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Social influence on associative learning: Double dissociation in high-functioning autism, earlystage behavioural variant frontotemporal dementia and Alzheimer’s disease Szabolcs Ke´ri a,b,c,* a

University of Szeged, Faculty of Medicine, Department of Physiology, Szeged, Hungary Nyı´rT Gyula Hospital e National Institute of Psychiatry and Addictions, Budapest, Hungary c Budapest University of Technology and Economics, Department of Cognitive Science, Budapest, Hungary b

article info

abstract

Article history:

Introduction: Most of our learning activity takes place in a social context. I examined how

Received 26 November 2013

social interactions influence associative learning in neurodegenerative diseases and

Reviewed 27 January 2014

atypical neurodevelopmental conditions primarily characterised by social cognitive and

Revised 3 February 2014

memory dysfunctions.

Accepted 18 February 2014

Methods: Participants were individuals with high-functioning autism (HFA, n ¼ 18), early-

Action editor Stefano Cappa

stage behavioural variant frontotemporal dementia (bvFTD, n ¼ 16) and Alzheimer’s dis-

Published online 3 March 2014

ease (AD, n ¼ 20). The leading symptoms in HFA and bvFTD were social and behavioural dysfunctions, whereas AD was characterised by memory deficits. Participants received

Keywords:

three versions of a paired associates learning task. In the game with boxes test, objects were

Autism

hidden in six candy boxes placed in different locations on the computer screen. In the game

Alzheimer’s disease

with faces, each box was labelled by a photo of a person. In the real-life version of the game,

Behavioural variant frontotemporal

participants played with real persons.

dementia

Results: Individuals with HFA and bvFTD performed well in the computer games, but failed

Paired associates learning

on the task including real persons. In contrast, in patients with early-stage AD, social in-

Social cognition

teractions boosted paired associates learning up to the level of healthy control volunteers.

Theory of Mind

Worse performance in the real life game was associated with less successful recognition of complex emotions and mental states in the Reading the Mind in the Eyes Test. Spatial span did not affect the results. Conclusions: When social cognition is impaired, but memory systems are less compromised (HFA and bvFTD), real-life interactions disrupt associative learning; when disease process impairs memory systems but social cognition is relatively intact (early-stage AD), social interactions have a beneficial effect on learning and memory. ª 2014 Elsevier Ltd. All rights reserved.

* University of Szeged, Department of Physiology, Do´m sq. 10, H6720 Szeged, Hungary. E-mail address: [email protected]. http://dx.doi.org/10.1016/j.cortex.2014.02.018 0010-9452/ª 2014 Elsevier Ltd. All rights reserved.

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1.

