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Keywords:

  • Behavior;
  • COMT;
  • copy number variants;
  • DAOA;
  • endophenotype;
  • genetics;
  • mutations, neurexin;
  • neuroimaging;
  • OXTR, phenotype;
  • psychiatry;
  • schizophrenia;
  • single nucleotide polymorphisms;
  • social cognition;
  • theory of mind;
  • 22q deletion syndrome, ZNF804A

Abstract

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

Genome-wide association studies in schizophrenia have recently made significant progress in our understanding of the complex genetic architecture of this disorder. Many genetic loci have been identified and now require functional investigation. One approach involves studying their correlation with neuroimaging and neurocognitive endophenotypes. Theory of Mind (ToM) deficits are well established in schizophrenia and they appear to fulfill criteria for being considered an endophenotype. We aim to review the behavioral and neuroimaging-based studies of ToM in schizophrenia, assess its suitability as an endophenotype, discuss current findings, and propose future research directions. Suitable research articles were sourced from a comprehensive literature search and from references identified through other studies. ToM deficits are repeatable, stable, and heritable: First-episode patients, those in remission and unaffected relatives all show deficits. Activation and structural differences in brain regions believed important for ToM are also consistently reported in schizophrenia patients at all stages of illness, although no research to date has examined unaffected relatives. Studies using ToM as an endophenotype are providing interesting genetic associations with both single nucleotide polymorphisms (SNPs) and specific copy number variations (CNVs) such as the 22q11.2 deletion syndrome. We conclude that ToM is an important cognitive endophenotype for consideration in future studies addressing the complex genetic architecture of schizophrenia, and may help identify more homogeneous clinical sub-types for further study

Theory of mind (ToM) refers to the cognitive ability of inferring agency, intentions, and beliefs that oneself and others hold and is thought to underlie much of what we consider to be unique about our species. The term was first coined by Premack and Woodruff (1978) in their seminal work with chimpanzees, investigating whether they had a ‘theory of mind’. The ability appears to have flourished in homo sapiens, possibly as an adaptation to increasingly complex social situations (Brothers 1990) and may be responsible for our astounding success over the past 150,000 years (Byrne & Bates 2007). Larger social group size is associated with increased neocortical size in the great apes, offering support for the social brain hypothesis in explaining the evolution of human cognitive abilities (Dunbar 2003). It has also been hypothesized that schizophrenia may be the costly by-product of social brain evolution. Burns (2006), a proponent of the social brain hypothesis, argues that human brain evolution has favored the abilities which allow us to maneuver successfully in a social environment, allowing homo sapiens to adapt and flourish in an unstable environment through collaboration and cooperation. He argues that the same genetic factors responsible for these social cognitive abilities may also be responsible for psychosis.

Our ability to infer mental states is apparent from an early age and although ToM is not thought to fully develop until age four to five (Wellman et al. 2001), the precursors, such as gaze following (Farroni et al. 2004) and face recognition (Valenza et al. 1996) have been observed in newborns. ToM deficits have been shown in a number of disorders including neuropsychiatric (e.g., bipolar disorder; (Bora et al. 2009b), neurodegenerative (e.g., frontotemporal dementia; (Gregory et al. 2002), neurodevelopmental, especially autistic spectrum disorders (ASDs) (Baron-Cohen et al. 1985), and acquired neurological disorders, such as following frontal lobe damage (Muller et al. 2010). In the last two decades, following the proposal of Frith (1992), ToM deficits have been suggested as key cognitive aspects of schizophrenia. Frith (1992) postulated that ToM is dysfunctional in people with schizophrenia and suggested it may be responsible for their difficulty monitoring mental states, both their own and others. He described schizophrenia as a disorder of self-monitoring and self-awareness and hypothesized that ToM deficits would be apparent, especially in those patients displaying positive symptoms such as hallucinations, thought broadcast and insertion, and delusions of control, reference, or persecution.

Genetics of schizophrenia

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

Schizophrenia is a highly heritable disorder with twin studies showing a heritability rate of approximately 80% (Cardno & Gottesman 2000; Sullivan et al. 2003). Although several environmental factors have been shown to influence rates of schizophrenia (Matheson et al. 2011), the strongest predictor is having relatives with the disorder (Sullivan et al. 2003). This has resulted in much endeavor to identify both common and rare genetic variants that together result in an individual being susceptible to the disorder. Several genome-wide association studies (GWAS) have been conducted (Owen et al. 2010) and although there have been several variants identified and replicated, a significant proportion of the heritability remains unknown. A GWAS conducted by Lee et al. (2012) (schizophrenia: 9087; controls: 12,171) has shown a substantial polygenic component associated with disease risk, and they estimate that 23% of variation in liability to schizophrenia is captured by commonly occurring single nucleotide polymorphisms (SNPs). Further evidence exists for a polygenic explanation of schizophrenia (Purcell et al. 2009), suggesting that schizophrenia may be the costly by-product maintained due to the individual advantages of genes that only result in disorder once a threshold has been reached. This offers a possible solution to the paradox of a disorder that results in reduced fecundity but is maintained at a steady rate in the population. In addition to SNPs, larger genomic variants have also been implicated in schizophrenia predisposition: for example, the International Schizophrenia Consortium (Consortium 2008) (schizophrenia: 3391; controls: 3181), identified large (>100kb), rare (<1% of population) chromosomal deletions and duplications associated with a 1.15-fold increase in the risk of schizophrenia. Large GWAS have helped to portray the genetic complexity of schizophrenia, but much work is still needed. Schizophrenia is a complex disorder or group of disorders and the genetic evidence to date suggests that overt disease is only expressed once a hypothetical threshold of liability is reached (Gottesman & Shields 1966). Given the complexity of the clinical phenotype, investigating endophenotypic or intermediate traits (e.g. neuropsychological and neuroimaging) that are both correlated with disease and situated closer to the genotype, may aid discovery and increase our understanding of how the complex genetic architecture influences schizophrenia.

