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1.  Theory of Mind in Schizophrenia and Asperger’s Syndrome: Relationship with Negative Symptoms 
Objective
Although previous studies have shown that the theory of mind (ToM) ability is impaired in Asperger’s Syndrome (AS) and in schizophrenia, few controlled studies compared the ToM performance between the two disorders. Besides, the relationship between the degree of ToM impairment and symptom dimensions is unclear, and presence of ToM impairment in remitted patients with schizophrenia is controversial. Here, we tested the hypothesis that schizophrenia patients with prominent negative symptoms were closer to AS patients and different than schizophrenia patients without prominent negative symptoms and healthy controls in terms of ToM functioning.
Method
Fourteen patients with AS, 20 with schizophrenia and 20 healthy controls, matched by age, educational level and IQ scores were enrolled. AS was diagnosed according to the DSM-IV criteria and independently confirmed by two psychiatrists. Schizophrenia patients were diagnosed by the Turkish version of Structured Clinical Interview for DSM-IV Diagnosis (SCID-I) and symptom severity was evaluated with the Scale for the Assessment of Negative and Positive Symptoms. Schizophrenia group consisted of clinically stable patients. The ToM battery included stories to assess first and second order false belief tasks (ToM1 and ToM2). The full-scale IQ, Verbal Comprehension, Freedom from Distractibility and Perceptual Organization scores were assessed by Weschler Adult Intelligence Scale–Revised (WAIS-R). Non-parametric tests were used to compare the neuropsychological performances of the three groups. In order to investigate whether schizophrenia patients with prominent negative symptoms were similar to AS patients, schizophrenia patients were divided into high (Sch-HN) and low (Sch-LN) negative-symptom subgroups by median split. For these four groups (AS, Sch-HN, Sch-LN, and controls) between group comparisons were performed. Correlations between the clinical measures and ToM performance were assessed by Spearman correlation test.
Results
AS and schizophrenia patients performed significantly worse than controls in the ToM2 task, while the AS group had worse ToM1 performance than both schizophrenia patients and healthy controls. The Sch-HN subgroup had significantly lower ToM2 scores than the Sch-LN patients, and worse ToM1 functioning than the controls.
Conclusions
These results suggest that clinically stable schizophrenia patients have ToM impairments. Sch-HN group performed comparably poorly as the AS group, while the Sch-LN group was relatively spared. The most profoundly impaired patients with schizophrenia in terms of ToM functioning were represented by those with high negative symptoms (Sch-HN). Similar to AS, as a neurodevelopmental impairment, these patients may not have developed ToM ability, or they may have lost their ToM capacity as a result of a neurodegenerative process during the illness. Supplementary studies using other methods (e.g., neuroimaging, neurophysiology) may highlight the brain regions that are affected differentially in AS and schizophrenia, the relationship of ToM impairments and negative symptoms, and the role of ToM impairments in the neurodevelopmental or neurodegenerative hypothesis of schizophrenia.
PMCID: PMC4288770  PMID: 25584026
Theory of mind; schizophrenia; Asperger’s syndrome; Asperger’s disorder; negative symptoms; cognitive deficits
2.  Growing Up with Asperger’s Syndrome: Developmental Trajectory of Autobiographical Memory 
Autobiographical memory (AM) and social cognition share common properties and both are affected in autism spectrum disorders (ASD). So far, most of the scant research in ASD has concerned adults, systematically reporting impairment of the episodic component. The only study to be conducted with children concluded that they have poorer personal semantic knowledge than typical developing children. The present study explores the development of both components of AM in an 8-year-old boy diagnosed with Asperger’s syndrome, based on three examinations in 2007, 2008, and 2010. On each occasion, he underwent a general neuropsychological assessment including theory of mind (ToM) tasks, and a specially designed AM task allowing us to test both the semantic and the episodic components for three lifetime periods (current year, previous year, and earlier years). We observed difficulties in strategic retrieval and ToM, with a significant improvement between the second and third examinations. Regarding AM, different patterns of performance were noted in all three examinations: (1) relative preservation of current year personal knowledge, but impairment for the previous and earlier years, and (2) impairment of episodic memory for the current and previous year, but performances similar to those of controls for the earlier years. The first pattern can be explained by abnormal forgetting and by the semanticization mechanism, which needs verbal communication and social interaction to be efficient. The second pattern suggests that the development of episodic memory only reached the stage of “event memory.” This term refers to memory for personal events lacking in details or spatiotemporal specificity, and is usually observed in children younger than five. We conclude that the abnormal functioning of social cognition in ASD, encompassing social, and personal points of view, has an impact on both components of AM.
doi:10.3389/fpsyg.2012.00605
PMCID: PMC3542927  PMID: 23335906
autobiographical memory; autism; child; theory of mind; episodic memory; semantic memory
3.  Using Fiction to Assess Mental State Understanding: A New Task for Assessing Theory of Mind in Adults 
PLoS ONE  2013;8(11):e81279.
