Neural systems for social cognition in Klinefelter syndrome (47,XXY): evidence from fMRI

Klinefelter syndrome (KS) is a chromosomal condition (47, XXY) that may help us to unravel gene-brain behavior pathways to psychopathology. The phenotype includes social cognitive impairments and increased risk for autism traits. We used functional MRI to study neural mechanisms underlying social information processing. Eighteen nonclinical controls and thirteen men with XXY were scanned during judgments of faces with regard to trustworthiness and age. While judging faces as untrustworthy in comparison to trustworthy, men with XXY displayed less activation than controls in (i) the amygdala, which plays a key role in screening information for socio-emotional significance, (ii) the insula, which plays a role in subjective emotional experience, as well as (iii) the fusiform gyrus and (iv) the superior temporal sulcus, which are both involved in the perceptual processing of faces and which were also less involved during age judgments in men with XXY. This is the first study showing that KS can be associated with reduced involvement of the neural network subserving social cognition. Studying KS may increase our understanding of the genetic and hormonal basis of neural dysfunctions contributing to abnormalities in social cognition and behavior, which are considered core abnormalities in psychiatric disorders such as autism and schizophrenia.     

An investigation of the relationship between activation of a social cognitive neural network and social functioning

Previous work examining the neurobiological substrates of social cognition in healthy individuals has reported modulation of a social cognitive network such that increased activation of the amygdala, fusiform gyrus, and superior temporal sulcus are evident when individuals judge a face to be untrustworthy as compared with trustworthy. We examined whether this pattern would be present in individuals with schizophrenia who are known to show reduced activation within these same neural regions when processing faces. Additionally, we sought to determine how modulation of this social cognitive network may relate to social functioning. Neural activation was measured using functional magnetic resonance imaging with blood oxygenation level dependent contrast in 3 groups of individuals--nonparanoid individuals with schizophrenia, paranoid individuals with schizophrenia, and healthy controls--while they rated faces as either trustworthy or untrustworthy. Analyses of mean percent signal change extracted from a priori regions of interest demonstrated that both controls and nonparanoid individuals with schizophrenia showed greater activation of this social cognitive network when they rated a face as untrustworthy relative to trustworthy. In contrast, paranoid individuals did not show a significant difference in levels of activation based on how they rated faces. Further, greater activation of this social cognitive network to untrustworthy faces was significantly and positively correlated with social functioning. These findings indicate that impaired modulation of neural activity while processing social stimuli may underlie deficits in social cognition and social dysfunction in schizophrenia.     

Cognition sociale dans la schizophrénie et les troubles du spectre de l’autisme : points de convergences et différences fonctionnelles

Introduction

Schizophrenia and autistic spectrum disorder (ASD) are two neurodevelopmental disorders that have different symptom presentations, ages of onset and developmental courses. Both schizophrenia and ASD are characterized by marked deficit in communication, social interactions, affects and emotions. Social cognitive impairments in ASD and schizophrenia were demonstrated separately in both disorders. It was reported that these impairments have direct relation with social deficits of both disorders. The apparent similarity between social cognition impairments in ASD and schizophrenia highlights questions about the existence of common or different neurocognitive mechanisms related to social dysfunctions. In order to examine these questions, the present article provides a comprehensive review of all published studies which directly compare individuals with ASD and schizophrenia on the same cognitive tasks of social cognition.

Altered Amygdala Connectivity Within the Social Brain in Schizophrenia

Background: Impairments in social cognition have been described in schizophrenia and relate to core symptoms of the disorder. Social cognition is subserved by a network of brain regions, many of which have been implicated in schizophrenia. We hypothesized that deficits in connectivity between components of this social brain network may underlie the social cognition impairments seen in the disorder. Methods: We investigated brain activation and connectivity in a group of individuals with schizophrenia making social judgments of approachability from faces (n = 20), compared with a group of matched healthy volunteers (n = 24), using functional magnetic resonance imaging. Effective connectivity from the amygdala was estimated using the psychophysiological interaction approach. Results: While making approachability judgments, healthy participants recruited a network of social brain regions including amygdala, fusiform gyrus, cerebellum, and inferior frontal gyrus bilaterally and left medial prefrontal cortex. During the approachability task, healthy participants showed increased connectivity from the amygdala to the fusiform gyri, cerebellum, and left superior frontal cortex. In comparison to controls, individuals with schizophrenia overactivated the right middle frontal gyrus, superior frontal gyrus, and precuneus and had reduced connectivity between the amygdala and the insula cortex. Discussion: We report increased activation of frontal and medial parietal regions during social judgment in patients with schizophrenia, accompanied by decreased connectivity between the amygdala and insula. We suggest that the increased activation of frontal control systems and association cortex may reflect a compensatory mechanism for impaired connectivity of the amygdala with other parts of the social brain networks in schizophrenia.Key words: fMRI, social cognition, approachability, psychosis, neural, psychophysiological interaction     

