Perspective-taking abilities in the balance between autism tendencies and psychosis proneness

Difficulties with the ability to appreciate the perspective of others (mentalizing) is central to both autism and schizophrenia spectrum disorders. While the disorders are diagnostically independent, they can co-occur in the same individual. The effect of such co-morbidity is hypothesized to worsen mentalizing abilities. The recent influential ‘diametric brain theory’, however, suggests that the disorders are etiologically and phenotypically diametrical, predicting opposing effects on one''s mentalizing abilities. To test these contrasting hypotheses, we evaluated the effect of psychosis and autism tendencies on the perspective-taking (PT) abilities of 201 neurotypical adults, on the assumption that autism tendencies and psychosis proneness are heritable dimensions of normal variation. We show that while both autism tendencies and psychosis proneness induce PT errors, their interaction reduced these errors. Our study is, to our knowledge, the first to observe that co-occurring autistic and psychotic traits can exert opposing influences on performance, producing a normalizing effect possibly by way of their diametrical effects on socio-cognitive abilities. This advances the notion that some individuals may, to some extent, be buffered against developing either illness or present fewer symptoms owing to a balanced expression of autistic and psychosis liability.     

Mentalizing deficits constrain belief in a personal God

Religious believers intuitively conceptualize deities as intentional agents with mental states who anticipate and respond to human beliefs, desires and concerns. It follows that mentalizing deficits, associated with the autistic spectrum and also commonly found in men more than in women, may undermine this intuitive support and reduce belief in a personal God. Autistic adolescents expressed less belief in God than did matched neuro-typical controls (Study 1). In a Canadian student sample (Study 2), and two American national samples that controlled for demographic characteristics and other correlates of autism and religiosity (Study 3 and 4), the autism spectrum predicted reduced belief in God, and mentalizing mediated this relationship. Systemizing (Studies 2 and 3) and two personality dimensions related to religious belief, Conscientiousness and Agreeableness (Study 3), failed as mediators. Mentalizing also explained the robust and well-known, but theoretically debated, gender gap in religious belief wherein men show reduced religious belief (Studies 2-4).     

Is He Being Bad? Social and Language Brain Networks during Social Judgment in Children with Autism

Individuals with autism often violate social rules and have lower accuracy in identifying and explaining inappropriate social behavior. Twelve children with autism (AD) and thirteen children with typical development (TD) participated in this fMRI study of the neurofunctional basis of social judgment. Participants indicated in which of two pictures a boy was being bad (Social condition) or which of two pictures was outdoors (Physical condition). In the within-group Social–Physical comparison, TD children used components of mentalizing and language networks [bilateral inferior frontal gyrus (IFG), bilateral medial prefrontal cortex (mPFC), and bilateral posterior superior temporal sulcus (pSTS)], whereas AD children used a network that was primarily right IFG and bilateral pSTS, suggesting reduced use of social and language networks during this social judgment task. A direct group comparison on the Social–Physical contrast showed that the TD group had greater mPFC, bilateral IFG, and left superior temporal pole activity than the AD group. No regions were more active in the AD group than in the group with TD in this comparison. Both groups successfully performed the task, which required minimal language. The groups also performed similarly on eyetracking measures, indicating that the activation results probably reflect the use of a more basic strategy by the autism group rather than performance disparities. Even though language was unnecessary, the children with TD recruited language areas during the social task, suggesting automatic encoding of their knowledge into language; however, this was not the case for the children with autism. These findings support behavioral research indicating that, whereas children with autism may recognize socially inappropriate behavior, they have difficulty using spoken language to explain why it is inappropriate. The fMRI results indicate that AD children may not automatically use language to encode their social understanding, making expression and generalization of this knowledge more difficult.     

Structural Alterations of the Social Brain: A Comparison between Schizophrenia and Autism

Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.     

Why Do You Believe in God? Relationships between Religious Belief,Analytic Thinking,Mentalizing and Moral Concern