Social functioning depends on the ability to attribute and reason about the mental states of others – an ability known as theory of mind (ToM). Research in this field is limited by the use of tasks in which ceiling effects are ubiquitous, rendering them insensitive to individual differences in ToM ability and instances of subtle ToM impairment. Here, we present data from a new ToM task – the Short Story Task (SST) - intended to improve upon many aspects of existing ToM measures. More specifically, the SST was designed to: (a) assess the full range of individual differences in ToM ability without suffering from ceiling effects; (b) incorporate a range of mental states of differing complexity, including epistemic states, affective states, and intentions to be inferred from a first- and second-order level; (c) use ToM stimuli representative of real-world social interactions; (d) require participants to utilize social context when making mental state inferences; (e) exhibit adequate psychometric properties; and (f) be quick and easy to administer and score. In the task, participants read a short story and were asked questions that assessed explicit mental state reasoning, spontaneous mental state inference, and comprehension of the non-mental aspects of the story. Responses were scored according to a rubric that assigned greater points for accurate mental state attributions that included multiple characters’ mental states. Results demonstrate that the SST is sensitive to variation in ToM ability, can be accurately scored by multiple raters, and exhibits concurrent validity with other social cognitive tasks. The results support the effectiveness of this new measure of ToM in the study of social cognition. The findings are also consistent with studies demonstrating significant relationships among narrative transportation, ToM, and the reading of fiction. Together, the data indicate that reading fiction may be an avenue for improving ToM ability.
doi:10.1371/journal.pone.0081279
PMCID: PMC3820595  PMID: 24244736
4.  Neural processing associated with cognitive and affective Theory of Mind in adolescents and adults 
Theory of Mind (ToM) is the ability to attribute thoughts, intentions and beliefs to others. This involves component processes, including cognitive perspective taking (cognitive ToM) and understanding emotions (affective ToM). This study assessed the distinction and overlap of neural processes involved in these respective components, and also investigated their development between adolescence and adulthood. While data suggest that ToM develops between adolescence and adulthood, these populations have not been compared on cognitive and affective ToM domains. Using fMRI with 15 adolescent (aged 11–16 years) and 15 adult (aged 24–40 years) males, we assessed neural responses during cartoon vignettes requiring cognitive ToM, affective ToM or physical causality comprehension (control). An additional aim was to explore relationships between fMRI data and self-reported empathy. Both cognitive and affective ToM conditions were associated with neural responses in the classic ToM network across both groups, although only affective ToM recruited medial/ventromedial PFC (mPFC/vmPFC). Adolescents additionally activated vmPFC more than did adults during affective ToM. The specificity of the mPFC/vmPFC response during affective ToM supports evidence from lesion studies suggesting that vmPFC may integrate affective information during ToM. Furthermore, the differential neural response in vmPFC between adult and adolescent groups indicates developmental changes in affective ToM processing.
doi:10.1093/scan/nsr023
PMCID: PMC3252629  PMID: 21467048
Theory of Mind; empathy; adolescence; development; fMRI
5.  The neural basis of theory of mind and its relationship to social functioning and social anhedonia in individuals with schizophrenia☆ 
NeuroImage : Clinical  2013;4:154-163.
Theory of mind (ToM), the ability to attribute and reason about the mental states of others, is a strong determinant of social functioning among individuals with schizophrenia. Identifying the neural bases of ToM and their relationship to social functioning may elucidate functionally relevant neurobiological targets for intervention. ToM ability may additionally account for other social phenomena that affect social functioning, such as social anhedonia (SocAnh). Given recent research in schizophrenia demonstrating improved neural functioning in response to increased use of cognitive skills, it is possible that SocAnh, which decreases one's opportunity to engage in ToM, could compromise social functioning through its deleterious effect on ToM-related neural circuitry. Here, twenty individuals with schizophrenia and 18 healthy controls underwent fMRI while performing the False-Belief Task. Aspects of social functioning were assessed using multiple methods including self-report (Interpersonal Reactivity Index, Social Adjustment Scale), clinician-ratings (Global Functioning Social Scale), and performance-based tasks (MSCEIT—Managing Emotions). SocAnh was measured with the Revised Social Anhedonia Scale. Region-of-interest and whole-brain analyses revealed reduced recruitment of medial prefrontal cortex (MPFC) for ToM in individuals with schizophrenia. Across all participants, activity in this region correlated with most social variables. Mediation analysis revealed that neural activity for ToM in MPFC accounted for the relationship between SocAnh and social functioning. These findings demonstrate that reduced recruitment of MPFC for ToM is an important neurobiological determinant of social functioning. Furthermore, SocAhn may affect social functioning through its impact on ToM-related neural circuitry. Together, these findings suggest ToM ability as an important locus for intervention.
Highlights
•Individuals with schizophrenia exhibited reduced recruitment of MPFC for ToM.•MPFC and RTPJ activities correlate with measures of social functioning and ability.•MPFC activity mediates the relationship between social anhedonia and functioning.•Neural circuitry supporting ToM may represent an important area for remediation.