Introduction

Researchers and clinicians routinely use laboratory tests to assess learning and memory in different patients with cognitive dysfunctions. Despite the widespread application of this approach, neuropsychological tests of learning and memory do not take into consideration the inherently social nature of knowledge acquisition, expression and transmission in humans and animals. Studies of social cognition emphasize notions such as attribution, attitudes, cultural symbols, recognition of complex emotions, and empathizing with the feelings and thoughts of others (Adolphs, 2009; Cacioppo & Decety, 2011; Fiske & Taylor, 2013; Frith & Frith, 2012), but rarely consider how episodic memory traces are recruited to maintain and promote interpersonal interactions and social bonds (e.g., who was cooperative and aggressive?, who owns behaviourally relevant objects?) (Brennan & Kendrick, 2006; Davidson, Drouin, Kwan, Moscovitch, & Rosenbaum, 2012; Emery & Clayton, 2004; review in Allen & Fortin, 2013). The conceptual and philosophical difference between “learning and memory research” and “social cognitive research” has practical relevance: based on the clinical features, physicians differentiate diseases characterised by social dysfunctions and neuropsychiatric symptoms [e.g., behavioural variant frontotemporal dementia (bvFTD) and autismspectrum disorders] and diseases characterised by cognitive deficits, for instance, the loss of episodic memory [e.g., earlystage Alzheimer’s disease (AD)] (Frith, 2012; Hodges, 2013). New data from bvFTD, however, indicate that this dichotomy is much too simplistic, and clinically relevant memory deficits are present in bvFTD (Hornberger & Piguet, 2012). The purpose of the work presented here was to address the interaction between these two domains. Specifically, I studied how real-life social interactions may affect objecteplace associative learning and short-term spatial memory in mostly “social” and “memory” disorders. To achieve this aim, I compared the performance of patients with early-stage bvFTD, AD and high-functioning autism (HFA) on a paired associates learning (PAL) task administered in a laboratory setting and a real-life setting with actors. In a classic PAL test, participants learn where objects are hidden via the acquisition of objectelocation associations. Extensive evidence suggests that laboratory PAL tests are sensitive to the pathology of the medial temporal lobe, including the hippocampal formation, which is a core structure in the pathophysiology of AD (Blackwell et al., 2004; O’Connell et al., 2004; Sahakian et al., 1988; Swainson et al., 2001). In contrast, the majority of studies reported normal PAL and other cue-induced recall performances in individuals with HFA (review in Boucher, Mayes, & Bigham, 2012). Considering bvFTD, recent results suggest that, contrary to the predominant clinical conceptualisation of the illness (Neary et al., 1998), episodic memory is impaired (Hornberger & Piguet, 2012). However, patients with early-stage bvFTD showed normal performances on PAL tasks, e.g., faceeplace associations (Clague, Dudas, Thompson, Graham, & Hodges, 2005), or their deficit was much less pronounced than that of patients with AD (Lee, Rahman, Hodges, Sahakian, & Graham, 2003). Overall, PAL is

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optimal to model and compare different laboratory tasks and real-life learning scenarios. I had two main hypotheses. First, based on data from previous studies introduced above, I expected impaired laboratory PAL performance in AD and intact or less affected laboratory PAL performance in HFA and bvFTD. The second assumption was that when real persons sitting in different locations hid objects, that is, in a real-life version of the PAL task, individuals with social dysfunctions (HFA and bvFTD) would display an impoverished performance, whereas patients with AD would not show a further decline or improve performance relative to the laboratory PAL task. The basis of this assumption was that social functions, e.g., the representation of mental states of others, are implicated in real-life learning, and deficient social cognition might interfere with memory in bvFTD and HFA. If dysfunctional real-life PAL were due to altered social cognition in HFA and bvFTD, worse performance on advanced affective Theory of Mind (ToM) tests (e.g., the identification of complex social emotions and attribution of mental states) would be associated with poorer reallife PAL performance.

2.

Materials and methods

2.1.

Participants

Individuals with AD, bvFTD and HFA were enrolled at the National Institute of Psychiatry and Addictions, Budapest (North Hungary) and the University of Szeged, Faculty of Medicine, Szeged (South Hungary). Specialists referred patients to these centres from the whole country. We focused on recently diagnosed patients with bvFTD and AD (time since diagnosis less than 1 year) to avoid confounding effects due to generalized cognitive dysfunctions and chronic behavioural and psychological symptoms. Young and elderly control participants with negative history for neurological and psychiatric disorders were recruited via email advertisements and personal networks. Diagnoses were made according to established criteria: National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDSeADRDA) for probable AD (McKhann et al., 1984), LundeManchester criteria for bvFTD (Neary et al., 1998) and Autism Diagnostic Interview, Revised (Lord, Rutter, & Le Couteur, 1994) for HFA. Patients with bvFTD were also evaluated according to the International Consensus Criteria for bvFTD (Rascovsky et al., 2011). All patients met the criteria of probable bvFTD (at least three of six behavioural symptoms, significant functional decline, and neuroimaging evidence of frontal lobe atrophy). Frontal lobe atrophy was described by the Kipps index (Kipps et al., 2007). Medial temporal lobe atrophy was evaluated using the Scheltens scale (Scheltens et al., 1992). In addition to standard diagnostic tools, a cerebrospinal fluid biomarker was available, the phosphorylated tau/amyloid beta 42 (Ab42) ratio, which distinguishes AD from bvFTD with high sensitivity and specificity (cut-off: .21) (de Souza et al., 2011). The following scales and tests were used to assess clinical symptoms and background cognitive status: Mini-Mental State Examination (MMSE) (Folstein, Folstein, & McHugh, 1975), Addenbrooke’s Cognitive Evaluation (ACE)