Prior work has established that analytic thinking is associated with disbelief in God, whereas religious and spiritual beliefs have been positively linked to social and emotional cognition. However, social and emotional cognition can be subdivided into a number of distinct dimensions, and some work suggests that analytic thinking is in tension with some aspects of social-emotional cognition. This leaves open two questions. First, is belief linked to social and emotional cognition in general, or a specific dimension in particular? Second, does the negative relationship between belief and analytic thinking still hold after relationships with social and emotional cognition are taken into account? We report eight hypothesis-driven studies which examine these questions. These studies are guided by a theoretical model which focuses on the distinct social and emotional processing deficits associated with autism spectrum disorders (mentalizing) and psychopathy (moral concern). To our knowledge no other study has investigated both of these dimensions of social and emotion cognition alongside analytic thinking. We find that religious belief is robustly positively associated with moral concern (4 measures), and that at least part of the negative association between belief and analytic thinking (2 measures) can be explained by a negative correlation between moral concern and analytic thinking. Using nine different measures of mentalizing, we found no evidence of a relationship between mentalizing and religious or spiritual belief. These findings challenge the theoretical view that religious and spiritual beliefs are linked to the perception of agency, and suggest that gender differences in religious belief can be explained by differences in moral concern. These findings are consistent with the opposing domains hypothesis, according to which brain areas associated with moral concern and analytic thinking are in tension.     

Cognition in Males and Females with Autism: Similarities and Differences

The male bias in autism spectrum conditions (ASC) has led to females with ASC being under-researched. This lack of attention to females could hide variability due to sex that may explain some of the heterogeneity within ASC. In this study we investigate four key cognitive domains (mentalizing and emotion perception, executive function, perceptual attention to detail, and motor function) in ASC, to test for similarities and differences between males and females with and without ASC (n = 128 adults; n = 32 per group). In the mentalizing and facial emotion perception domain, males and females with ASC showed similar deficits compared to neurotypical controls. However, in attention to detail and dexterity involving executive function, although males with ASC showed poorer performance relative to neurotypical males, females with ASC performed comparably to neurotypical females. We conclude that performance in the social-cognitive domain is equally impaired in male and female adults with ASC. However, in specific non-social cognitive domains, performance within ASC depends on sex. This suggests that in specific domains, cognitive profiles in ASC are modulated by sex.     

Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism

Mitochondria play important roles in generation of free radicals, ATP formation, and in apoptosis. We studied the levels of mitochondrial electron transport chain (ETC) complexes, that is, complexes I, II, III, IV, and V, in brain tissue samples from the cerebellum and the frontal, parietal, occipital, and temporal cortices of subjects with autism and age-matched control subjects. The subjects were divided into two groups according to their ages: Group A (children, ages 4-10 years) and Group B (adults, ages 14-39 years). In Group A, we observed significantly lower levels of complexes III and V in the cerebellum (p<0.05), of complex I in the frontal cortex (p<0.05), and of complexes II (p<0.01), III (p<0.01), and V (p<0.05) in the temporal cortex of children with autism as compared to age-matched control subjects, while none of the five ETC complexes was affected in the parietal and occipital cortices in subjects with autism. In the cerebellum and temporal cortex, no overlap was observed in the levels of these ETC complexes between subjects with autism and control subjects. In the frontal cortex of Group A, a lower level of ETC complexes was observed in a subset of autism cases, that is, 60% (3/5) for complexes I, II, and V, and 40% (2/5) for complexes III and IV. A striking observation was that the levels of ETC complexes were similar in adult subjects with autism and control subjects (Group B). A significant increase in the levels of lipid hydroperoxides, an oxidative stress marker, was also observed in the cerebellum and temporal cortex in the children with autism. These results suggest that the expression of ETC complexes is decreased in the cerebellum and the frontal and temporal regions of the brain in children with autism, which may lead to abnormal energy metabolism and oxidative stress. The deficits observed in the levels of ETC complexes in children with autism may readjust to normal levels by adulthood.     

Brain Region-Specific Glutathione Redox Imbalance in Autism

Autism is a heterogeneous, behaviorally defined neurodevelopmental disorder. Recently, we reported a brain region-specific increase in lipid peroxidation, and deficits in mitochondrial electron transport chain complexes in autism, suggesting the role of oxidative stress and mitochondrial dysfunction in the pathophysiology of autism. However, the antioxidant status of the brain is not known in autism. Glutathione is a major endogenous antioxidant that plays a crucial role in protecting cells from exogenous and endogenous toxins, particularly in the central nervous system. The present study examines the concentrations of glutathione (GSH, reduced form; and GSSG, oxidized form) and the redox ratio of GSH to GSSG (marker of oxidative stress) in different regions of brains from autistic subjects and age-matched control subjects. In the cerebellum and temporal cortex from subjects with autism, GSH levels were significantly decreased by 34.2 and 44.6 %, with a concomitant increase in the levels of GSSG by 38.2 and 45.5 %, respectively, as compared to the control group. There was also a significant decrease in the levels of total GSH (tGSH) by 32.9 % in the cerebellum, and by 43.1 % in the temporal cortex of subjects with autism. In contrast, there was no significant change in GSH, GSSG and tGSH levels in the frontal, parietal and occipital cortices in autism versus control group. The redox ratio of GSH to GSSG was also significantly decreased by 52.8 % in the cerebellum and by 60.8 % in the temporal cortex of subjects with autism, suggesting glutathione redox imbalance in the brain of individuals with autism. These findings indicate that autism is associated with deficits in glutathione antioxidant defense in selective regions of the brain. We suggest that disturbances in brain glutathione homeostasis may contribute to oxidative stress, immune dysfunction and apoptosis, particularly in the cerebellum and temporal lobe, and may lead to neurodevelopmental abnormalities in autism.     