doi:10.1016/j.nicl.2013.11.006
PMCID: PMC3871293  PMID: 24371798
Schizophrenia; Theory of mind; Social functioning; Social anhedonia; fMRI
6.  Deficits in Mental State Attributions in Individuals with 22q11.2 Deletion Syndrome (Velo-Cardio-Facial Syndrome) 
Velo-cardio-facial syndrome (VCFS; 22q11.2 deletion syndrome) results from a genetic mutation that increases risk for Autism Spectrum Disorder (ASD). We compared Theory of Mind (ToM) skills in 63 individuals with VCFS (25% with an ASD diagnosis) and 43 typically-developing controls, and investigated the relationship of ToM to reciprocal social behavior. We administered a video-based task to assess mentalizing at two sites (UCLA and SUNY Upstate Medical University). The videos depicted interactions representing complex mental states (ToM condition), or simple movements (Random condition). Verbal descriptions of the videos were rated for Intentionality (i.e., mentalizing) and Appropriateness. Using Repeated Measures ANOVA, we assessed the effects of VCFS and ASD on Intentionality and Appropriateness, and the relationship of mentalizing to Social Responsiveness Scale (SRS) scores. Results indicated that individuals with VCFS overall had lower Intentionality and Appropriateness scores than controls for ToM, but not for Random scenes. In the SUNY sample, individuals with VCFS, both with and without ASD, performed more poorly than controls on the ToM condition; however, in the UCLA sample, only individuals with VCFS without ASD performed significantly worse than controls on the ToM condition. Controlling for site and age, performance on the ToM condition was significantly correlated with SRS scores. Individuals with VCFS, regardless of an ASD diagnosis, showed impairments in the spontaneous attribution of mental states to abstract visual stimuli, which may underlie real-life problems with social interactions. A better understanding of the social deficits in VCFS is essential for the development of targeted behavioral interventions.
doi:10.1002/aur.1252
PMCID: PMC3528795  PMID: 22962003
22q11.2 deletion syndrome; Velo-cardio-facial syndrome; Theory of Mind; Autism Spectrum Disorders; reciprocal social behavior; social cognition
7.  The reciprocal relationship between executive function and theory of mind in middle childhood: a 1-year longitudinal perspective 
There is robust evidence showing a link between executive function (EF) and theory of mind (ToM) in 3- to 5-year-olds. However, it is unclear whether this relationship extends to middle childhood. In addition, there has been much discussion about the nature of this relationship. Whereas some authors claim that ToM is needed for EF, others argue that ToM requires EF. To date, however, studies examining the longitudinal relationship between distinct subcomponents of EF [i.e., attention shifting, working memory (WM) updating, inhibition] and ToM in middle childhood are rare. The present study examined (1) the relationship between three EF subcomponents (attention shifting, WM updating, inhibition) and ToM in middle childhood, and (2) the longitudinal reciprocal relationships between the EF subcomponents and ToM across a 1-year period. EF and ToM measures were assessed experimentally in a sample of 1,657 children (aged 6–11 years) at time point one (t1) and 1 year later at time point two (t2). Results showed that the concurrent relationships between all three EF subcomponents and ToM pertained in middle childhood at t1 and t2, respectively, even when age, gender, and fluid intelligence were partialled out. Moreover, cross-lagged structural equation modeling (again, controlling for age, gender, and fluid intelligence, as well as for the earlier levels of the target variables), revealed partial support for the view that early ToM predicts later EF, but stronger evidence for the assumption that early EF predicts later ToM. The latter was found for attention shifting and WM updating, but not for inhibition. This reveals the importance of studying the exact interplay of ToM and EF across childhood development, especially with regard to different EF subcomponents. Most likely, understanding others’ mental states at different levels of perspective-taking requires specific EF subcomponents, suggesting developmental change in the relations between EF and ToM across childhood.
doi:10.3389/fpsyg.2014.00655
PMCID: PMC4068105  PMID: 25009527
executive function; theory of mind; longitudinal; middle childhood; attention shifting; inhibition; working memory updating
8.  Sequences of Mind Development in Boys with Autism Spectrum Disorder 
ISRN Neurology  2012;2012:637453.
Autism is a pervasive neurodevelopment disorder, primarily encompassing difficulties in the social, language, and communicative domains. One of the most common social cognitive theories of autism is based on theory of mind (ToM), the “mentalizing” ability needed to infer that others have their own beliefs and desires in order to understand their behavior. In the current study, this hypothesis was tested using Wellman and Liu's scaled ToM tasks. These were employed in the assessment of ToM development of verbal, school-aged high-functioning boys with autism spectrum disorder (ASD). The results indicated that children with ASD performed significantly worse than normal children on ToM tasks (Z = 4.7; P < 0 .001). However, it was shown that some of the ASD children were able to pass desire and false-belief tasks whereas none of them could succeed in knowledge and real-apparent emotion tasks.
doi:10.5402/2012/637453
PMCID: PMC3523140  PMID: 23304550
9.  Theory of Mind in Patients at Clinical High Risk for Psychosis 
Schizophrenia research  2011;131(1-3):11-17.
Background
Patients with schizophrenia have a decreased ability to interpret the intentions of other individuals, called Theory of Mind (ToM). As capacity for ToM normally advances with brain maturation, research on ToM in individuals at heightened clinical risk for psychosis may reveal developmental differences independent of disease based differences.
Methods
We examined ToM in at clinical high risk and schizophrenia patients as well as healthy controls: 1) 63 clinical high risk (CHR) patients and 24 normal youths ascertained by a CHR program; and 2) in 13 schizophrenia cases and 14 normal adults recruited through a schizophrenia program. ToM measures included first- and second-order false belief cartoon tasks (FBT) and two “higher order” tasks (“Strange Stories Task” (SST) and the “Reading the Mind in the Eyes” task). In the first study, CHR patients and normal youths were also assessed for cognition, “prodromal” symptoms and social function.
