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Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterised by impaired social interaction and communication, restricted interests and repetitive behaviours. The severity of these characteristics are posited to lie on a continuum extending into the typical population, and typical adults' performance on behavioural tasks that are impaired in ASD is correlated with the extent to which they display autistic traits (as measured by Autism Spectrum Quotient, AQ). Individuals with ASD also show structural and functional differences in brain regions involved in social perception. Here we show that variation in AQ in typically developing individuals is associated with altered brain activity in the neural circuit for social attention perception while viewing others' eye gaze. In an fMRI experiment, participants viewed faces looking at variable or constant directions. In control conditions, only the eye region was presented or the heads were shown with eyes closed but oriented at variable or constant directions. The response to faces with variable vs. constant eye gaze direction was associated with AQ scores in a number of regions (posterior superior temporal sulcus, intraparietal sulcus, temporoparietal junction, amygdala, and MT/V5) of the brain network for social attention perception. No such effect was observed for heads with eyes closed or when only the eyes were presented. The results demonstrate a relationship between neurophysiology and autism spectrum traits in the typical (non-ASD) population and suggest that changes in the functioning of the neural circuit for social attention perception is associated with an extended autism spectrum in the typical population.

Highlights

► Autistic spectrum might extend to typically developing (TD) individuals. ► We studied TD individuals with varying Autism Spectrum Quotient (AQ). ► AQ correlated with BOLD response to viewing variable vs. constant eye gaze. ► AQ did not correlate with response to directional control stimuli. ► Neurophysiology and autism spectrum traits are associated in non-AS individuals.

Previous evidence suggests that directional social cues (e.g., eye gaze) cause automatic shifts in attention toward gaze direction. It has been proposed that automatic attentional orienting driven by social cues (social orienting) involves a different neural network from automatic orienting driven by nonsocial cues. However, previous neuroimaging studies on social orienting have only compared gaze cues to symbolic cues, which typically engage top-down mechanisms. Therefore, we directly compared the neural activity involved in social orienting to that involved in purely automatic nonsocial orienting. Twenty participants performed a spatial cueing task consisting of social (gaze) cues and automatic nonsocial (peripheral squares) cues presented at short and long stimulus (cue-to-target) onset asynchronies (SOA), while undergoing fMRI. Behaviorally, a facilitation effect was found for both cue types at the short SOA, while an inhibitory effect (inhibition of return: IOR) was found only for nonsocial cues at the long SOA. Imaging results demonstrated that social and nonsocial cues recruited a largely overlapping fronto-parietal network. In addition, social cueing evoked greater activity in occipito-temporal regions at both SOAs, while nonsocial cueing recruited greater subcortical activity, but only for the long SOA (when IOR was found). A control experiment, including central arrow cues, confirmed that the occipito-temporal activity was at least in part due to the social nature of the cue and not simply to the location of presentation (central vs. peripheral). These results suggest an evolutionary trajectory for automatic orienting, from predominantly subcortical mechanisms for nonsocial orienting to predominantly cortical mechanisms for social orienting.

This study used eye-tracking to examine visual attention to faces and objects in adolescents with autism spectrum disorder (ASD) and typical peers. Point of gaze was recorded during passive viewing of images of human faces, inverted human faces, monkey faces, three-dimensional curvilinear objects, and two-dimensional geometric patterns. Individuals with ASD obtained lower scores on measures of face recognition and social-emotional functioning but exhibited similar patterns of visual attention. In individuals with ASD, face recognition performance was associated with social adaptive function. Results highlight heterogeneity in manifestation of social deficits in ASD and suggest that naturalistic assessments are important for quantifying atypicalities in visual attention.

The present study aimed to explore the neural correlates of two characteristic deficits in autism spectrum disorders (ASD); social impairment and restricted, repetitive behavior patterns. To this end, we used comparable experiences of social exclusion and rule violation to probe potentially atypical neural networks in ASD. In children and adolescents with and without ASD, we used the interactive ball-toss game (Cyberball) to elicit social exclusion and a comparable game (Cybershape) to elicit a non-exclusive rule violation. Using functional magnetic resonance imaging (fMRI), we identified group differences in brain responses to social exclusion and rule violation. Though both groups reported equal distress following exclusion, the right insula and ventral anterior cingulate cortex were hypoactive during exclusion in children with ASD. In rule violation, right insula and dorsal prefrontal cortex were hyperactive in ASD. Right insula showed a dissociation in activation; it was hypoactive to social exclusion and hyperactive to rule violation in the ASD group. Further probed, different regions of right insula were modulated in each game, highlighting differences in regional specificity for which subsequent analyses revealed differences in patterns of functional connectivity. These results demonstrate neurobiological differences in processing social exclusion and rule violation in children with ASD.