Another important set of findings supports the existence of a shared genetic liability between schizophrenia and other mental disorders. A number of the common SNPs and rare structural variants identified in schizophrenia have also been associated with bipolar disorder (Purcell et al. 2009), autism (Weiss et al. 2009; Sebat et al. 2007), mental retardation (Mefford et al. 2008; Sharp et al. 2008), and attention-deficit hyperactivity disorder (ADHD) (Williams et al. 2010). These findings lend further support to the use of an endophenotypic approach as a number of these disorders also share cognitive and neurophysiological dysfunctions (Millan et al. 2012) including ToM deficits (Baron-Cohen et al. 1985; Bora et al. 2009b; Thirion-Marissiaux & Nader-Grosbois 2008; Uekermann et al. 2010). ToM dysfunction and the neural systems responsible have been investigated in schizophrenia in a number of studies using different tasks. The following review will summarize the behavioral, functional and structural imaging findings, and assess the evidence for ToM functioning as a trait marker and its suitability as an endophenotype in genetic studies of schizophrenia. Moreover, it will review the first studies to associate specific genetic/genomic variants with ToM functioning across psychiatric diagnostic boundaries, focusing on candidate genes with suggestive or genome-wide significant association with schizophrenia.

ToM functioning

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

ToM is now thought to encompass two components: mental state decoding or social-perceptual ability and mental state reasoning or social-cognitive ability (Tager-Flusberg & Sullivan 2000). Social perceptual ability refers to the ability to detect socially relevant stimuli such as gaze or gesturing. A study using a gaze judgment task found individuals with schizophrenia are more likely to misinterpret the direction of another persons gaze, specifically when the gaze is not directed at them (Hooker & Park 2005). Difficulty imitating hand gestures or facial expressions has also been identified in individuals with schizophrenia (Park et al. 2008). Social perceptual ability may also refer to implicit or online metalizing. Tasks such as the Triangles Task (Castelli et al. 2000) allow ToM to be measured without relying on explicit responses that may rely on executive systems. The task involves viewing triangles moving around a screen with the interaction being random, goal-directed (physical), or socially complex (mental). When asked to describe the animations used in the Triangles Task, individuals with schizophrenia who scored highly on negative or paranoid scales were less accurate in determining the correct interaction. All schizophrenia patients used inappropriate language when asked to describe the scenes compared with healthy controls (Russell et al. 2006).

The ability to represent the mental state of others and understand that these may differ from your own underlies the key cognitive aspect of ToM functioning or mental state reasoning. This has predominantly been examined using a false-belief task, where the false-belief of another requires a representation that is distinct from the participant's own representation or belief. One of the most established and well-known tests for assessing false-beliefs is the Sally-Anne test (Wimmer & Perner 1983). Sally places a marble in her basket and leaves the room. Whilst she is out of the room, Anne takes the marble and puts it in her own box. Sally returns and the subject is asked, ‘where will Sally look for the marble?’ The correct answer being in her basket, indicating that the subject was able to take an alternative perspective. Children under four generally fail this test and children with autistic spectrum disorder do not reach the same level of performance until later in development (Baron-Cohen 1991). The key cognitive capacity required by the subject is the ability to meta-represent Sally's mental state (‘the marble is in the basket’ and realize that she will hold a view differing from both her own and reality (‘the marble is in the box’). Numerous studies have found ToM deficits in schizophrenia using first-order ToM tasks especially for those patients with negative symptoms (Corcoran et al. 1995, 1997; Frith & Corcoran 1996; Pickup & Frith 2001), although not all (Pickup & Frith 2001).

It is often not sufficient to merely represent the beliefs that another person has about a particular situation as tested in first-order belief tests such as the Sally-Anne. In most human interactions it is necessary to understand the beliefs that someone else has about another person's belief and so on. This recursive inference allows for complex social interaction and aids in collaborative endeavor. This can be measured using a second-order belief test that assesses a subject's ability to understand that one person has a false-belief about another's belief. In a study involving 46 symptomatic schizophrenia patients and 44 non-symptomatic controls, Frith and Corcoran (1996) found that patients with positive symptoms (paranoid delusions) were impaired on questions pertaining to first and second-order false beliefs using short stories read aloud. Patients with behavioral signs (incoherence or negative symptoms) were impaired on false belief tasks but this deficit was confounded by memory problems. Patients with symptoms of passivity (e.g. delusions of control) and those in remission showed no deficit compared with controls. Doody et al. (1998) also studied first and second-order belief in subjects with schizophrenia and normal pre-morbid IQ, schizophrenia with low pre-morbid IQ (mild learning disability range), affective disorder (unipolar and bipolar depression), mild learning disability with no history of psychiatric illness, and healthy controls. They found that impaired ToM is unique to schizophrenia on second-order false belief tasks and that the deficit is greater in subjects with low pre-morbid IQ. Drury et al. (1998) also used second-order false belief tasks but found that patients in remission no longer showed ToM deficits and also improved on a memory task, suggesting that ToM abilities may be confounded by attention and memory ability. Understanding irony is another technique used to assess second-order false beliefs. Mitchley et al. (1998) reported that schizophrenia patients were impaired in the understanding of irony and although associated with lower IQ, this deficit remained significant after IQ was controlled for. Herold et al. (2002) investigated first and second-order ToM tasks as well as tests of metaphor and irony in 20 paranoid schizophrenia patients in remission and 20 healthy controls. They observed that the ability to correctly interpret irony was the main difference between patients and controls. Understanding metaphor, irony, and faux pas are examples of higher-order false belief tasks where subjects are required to infer the true meaning of utterances or short stories. Langdon et al. (2002) reported that people with schizophrenia are significantly worse at appreciating irony and metaphor than healthy controls and found that both made independent contributions to discriminating patients from controls. Moreover, patients with positive thought disorder (derailment, tangentiality, incoherence, illogicality, circumstantiality, pressure of speech, distractible speech and clanging) were impaired on the metaphor task whilst patients with negative thought disorder (poverty of speech, poverty of content of speech, blocking and increased latency) showed deficits in the irony task. This highlights the intricacy of mentalizing abilities and emphasizes the need to study clinical subtypes in schizophrenia research, especially involving ToM. There are excellent reviews by Brune (2005) and Harrington et al. (2005) that offer a comprehensive outline of ToM and schizophrenia and should be referred to for a more comprehensive review of the behavioral aspects of ToM functioning in schizophrenia.