Results
Errors on first- and second-order false belief tasks were made primarily by patients. CHR patients and their young comparison group had equivalent performance on higher order ToM, which was not significantly different from the worse ToM performance of schizophrenia patients and the higher performance of normal adult controls. In the combined dataset from both studies, all levels of ToM were associated with IQ, controlling for age and sex. ToM bore no relation to explicit memory, prodromal symptoms, social function, or later transition to psychosis.
Conclusions
Higher order ToM capacity was equally undeveloped in high risk cases and younger controls, suggesting performance on these tasks is not fully achieved until adulthood. This study also replicates the association of IQ with ToM performance described in previous studies of schizophrenia.
doi:10.1016/j.schres.2011.06.005
PMCID: PMC3159813  PMID: 21757324
psychosis; theory of mind; IQ; risk; prodrome
10.  Integrating intention and context: assessing social cognition in adults with Asperger syndrome 
Deficits in social cognition are an evident clinical feature of the Asperger syndrome (AS). Although many daily life problems of adults with AS are related to social cognition impairments, few studies have conducted comprehensive research in this area. The current study examined multiple domains of social cognition in adults with AS assessing the executive functions (EF) and exploring the intra and inter-individual variability. Fifteen adult's diagnosed with AS and 15 matched healthy controls completed a battery of social cognition tasks. This battery included measures of emotion recognition, theory of mind (ToM), empathy, moral judgment, social norms knowledge, and self-monitoring behavior in social settings. We controlled for the effect of EF and explored the individual variability. The results indicated that adults with AS had a fundamental deficit in several domains of social cognition. We also found high variability in the social cognition tasks. In these tasks, AS participants obtained mostly subnormal performance. EF did not seem to play a major role in the social cognition impairments. Our results suggest that adults with AS present a pattern of social cognition deficits characterized by the decreased ability to implicitly encode and integrate contextual information in order to access to the social meaning. Nevertheless, when social information is explicitly presented or the situation can be navigated with abstract rules, performance is improved. Our findings have implications for the diagnosis and treatment of individuals with AS as well as for the neurocognitive models of this syndrome.
doi:10.3389/fnhum.2012.00302
PMCID: PMC3492863  PMID: 23162450
Asperger syndrome; contextual social cognition; executive functions; individual variability
11.  Investigating the Genetic Basis of Theory of Mind (ToM): The Role of Catechol-O-Methyltransferase (COMT) Gene Polymorphisms 
PLoS ONE  2012;7(11):e49768.
The ability to deduce other persons' mental states and emotions which has been termed ‘theory of mind (ToM)’ is highly heritable. First molecular genetic studies focused on some dopamine-related genes, while the genetic basis underlying different components of ToM (affective ToM and cognitive ToM) remain unknown. The current study tested 7 candidate polymorphisms (rs4680, rs4633, rs2020917, rs2239393, rs737865, rs174699 and rs59938883) on the catechol-O-methyltransferase (COMT) gene. We investigated how these polymorphisms relate to different components of ToM. 101 adults participated in our study; all were genetically unrelated, non-clinical and healthy Chinese subjects. Different ToM tasks were applied to detect their theory of mind ability. The results showed that the COMT gene rs2020917 and rs737865 SNPs were associated with cognitive ToM performance, while the COMT gene rs5993883 SNP was related to affective ToM, in which a significant gender-genotype interaction was found (p = 0.039). Our results highlighted the contribution of DA-related COMT gene on ToM performance. Moreover, we found out that the different SNP at the same gene relates to the discriminative aspect of ToM. Our research provides some preliminary evidence to the genetic basis of theory of mind which still awaits further studies.
doi:10.1371/journal.pone.0049768
PMCID: PMC3507837  PMID: 23209597
12.  Theory of mind and social inference in children and adolescents with bipolar disorder 
Psychological medicine  2008;38(6):791-800.
Background
Deficits in theory of mind (ToM), or the ability to infer what another person is thinking or feeling, have been reported in manic and euthymic adults with bipolar disorder. To date, there have been no investigations of ToM in pediatric bipolar disorder (PBD). The aim of the current study was to investigate this ability in PBD patients and healthy controls.
Method
PBD patients (n=26) and intellectually and demographically similar healthy comparison subjects (n=20) were administered two ToM tasks. In the Affective Story Task, subjects were read positive-, negative- and neutralvalenced stories, and were assessed on their ability to recognize that a misleading series of events could lead one character to develop a false belief about another character. On the Hinting Task, subjects were required to infer the real intentions behind subtle hints.
Results
The PBD group performed significantly more poorly than controls on the Hinting Task and the positive and negative conditions of the Affective Story Task. In the PBD group only, younger age, earlier illness onset and manic symptoms were associated with poorer ToM performance.