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(Mathuranath, Nestor, Berrios, Rakowicz, & Hodges, 2000; Stacho´, Duda´s, Iva´dy, Kothencz, & e´s Janka, 2003), Neuropsychiatric Inventory (Cummings et al., 1994), Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler, 1999) and the Autism Quotient (Baron-Cohen, Wheelwright, Skinner, Martin, & Clubley, 2001). Patients with bvFTD and AD also received a battery of neuropsychological tests assessing memory [logical memory subtest of the Wechsler Memory Scale e Revised (Wechsler, 1987); Rey Complex Figure Test, 45min recall (Ko´nya & Verseghi, 1995; Rey, 1941)], visuospatial functions [Rey Complex Figure Test Copy (Ko´nya & Verseghi, 1995; Rey, 1941)], and executive functions [verbal fluency (Benton, 1968); Wisconsin Card Sorting Test (WCST), modified (Nelson, 1976)] to confirm the diagnosis and clinical characterisation. Table 1 depicts the demographic and clinical data. Neuroradiological evaluation (confirmed by two independent raters), biomarker measurements and clinical assessments were carried out by trained specialists who were blind to the diagnosis and to the aim of the study. After the detailed description of the study, all participants gave written informed consent. The study was done in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review board.

2.2.

PAL

The procedure was modified after the Cambridge Neuropsychological Test Automated Battery (CANTAB) PAL test (Sahakian et al., 1988). In the basic computer game (game with boxes), six objects (candies) were hidden in six candy boxes placed in different locations on the computer screen (i-PAN4

MC, Keith & Koep, Wuppertal, Germany) (Fig. 1A). The objects had different shapes and colours (circle, triangle, square, diamond, red, green, blue, yellow, pink and brown). The boxes were opened for 3 sec in a randomised order. After this observation period, one of the objects was presented in the middle on the screen. The task was to touch the box where the object was originally hidden. When the participant made a mistake, the boxes were opened again. In the game with faces version, each box was labelled by a photo of a real person who owned and liked the candy and participated in the real-life version of the task (see below). The facial expression of the persons was neutral as confirmed by two independent raters who were blind to the aim of the study. I also designed a real-life version of the game. This version included social interactions in the sense that participants attached a meaning to their actions in an interpersonal context (Weber, 1978). All experiments were performed in the same room (12 m2, 50 cd/m2 background luminance, 21  C, white walls with no ornaments). Six individuals sat in the room in a similar spatial arrangement to that used in the computer games, together with the study participant in the middle (Fig. 1B). The six assistants were naı¨ve to the aim of the study. Each assistant had a candy hidden in his or her boxes. Similar to the computer games, each assistant showed his or her candy by opening the boxes for 3 sec. Candies differed in shape and colour identical to the computer game. After this observation period, another study-naı¨ve assistant showed one of the candies to the study participant. The task was to give the candy to the person who liked and owned that. When the study participant made an error, the candy was eliminated, and the observation period started again. All sessions were videotaped. Two independent raters ensured that the

Table 1 e Clinical, demographic and background neuropsychological characteristics of the participants.