Neuroanatomical and neurofunctional markers of social cognition in autism spectrum disorder

Social impairments in autism spectrum disorder (ASD), a hallmark feature of its diagnosis, may underlie specific neural signatures that can aid in differentiating between those with and without ASD. To assess common and consistent patterns of differences in brain responses underlying social cognition in ASD, this study applied an activation likelihood estimation (ALE) meta‐analysis to results from 50 neuroimaging studies of social cognition in children and adults with ASD. In addition, the group ALE clusters of activation obtained from this was used as a social brain mask to perform surface‐based cortical morphometry (SBM) in an empirical structural MRI dataset collected from 55 ASD and 60 typically developing (TD) control participants. Overall, the ALE meta‐analysis revealed consistent differences in activation in the posterior superior temporal sulcus at the temporoparietal junction, middle frontal gyrus, fusiform face area (FFA), inferior frontal gyrus (IFG), amygdala, insula, and cingulate cortex between ASD and TD individuals. SBM analysis showed alterations in the thickness, volume, and surface area in individuals with ASD in STS, insula, and FFA. Increased cortical thickness was found in individuals with ASD, the IFG. The results of this study provide functional and anatomical bases of social cognition abnormalities in ASD by identifying common signatures from a large pool of neuroimaging studies. These findings provide new insights into the quest for a neuroimaging‐based marker for ASD. Hum Brain Mapp 37:3957–3978, 2016. © 2016 Wiley Periodicals, Inc.     

Orienting to social stimuli differentiates social cognitive impairment in autism and schizophrenia

Both autism and schizophrenia feature deficits in aspects of social cognition that may be related to amygdala dysfunction, but it is unclear whether these are similar or different patterns of impairment. We compared the visual scanning patterns and emotion judgments of individuals with autism, individuals with schizophrenia and controls on a task well characterized with respect to amygdala functioning. On this task, eye movements of participants are recorded as they assess emotional content within a series of complex social scenes where faces are either included or digitally erased. Results indicated marked abnormalities in visual scanning for both disorders. Controls increased their gaze on face regions when faces were present to a significantly greater degree than both the autism or schizophrenia groups. While the control and the schizophrenia groups oriented to face regions faster when faces were present compared to when they were absent, the autism group oriented at the same rate in both conditions. The schizophrenia group, meanwhile, exhibited a delay in orienting to face regions across both conditions, although whether anti-psychotic medication contributed to this effect is unclear. These findings suggest that while processing emotional information in social scenes, both individuals with autism and individuals with schizophrenia fixate faces less than controls, although only those with autism fail to orient to faces more rapidly based on the presence of facial information. Autism and schizophrenia may therefore share an abnormality in utilizing facial information for assessing emotional content in social scenes, but differ in the ability to seek out socially relevant cues from complex stimuli. Impairments in social orienting are discussed within the context of evidence suggesting the role of the amygdala in orienting to emotionally meaningful information.     

Abnormal processing of social information from faces in autism

Autism has been thought to be characterized, in part, by dysfunction in emotional and social cognition, but the pathology of the underlying processes and their neural substrates remain poorly understood. Several studies have hypothesized that abnormal amygdala function may account for some of the impairments seen in autism, specifically, impaired recognition of socially relevant information from faces. We explored this issue in eight high-functioning subjects with autism in four experiments that assessed recognition of emotional and social information, primarily from faces. All tasks used were identical to those previously used in studies of subjects with bilateral amygdala damage, permitting direct comparisons. All subjects with autism made abnormal social judgments regarding the trustworthiness of faces; however, all were able to make normal social judgments from lexical stimuli, and all had a normal ability to perceptually discriminate the stimuli. Overall, these data from subjects with autism show some parallels to those from neurological subjects with focal amygdala damage. We suggest that amygdala dysfunction in autism might contribute to an impaired ability to link visual perception of socially relevant stimuli with retrieval of social knowledge and with elicitation of social behavior.     