Conclusions
Consistent with past findings in adult bipolar disorder (BD), PBD youth performed more poorly than controls on ToM tasks. Data suggest that ToM ability may be more impaired in affectively charged contexts. Additionally, an earlier onset of illness among PBD youth may interfere with the development of social-cognitive skills. ToM disturbances may be a useful treatment target in PBD, with the aim of facilitating more accurate assessment of social cues and better interpersonal functioning.
doi:10.1017/S0033291707002541
PMCID: PMC3221606  PMID: 18208632
Pediatric bipolar disorder; social cognition; social inference; theory of mind
13.  Neural bases of Theory of Mind in children with autism spectrum disorders and children with conduct problems and callous-unemotional traits 
Developmental Science  2014;17(5):786-796.
Individuals with autism spectrum disorders (ASD) have difficulty understanding other minds (Theory of Mind; ToM), with atypical processing evident at both behavioural and neural levels. Individuals with conduct problems and high levels of callous-unemotional (CU) traits (CP/HCU) exhibit reduced responsiveness to others' emotions and difficulties interacting with others, but nonetheless perform normally in experimental tests of ToM. The present study aimed to examine the neural underpinnings of ToM in children (aged 10–16) with ASD (N = 16), CP/HCU (N = 16) and typically developing (TD) controls (N = 16) using a non-verbal cartoon vignette task. Whilst individuals with ASD were predicted to show reduced fMRI responses across regions involved in ToM processing, CP/HCU individuals were predicted to show no differences compared with TD controls. The analyses indicated that neural responses did not differ between TD and CP/HCU groups during ToM. TD and CP/HCU children exhibited significantly greater medial prefrontal cortex responses during ToM than did the ASD group. Within the ASD group, responses in medial prefrontal cortex and right temporoparietal junction (TPJ) correlated with symptom severity as measured by the Autism Diagnostic Observation Schedule (ADOS). Findings suggest that although both ASD and CP/HCU are characterized by social difficulties, only children with ASD display atypical neural processing associated with ToM.
doi:10.1111/desc.12167
PMCID: PMC4316185  PMID: 24636205
14.  Theory of mind skills are related to gray matter volume in the ventromedial prefrontal cortex in schizophrenia 
Biological psychiatry  2011;70(12):1169-1178.
Background
Among individuals with schizophrenia, deficits in theory of mind (ToM) skills predict poor social functioning. Therefore, identifying the neural basis of ToM may assist the development of treatments that improve social outcomes. Despite growing evidence that the ventromedial prefrontal cortex (VMPFC) facilitates ToM skills among healthy individuals, methodological challenges, such as the influence of general cognitive deficits, have made it difficult to identify the relationship between ToM processing and VMPFC function in schizophrenia.
Methods
We used voxel-based morphometry (VBM) and a multi-method behavioral assessment of ToM processing, including performance-based (Recognition of Faux Pas Test), self-report (Interpersonal Reactivity Index, Perspective-Taking), and interview-rated (Quality of Life Scale–Empathy score) ToM assessments, to investigate whether ToM skills were related to VMPFC gray matter volume (GMV). Standardized neuropsychological measures were used to assess global cognition. 21 schizophrenia and 17 healthy control subjects participated.
Results
Between-group behavioral analyses showed that, as compared to healthy participants, schizophrenia participants had worse ToM performance and lower self-reported ToM processing in daily life. The between-group analysis of GMV showed that schizophrenia participants had less VMPFC GMV than healthy participants. Moreover, among schizophrenia participants, all three measures of ToM processing were associated with VMPFC GMV, such that worse ToM skills were related to less VMPFC GMV. This association remained strong for self-reported and interview-rated ToM skills even when controlling for the influence of global cognition.
Conclusions
The findings suggest that among individuals with schizophrenia, reduced VMPFC GMV is specifically associated with deficits using ToM skills to enhance social relationships.
doi:10.1016/j.biopsych.2011.07.027
PMCID: PMC3432316  PMID: 21917239
mentalizing; theory of mind; empathy; schizophrenia; social functioning; MRI
15.  From Fancy to Reason: Scaling Deaf and Hearing Children’s Understanding of Theory of Mind and Pretence 
We examined deaf and hearing children’s progression of steps in theory-of-mind (ToM) development including their understanding of social pretending. Ninety-three children (33 deaf; 60 hearing) aged 3 to 13 years were tested on a set of six closely-matched ToM tasks. Results showed that deaf children were delayed substantially behind hearing children in understanding pretending, false belief and other ToM concepts, in line with their delayed uptake of social pretend play. By using a scaling methodology, we confirmed previous evidence of a consistent five-step developmental progression for both groups. Moreover, by including social pretence understanding, both deaf and hearing children’s ToM sequences were shown to extend reliably to six sequential developmental steps. Finally and focally, even though both groups’ sequences were six steps long, the placement of pretence relative to other ToM milestones varied with hearing status. Deaf children understood social pretending at an earlier step in the ToM sequence than hearing children, albeit at a later chronological age. Theoretically, the findings are relevant to questions about how universal developmental progressions come together along with culturally-distinctive inputs and biological factors (such as hearing loss) to set the pace for ToM development.
PMCID: PMC3086259  PMID: 19998533
16.  Social Cognition in 22q11.2 Microdeletion Syndrome: Relevance to Psychosis 
Schizophrenia research  2012;142(0):99-107.