Functional Connectivity of the Caudal Anterior Cingulate Cortex Is Decreased in Autism

The anterior cingulate cortex (ACC) is frequently reported to have functionally distinct sub-regions that play key roles in different intrinsic networks. However, the contribution of the ACC, which is connected to several cortical areas and the limbic system, to autism is not clearly understood, although it may be involved in dysfunctions across several distinct but related functional domains. By comparing resting-state fMRI data from persons with autism and healthy controls, we sought to identify the abnormalities in the functional connectivity (FC) of ACC sub-regions in autism. The analyses found autism-related reductions in FC between the left caudal ACC and the right rolandic operculum, insula, postcentral gyrus, superior temporal gyrus, and the middle temporal gyrus. The FC (z-scores) between the left caudal ACC and the right insula was negatively correlated with the Stereotyped Behaviors and Restricted Interests scores of the autism group. These findings suggest that the caudal ACC is recruited selectively in the pathomechanism of autism.     

Metacognition and mentalizing are associated with distinct neural representations of decision uncertainty

Metacognition and mentalizing are both associated with meta-level mental state representations. Conventionally, metacognition refers to monitoring one’s own cognitive processes, while mentalizing refers to monitoring others’ cognitive processes. However, this self-other dichotomy is insufficient to delineate the 2 high-level mental processes. We here used functional magnetic resonance imaging (fMRI) to systematically investigate the neural representations of different levels of decision uncertainty in monitoring different targets (the current self, the past self [PS], and others) performing a perceptual decision-making task. Our results reveal diverse formats of internal mental state representations of decision uncertainty in mentalizing, separate from the associations with external cue information. External cue information was commonly represented in the right inferior parietal lobe (IPL) across the mentalizing tasks. However, the internal mental states of decision uncertainty attributed to others were uniquely represented in the dorsomedial prefrontal cortex (dmPFC), rather than the temporoparietal junction (TPJ) that also represented the object-level mental states of decision inaccuracy attributed to others. Further, the object-level and meta-level mental states of decision uncertainty, when attributed to the PS, were represented in the precuneus and the lateral frontopolar cortex (lFPC), respectively. In contrast, the dorsal anterior cingulate cortex (dACC) represented currently experienced decision uncertainty in metacognition, and also uncertainty about the estimated decision uncertainty (estimate uncertainty), but not the estimated decision uncertainty per se in mentalizing. Hence, our findings identify neural signatures to clearly delineate metacognition and mentalizing and further imply distinct neural computations on internal mental states of decision uncertainty during metacognition and mentalizing.

The relationship between metacognition and mentalizing is still a matter of debate, as both are associated with meta-representations. This study adapts a task paradigm used in metacognition to apply in mentalizing and compares the neural representations of decision uncertainty in metacognition and mentalizing.     

A behavioral comparison of male and female adults with high functioning autism spectrum conditions

Autism spectrum conditions (ASC) affect more males than females in the general population. However, within ASC it is unclear if there are phenotypic sex differences. Testing for similarities and differences between the sexes is important not only for clinical assessment but also has implications for theories of typical sex differences and of autism. Using cognitive and behavioral measures, we investigated similarities and differences between the sexes in age- and IQ-matched adults with ASC (high-functioning autism or Asperger syndrome). Of the 83 (45 males and 38 females) participants, 62 (33 males and 29 females) met Autism Diagnostic Interview-Revised (ADI-R) cut-off criteria for autism in childhood and were included in all subsequent analyses. The severity of childhood core autism symptoms did not differ between the sexes. Males and females also did not differ in self-reported empathy, systemizing, anxiety, depression, and obsessive-compulsive traits/symptoms or mentalizing performance. However, adult females with ASC showed more lifetime sensory symptoms (p = 0.036), fewer current socio-communication difficulties (p = 0.001), and more self-reported autistic traits (p = 0.012) than males. In addition, females with ASC who also had developmental language delay had lower current performance IQ than those without developmental language delay (p<0.001), a pattern not seen in males. The absence of typical sex differences in empathizing-systemizing profiles within the autism spectrum confirms a prediction from the extreme male brain theory. Behavioral sex differences within ASC may also reflect different developmental mechanisms between males and females with ASC. We discuss the importance of the superficially better socio-communication ability in adult females with ASC in terms of why females with ASC may more often go under-recognized, and receive their diagnosis later, than males.     