Abnormal eye contact is a core symptom of autism spectrum disorders (ASD), though little is understood of the neural bases of gaze processing in ASD. Competing hypotheses suggest that individuals with ASD avoid eye contact due to the anxiety-provoking nature of direct eye gaze or that eye-gaze cues hold less interest or significance to children with ASD. The current study examined the effects of gaze direction on neural processing of emotional faces in typically developing (TD) children and those with ASD. While undergoing functional magnetic resonance imaging (fMRI), 16 high-functioning children and adolescents with ASD and 16 TD controls viewed a series of faces depicting emotional expressions with either direct or averted gaze. Children in both groups showed significant activity in visual-processing regions for both direct and averted gaze trials. However, there was a significant group by gaze interaction such that only TD children showed reliably greater activity in ventrolateral prefrontal cortex for direct versus averted gaze. The ASD group showed no difference between direct and averted gaze in response to faces conveying negative emotions. These results highlight the key role of eye gaze in signaling communicative intent and suggest altered processing of the emotional significance of direct gaze in children with ASD.

Background

Individuals diagnosed with autism spectrum disorder (ASD) exhibit lifelong abnormalities in the adaptive allocation of visual attention. The ubiquitous nature of attentional impairments in ASD has led some authors to hypothesize that atypical attentional modulation may be a factor in the development of higher-level sociocommunicative deficits.

Method

Participants were 20 children with ASD and 20 age- and Nonverbal IQ-matched typically developing (TD) children. We used the Attention Network Test (ANT) to investigate the efficiency and independence of three discrete attentional networks: alerting, orienting, and executive control. Additionally, we sought to investigate the relationship between each attentional network and measures of sociocommunicative symptom severity in children with ASD.

Results

Results indicate that the orienting, but not alerting or executive control, networks may be impaired in children with ASD. In contrast to TD children, correlational analyses suggest that the alerting and executive control networks may not function as independently in children with ASD. Additionally, an association was found between the alerting network and social impairment and between the executive control network and IQ in children with ASD.

Conclusions

The results provide further evidence of an impairment in the visuospatial orienting network in ASD and suggest that there may be greater interdependence of alerting and executive control networks in ASD. Furthermore, decreased ability to efficiently modulate levels of alertness was related to increased sociocommunicative deficits, suggesting that domain-general attentional function may be associated with ASD symptomatology.

Individuals with autism spectrum disorders (ASDs) have significant visuomotor processing deficits, atypical motoric behavior, and often substantial problems connecting socially. We suggest that the perceptual, attentional, and adaptive timing deficiencies associated with autism might directly impact the ability to become a socially connected unit with others. Using a rocking chair paradigm previously employed with typical adults, we demonstrate that typically-developing (TD) children exhibit spontaneous social rocking with their caregivers. In contrast, children diagnosed with ASD do not demonstrate a tendency to rock in a symmetrical state with their parents. We argue that the movement of our bodies is one of the fundamental ways by which we connect with our environment and, especially, ground ourselves in social environments. Deficiencies in perceiving and responding to the rhythms of the world may have serious consequences for the ability to become adequately embedded in a social context.