22q11.2 deletion syndrome (22qDS) represents one of the largest known genetic risk factors for schizophrenia. Approximately 30% of individuals with 22qDS develop psychotic illness in adolescence or young adulthood. Given that deficits in social cognition are increasingly viewed as a central aspect of idiopathic schizophrenia, we sought to investigate abilities in this domain as a predictor of psychotic symptoms in 22qDS participants. We assessed multiple domains of social and non-social cognition in 22qDS youth to: 1) characterize performance across these domains in 22qDS, and identify whether 22qDS participants fail to show expected patterns of age-related improvements on these tasks; and 2) determine whether social cognition better predicts positive and negative symptoms than does non-social cognition. Task domains assessed were: emotion recognition and differentiation, Theory of Mind (ToM), verbal knowledge, abstract reasoning, working memory, and processing speed. Positive and negative symptoms were measured using scores obtained from the Structured Interview for Prodromal Symptoms (SIPS). 22qDS participants (N=31, mean age: 15.9) showed the largest impairment, relative to healthy controls (N=31, mean age: 15.6), on measures of ToM and processing speed. In contrast to controls, 22qDS participants did not show age-related improvements on measures of working memory and verbal knowledge. Notably, ToM performance was the best predictor of positive symptoms in 22qDS, accounting for 39% of the variance in symptom severity. Processing speed emerged as the best predictor of negative symptoms, accounting for 37% of the variance in symptoms. Given that ToM was a robust predictor of positive symptoms in our sample, these findings suggest that social cognition may be a valuable intermediate trait for predicting the development of psychosis.
doi:10.1016/j.schres.2012.10.007
PMCID: PMC3714207  PMID: 23122739
22q11.2 Microdeletion Syndrome; social cognition; schizophrenia; prodromal; psychosis
17.  Theory of Mind, Language and Adaptive Functioning in ASD: A Neuroconstructivist Perspective 
Introduction
Neuroconstructivist theories of development highlight the potential effect one developmental domain may have on constraining or facilitating another. Empirical validation of this theory requires further testing in autism spectrum disorders (ASD), and may illuminate the complex interplay of developmental trajectories, particularly in the relationship between predictor and outcome variables. In ASD, language ability is an early predictor of important functional outcomes such as communication and socialization. We aimed to investigate whether theory of mind (ToM) mediates the relation between language ability and adaptive functioning in more cognitively able children with ASD (IQ > 70).
Methods
Thirty-nine children were followed prospectively every two years from 4–6 years to 12–14 years. Their language and theory of mind abilities and adaptive functioning were tested using the Test of Language Development-2 (the independent variable, at age 6–8 years), the “Eyes Test” (a measure of ToM, the mediator, at age 10–12) and the Vineland Adaptive Behaviour Scales (the outcome variable, at age 12–14).
Results
ToM mediated an association between language and adaptive functioning in the communication domain, but not in the social domain.
Conclusion
These results challenge the usefulness of ToM as a unifying theory for ASD deficits and highlight the potential usefulness of a neuroconstructivist framework for prospective studies.
PMCID: PMC3565710  PMID: 23390428
autism; Asperger Syndrome; language; theory of mind; mediation; autisme; syndrome d’Asperger; langage; théorie de l’esprit; médiation
18.  Comparing the neural correlates of affective and cognitive theory of mind using fMRI: Involvement of the basal ganglia in affective theory of mind 
Theory of Mind (ToM) is the ability to infer other people’s mental states like intentions or desires. ToM can be differentiated into affective (i.e., recognizing the feelings of another person) and cognitive (i.e., inferring the mental state of the counterpart) subcomponents. Recently, subcortical structures such as the basal ganglia (BG) have also been ascribed to the multifaceted concept ToM and most BG disorders have been reported to elicit ToM deficits. In order to assess both the correlates of affective and cognitive ToM as well as involvement of the basal ganglia, 30 healthy participants underwent event-related fMRI scanning, neuropsychological testing, and filled in questionnaires concerning different aspects of ToM and empathy. Directly contrasting affective (aff) as well as cognitive (cog) ToM to the control (phy) condition, activation was found in classical ToM regions, namely parts of the temporal lobe including the superior temporal sulcus, the supplementary motor area, and parietal structures in the right hemisphere. The contrast aff > phy yielded additional activation in the orbitofrontal cortex on the right and the cingulate cortex, the precentral and inferior frontal gyrus and the cerebellum on the left. The right BG were recruited in this contrast as well. The direct contrast aff > cog showed activation in the temporoparietal junction and the cingulate cortex on the right as well as in the left supplementary motor area. The reverse contrast cog > aff however did not yield any significant clusters. In summary, affective and cognitive ToM partly share neural correlates but can also be differentiated anatomically. Furthermore, the BG are involved in affective ToM and thus their contribution is discussed as possibly providing a motor component of simulation processes, particularly in affective ToM.