Male/female Age (years)a Education (years) MMSE ACE Logical memory, immediateb Logical memory, delayedb Rey Figure, recallb Rey Figure, copy Verbal fluencyc WCST, categories competedc WCST, perseverativec errors Neuropsychiatric Inventoryd Kipps scale (frontal atrophy) Scheltens index (medial temporal lobe atrophy) IQ Autism-spectrum quotient Reading the Mind in the eyese

HFA (n ¼ 18)

bvFTD (n ¼ 16)

14/4 28.5 (12.0) 12.2 (3.4) e e e e e e e e e e e e 112.6 (11.3) 35.9 (5.2) 21.1 (4.3)

10/6 58.9 (7.3) 11.7 (4.9) 26.9 (1.4) 83.5 (6.1) 8.9 (3.6) 6.4 (3.8) 18.3 (8.6) 33.5 (5.9) 28.3 (11.5) 4.2 (1.0) 13.6 (7.8) 45.6 (13.3) 2.3 (.2) 0 e e 20.6 (3.9)

AD (n ¼ 20) 12/8 66.2 (7.9) 11.5 (3.1) 26.5 (3.4) 84.2 (5.7) 5.4 (3.2) 1.4 (2.8) 7.2 (6.3) 32.7 (7.5) 41.7 (12.4) 5.4 (.9) 5.0 (3.1) 6.5 (3.6) 0 2.0 (.4) e e 26.7 (4.2)

Young controls (n ¼ 20)

Elderly controls (n ¼ 20)

13/7

12/8 29.1 (10.4) 12.0 (4.6) e e e e e e e e

60.1 (7.4) 11.9 (5.0) 28.5 (1.3) e e e e e e e

e e e 110.4 (10.5) e 29.0 (3.5)

e 0 0 e e 26.1 (4.5)

Data are mean (standard deviation) with the exception of gender distribution. a Patients with bvFTD and AD were matched for elderly controls, and individuals with HFA were matched for young controls in age (ps > .5). b Patients with AD were impaired on tests of memory relative to patients with bvFTD (ps < .05). c Patients with bvFTD were impaired on tests of executive functions relative to patients with AD (ps < .05). d Patients with bvFTD showed more severe behavioural and psychological symptoms relative to patients with AD (p < .01). e Individuals with HFA and bvFTD showed lower scores compared to age-matched controls (p < .01).

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emotional expression of the assistants remained neutral and did not change across test sessions. The assistants were instructed not to navigate the study participants with gaze or other forms of non-verbal communication. The order of test presentation (game with boxes and faces, real-life) was counterbalanced across participants. The photos appearing on the boxes displayed the faces of the assistants who participated in the real-life PAL test. The dependent measure was the number of errors in each PAL test. I observed no order effect (p > .5). When all tests were finished, participants rated their anxiety, discomfort and arousal on 10-point Likert-like scales. There were no significant differences for computerised and real-life games. Individuals with bvFTD, AD and HFA did not differ from control volunteers (ps > .2). This suggests that any difference found across groups and test types cannot be explained by different levels of anxiety, discomfort or arousal.

2.3.

Spatial span

Participants received the computerised and real-life versions of the Corsi Block Tapping task (Milner, 1971; Owen, Downes, Sahakian, Polkey, & Robbins, 1990). Participants were requested to observe a sequence of boxes opened on the computer screen. The candy in the box should have been neglected; instead, the task was to retain the sequence and to reiterate that after the observation period. After each successful repetition of the sequence, the number of boxes opened in the following sequence was increased by one to a maximum of nine boxes. If the answer was wrong, another sequence was presented. The test was finished when the participant was not able to recall the sequence on three consecutive trials at a given length of the sequence. The measure of the spatial short-term memory was the longest length of sequence at which the participant had correctly recalled at least one sequence (Milner, 1971; Owen et al., 1990). In the computerised versions of the task, we administered a

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game with boxes and a game with faces version similar to the PAL test. In the real-life version of the spatial span task, nine individuals sat in a room together with the study participant. Similar to the computer games, they showed up their candies with an increasing sequence length. The task was to replicate the sequence. Spatial short-term memory was defined and measured in the same way as in the computer games. The setting for the real-life spatial span task was identical to that of the real-life PAL test.