Independence of ToM from other cognitive domains

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

There is continuing debate about the independence of ToM functioning and whether a separate ToM network or module exists (e.g. (Carrington & Bailey 2009). The majority of the research has focused on autism due to ToM deficits being considered central to the disorder and the seminal work carried out in the 1980s. It was found that children with autism perform worse than children with other neurodevelopmental disorders on tasks that test concepts of false belief whilst performing comparably on other tests of cognitive ability, such as the British Picture Vocabulary Scale or the Leiter International Performance Scale (Baron-Cohen et al. 1985; Baron-Cohen 1989). A number of studies aimed to establish the independence of a ToM mechanism or module (ToMM) with Leslie and Frith (1990) suggesting that a deficit in the ToMM would result in domain-specific cognitive impairments such as (1) an impairment in the normal capacity to develop propositional attitude concepts; (2) difficulty with representing imaginary situations in relation to agents' attitudes; (3) difficulties with processing metarepresentations. These domain-specific impairments in autism have attracted some support (Leslie & Thaiss 1992; Leslie 1994), while more general measures of cognitive functioning have been observed to be dissociated in autism (Doody et al. 1998; Pickup & Frith 2001), bipolar disorder (Wolf et al. 2010) and tic disorder (Channon et al. 2004).

Several studies have examined both ToM and executive functioning in schizophrenia with mixed results depending on the tasks and groups assessed. Langdon et al. (2001) investigated the executive dysfunction hypothesis as an explanation for poor performance on ToM tasks and hypothesized that two executive functions would likely explain the deficits: (1) the ability to disengage and inhibit salient information and (2) the ability to manipulate representations of hypothetical situations. A false-belief picture-sequencing task was administered, measuring ToM, as well as a picture-sequencing task requiring the participant to disengage from salient information, and the Tower of London task to measure executive planning. Ability to infer false-belief picture sequencing remained a valid predictor of patient status after adjusting for performance on both executive functioning tasks as well as a task measuring visual memory. Several studies support ToM deficits as specific rather than as a result of a general cognitive deficit with evidence available across numerous ToM tasks (Brunet et al. 2003; Corcoran et al. 1995, 1997; Frith & Corcoran 1996; Mitchley et al. 1998; Sarfati & Hardy-Bayle 1999). A meta-analysis (Pickup 2008) concluded that ToM functioning remained a valid predictor of schizophrenia status after executive functioning was corrected for, but highlighted the importance for future fMRI studies to investigate executive functioning and ToM networks in the same sample in order to show dissociable neural networks. Another meta-analysis (Bora et al. 2009a) also found that general intellectual deficits partially contributed to ToM functioning in participants with schizophrenia, but only in those in remission.

As schizophrenia is associated with a decline in cognition across multiple domains, it can be difficult to determine if any one specific aspect is relevant to the disease process or outcome. However, McGlade et al. (2008) found that performance on The Eyes Task remained a significant predictor of social outcome after accounting for the variance predicted by symptom severity and verbal IQ. This finding, coupled with further evidence of social cognition mediating the relationship between cognitive and social functioning (Addington et al. 2006), suggests that ToM, in particular perceptual or decoding ToM, is an important cognitive aspect in understanding schizophrenia. A systematic review by Mehta et al. (2013), of nine studies that had applied a factor analysis to both social and neurocognition in schizophrenia, concluded that they represented distinct cognitive factors, with only one of the nine studies not supporting the separateness of the two dimensions. Further, they looked at factors within social cognition but found inconsistencies within the literature and suggested scope for future research.

As ToM is only one component within the broader construct of social cognition, it is important to consider the dissociation and overlap with other aspects such as empathy, emotion processing, face recognition, and attribution bias. Empathy is often erroneously used interchangeably with ToM. Whilst ToM refers to our ability to understand and internally represent the mental states of oneself and others, empathy refers to our ability to share feelings and sensations. For example, one could feel sad if witnessing that another is sad (empathy), but not understand why that person is sad (ToM). In addition to ToM deficits, patients with schizophrenia also show deficits on tasks measuring empathy (Derntl et al. 2009). Empathy has been found to rely on sensorimotor regions as well as limbic and paralimbic structures, whereas ToM recruits temporal and prefrontal regions (Singer 2006). An example of this neural dissociation is apparent in an fMRI study of healthy adults by Vollm et al. (2006). They found the amygdala, paracingulate, and anterior and posterior cingulate cortex were recruited when viewing cartoons requiring empathy whereas the cartoons requiring ToM recruited bilateral orbitofrontal, middle frontal gyrus, cuneus, and superior temporal regions. Both tasks recruited temporoparietal and ventromedial cortices, as well as bilateral temporal poles. Using the same task as Vollm et al. (2006) in patients with schizophrenia, Benedetti et al. (2009) observed that regions of the posterior temporal lobe (BA 22 & 42) were both functionally and structurally associated with deficits in ToM and empathy, but that more research is needed using a range of empathy and ToM measures.

Perceptual aspects of social cognition are also impaired in schizophrenia, suggesting a dysfunction early in the decoding of social information that may be important to understanding higher-level ToM deficits. A meta-analysis of 112 studies assessing social cognition in schizophrenia by Savla et al. (2012) found consistent deficits on a wide range of social cognition tasks in patients, with large effect sizes for social perception (Hedge's g = 1.04), emotion perception (g = 0.89), emotion processing (g = 0.88), as well as ToM (g = 0.96). A meta-analysis of 28 studies by Chan et al. (2010) concluded that patients with schizophrenia have moderate to severe impairment in perception of facial emotion, with others showing similar findings using auditory emotion cues (Gold et al. 2012). Interestingly, de Achaval et al. (2010) found that, unaffected relatives and healthy participants' scores on a ToM task and facial emotion task were significantly correlated, but not in patients with schizophrenia, concluding that patterns of social cognition deficits may be different in patients.