doi:10.2478/v10053-008-0129-6
PMCID: PMC3709103  PMID: 23853676
fMRI; affective and cognitive theory of mind; ToM; mentalizing; basal ganglia; simulation; social cognition
19.  Switching language switches mind: linguistic effects on developmental neural bases of ‘Theory of Mind’ 
Theory of mind (ToM)—our ability to predict behaviors of others in terms of their underlying intentions—has been examined through false-belief (FB) tasks. We studied 12 Japanese early bilingual children (8−12 years of age) and 16 late bilingual adults (18−40 years of age) with FB tasks in Japanese [first language (L1)] and English [second language (L2)], using fMRI. Children recruited more brain regions than adults for processing ToM tasks in both languages. Moreover, children showed an overlap in brain activity between the L1 and L2 ToM conditions in the medial prefrontal cortex (mPFC). Adults did not show such a convergent activity in the mPFC region, but instead, showed brain activity that varied depending on the language used in the ToM task. The developmental shift from more to less ToM specific brain activity may reflect increasing automatization of ToM processing as people age. These results also suggest that bilinguals recruit different resources to understand ToM depending on the language used in the task, and this difference is greater later in life.
doi:10.1093/scan/nsm039
PMCID: PMC2569814  PMID: 19015096
fMRI; theory of mind; cognitive development; language; bilingualism; medial prefrontal cortex
20.  Zinc finger protein 804A (ZNF804A) and verbal deficits in individuals with autism 
Background
In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism.
Methods
We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition.
Results
We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001).
Limitations
Study limitations include our small sample size of postmortem brains.
Conclusion
Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.
doi:10.1503/jpn.130126
PMCID: PMC4160358  PMID: 24866414
21.  Cognitive, Affective, and Conative Theory of Mind (ToM) in Children with Traumatic Brain Injury 
We studied three forms of dyadic communication involving theory of mind (ToM) in 82 children with traumatic brain injury (TBI) and 61 children with orthopedic injury (OI): Cognitive (concerned with false belief), Affective (concerned with expressing socially deceptive facial expressions), and Conative (concerned with influencing another’s thoughts or feelings). We analyzed the pattern of brain lesions in the TBI group and conducted voxel-based morphometry for all participants in five large-scale functional brain networks, and related lesion and volumetric data to ToM outcomes. Children with TBI exhibited difficulty with Cognitive, Affective, and Conative ToM. The perturbation threshold for Cognitive ToM is higher than that for Affective and Conative ToM, in that Severe TBI disturbs Cognitive ToM but even Mild-Moderate TBI disrupt Affective and Conative ToM. Childhood TBI was associated with damage to all five large-scale brain networks. Lesions in the Mirror Neuron Empathy network predicted lower Conative ToM involving ironic criticism and empathic praise. Conative ToM was significantly and positively related to the package of Default Mode, Central Executive, and Mirror Neuron Empathy networks and, more specifically, to two hubs of the Default Mode network, the posterior cingulate/retrosplenial cortex and the hippocampal formation, including entorhinal cortex and parahippocampal cortex.
doi:10.1016/j.dcn.2012.11.006
PMCID: PMC3620837  PMID: 23291312
22.  Evidence of Social Understanding Impairment in Patients with Amyotrophic Lateral Sclerosis 
PLoS ONE  2011;6(10):e25948.
The present study aims at clarifying the nature of the Theory of Mind (ToM) deficits associated with Amyotrophic Lateral Sclerosis (ALS). ToM is the ability to attribute mental states such as intentions and beliefs to others in order to understand and predict their behaviour and to behave accordingly. Several neuroimaging studies reported the prefrontal cortices as the brain region underlying a key ToM ability, i.e. the comprehension of social intentions. Dysfunction of the prefrontal cortices in patients with ALS has been indicated by a range of neuroimaging studies. The frontal syndrome that appears to characterize up to 50% of ALS has been noted to be similar to the profile that characterizes patients with frontotemporal dementia (FTD), a neurodegenerative condition characterised by ToM deficits. In the present paper, we hypothesize that the performance of patients with ALS is significantly worse than healthy controls' performance on tasks requiring the comprehension of social contexts, whereas patients' performance is comparable to healthy controls' performance on tasks not requiring the comprehension of social contexts. To this end, we tested 15 patients with ALS with an experimental protocol that distinguishes between private (non-social) intentions and social intentions. The pattern of results followed the experimental hypothesis: the performance of patients with ALS and healthy controls significantly differed on the comprehension of social context only, with an impairment in patients with ALS. Single case analysis confirmed the findings at an individual level. The present study is the first which has examined and compared the understanding of social and non-social contexts in patients with ALS and shown a specific and selective deficit in the former only. The current findings further support the notion of a continuum of cognitive dysfunction ranging from ALS to FTD, with parallel cognitive profiles in both disorders.
doi:10.1371/journal.pone.0025948
PMCID: PMC3187828  PMID: 21998727
23.  Theory of mind deficits in patients with esophageal cancer combined with depression 
AIM: To characterize the two components of theory of mind (ToM) in patients with esophageal cancer combined with depression.
METHODS: Sixty-five patients with esophageal cancer combined with depression (depressed group) and 62 normal controls (control group) were assessed using reading the mind in the eyes test, faux pas task, verbal fluency test, digit span test and WAIS IQ test. The depressed group was divided into two subgroups including psychotic depressed (PD) group (32 cases) and nonpsychotic depressed (NPD) group (33 cases). The clinical symptoms of patients were assessed using Beck depression inventory version II and brief psychiatric reacting scale (BPRS).