Enhanced visual temporal resolution in autism spectrum disorders

Cognitive functions that rely on accurate sequencing of events, such as action planning and execution, verbal and nonverbal communication, and social interaction rely on well-tuned coding of temporal event-structure. Visual temporal event-structure coding was tested in 17 high-functioning adolescents and adults with autism spectrum disorder (ASD) and mental- and chronological-age matched typically-developing (TD) individuals using a perceptual simultaneity paradigm. Visual simultaneity thresholds were lower in individuals with ASD compared to TD individuals, suggesting that autism may be characterised by increased parsing of temporal event-structure, with a decreased capability for integration over time. Lower perceptual simultaneity thresholds in ASD were also related to increased developmental communication difficulties. These results are linked to detail-focussed and local processing bias.     

Brain region-specific decrease in the activity and expression of protein kinase A in the frontal cortex of regressive autism

Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP-dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-α), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-α) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.     

The disappearing seasonality of autism conceptions in california

Background

Autism incidence and prevalence have increased dramatically in the last two decades. The autism caseload in California increased 600% between 1992 and 2006, yet there is little consensus as to the cause. Studying the seasonality of conceptions of children later diagnosed with autism may yield clues to potential etiological drivers.

Objective

To assess if the conceptions of children later diagnosed with autism cluster temporally in a systematic manner and whether any pattern of temporal clustering persists over time.

Method

We searched for seasonality in conceptions of children later diagnosed with autism by applying a one-dimensional scan statistic with adaptive temporal windows on case and control population data from California for 1992 through 2000. We tested for potential confounding effects from known risk factors using logistic regression models.

Results

There is a consistent but decreasing seasonal pattern in the risk of conceiving a child later diagnosed with autism in November for the first half of the study period. Temporal clustering of autism conceptions is not an artifact of composition with respect to known risk factors for autism such as socio-economic status.

Conclusion

There is some evidence of seasonality in the risk of conceiving a child later diagnosed with autism. Searches for environmental factors related to autism should allow for the possibility of risk factors or etiological drivers that are seasonally patterned and that appear and remain salient for a discrete number of years.     

Simulating Fiction: Individual Differences in Literature Comprehension Revealed with fMRI

When we read literary fiction, we are transported to fictional places, and we feel and think along with the characters. Despite the importance of narrative in adult life and during development, the neurocognitive mechanisms underlying fiction comprehension are unclear. We used functional magnetic resonance imaging (fMRI) to investigate how individuals differently employ neural networks important for understanding others’ beliefs and intentions (mentalizing), and for sensori-motor simulation while listening to excerpts from literary novels. Localizer tasks were used to localize both the cortical motor network and the mentalizing network in participants after they listened to excerpts from literary novels. Results show that participants who had high activation in anterior medial prefrontal cortex (aMPFC; part of the mentalizing network) when listening to mentalizing content of literary fiction, had lower motor cortex activity when they listened to action-related content of the story, and vice versa. This qualifies how people differ in their engagement with fiction: some people are mostly drawn into a story by mentalizing about the thoughts and beliefs of others, whereas others engage in literature by simulating more concrete events such as actions. This study provides on-line neural evidence for the existence of qualitatively different styles of moving into literary worlds, and adds to a growing body of literature showing the potential to study narrative comprehension with neuroimaging methods.     

The Social Bayesian Brain: Does Mentalizing Make a Difference When We Learn?

When it comes to interpreting others'' behaviour, we almost irrepressibly engage in the attribution of mental states (beliefs, emotions…). Such "mentalizing" can become very sophisticated, eventually endowing us with highly adaptive skills such as convincing, teaching or deceiving. Here, sophistication can be captured in terms of the depth of our recursive beliefs, as in "I think that you think that I think…" In this work, we test whether such sophisticated recursive beliefs subtend learning in the context of social interaction. We asked participants to play repeated games against artificial (Bayesian) mentalizing agents, which differ in their sophistication. Critically, we made people believe either that they were playing against each other, or that they were gambling like in a casino. Although both framings are similarly deceiving, participants win against the artificial (sophisticated) mentalizing agents in the social framing of the task, and lose in the non-social framing. Moreover, we find that participants'' choice sequences are best explained by sophisticated mentalizing Bayesian learning models only in the social framing. This study is the first demonstration of the added-value of mentalizing on learning in the context of repeated social interactions. Importantly, our results show that we would not be able to decipher intentional behaviour without a priori attributing mental states to others.     

