 ) 1 9 e3 0

Phukan, J., Elamin, M., Bede, P., Jordan, N., Gallagher, L., Byrne, S., et al. (2012). The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. Journal of Neurology, Neurosurgery, and Psychiatry, 83(1), 102e108. Phukan, J., Pender, N. P., & Hardiman, O. (2007). Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurology, 6, 994e1003. € lle, M., Born, J., Pinkhardt, E. H., Ju¨rgens, R., Becker, W., Mo Ludolph, A. C., et al. (2008). Signs of impaired selective attention in patients with amyotrophic lateral sclerosis. Journal of Neurology, 255, 532e538. Qureshi, A. W., Apperly, I. A., & Samson, D. (2010). Executive function is necessary for perspective selection, not Level-1 visual perspective calculation: evidence from a dual-task study of adults. Cognition, 117, 230e236. Raaphorst, J., de Visser, M., Linssen, W. H. J. P., de Haan, R. J., & Schmand, B. (2010). The cognitive profile of amyotrophic lateral sclerosis: a meta-analysis. Amyotrophic Lateral Sclerosis, 11, 27e37. Rakoczy, H., Harder-Kasten, A., & Sturm, L. (2012). The decline of theory of mind in old age is (partly) mediated by developmental changes in domain-general abilities. British Journal of Psychology, 103, 58e72. Rascovsky, K., Hodges, J. R., Knopman, D., Mendez, M. F., Kramer, J. H., Neuhaus, J., et al. (2011). Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain, 134, 2456e2477. Ringholz, G. M., Appel, S. H., Bradshaw, M., Cooke, N. A., Mosnik, D. M., & Schulz, P. E. (2005). Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology, 65, 586e590. Roca, M., Torralva, T., Gleichgerrcht, E., Woolgar, A., Thompson, R., Duncan, J., et al. (2011). The role of area 10 (BA10) in human multitasking and in social cognition: a lesion study. Neuropsychologia, 49, 3525e3531. € hnel, K., Meinhardt, J., & Rothmayr, C., Sodian, B., Hajak, G., Do Sommer, M. (2011). Common and distinct neural networks for false-belief reasoning and inhibitory control. NeuroImage, 56, 1705e1713.  , M. R., Sabatelli, M., Conforti, F. L., Zollino, M., Mora, G., Monsurro Volanti, P., et al. (2012). C9ORF72 hexanucleotide repeat expansions in the Italian sporadic ALS population. Neurobiology of Aging, 33(8), 1848.e15e1848.e20. Sabbagh, M. A., Moses, L. J., & Shiverick, S. (2006). Executive functioning and preschoolers' understanding of false beliefs, false photographs, and false signs. Child Development, 77(4), 1034e1049. Samson, D., Apperly, I. A., & Humphreys, G. W. (2007). Error analyses reveal contrasting deficits in “theory of mind”: neuropsychological evidence from a 3-option false belief task. Neuropsychologia, 45, 2561e2569. Samson, D., Apperly, I. A., Kathirgamanathan, U., & Humphreys, G. W. (2005). Seeing it my way: a case of a selective deficit in inhibiting self-perspective. Brain, 128, 1102e1111. Saxe, R., & Powell, L. J. (2006). It's the thought that counts: specific brain regions for one component of theory of mind. Psychological Science, 17, 692e699.

Saxe, R., & Wexler, A. (2005). Making sense of another mind: the role of the right temporo-parietal junction. Neuropsychologia, 43, 1391e1399. Shany-Ur, T., Poorzand, P., Grossman, S. N., Growdon, M. E., Jang, J. Y., Ketelle, R. S., et al. (2012). Comprehension of insincere communication in neurodegenerative disease: lies, sarcasm, and theory of mind. Cortex, 48, 1329e1341. Snowden, J. S., Gibbons, Z. C., Blackshaw, A., Doubleday, E., Thompson, J., Craufurd, D., et al. (2003). Social cognition in frontotemporal dementia and Huntington's disease. Neuropsychologia, 41, 688e701. € hnel, K., Sodian, B., Meinhardt, J., Thoermer, C., & Sommer, M., Do Hajak, G. (2007). Neural correlates of true and false belief reasoning. NeuroImage, 35, 1378e1384. Strong, M. J., Grace, G. M., Freedman, M., Lomen-Hoerth, C., Woolley, S., Goldstein, L. H., et al. (2009). Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis, 10, 131e146. Strong, M. J., Grace, G. M., Orange, J. B., Leeper, H. A., Menon, R. S., & Aere, C. (1999). A prospective study of cognitive impairment in ALS. Neurology, 53, 1665e1670. Stuss, D. T., Gallup, G. G., & Alexander, M. P. (2001). The frontal lobes are necessary for “theory of mind”. Brain, 124, 279e286. Taylor, L. J., Brown, R. G., Tsermentseli, S., Al-Chalabi, A., Shaw, C. E., Ellis, C. M., et al. (2013). Is language impairment more common than executive dysfunction in amyotrophic lateral sclerosis? Journal of Neurology, Neurosurgery and Psychiatry, 84, 494e498. Torralva, T., Kipps, C. M., Hodges, J. R., Clark, L., Bekinschtein, T., Roca, M., et al. (2007). The relationship between affective decision-making and theory of mind in the frontal variant of fronto-temporal dementia. Neuropsychologia, 45, 342e349. Torralva, T., Roca, M., Gleichgerrcht, E., Bekinschtein, T., & Manes, F. (2009). A neuropsychological battery to detect specific executive and social cognitive impairments in early frontotemporal dementia. Brain, 132, 1299e1309. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., et al. (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage, 15, 273e289. Van Overwalle, F., & Baetens, K. (2009). Understanding others' actions and goals by mirror and mentalizing systems: a metaanalysis. NeuroImage, 48(3), 564e584. Van der Meer, L., Groenewold, N. A., Nolen, W. A., Pijnenborg, M., & Aleman, A. (2011). Inhibit yourself and understand the other: neural basis of distinct processes underlying theory of mind. NeuroImage, 56, 2364e2374. Wechsler, D. (2000). Echelle d'intelligence de Wechsler pour adultes3eme edition. Manuel. Paris: ECPA. Wilson, C. M., Grace, G. M., Munoz, D. G., He, B. P., & Strong, M. J. (2001). Cognitive impairment in sporadic ALS: a pathologic continuum underlying a multisystem disorder. Neurology, 57, 651e657. Wimmer, H., & Perner, J. (1983). Beliefs about beliefs: representation and constraining function of wrong beliefs in young children's understanding of deception. Cognition, 13, 103e128.