Attributional bias is another key social cognitive aspect, especially for the formation of persecutory or paranoid delusions (Garety et al. 2001). An externalizing bias (blaming negative events on external factors) coupled with a personalizing bias (blaming others rather than circumstance) leads to the formation of persecutory or paranoid beliefs. ToM had been suggested as a key cognitive mediator, especially for personalizing bias, with a dysfunctional ToM compromising a more difficult situational explanation to be reached (Bentall et al. 2001). However, a study by Langdon et al. (2006), provided evidence that personalizing bias and ToM were not associated and may represent separate aspects of social cognition.

Although much work is required to determine the independence of ToM functioning the distinct neural networks associated with ToM tasks, discussed later in this review, provide further evidence that functioning in this domain will not be completely explained by functioning in other cognitive domains. However, further evidence is required to explore the nature of the relationship between ToM and neurocognition, including other aspects of social cognition, the underlying neural architecture, and its relevance to schizophrenia.

Importance of ToM as an endophenotype of schizophrenia

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

The finding that ToM deficits are present in schizophrenia has inevitably led to ToM being evaluated as an endophenotype for use in genetic studies. There remains doubt as to whether ToM fulfills criteria for valid endophenotype status, suggested by Gottesman and Gould (2003). For a biomarker to be relevant to understanding the underlying genetic architecture of a disorder, it must: (1) be associated with illness in the population; studies above seem to confirm that ToM fulfills this criterion; (2) be heritable; conflicting evidence exists as to the genetic influence on ToM variation in healthy children, with evidence for genetic influences (Hughes & Cutting 1999) countered with evidence for largely shared and non-shared environmental factors (Hughes et al. 2005). Recent studies finding genetic associations with ToM functioning (Xia et al. 2012), strengthen the evidence for a genetic component to ToM functioning; (3) be state-independent (i.e. manifest in an individual whether or not illness is active, namely prior to disease onset and during remission). There is some debate as to whether ToM deficits in schizophrenia are state or trait related. Frith (1992) initially proposed that ToM deficits were state related and found that deficits were not apparent when the patients remitted (Frith & Corcoran 1996). However, several studies have suggested otherwise. Herold et al. (2002) found significant ToM deficits remained in remitted patients on a task involving the interpretation of conversations involving irony. Although this was only a small study, it was the first to suggest that ToM deficits are not only apparent in the acute phase and that ToM may be a valuable endophenotype of schizophrenia. Several other studies have investigated ToM deficits in schizophrenia with the majority showing that deficits remain in remitted patients. Two meta-analyses (Bora et al. 2009a; Sprong et al. 2007) also confirmed that ToM deficits are evident in remitted patients suggesting state independence and fuelling interest in ToM as a trait marker. However, Bora et al. (2009a) cautioned that the exact nature of remission was not clearly documented in a number of the studies included in the meta-analyses and therefore residual symptoms may persist and influence ToM functioning; (4) co-segregate with illness in families; to date, this has not been addressed; (5) be found in unaffected family members at a higher rate than in the general population, but lower than in affected family members. Irani et al. (2006) studied ToM deficits using a Mind in the Eyes Test (Baron-Cohen et al. 2001) in first-degree relatives of people with schizophrenia, and observed that those relatives with high schizotypal scores according to the Schizotypal Personality Questionnaire (SPQ, (Raine 1991), attained deficits intermediate between those with schizophrenia and healthy controls. This supports previous research by Janssen et al. (2003) who also showed intermediate deficits in non-psychotic relatives using a hinting task but suggests that intermediate ToM deficits may be associated with subclinical symptoms in relatives. Others, using different measures of ToM have also shown intermediate effects in relatives (Anselmetti et al. 2009; de Achaval et al. 2010, 2011).

Compared with ToM behavioral tasks there has been a paucity of research into the neural activation associated with ToM in those at genetic risk for developing schizophrenia or relatives of those affected. Marjoram et al. (2006) first addressed this issue using a visual joke fMRI paradigm in an age and IQ-matched cohort of high-risk subjects. The high-risk group was defined as having two or more first or second-degree relatives with schizophrenia and was divided into those who had experienced psychotic symptoms and those who had not. They found both state and trait mediated effects and interpreted their findings as evidence for an impaired neural circuit for ToM in those at high risk of developing schizophrenia. They suggested that those at high-risk over-activated alternate neural circuits in the frontal cortex (BA6 and 8) compared with controls and that this system fails in the presence of psychotic symptoms.

A more recent study by Brune et al. (2011) investigated neural activation in a group of prodromal, at-risk subjects in comparison with manifest schizophrenia and healthy controls using a picture sequencing task and questionnaire. They also observed that those at high-risk over-activated regions in the posterior cingulate cortex, temporal areas, and precuneus compared with controls, but showed greater activation in the prefrontal, limbic, and temporo-parietal areas than those with manifest schizophrenia. Further evidence for ToM networks being considered a trait marker for schizophrenia is provided by the study carried out by de Achaval et al. (2011). They found that siblings discordant for schizophrenia showed decreased activity in structures associated with the ToM network. Using a ‘ToM in the faces’ paradigm they found that both patients and their unaffected siblings failed to activate areas in the right hemisphere of the previously established ToM neural network compared with healthy controls. The fact that unaffected relatives showed activation intermediate between that shown by schizophrenia patients and healthy controls supports ToM as an endophenotype.

People who score high on schizotypy scales also show deficits in ToM functioning (Pickup 2006). Modinos et al. (2010) compared the neural activation between high and low scorers on the positive-dimension of the Community Assessment of Psychic Experiences questionnaire (CAPE) using a task that involved the ability to judge mental states based on verbal and eye-gaze cues. They found that the ‘high psychosis proneness’ group recruited a region within the anterior PFC (BA 10) to a greater extent in a second-order task compared with first-order tasks compared with controls. The authors suggest that this increase is evidence of impaired ToM circuitry and could represent an area of interest for schizophrenia proneness. They also found increased activation in dorsal and ventral PFC (BA 9/46) similar to the findings of Russell et al. (2000) who showed less activation in these regions when participants were making errors. The results from this study add further evidence that alterations in ToM circuitry may be associated with proneness to psychosis and should be considered trait markers of schizophrenia.