Reduced activity of protein kinase C in the frontal cortex of subjects with regressive autism: relationship with developmental abnormalities

Autism is a neurodevelopmental disorder with unknown etiology. In some cases, typically developing children regress into clinical symptoms of autism, a condition known as regressive autism. Protein kinases are essential for G-protein-coupled receptor-mediated signal transduction, and are involved in neuronal functions, gene expression, memory, and cell differentiation. Recently, we reported decreased activity of protein kinase A (PKA) in the frontal cortex of subjects with regressive autism. In the present study, we analyzed the activity of protein kinase C (PKC) in the cerebellum and different regions of cerebral cortex from subjects with regressive autism, autistic subjects without clinical history of regression, and age-matched control subjects. In the frontal cortex of subjects with regressive autism, PKC activity was significantly decreased by 57.1% as compared to age-matched control subjects (p = 0.0085), and by 65.8% as compared to non-regressed autistic subjects (p = 0.0048). PKC activity was unaffected in the temporal, parietal and occipital cortices, and in the cerebellum in both autism groups, i.e., regressive and non-regressed autism as compared to control subjects. These results suggest brain region-specific alteration of PKC activity in the frontal cortex of subjects with regressive autism. Further studies showed a negative correlation between PKC activity and restrictive, repetitive and stereotyped pattern of behavior (r= -0.084, p = 0.0363) in autistic individuals, suggesting involvement of PKC in behavioral abnormalities in autism. These findings suggest that regression in autism may be attributed, in part, to alterations in G-protein-coupled receptor-mediated signal transduction involving PKA and PKC in the frontal cortex.     

Characterizing maternal isolation-induced ultrasonic vocalizations in a gene–environment interaction rat model for autism

Deficits in social communication and language development belong to the earliest diagnostic criteria of autism spectrum disorders. Of the many risk factors for autism spectrum disorder, the contactin-associated protein-like 2 gene, CNTNAP2, is thought to be important for language development. The present study used a rat model to investigate the potential compounding effects of autism spectrum disorder risk gene mutation and environmental challenges, including breeding conditions or maternal immune activation during pregnancy, on early vocal communication in the offspring. Maternal isolation-induced ultrasonic vocalizations from Cntnap2 wildtype and knockout rats at selected postnatal days were analyzed for their acoustic, temporal and syntax characteristics. Cntnap2 knockout pups from heterozygous breeding showed normal numbers and largely similar temporal structures of ultrasonic vocalizations to wildtype controls, whereas both parameters were affected in homozygously bred knockouts. Homozygous breeding further exacerbated altered pitch and transitioning between call types found in Cntnap2 knockout pups from heterozygous breeding. In contrast, the effect of maternal immune activation on the offspring's vocal communication was confined to call type syntax, but left ultrasonic vocalization acoustic and temporal organization intact. Our results support the “double-hit hypothesis” of autism spectrum disorder risk gene–environment interactions and emphasize that complex features of vocal communication are a useful tool for identifying early autistic-like features in rodent models.     

Differentiating Self-Projection from Simulation during Mentalizing: Evidence from fMRI

We asked participants to predict which of two colors a similar other (student) and a dissimilar other (retiree) likes better. We manipulated if color-pairs were two hues from the same color-category (e.g. green) or two conceptually different colors (e.g. green versus blue). In the former case, the mental state that has to be represented (i.e., the percept of two different hues of green) is predominantly non-conceptual or phenomenal in nature, which should promote mental simulation as a strategy for mentalizing. In the latter case, the mental state (i.e. the percept of green versus blue) can be captured in thought by concepts, which facilitates the use of theories for mentalizing. In line with the self-projection hypothesis, we found that cortical midline areas including vmPFC / orbitofrontal cortex and precuneus were preferentially activated for mentalizing about a similar other. However, activation was not affected by the nature of the color-difference, suggesting that self-projection subsumes simulation-like processes but is not limited to them. This indicates that self-projection is a universal strategy applied in different contexts—irrespective of the availability of theories for mentalizing. Along with midline activations linked to self-projection, we also observed activation in right lateral frontal and dorsal parietal areas showing a theory-like pattern. Taken together, this shows that mentalizing does not operate based on simulation or theory, but that both strategies are used concurrently to predict the choices of others.