Autism spectrum disorders are characterized by cognitive control deficits as well as impairments in social interactions. However, the brain mechanisms mediating the interactive effects of these deficits have not been addressed. We employed event-related functional magnetic resonance imaging (fMRI) to examine the effects of processing directional information from faces on activity within brain regions mediating cognitive control. High-functioning individuals with autism and age-, gender-, and IQ-matched neurotypical individuals attended to the direction of a centrally-presented arrow or gaze stimulus with similar flanker stimuli oriented in the same (“congruent”) or opposite (“incongruent”) direction. The incongruent arrow condition was examined to assess functioning of brain regions mediating cognitive control in a context without social-cognitive demands, whereas the incongruent gaze condition assessed functioning of the same brain regions in a social-cognitive context. Consistent with prior studies, the incongruent arrow condition recruited activity in bilateral midfrontal gyrus, right inferior frontal gyrus, bilateral intraparietal sulcus, and the anterior cingulate relative to the congruent arrow condition in neurotypical participants. Notably, there were not diagnostic group differences in patterns of regional fMRI activation in response to the arrow condition. However, while viewing the incongruent gaze stimuli, although neurotypical participants recruited the same brain regions, participants with autism showed marked hypoactivation in these areas. These findings suggest that processing social-cognitive stimuli interferes with functioning of brain regions recruited during cognitive control tasks in autism. Implications for research into cognitive control deficits in autism are discussed.

Atypical face processing plays a key role in social interaction difficulties encountered by individuals with autism. In the current fMRI study, the Thatcher illusion was used to investigate several aspects of face processing in 20 young adults with high-functioning autism spectrum disorder (ASD) and 20 matched neurotypical controls. “Thatcherized” stimuli were modified at either the eyes or the mouth and participants discriminated between pairs of faces while cued to attend to either of these features in upright and inverted orientation. Behavioral data confirmed sensitivity to the illusion and intact configural processing in ASD. Directing attention towards the eyes vs. the mouth in upright faces in ASD led to (1) improved discrimination accuracy; (2) increased activation in areas involved in social and emotional processing; (3) increased activation in subcortical face-processing areas. Our findings show that when explicitly cued to attend to the eyes, activation of cortical areas involved in face processing, including its social and emotional aspects, can be enhanced in autism. This suggests that impairments in face processing in autism may be caused by a deficit in social attention, and that giving specific cues to attend to the eye-region when performing behavioral therapies aimed at improving social skills may result in a better outcome.

Despite significant social difficulties, children with autism spectrum disorder (ASD) are vulnerable to the effects of social exclusion. We recorded EEG while children with ASD and typical peers played a computerized game involving peer rejection. Children with ASD reported ostracism-related distress comparable to typically developing children. Event-related potentials (ERPs) indicated a distinct pattern of temporal processing of rejection events in children with ASD. While typically developing children showed enhanced response to rejection at a late slow wave indexing emotional arousal and regulation, those with autism showed attenuation at an early component, suggesting reduced engagement of attentional resources in the aversive social context. Results emphasize the importance of studying the time course of social information processing in ASD; they suggest distinct mechanisms subserving similar overt behavior and yield insights relevant to development and implementation of targeted treatment approaches and objective measures of response to treatment.

The autism spectrum disorders (ASDs) arise from a diverse array of genetic and environmental origins that disrupt the typical developmental trajectory of neural connectivity and synaptogenesis. ASDs are marked by dysfunctional social behavior and cognition, among other deficits. Greater understanding of the biological substrates of typical social behavior in animal models will further our understanding of the etiology of ASDs. Despite the precision and tractability of molecular genetics models of ASDs in rodents, these organisms lack the complexity of human social behavior, thus limiting their impact on understanding ASDs to basic mechanisms. Non-human primates (NHPs) provide an attractive, complementary model for ASDs, due in part to the complexity and dynamics of social structures, reliance on vision for social signaling, and deep homology in brain circuitry mediating social behavior and reward. This knowledge is based on a rich literature, compiled over 50 years of observing primate behavior in the wild, which, in the case of rhesus macaques, is complemented by a large body of research characterizing neuronal activity during cognitive behavior. Several recent developments in this field are directly relevant to ASDs, including how the brain represents the perceptual features of social stimuli, how social information influences attention processes in the brain, and how the value of social interaction is computed. Because the symptoms of ASDs may represent extreme manifestations of traits that vary in intensity within the general population, we will additionally discuss ways in which nonhuman primates also show variation in social behavior and reward sensitivity. In cases where variation in species-typical behavior is analogous to similar variations in human behavior, we believe that study of the neural circuitry underlying this variation will provide important insights into the systems-level mechanisms contributing to ASD pathology.