RESULTS: There was a significant difference between the depressed group and the control group on tasks involving ToM social perceptual components (mind reading: t = 7.39, P < 0.01) and tests involving ToM social cognitive components (faux pas questions: t = 13.75, P < 0.01), respectively. A significant difference was also found among the PD group, the NPD group and the control group on mind reading (F = 32.98, P < 0.01) and faux pas questions (χ2 = 78.15, P < 0.01), respectively. The PD group and NPD group performed worse than normal group controls both on mind reading and faux pas questions (P < 0.05). The PD group performed significantly worse than the NPD group on tasks involving ToM (mind reading: F = 18.99, P < 0.01; faux pas questions: F = 36.01, P < 0.01). In the depressed group, there was a negative correlation between ToM performances and BPRS total score (mind reading: r = -0.35, P < 0.01; faux pas questions: r = -0.51, P < 0.01), and between ToM performances and hostile suspiciousness factor score (mind reading: r = -0.75, P < 0.01; faux pas questions: r = -0.73, P < 0.01), respectively.
CONCLUSION: The two components of ToM are both impaired in patients with esophageal cancer combined with depression. This indicates that there may be an association between ToM deficits and psychotic symptoms in clinical depression.
doi:10.3748/wjg.v19.i19.2969
PMCID: PMC3660823  PMID: 23704831
Esophageal cancer combined with depression; Theory of mind; Social perceptual component; Social cognitive component
24.  Spatial navigation, episodic memory, episodic future thinking, and theory of mind in children with autism spectrum disorder: evidence for impairments in mental simulation? 
Frontiers in Psychology  2014;5:1411.
This study explored spatial navigation alongside several other cognitive abilities that are thought to share common underlying neurocognitive mechanisms (e.g., the capacity for self-projection, scene construction, or mental simulation), and which we hypothesized may be impaired in autism spectrum disorder (ASD). Twenty intellectually high-functioning children with ASD (with a mean age of ~8 years) were compared to 20 sex, age, IQ, and language ability matched typically developing children on a series of tasks to assess spatial navigation, episodic memory, episodic future thinking (also known as episodic foresight or prospection), theory of mind (ToM), relational memory, and central coherence. This is the first study to explore these abilities concurrently within the same sample. Spatial navigation was assessed using the “memory island” task, which involves finding objects within a realistic, computer simulated, three-dimensional environment. Episodic memory and episodic future thinking were assessed using a past and future event description task. ToM was assessed using the “animations” task, in which children were asked to describe the interactions between two animated triangles. Relational memory was assessed using a recognition task involving memory for items (line drawings), patterned backgrounds, or combinations of items and backgrounds. Central coherence was assessed by exploring differences in performance across segmented and unsegmented versions of block design. Children with ASD were found to show impairments in spatial navigation, episodic memory, episodic future thinking, and central coherence, but not ToM or relational memory. Among children with ASD, spatial navigation was found to be significantly negatively related to the number of repetitive behaviors. In other words, children who showed more repetitive behaviors showed poorer spatial navigation. The theoretical and practical implications of the results are discussed.
doi:10.3389/fpsyg.2014.01411
PMCID: PMC4256988  PMID: 25538661
autism spectrum disorder; episodic future thinking; episodic memory; mental simulation; scene construction; self-projection; spatial navigation; theory of mind
25.  Autism Spectrum Disorders and Schizophrenia: Meta-Analysis of the Neural Correlates of Social Cognition 
PLoS ONE  2011;6(10):e25322.
Context
Impaired social cognition is a cardinal feature of Autism Spectrum Disorders (ASD) and Schizophrenia (SZ). However, the functional neuroanatomy of social cognition in either disorder remains unclear due to variability in primary literature. Additionally, it is not known whether deficits in ASD and SZ arise from similar or disease-specific disruption of the social cognition network.
Objective
To identify regions most robustly implicated in social cognition processing in SZ and ASD.
Data Sources
Systematic review of English language articles using MEDLINE (1995–2010) and reference lists.
Study Selection
Studies were required to use fMRI to compare ASD or SZ subjects to a matched healthy control group, provide coordinates in standard stereotactic space, and employ standardized facial emotion recognition (FER) or theory of mind (TOM) paradigms.
Data Extraction
Activation foci from studies meeting inclusion criteria (n = 33) were subjected to a quantitative voxel-based meta-analysis using activation likelihood estimation, and encompassed 146 subjects with ASD, 336 SZ patients and 492 healthy controls.
Results
Both SZ and ASD showed medial prefrontal hypoactivation, which was more pronounced in ASD, while ventrolateral prefrontal dysfunction was associated mostly with SZ. Amygdala hypoactivation was observed in SZ patients during FER and in ASD during more complex ToM tasks. Both disorders were associated with hypoactivation within the Superior Temporal Sulcus (STS) during ToM tasks, but activation in these regions was increased in ASD during affect processing. Disease-specific differences were noted in somatosensory engagement, which was increased in SZ and decreased in ASD. Reduced thalamic activation was uniquely seen in SZ.
Conclusions
Reduced frontolimbic and STS engagement emerged as a shared feature of social cognition deficits in SZ and ASD. However, there were disease- and stimulus-specific differences. These findings may aid future studies on SZ and ASD and facilitate the formulation of new hypotheses regarding their pathophysiology.
doi:10.1371/journal.pone.0025322
PMCID: PMC3187762  PMID: 21998649

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