Neural activation associated with theory of mind tasks in schizophrenia

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

ToM and other social cognition tasks have been investigated in a large number of fMRI studies using both healthy and clinical populations. A consistent pattern of activation across studies involving the mPFC, TPJ, aCC, precuneus, left inferior frontal cortex, insular, and superior temporal gyrus has resulted in this network being referred to as the ‘social brain’ (Frith & Frith 2007) (see Fig. 1), with a meta-analysis suggesting that mPFC and TPJ are particularly important for ToM with tasks involving integration of social information activating the mPFC and the TPJ recruited in order to infer intentionality and goals at a relatively perceptual level (Van Overwalle 2009).

image

Figure 1. The social brain. Areas shaded in black represent areas consistently activated in ToM tasks in healthy controls and include temporoparietal junction (TPJ), precuneus (PC), medial preformtal cortex (mPFC), left inferior frontal cortex (lIFC), superior temporal gyrus (STG). Arrows indicate regions showing hypoactivation in the thalamus (Th), middle temporal gyrus (MTG), and mPFC, and hyperactivation in the posterior cingulate cortex (pCC), somatosensory cortices (SSC), and the STG in schizophrenia patients compared with controls according to the meta-analysis by Sugranyes et al. (2011).

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A number of studies have shown neural activation differences between schizophrenia patients and healthy controls with a meta-analysis suggesting reduced activation in the mPFC, middle temporal gyrus, and the thalamus and increased activation in the pCC, superior temporal gyrus, and within the somatosensory cortices in the paracentral lobule (Sugranyes et al. 2011) (see Fig. 1). This pattern of activation suggests that schizophrenia patients may be overly sensitive to perceiving agency and intentions represented by the increased activation in the sensory and perceptual aspects of ToM, but may be unable to integrate this information with higher cognitive functions as highlighted by the hypoactive mPFC. This could be particularly important in patients with predominantly positive symptoms. However, patients with paranoid schizophrenia showed reduced activation in both mPFC and right TPJ compared with healthy controls when viewing a series of cartoon strips representing a social intention (e.g. someone preparing a romantic dinner). Hyperactivation in the mPFC and TPJ was shown in the physical condition (e.g. wind blowing over a glass) compared with healthy controls, with the authors suggesting that this may represent evidence of a hyperactive intention detector that fails to deactivate when viewing socially neutral or intention-free scenes (Walter et al. 2009).

An fMRI study by Brune et al. (2008) compared nine schizophrenia patients with passivity symptoms (voice-commanding hallucinations, persecutory delusions, thought insertion, or transference) with thirteen healthy controls on a similar cartoon based ToM task. Although performance on the ToM measure was not significantly different between the groups, activation differences were found. Hypoactivation of anterior regions, such as the right aCC, insula, thalamus, and striatum characterized patients compared to controls, with hyperactivation in the somatosensory cortices in the paracentral lobule, middle and superior temporal gyrus, precuneus, thalamus, left supramarginal gyrus, and right frontal middle frontal gyrus. The authors noted that the regions under-activated were typical of tasks measuring ToM and the regions are consistently involved in thought requiring self-reference and may explain the passivity symptoms experienced by these patients.

Neuroimaging studies investigating ToM functioning in schizophrenia have tended to investigate explicit ToM functioning, where the participant has to retrospectively infer the mental states of others and apply this to a question at hand. This adds a cognitive demand and tends to recruit regions in the mPFC and the temporo-parietal junction (Amodio & Frith 2006; Saxe & Wexler 2005). Perhaps a more ecologically valid approach is to look at implicit ToM functioning where the participant is automatically inferring the mental state of others and is doing it ‘online’ without having to retrospectively attribute mental state on instruction. Using the Triangles Task (Castelli et al. 2000), Das et al. (2011) showed that male patients with schizophrenia showed significantly diminished activity in the right superior temporal gyrus, at the temporo-parietal junction, and bilaterally within the inferior frontal gyri when watching a mental interaction between two triangles compared with random movement. Using the same task, Pedersen et al. (2012) observed that the ToM network might be delayed in schizophrenia. They split the 24-second animations into two and compared activation between those with schizophrenia and age- and sex- matched controls, finding that the patient's activation in the second half of the animations matched those of the healthy controls in the first half. The authors suggest that patients took longer to activate higher-level ToM processes than controls, although this fails to explain the difference in accuracy in correctly inferring the interaction between the triangles, seen between patients and controls.

The default mode network (DMN) describes a number of brain regions found to connect both functionally and anatomically with recent evidence suggesting that this network is dysfunctional in schizophrenia (Whitfield-Gabrieli et al. 2009) as well as other psychiatric conditions (Broyd et al. 2009). This network has been strongly associated with ToM functioning with studies showing significant activation in this area when performing ToM tasks (Das et al. 2012; Spreng & Grady 2010). For example, Spreng and Grady (2010) found activation in the DMN associated with ToM, autobiographical memory, and thinking about future events with ToM tasks showing greater activation in lateral DMN areas. With autobiographical memory dysfunction observed in schizophrenia (Riutort et al. 2003) as well as recent studies showing deficits in future thinking (D'Argembeau et al. 2008; Raffard et al. 2010), the DMN could be a key network in understanding the disease. Genetic control over both the structure and connectivity of the DMN (Glahn et al. 2010), evidence of hyperactivity and hyperconnectivity of the network in first-degree relatives (Whitfield-Gabrieli et al. 2009), as well as those with schizophrenia (Broyd et al. 2009; Whitfield-Gabrieli et al. 2009), provides strong evidence for the DMN to be considered in schizophrenia endophenotype studies, especially those focusing on ToM.