Amygdala Habituation and Prefrontal Functional Connectivity in Youth With Autism Spectrum Disorders

ObjectiveAmygdala habituation, the rapid decrease in amygdala responsiveness to the repeated presentation of stimuli, is fundamental to the nervous system. Habituation is important for maintaining adaptive levels of arousal to predictable social stimuli and decreased habituation is associated with heightened anxiety. Input from the ventromedial prefrontal cortex (vmPFC) regulates amygdala activity. Although previous research has shown abnormal amygdala function in youth with autism spectrum disorders (ASD), no study has examined amygdala habituation in a young sample or whether habituation is related to amygdala connectivity with the vmPFC.MethodData were analyzed from 32 children and adolescents with ASD and 56 typically developing controls who underwent functional magnetic resonance imaging while performing a gender identification task for faces that were fearful, happy, sad, or neutral. Habituation was tested by comparing amygdala activation to faces during the first half versus the second half of the session. VmPFC-amygdala connectivity was examined through psychophysiologic interaction analysis.ResultsYouth with ASD had decreased amygdala habituation to sad and neutral faces compared with controls. Moreover, decreased amygdala habituation correlated with autism severity as measured by the Social Responsiveness Scale. There was a group difference in vmPFC-amygdala connectivity while viewing sad faces, and connectivity predicted amygdala habituation to sad faces in controls.ConclusionsSustained amygdala activation to faces suggests that repeated face presentations are processed differently in individuals with ASD, which could contribute to social impairments. Abnormal modulation of the amygdala by the vmPFC may play a role in decreased habituation.     

Social Cognition Deficits Among Individuals at Familial High Risk for Schizophrenia

Social cognition in young relatives of schizophrenia probands (N = 70) and healthy controls (N = 63) was assessed using the Penn Emotion Recognition Test-40 to examine the presence of social cognitive deficits in individuals at risk for the disorder. Measures of neurocognitive function and prodromal psychopathology were collected to assess the cognitive and clinical correlates of social cognitive impairments in at-risk relatives. Results indicated that when compared with healthy controls, individuals at familial high risk for schizophrenia were significantly more likely to overattribute emotions to neutral faces, with such individuals frequently misinterpreting neutral faces as negative. In addition, at-risk individuals had significantly greater reaction times when completing emotion recognition tasks, regardless of valence. Impairments in neurocognition were largely independent of social cognitive performance, and emotion recognition impairments persisted after adjusting for deficits in neurocognitive function. Further, social cognitive impairments in the interpretation of neutral faces were significantly associated with greater positive and general prodromal psychopathology, whereas neurocognitive impairments were only associated with disorganization. These results suggest that impairments in social cognition may be unique endophenotypes for schizophrenia.     

Does bilateral damage to the human amygdala produce autistic symptoms?

A leading neurological hypothesis for autism postulates amygdala dysfunction. This hypothesis has considerable support from anatomical and neuroimaging studies. Individuals with bilateral amygdala lesions show impairments in some aspects of social cognition. These impairments bear intriguing similarity to those reported in people with autism, such as impaired recognition of emotion in faces, impaired theory of mind abilities, failure to fixate eyes in faces, and difficulties in regulating personal space distance to others. Yet such neurological cases have never before been assessed directly to see if they meet criteria for autism spectrum disorders (ASD). Here we undertook such an investigation in two rare participants with developmental-onset bilateral amygdala lesions. We administered a comprehensive clinical examination, as well as the Autism Diagnostic Observation Schedule (ADOS), the Social Responsiveness Scale (SRS), together with several other standardized questionnaires. Results from the two individuals with amygdala lesions were compared with published norms from both healthy populations as well as from people with ASD. Neither participant with amygdala lesions showed any evidence of autism across the array of different measures. The findings demonstrate that amygdala lesions in isolation are not sufficient for producing autistic symptoms. We suggest instead that it may be abnormal connectivity between the amygdala and other structures that contributes to autistic symptoms at a network level.     

Autism is characterized by dorsal anterior cingulate hyperactivation during social target detection

Though the functional neural correlates of impaired cognitive control and social dysfunction in autism spectrum disorders (ASD) have been delineated, brain regions implicated in poor cognitive control of social information is a novel area of autism research. We recently reported in a non-clinical sample that detection of ‘social oddball’ targets activated a portion of the dorsal anterior cingulate gyrus and the supracalcarine cortex (Dichter, Felder, Bodfish, Sikich, and Belger, 2009). In the present investigation, we report functional magnetic resonance imaging results from individuals with ASD who completed the same social oddball task. Between-group comparisons revealed generally greater activation in the ASD group to both social and non-social targets. When responses to social and non-social targets were contrasted, the ASD group showed relatively greater activation in the right and middle inferior frontal gyri and a region in dorsomedial prefrontal cortex that abuts the dorsal anterior cingulate (Brodmann''s Area 32). Further, dorsal anterior cingulate activation to social targets predicted the severity of social impairments in a subset of the ASD sample. These data suggest that the dorsal anterior cingulate mediates social target detection in neurotypical individuals and is implicated in deficits of cognitive control of social information in ASD.     