2.4.

Reading the Mind in the Eyes Test (RMET)

To characterise the perception of complex social emotions and mental state attribution, I used the RMET, which is a common method to evaluate advanced affective ToM and mentalisation in individuals with altered social cognition (Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001). The test consisted of 36 photographs of the eye regions of faces of actors and actresses, expressing social emotions and mental states (e.g., confused, enthusiastic, hopeful and offended). Four words referring to mental states were presented together with each photograph. The task was to determine which of the four words described the mental state of the protagonist on the photograph. The dependent measure was the number of correct responses.

2.5.

Statistical analysis

I used STATISTICA 11 (StatSoft, Inc., Tulsa) and Prism 6 (GpahPad, Inc., La Jolla) softwares for data analysis. After the analysis of data distribution with KolmogoroveSmirnov tests, analyses of variance (ANOVAs) were applied, followed by Bonferroni post-hoc tests. In the ANOVA, the betweensubjects factor was group (AD, bvFTD, HFA and control groups), whereas the within-subjects factor was the test type (game with boxes, faces, real-life task). Pearson’s product moment correlation coefficients (r) were calculated between PAL and RMET results. Partial correlation analyses with ACE

Fig. 1 e Illustration of the experiments. (A) Candy boxes in six different locations on the computer screen (game with boxes). In the game with faces test, the same boxes were used labelled by the photographs of their owners. (B) Spatial location of six chairs used by the assistants in the real-life version of the task. The assistant had the same boxes as used in the computer games hiding their candies.

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accordance with the between-group differences (p < .01) (Fig. 2, Table 2).

3.2.

The results are shown in Fig. 3 and Table 2. The ANOVA indicated a significant main effect of group [F(4, 89) ¼ 4.02, p < .01]. The effect of test type (faces, boxes, real-life) and the two-way interaction were not significant (ps > .5). Bonferroni tests revealed significantly reduced spatial span in bvFTD relative to age-matched control participants when all conditions were collapsed together (p < .05). AD patients and HFA individuals did not show significantly reduced spatial span (ps > .1) (Fig. 3 and Table 2).

Fig. 2 e Mean number of errors from the PAL tasks (real-life task, computer game with boxes and faces). Individuals with HFA and bvFTD performed worse than control individuals in the real-life task, whereas patients with AD did so in the computerised tasks. Healthy control individuals showed homogeneous levels of performance across all task conditions. *p < .001 (Bonferroni tests, relative to age-matched control subjects). Data are mean, error bars indicate standard deviations.

3.3.

and spatial span scores were used to exclude non-specific effects. The level of statistical significance was a < .05.

Results

3.1.

PAL

Fig. 2 and Table 2 depict the results from the three PAL tests (game with boxes, faces, real-life PAL). The ANOVA conducted on the errors revealed significant main effects of group [F(4, 89) ¼ 14.95, p < .001] and test type [F(2, 178) ¼ 9.79, p < .001]. The two-way interaction between group and test type was also significant [F(8, 178) ¼ 32.42, p < .001]. Bonferroni tests conducted on the two-way interaction revealed that patients with AD had more errors in both computer games (boxes and faces) relative to age-matched controls (p < .001). In contrast, the performance of patients with HFA and bvFTD was intact (p > .5). In the real-life PAL test, the results were the opposite: patients with AD had spared performance, whereas HFA and bvFTD individuals displayed significant impairments relative to control participants (p < .001). Bonferroni tests also indicated within-group differences across test conditions in

RMET

A one-way ANOVA conducted on the correct responses revealed a significant main effect of group [F(4, 89) ¼ 14.4, p < .001]. Bonferroni tests indicated that individuals with HFA and bvFTD had significantly lower scores relative to the agematched control groups (p < .01). Patients with AD displayed intact RMET performance (p > .5) (Table 1).

3.4.

3.