Structural differences associated with theory of mind in schizophrenia

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

Most studies investigating neural correlates of ToM functioning use functional imaging and observe predicted patterns of altered activation in ToM networks. However, some studies show reduced and others increased activation, leading to interpretation difficulties. Functional aspects, such as performance, attention, and motivation, do not confound structural imaging, and thereby provide a useful ally to functional studies.

Benedetti et al. (2009) looked at both functional and structural correlates of ToM functioning in schizophrenia using a cartoon task. Functionally, the results were similar to those found in Brune et al.'s (2008) study, with significant difference in activation in the right posterior superior temporal lobe, left TPJ and temporal pole, and white matter adjacent to the mPFC. They then investigated structural differences in these regions and found grey matter reduction in patients compared with controls in the right posterior superior and transverse temporal gyrus. In the same areas, reduced performance on the ToM task also correlated with lower grey matter volume. The authors suggest that the deficit in ToM observed in schizophrenia is due to a structural deficit within core areas of the ToM neural network effected during the early stages of the disease process.

Extensive research demonstrates that cortical volume reduction occurs after the onset of illness (DeLisi 2008; Salisbury et al. 2007). Herold et al. (2009) investigated the association between ToM deficit and structural abnormalities within 18 people within the early stages of schizophrenia (<5 years) and 21 healthy controls. The ToM task involved a faux pas task administered outside the scanner. Structural data was acquired using T1-weighted structural volumes using a 1T scanner. After controlling for differences related to IQ and total intracranial volume, faux pas scores were associated with gray matter density reduction in right medial frontal gyrus, left orbitofrontal superior gyrus, left inferior temporal gyrus and bilaterally in temporal poles. Using the mind in the eyes task, Hirao et al. (2008) also found that prefrontal cortical reduction, specifically grey-matter in the left ventrolateral PFC, predicted ToM performance.

Hooker et al. (2011) furthered the evidence for the vMPFC being important for ToM functioning, using both performance-based and self-report measures. In a group of 21 people with schizophrenia or schizoaffective disorder and 17 healthy controls and using T1-weighted images acquired with a 4T scanner, they found that vMPFC grey matter density was reduced in schizophrenia and this correlated with ToM functioning assessed through both methods.

Genetic associations with ToM functioning

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

The increasing interest in endophenotypes of psychiatric disorders has led research into the association between cognitive functioning and genetic markers for disease. However, although a number of studies (Gur et al. 2007) have addressed the relationship between cognitive domains such as working memory, executive functioning, and memory, few have investigated ToM functioning. Evidence from genetics and neuroscience has led researchers to think outside traditional diagnostic categories and instead look at the underlying genetic, cognitive, and neural circuitry. As a number of common and rare genetic variants are associated with more than one psychiatric disorder (Smoller et al. 2013) and with ToM deficits also shared, it is pragmatic to address the genetic associations with ToM across diagnostic boundaries. Examples of genes acting across diagnostic boundaries to influence shared cognitive traits implicated in the disease process is encouraging for the validity of the endophenotypic approach to psychiatric genetics and provides support for the National Institute of Mental Health's (NIMH) approach of moving away from traditional diagnostic boundaries (Morris & Cuthbert 2012). One genetic variant that has been associated with ToM functioning within clinical patients is the oxytocin receptor gene (OXTR). Single SNPs and haplotypes within the OXTR were found to be associated with ASD and total score on the Vineland Adaptive Behaviour Scales (VABS) in a cohort of ASD children and their families (Lerer et al. 2008). Further research in a cohort of children with Attention Deficit Hyperactivity Disorder (ADHD) found that the AA genotype at SNP rs53576 or TT genotype at SNP rs13316193 within the OXTR gene was associated with better social ability as rated on the Social and Communications Disorders Checklist (SCDC) (Park et al. 2010). Although the evidence for association between schizophrenia and polymorphisms in the OXTR gene is inconclusive (Souza et al. 2010; Teltsh et al. 2012), investigating the association between OXTR and ToM may help explain social deficits apparent in schizophrenia. It has been suggested that the effect of oxytocin on social behavior is mediated by the amygdala and its dopaminergic connections (Rosenfeld et al. 2011). As the dopaminergic system is widely considered to be dysfunctional in schizophrenia associations between genetic variants impacting dopamine functioning and aspects of social cognition should be further explored (Table 1).