The influence of 5-HTTLPR transporter genotype on amygdala-subgenual anterior cingulate cortex connectivity in autism spectrum disorder

Social deficits in autism spectrum disorder (ASD) are linked to amygdala functioning and functional connection between the amygdala and subgenual anterior cingulate cortex (sACC) is involved in the modulation of amygdala activity. Impairments in behavioral symptoms and amygdala activation and connectivity with the sACC seem to vary by serotonin transporter-linked polymorphic region (5-HTTLPR) variant genotype in diverse populations. The current preliminary investigation examines whether amygdala-sACC connectivity differs by 5-HTTLPR genotype and relates to social functioning in ASD. A sample of 108 children and adolescents (44 ASD) completed an fMRI face-processing task. Youth with ASD and low expressing 5-HTTLPR genotypes showed significantly greater connectivity than youth with ASD and higher expressing genotypes as well as typically developing (TD) individuals with both low and higher expressing genotypes, in the comparison of happy vs. baseline faces and happy vs. neutral faces. Moreover, individuals with ASD and higher expressing genotypes exhibit a negative relationship between amygdala-sACC connectivity and social dysfunction. Altered amygdala-sACC coupling based on 5-HTTLPR genotype may help explain some of the heterogeneity in neural and social function observed in ASD. This is the first ASD study to combine genetic polymorphism analyses and functional connectivity in the context of a social task.     

Abnormal activation of the social brain during face perception in autism

ASD involves a fundamental impairment in processing social-communicative information from faces. Several recent studies have challenged earlier findings that individuals with autism spectrum disorder (ASD) have no activation of the fusiform gyrus (fusiform face area, FFA) when viewing faces. In this study, we examined activation to faces in the broader network of face-processing modules that comprise what is known as the social brain. Using 3T functional resonance imaging, we measured BOLD signal changes in 10 ASD subjects and 7 healthy controls passively viewing nonemotional faces. We replicated our original findings of significant activation of face identity-processing areas (FFA and inferior occipital gyrus, IOG) in ASD. However, in addition, we identified hypoactivation in a more widely distributed network of brain areas involved in face processing [including the right amygdala, inferior frontal cortex (IFC), superior temporal sulcus (STS), and face-related somatosensory and premotor cortex]. In ASD, we found functional correlations between a subgroup of areas in the social brain that belong to the mirror neuron system (IFC, STS) and other face-processing areas. The severity of the social symptoms measured by the Autism Diagnostic Observation Schedule was correlated with the right IFC cortical thickness and with functional activation in that area. When viewing faces, adults with ASD show atypical patterns of activation in regions forming the broader face-processing network and social brain, outside the core FFA and IOG regions. These patterns suggest that areas belonging to the mirror neuron system are involved in the face-processing disturbances in ASD.     

Deficits in social cognition: a marker for psychiatric disorders?

Research on social cognition focuses on several human abilities with a huge diversity in the approaches to tap the different functions. Empathy, for instance, is a rather elaborated human ability, and several recent studies point to significant impairments in patients suffering from psychiatric disorders, such as schizophrenia or autism. Neuroimaging data from these patients commonly indicate neural dysfunctions accompanying the behavioral deficits. Studying the neural correlates of social cognition is of particular importance, because deficits in these domains may explain the major dysfunctions in psychiatric disorders that prevent effective (re) integration into work and social life. It has also become clearer that social cognition deficits, similar to emotion dysfunctions, may represent trait markers and endophenotypes of the diseases. However, there are several challenges for future studies on social cognitive dysfunctions: on the one hand, the complexity of the constructs and thus the variety of definitions which make it hard to develop adequate tasks. On the other hand, results are needed that particularly address the disorder specificity of these impairments, as well as their potential as endophenotypes via analyzing people at high-risk and their relatives.     

An evaluation of Miranda rights and interrogation in autism spectrum disorders

The primary deficits present in autism spectrum disorders (ASD) may lead to increased susceptibility to involvement in the criminal justice system. The same deficits may also cause individuals with ASD to be more vulnerable to interrogation techniques and other aspects of the legal system. Due to the increased level of vulnerability as well as impairments in social cognition, individuals with ASD may have difficulty understanding their legal rights, more specifically their Miranda rights. This review explores Miranda comprehension in general and how the specific deficits found in ASD may impact Miranda comprehension.     

Cross-sensory gating in schizophrenia and autism spectrum disorder: EEG evidence for impaired brain connectivity?