Spatial span

Correlations between RMET and PAL

Fig. 4 shows the correlations between RMET scores and reallife PAL performance. Better mental state recognition in the RMET was associated with fewer errors in the real-life PAL test in HFA, bvFTD and AD (rs < .45, ps < .05). Partial correlation analyses including ACE and spatial span scores did not change these results (ps < .05). RMET scores were not related to performances in the computerised PAL games (.1 > rs > .1, ps > .1).

4.

Discussion

The results of the present study suggest that social context may have positive or negative impact on associative learning in different clinical conditions. In individuals with social cognitive impairments and behavioural and psychological alterations (HFA and bvFTD), associative learning was impaired in real-life conditions, but not in laboratory settings

Table 2 e Results from the PAL and spatial span tasks. HFA (n ¼ 18)

bvFTD (n ¼ 16)

AD (n ¼ 20)

Young controls (n ¼ 20)

Elderly controls (n ¼ 20)

PAL Game with boxes Game with faces Real-life

8.4 (3.6) 10.3 (5.7) 21.5 (8.9)*

9.8 (4.0) 10.8 (3.8) 20.3 (9.9)*

21.6 (6.3)* 19.4 (5.9)* 9.6 (3.1)

8.3 (3.5) 8.1 (3.5) 8.6 (3.8)

9.7 (3.6) 9.4 (3.6) 9.4 (3.7)

Spatial span Game with boxes Game with faces Real-life

5.3 (1.2) 5.6 (1.5) 5.5 (1.8)

4.4 (1.3)* 4.2 (1.4)* 4.4 (1.0)*

4.8 (1.5) 4.5 (1.2) 4.8 (1.1)

5.3 (1.4) 5.5 (1.4) 5.6 (1.2)

5.4 (1.4) 5.7 (1.5) 5.5 (1.1)

Data are mean (standard deviation). PAL was characterised by the mean number of errors. Spatial span was the longest length of sequence at which the participant had correctly recalled at least one sequence. *p < .05 (Bonferroni post-hoc tests from comparisons with age-matched control individuals).

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Fig. 3 e Results from the spatial span task. Spatial span was the longest length of sequence at which the participant had correctly recalled at least one sequence. Patients with bvFTD performed worse than age-matched control individuals in all tasks (real-life task, computer games with boxes and faces). Individuals with HFA and patients with AD did not differ from age-matched control individuals. *p < .05 (Bonferroni tests, relative to agematched control subjects). Data are mean, error bars indicate standard deviations.

(computerised tests), whereas in patients thought to be characterised by memory dysfunctions (early-stage AD), reallife social context robustly boosted associate learning up to the level of healthy age-matched controls. This positive impact of social interaction is broadly consistent with heightened emotional contagion associated with temporal lobe atrophy in AD (Sturm et al., 2013), although we ensured that social interactions remained neutral in this experimental setting.

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Unexpectedly, spatial span was only numerically, but not statistically, worse in AD compared to control individuals (Mandal, Joshi, & Saharan, 2012). The early stage of disease and the small sample size may explain this negative finding. In addition, AD patients with predominantly amnestic features often show relatively spared performances on tasks of attention, working memory and executive functions (Stopford, Thompson, Neary, Richardson, & Snowden, 2012). Worse affective ToM (recognition of complex social emotions and mental states) was associated with less efficient associative learning in real-life scenarios, but not in standard laboratory tests. Notably, this effect was specific for PAL, which is primarily related to the functioning of the medial temporal lobe (Blackwell et al., 2004; O’Connell et al., 2004; de Rover et al., 2011; Sahakian et al., 1988; Swainson et al., 2001), but not for spatial short-term memory. These results may indicate an interaction between neuronal networks for affective ToM (i.e., a circuit centred on the medial prefrontal cortex) and PAL (i.e., a circuit centred on the hippocampal formation). One may speculate that relatively spared affective ToM circuits enhance the functioning of medial temporal lobe structures when social stimuli are stood by, as we observed in the case of early-stage AD patients. Zhou et al. (2010) demonstrated decreased connectivity of the “Default Mode Network” to posterior hippocampus in AD, together with an increased connectivity of the emotion-relevant “Salience Network” (anterior cingulate and frontoinsular region) (for a review and meta-analysis, see Jacobs, Radua, Lu¨ckmann, & Sack, 2013). This pattern of connectivity may be particularly relevant in the retrieval of episodic memory traces (Sestieri, Corbetta, Romani, & Shulman, 2011). Results from amnestic