Table 1. Schizophrenia candidate genes/genomic regions and association with ToM functioning
Gene/GenomicregionAuthorClinical groupStudy typeNFindings
OXTR(Lerer et al. 2008)ASDClinical152In children and young adults with ASD, SNPs within the OXTR gene (rs4686301 and rs6770632) associated with social functioning as measured by the Vineland Adaptive Behavior Scales (VABS).
OXTR(Park et al. 2010)ADHDClinical112In children with ADHD, 2 SNPs within the OXTR gene (rs53576 and rs13316193) were associated with better social ability as measured by the Social and Communication Disorders Checklist.
DRD4(Lackner et al. 2012)Healthy ChildrenCognitive73In typically developing preschool children, carriers of the shorter allele in the DRD4 gene outperformed those with one or more longer alleles on tasks measuring representational ToM but not other measures of cognition.
COMT(Xia et al. 2012)Healthy AdultsCognitive101In healthy adults, 2 SNPs within the COMT gene (rs2020917 and rs737865) were associated with cognitive-ToM and 1 SNP (rs5993883) was related to affective-ToM.
COMT(Bassett et al. 2007)22q11.2DSCognitive73In patients with 22qDS, carriers of the Met allele outperformed those with the Val allele on a ToM task, Trails B, and olfactory identification, with comparative performance on the majority of other cognitive tasks used.
5-HT1A-receptor(Bosia et al. 2011)SZCognitive118Patients with the CC genotype in the promoter region (-1019) of the 5-HT1A-R gene, performed better on a ToM picture sequencing task but not on other cognitive tasks measuring a broad range of cognitive domains.
DAOA(Schultz et al. 2011)SZ/HCMRI52/42In schizophrenia patients with the DAOA Arg30Lys risk variant, reduced cortical thickness was found in areas crucial for ToM functioning, middle temporal, inferior parietal, and lateral occipital cortical areas. No effect found in healthy controls.
ZNF804A(Lencz et al. 2010)Healthy AdultsMRI39Risk allele carriers showed reductions in grey matter in regions comprising the ‘default mode network’.
ZNF804A(Walter et al. 2011)Healthy AdultsfMRI109Carriers of the ZNF804A schizophrenia risk allele showed a risk allele dose effect on neural activity in the medial prefrontal cortex, left temporo-parietal cortex, left inferior parietal cortex, and left inferior cortex. Suggestive evidence for reduced functional connectivity between frontal and temporo-parietal regions in risk allele carriers.
ZNF804A(Hargreaves et al. 2012)SZ/Healthy AdultsCognitive418/200No association between ZNF804A risk alleles and ToM in a large sample of SZ and healthy participants.
22q11.2DS(Niklasson et al. 2002)22q11.2DSCognitive20ToM deficits were apparent in patients with 22qDS but results were hard to interpret, as there was no comparative group or normative data available.
22q11.2DS(Chow et al. 2006)22q11.2DS with psychosis/ 22q11.2DS without psychosisCognitive27/29The presence of psychosis in patients with 22qDS showed significantly greater deficits across a wide range of neuropsychological tasks. The ToM task was found to have the greatest deficit within the tasks measuring social cognition.
22q11.2DS(Campbell et al. 2011)Children with 22q11.2DS/ Healthy ChildrenCognitive50/31Children with 22q11.2 DS showed a delay on social-cognitive tasks, specifically second-order false-belief and strange stories. Social-perceptual deficits within the 22q11.2 children were seen consistently across ages.
22q11.2DS(Jalbrzikowski et al. 2012)Adolescents with 22q11.2DS/Healthy ControlsCognitive31/31ToM was impaired in the 22q group and was the best predictor of positive symptoms.
22q11.2DS(Ho et al. 2012)Children and young adults with 22qDS/Healthy ControlsCognitive63/43The 22qDS group were impaired in the spontaneous attribution of mental states compared with typically developing controls

Genetic associations with ToM functioning have also been identified in normally developing preschool children, with those carrying the short allele of the DRD4 gene outperforming those with the long allele on several ToM tasks (Lackner et al. 2012). The catechol-O-methyltransferase (COMT) gene, important for dopamine metabolism, has also been associated with ToM performance in healthy Chinese adults, with the SNPs rs2020917 and rs737865 being associated with cognitive-ToM, whereas SNP rs5993883 was associated with affective-ToM (Xia et al. 2012). In patients with 22q11.2 DS, which affects the chromosomal region housing the COMT gene and is strongly associated with risk for schizophrenia, those with the Met genotype showed ToM deficits compared with those carrying the Val genotype (Bassett et al. 2007), again suggesting that dopamine may be important for ToM functioning.

Imaging genetics aims to identify structural and functional systems that mediate genetic vulnerability to mental disorders. The majority of functional imaging genetics studies in schizophrenia thus far have focused on working memory tasks (Meyer-Lindenberg & Zink 2007). However, due to the strong evidence for ToM deficits reflecting a trait marker for the disorder, genetic associations between schizophrenia risk alleles and ToM are being studied intensively. Bosia et al. (2011) examined the association between ToM ability and a 5-HT1A-receptor functional polymorphism in 118 participants with schizophrenia and observed participants with the CC genotype performed significantly better on a ToM picture sequencing task and this remained significant after accounting for other cognitive factors. Schultz et al. (2011) investigated the association between the glutaminergic regulatory gene risk variant DAOA Arg30Lys and brain structure in people with schizophrenia and healthy controls. They observed reduced cortical thickness in areas crucial for ToM functioning, namely the middle temporal, inferior parietal, and lateral occipital lobes, in schizophrenia patients only. Walter et al. (2011) investigated the neural activation during a ToM task and the association with a common variant within ZNF804A that has consistently shown strong evidence for susceptibility to schizophrenia. They found a significant risk allele dose effect in parts of the ToM network, the dorsomedial PFC and the left temporoparietal junction as well as in the human analogue of the mirror neuron system, the left inferior parietal cortex and the left inferior prefrontal cortex. They also found decreased functional connectivity between the right DLPFC and the left posterior temporal cortex and increased connectivity between the left temporoparietal junction and the left inferior PFC but the authors urged caution, as they were only significant at an uncorrected level. This was the first study to show genetic contribution to the neural network underpinning ToM functioning and offers support for both the endophenotypic approach to psychiatric genetics and for further investigation of neural networks associated with ToM and the association with genetic markers. Further support for ZNF804A in ToM functioning comes from evidence that carriers of the risk allele show reduced GM volume in regions comprising the ‘default mode network’, which shows considerable overlap with the ‘social brain’ (Lencz et al. 2010). Interestingly, patients with the risk variant show better cognitive performance on a range of neurocognitive tests shown to be impaired in schizophrenia (Walters et al. 2010), although initially a measure of ToM or other social cognitive task was not included. However, due to the findings of Walter et al. (2011) the sample was revisited and tested on two measures of ToM (Eyes of the Mind and Hinting tasks) but found no association with the risk allele in patients or controls (Hargreaves et al. 2012). However, attributional style was associated with the risk allele in healthy carriers, with higher personalizing bias in the risk carriers compared with non-carriers. The differing results between healthy participants and patients with schizophrenia serves as a warning against generalizing results across diagnostic boundaries, particularly concerning ZNF804A.