Autism spectrum disorders (ASD) and schizophrenia are both neurodevelopmental disorders that have extensively been associated with impairments in functional brain connectivity. Using a cross-sensory P50 suppression paradigm, this study investigated low-level audiovisual interactions on cortical EEG activation, which provides crucial information about functional integrity of connections between brain areas involved in cross-sensory processing in both disorders. Thirteen high functioning adult males with ASD, 13 high functioning adult males with schizophrenia, and 16 healthy adult males participated in the study. No differences in neither auditory nor cross-sensory P50 suppression were found between healthy controls and individuals with ASD. In schizophrenia, attenuated P50 responses to the first auditory stimulus indicated early auditory processing deficits. These results are in accordance with the notion that filtering deficits may be secondary to earlier sensory dysfunction. Also, atypical cross-sensory suppression was found, which implies that the cognitive impairments seen in schizophrenia may be due to deficits in the integrity of connections between brain areas involved in low-level cross-sensory processing.     

Time-varying amygdala response to emotional faces in generalized social phobia.

BACKGROUND: Individuals with social phobia (SP) have altered behavioral and neural responses to emotional faces and are hypothesized to have deficits in inhibiting emotion-related amygdala responses. We tested for such amygdala deficits to emotional faces in a sample of individuals with SP. METHOD: We used functional magnetic resonance imaging (fMRI) to examine the neural substrates of emotional face processing in 14 generalized SP (gSP) and 14 healthy comparison (HC) participants. Analyses focused on the temporal dynamics of the amygdala, prefrontal cortex (PFC), and fusiform face area (FFA) across blocks of neutral, fear, contempt, anger, and happy faces in gSP versus HC participants. RESULTS: Amygdala responses in participants with gSP occurred later than the HC participants to fear, angry, and happy faces. Parallel PFC responses were found for happy and fear faces. There were no group differences in temporal response patterns in the FFA. CONCLUSIONS: This finding might reflect a neural correlate of atypical orienting responses among individuals with gSP. Commonly reported SP deficits in habituation might reflect neural regions associated with emotional self-evaluations rather than the amygdala. This study highlights the importance of considering time-varying modulation when examining emotion-related processing in individuals with gSP.     

Schizophrenia and Autism as Contrasting Minds: Neural Evidence for the Hypo-Hyper-Intentionality Hypothesis

Both schizophrenia (SCZ) and autism spectrum disorder (ASD) are characterized by mentalizing problems and associated neural dysfunction of the social brain. However, the deficits in mental state attribution are somehow opposed: Whereas patients with SCZ tend to over-attribute intentions to agents and physical events (“hyper-intentionality”), patients with autism treat people as devoid of intentions (“hypo-intentionality”). Here we aimed to investigate whether this hypo-hyper-intentionality hypothesis can be supported by neural evidence during a mentalizing task. Using functional magnetic resonance imaging (fMRI), we investigated the neural responses and functional connectivity during reading others intention. Scanning was performed in 23 individuals with ASD, 18 with paranoid SCZ and 23 gender and IQ matched control subjects. Both clinical groups showed reduced brain activation compared to controls for the contrast intentional vs physical information processing in left posterior superior temporal sulcus (pSTS) and ventral medial prefrontal cortex (vMPFC) for SCZ, and right pSTS in ASD. As predicted, these effects were caused in a group specific way: Relative increased activation for physical information processing in SCZ that was also correlated with positive PANNS score and relative decreased activation for intentional information processing in ASD. Additionally, we could demonstrate opposed connectivity patterns between the right pSTS and vMPFC in the clinical groups, ie, increased for SCZ, decreased for ASD. These findings represent opposed neural signatures in key regions of the social brain as predicted by the hyper-hypo-intentionality hypothesis.     

Different fusiform activity to stranger and personally familiar faces in shy and social adults

Abstract

Although shyness is associated with deficits in different aspects of face processing including face recognition and facial emotions, we know relatively little about the neural correlates of face processing among individuals who are shy. Here we show reduced activation to stranger faces among shy adults in a key brain area involved in face processing. Event-related functional magnetic resonance imaging scans were acquired on 12 shy and 12 social young adults during the rapid presentation of stranger and personally familiar neutral faces. Shy adults exhibited significantly less bilateral activation in the fusiform face area (FFA) in response to stranger faces and significantly greater bilateral activation in the same region to personally familiar faces than their social counterparts. Shy adults also exhibited significantly greater right amygdala activation in response to stranger faces than social adults. Among social adults, stranger faces elicited greater FFA activation than personally familiar faces. Findings suggest that there are distinct patterns of neural activation in the FFA in response to viewing stranger and personally familiar faces among shy and social adults.