Fig. 4 e Correlations between real-life PAL and RMET performances in individuals with HFA, patients with bvFTD, AD and healthy control individuals.

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mild cognitive impairment, which often represents a prodromal stage of AD, revealed stronger activation of the medial frontal and anterior cingulate cortex during the RMET (Baglio et al., 2012). The authors interpreted their findings as a compensatory overactivity in the “Mirror Neuron Network” elicited by social signals. It is possible that social stimuli enhance the activity of these frontal areas in early-stage AD, which, in turn, will facilitate the emergence of associative memory traces in the medial temporal lobe. This hypothesis must be directly tested using functional imaging methods. On the other hand, compromised affective ToM circuits may also have a negative impact on the functioning of the medial temporal lobe in real-life social scenarios in individuals with HFA and bvFTD. The confounding effect of general cognitive dysfunctions is not likely because individuals with HFA with intact general cognitive abilities exhibited a similar pattern of performance to that of patients with bvFTD. Although the strict distinction between disorders with amnestic features (AD) versus behavioural and psychological symptoms (bvFTD) has been debated (Bertoux et al., 2013; Frisch et al., 2013; Graham et al., 2005; Hornberger, Piguet, Graham, Nestor, & Hodges, 2010; Hornberger et al., 2012; Irish, Hodges, & Piguet, 2013; Pocnet, Rossier, Antonietti, & von Gunten, 2013; Shi et al., 2005), we found intact laboratory PAL in bvFTD with significant affective ToM impairments and behavioural symptoms, and poor laboratory PAL in AD with intact affective ToM and minimal behavioural symptoms. This pattern of performance is consistent with the findings of several previous reports (PAL: Blackwell et al., 2004; Clague et al., 2005; O’Connell et al., 2004; Sahakian et al., 1988; Swainson et al., 2001; ToM: Adenzato, Cavallo, & Enrici, 2010; Gregory et al., 2002; Laisney et al., 2013; Le Bouc et al., 2012; Pardini et al., 2013; Poletti, Enrici, & Adenzato, 2012; Torralva, Roca, Gleichgerrcht, Bekinschtein, & Manes, 2009). The dominance of behavioural and executive dysfunction over episodic memory impairment in bvFTD is still a part of standard diagnostic criteria (Rascovsky et al., 2011). Medial temporal lobe atrophy was not detected in our earlystage bvFTD patients, whereas it was clearly present in AD. This neuroanatomical difference was confirmed with a validated and sensitive rating scale (Boutet et al., 2012) administered by independent experts who were naı¨ve to the clinical diagnosis, neuropsychological status and the aims of the study (but see also Barnes et al., 2006; de Souza et al., 2013). Using biologically validated diagnoses, Bertoux et al. (2013) showed that half of bvFTD patients had a deficit of all types of memory recall, which was as severe as memory deficits observed in AD patients. The other half of bvFTD patients had a delayed recall score similar to that of healthy control participants (Bertoux et al., 2013). It has been suggested that intact memory is observed in bvFTD because of the inclusion of so-called phenocopy patients who exhibit the behavioural features of bvFTD but do not progress to dementia (Kipps, Nestor, Dawson, Mitchell, & Hodges, 2008). Alternatively, a subgroup of patients with bvFTD has spared episodic memory (Bertoux et al., 2013). Although we do not have follow-up data, all bvFTD patients exhibited frontal lobe atrophy, which increases the likelihood of future progressive cognitive and behavioural deterioration. It is remarkable that intact laboratory PAL performance turned into a severe decrement in a real-life social context in