In addition to common risk variants, large rare copy number variants also offer an important avenue of research in the search for intermediate phenotypes that can further our understanding of how genes relate to behavior. In the area of schizophrenia research, the majority of this work has surrounded the deletion of chromosomal region 22q11.2, often referred to as velo-cardial facial syndrome (VCFS). Although a number of neurocognitive tasks have been employed in fMRI studies with 22q11.2 DS patients, as yet, no ToM tasks have been investigated. Social impairments are common in children with 22q11 deletions who are frequently described as being shy and withdrawn, socially immature, and as having difficulties initiating and maintaining positive peer relations (Golding-Kushner et al. 1985). They also present with high rates of psychiatric illness such as autistic spectrum disorder, affective disorders, and many (˜30%) later develop schizophrenia (Karayiorgou et al. 2010). The first study to address ToM deficits in 22qDS was conducted by Niklasson et al. (2002), who reported deficits, but with no control group or normative data, the results were not interpreted. Chow et al. (2006) looked at neurocognitive differences between 22qDS patients with and without psychosis. The differences were similar to those seen between patients with schizophrenia and healthy controls and the authors concluded that 22qDS was an excellent candidate for genetic models of schizophrenia. ToM functioning in the psychosis group showed the greatest deficit within the social cognitive tasks and overall along with verbal memory recall and bilateral motor control. Campbell et al. (2011) looked at both perceptual and cognitive aspects of ToM in children with 22qDS in comparison with typically developing controls. Whilst perceptual ToM remained impaired regardless of age, cognitive ToM deficits in 22q were only observed in the younger children, suggesting a delay rather than a continuing dysfunction. Deficits on an implicit ToM task have also been observed in 22qDS (Ho et al. 2012). Therefore, investigating the neural activation associated with ToM in patients with 22q11 syndrome could increase our knowledge of the ToM network, its relevance to the 22q11 deletion syndrome, and its importance to genetic models of schizophrenia more broadly. A single gene copy number variant associated with schizophrenia is the neurexin-1 (NRXN1) deletion (Kirov et al. 2009), which has also been associated with autism (Kim et al. 2008), marking NRXN1 as an excellent candidate for endophenotypic research. Encouraging evidence for the role of NRXN1 in social cognition has been provided in a study using NRXN1 knockout mice. Mice homozygous for NRXN1 had altered social approach and reduced social investigation (Grayton et al. 2013). As the NRXN1 deletion has been implicated in a range of neuropsychiatric disorders such as the ASDs, speech delay, intellectual disability, and schizophrenia, ToM deficits may be a common characteristic across diagnostic boundaries. Several other CNVs that have been associated with schizophrenia (1q21.1, 15q13.3, 16p11.2, 16p13.1, 17p12, and 22q13.3) have also been associated with the ASDs (Sebat et al. 2009), and ToM deficits as well as other social cognition tasks warrant further investigation. It is unclear to what degree these disorders overlap neurobiologically (Crespi et al. 2010). Studying ToM, a key deficit in autism, as well as other neurocognitive domains and structural markers, could provide evidence concerning the true nature of the relationship between autism and schizophrenia.

A great deal of caution must be taken when interpreting the evidence for ToM or other cognitive domains as endophenotypes of schizophrenia, based on findings from candidate gene studies. A number of the genes used in candidate gene studies are unlikely to remain as significant predictors of disease risk in large genome-wide association studies. Therefore, whilst gene variants may be associated with social functioning in people with schizophrenia and other psychiatric disorders, they will not directly assist in explaining the genetic influence on the risk of disease itself. As larger GWAS are completed, priority must be given to the common and rare variants with robust association with the disease itself in order to truly identify endophenotypes that may be disease specific or relevant across traditional diagnostic categories. Existing evidence from genetic variants with strong association with schizophrenia such as 22qDS and ZNF804A offer encouraging support for ToM to be assessed in other genes or genomic regions associated with schizophrenia.

Conclusions

  1. Top of page
  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References

As we come to more deeply understand the genetics of schizophrenia, a focus on the specific effects of both common and rare genetic variants on neurobiological and neuropsychological correlates, has begun in earnest. The purpose of this review was to present evidence for ToM functioning as a valid endophenotype of schizophrenia and to present the initial findings from studies linking genetic markers with social functioning. There are significant gaps in the literature regarding the genetic influence on ToM functioning and its potential use as an endophenotype. The nature of the cognitive process renders it difficult to use in animal studies, but simpler perceptual elements may be suitable as used in the NRXN1α knockout model mentioned above. The emerging field of epigenetics may also reveal how gene expression influences ToM functioning, and conversely, how social interaction feeds back to the molecular level and influences whether genes are ‘turned on or off’. For a detailed review on social genomics see (Slavich & Cole 2013). More fundamentally, the heritability of ToM functioning has not been sufficiently established and more work is required to confirm the status of ToM as a reliable endophenotype for schizophrenia research. Although ToM deficits are seen before the onset and in remission, this could be due to prodromal or residual aspects of psychosis. Research focusing on neural networks needs to include family members who share genetic risk and show that they lie intermediate to those with schizophrenia and non-related healthy participants. Understanding how genetic variants influence social functioning, the structures that underlie this ability, and its role in psychopathology, may play a vital role in understanding the complex relationship between genome and psychiatric phenotype. The importance of valid endophenotypes for mental illness has been underlined with the NIMH reorienting its research program away from DSM categories and towards Research Domain Criteria (RDoC). This dimensional approach aims to lay the groundwork for a diagnostic system that reflects the modern brain sciences. It aims to integrate genetics, neuroscience, and the behavioral sciences in order to better understand and ultimately treat mental illnesses (Morris & Cuthbert 2012). To date, few studies have addressed social functioning as a possible endophenotype of both common and rare schizophrenia associated genetic variants. Evidence from the ToM literature would suggest that ToM functioning and wider aspects of social cognition warrant consideration in studies attempting to show genetic association to endophenotypes of schizophrenia.

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  2. Abstract
  3. Genetics of schizophrenia
  4. ToM functioning
  5. Independence of ToM from other cognitive domains
  6. Importance of ToM as an endophenotype of schizophrenia
  7. Neural activation associated with theory of mind tasks in schizophrenia
  8. Structural differences associated with theory of mind in schizophrenia
  9. Genetic associations with ToM functioning
  10. Conclusions
  11. References
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