both individuals with HFA and bvFTD. I observed this effect despite the fact that healthy control volunteers performed similarly in all test conditions, suggesting that the real-life situation was neither easier nor more difficult for them than the computer games (Fig. 2). Soundesymbol and objectelocation PALs are spared in HFA (Williams, Goldstein, & Minshew, 2006a), but associative learning seems to be compromised when social information is included (faces and family pictures) (Williams, Goldstein, & Minshew, 2005; for a review of memory in HFA, see Boucher et al., 2012). Ostensive communication (eye contact, exaggerated intonation contours) impairs cognition even in healthy individuals (Ne´meth, Turcsik, Farkas, & Janacsek, 2013), but, in the present study, we made sure that social signals were standard and neutral. Nevertheless, sophisticated social factors, such as observing models and understanding behavioural goals of others, may have a vital role in episodic memory (Racsma´ny, Keresztes, Pajkossy, & Demeter, 2012). It is necessary to emphasize that a pure presence of social information in the PAL test (game with faces) was not sufficient to significantly alter task performance in bvFTD and HFA: only a full real-life situation had a significant impact on it. Williams, Goldstein, and Minshew (2006b) found the largest difference between individuals with HFA and control subjects in the Finger Windows task, in which the experimenter places a pencil into a series of holes in a plastic card and the task is to recall the sequence of it. This test resembles a real-life interaction. Furthermore, individuals with bvFTD and HFA were not significantly impaired on the laboratory PAL task with faces (only a numerical tendency was seen). This suggests that their deficient real-life PAL performance stems from social interactions and cannot be entirely explained by impaired facial processing (e.g., Keane, Calder, Hodges, & Young, 2002; Schultz et al., 2000). It is also worth mentioning that PAL does not include all elements needed to build up a complex episodic memory trace. Although association among items is an inherent characteristic of episodic memory, these associations need to be placed into a spatial and temporal context (i.e., when and where specific things happened) (Tulving, 1972). The loss of complex episodic memories in AD, including the recollection of memories of past social interactions, may contribute to cognitive ToM deficits (Moreau, Viallet, & Champagne-Lavau, 2013). Taking into consideration the current results from a simple PAL task, future studies are warranted to examine whether spared affective ToM in AD may help to encode and to retrieve new complex episodic memory traces, similarly to the case of basic emotions (e.g., Kazui et al., 2000; Moayeri, Cahill, Jin, & Potkin, 2000; but see Hamann, Monarch, & Goldstein, 2000; Mori et al., 1999). In summary, our results suggest that dysfunctions related to “hard-wired” neuronal anomalies and their behavioural consequences in neurodegenerative (bvFTD and AD) and neurodevelopmental conditions (HFA) are modulated by the social context, which can be beneficial or detrimental. Realworld interactions have a beneficial effect on associative learning when social cognitive functions are spared, but hinder it when individuals have altered social cognitive abilities. Potential mechanisms may include a disrupted connectivity between large-scale neuronal networks for social

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cognition and memory (Filippi et al., 2013; Zhou et al., 2010). To obtain more evidence for this hypothesis, a whole-brain structural and functional analysis is required together with a more extensive neuropsychological assessment. From a practical point of view, the present findings cast doubts on the generalizability and ecological validity of traditional pen-andpaper and computer-based neuropsychological assessments and emphasize the importance of human factors during clinical assessment.

Acknowledgements I am grateful to Ibolya Hala´sz, Katalin Kiss, Zolta´n Fekete, Oguz Kelemen and Henrik Vougt for their assistance in the recruitment and assessment of the patients and neuroimaging analysis. This research was realized in the frames of ´ MOP 4.2.4. A/2-11-1-2012-0001 “National Excellence ProTA gram e elaborating and operating an inland student and researcher personal support system”. The project was subsidized by the European Union and co-financed by the European Social Fund and the National Brain Research Program.

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