Children with Autism Spectrum Disorders (ASDs) are impaired in visually disengaging attention in both social and non-social contexts, impairments that may, in subtler form, also affect the infant siblings of children with an ASD (ASD-sibs). We investigated patterns of visual attention (gazing) in six-month-old ASD-sibs (n = 17) and the siblings of typically developing children (COMP-sibs; n =17) during the Face-to-Face/Still-Face Protocol (FFSF), in which parents are sequentially responsive, nonresponsive, and responsive to their infants. Throughout the protocol, ASD-sibs shifted their gaze to and from their parents' faces less frequently than did COMP-sibs. The mean durations of ASD-sibs’ gazes away from their parents' faces were longer than those of COMP-sibs. ASD-sibs and COMP-sibs did not differ in the mean durations of gazes at their parents' faces. In sum, ASD-sibs showed no deficits in visual interest to their parents’ faces, but greater interest than COMP-sibs in non-face stimuli.

Background

Visual behavior is known to be atypical in Autism Spectrum Disorders (ASD). Monitor-based eye-tracking studies have measured several of these atypicalities in individuals with Autism. While atypical behaviors are known to be accentuated during natural interactions, few studies have been made on gaze behavior in natural interactions. In this study we focused on i) whether the findings done in laboratory settings are also visible in a naturalistic interaction; ii) whether new atypical elements appear when studying visual behavior across the whole field of view.

Methodology/Principal Findings

Ten children with ASD and ten typically developing children participated in a dyadic interaction with an experimenter administering items from the Early Social Communication Scale (ESCS). The children wore a novel head-mounted eye-tracker, measuring gaze direction and presence of faces across the child's field of view. The analysis of gaze episodes to faces revealed that children with ASD looked significantly less and for shorter lapses of time at the experimenter. The analysis of gaze patterns across the child's field of view revealed that children with ASD looked downwards and made more extensive use of their lateral field of view when exploring the environment.

Conclusions/Significance

The data gathered in naturalistic settings confirm findings previously obtained only in monitor-based studies. Moreover, the study allowed to observe a generalized strategy of lateral gaze in children with ASD when they were looking at the objects in their environment.

Background

One hypothesis for the social deficits that characterize autism spectrum disorders (ASD) is diminished neural reward response to social interaction and attachment. Prior research using established monetary reward paradigms as a test of non-social reward to compare with social reward may involve confounds in the ability of individuals with ASD to utilize symbolic representation of money and the abstraction required to interpret monetary gains. Thus, a useful addition to our understanding of neural reward circuitry in ASD includes a characterization of the neural response to primary rewards.

Method

We asked 17 children with ASD and 18 children without ASD to abstain from eating for at least four hours before an MRI scan in which they viewed images of high-calorie foods. We assessed the neural reward network for increases in the blood oxygenation level dependent (BOLD) signal in response to the food images

Results

We found very similar patterns of increased BOLD signal to these images in the two groups; both groups showed increased BOLD signal in the bilateral amygdala, as well as in the nucleus accumbens, orbitofrontal cortex, and insula. Direct group comparisons revealed that the ASD group showed a stronger response to food cues in bilateral insula along the anterior-posterior gradient and in the anterior cingulate cortex than the control group, whereas there were no neural reward regions that showed higher activation for controls than for ASD.

Conclusion

These results suggest that neural response to primary rewards is not diminished but in fact shows an aberrant enhancement in children with ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by language and communication impairments, social impairments, and repetitive behaviors or restricted interests. Previous studies of semantic functions have found differences in semantic processing and differences in the activation of the language network in adults with ASD compared to controls. The goal of this study is to examine semantic functions in adolescents with ASD compared to typically developing adolescents. We utilized fMRI with a reading version of a response-naming task to investigate activation in 12 right-handed adolescent boys with ASD and 12 typically developing boys. Both groups performed the task at ceiling levels. Boys with ASD had significantly stronger activation than controls in Broca's area, which was less left lateralized in ASD individuals. Controls had a significant correlation between frontal and temporal language area activation in the left hemisphere, whereas ASD adolescents did not. Direct group comparisons revealed additional regions activated in the ASD group relative to the control group. These results suggest differences in semantic organization, approaches to the semantic task, or efficiency in semantic processing in ASD adolescents relative to typically developing adolescents.

Background

Autism spectrum disorders (ASD) are associated with severe impairments in social functioning. Because faces provide nonverbal cues that support social interactions, many studies of ASD have examined neural structures that process faces, including the amygdala, ventromedial prefrontal cortex and superior and middle temporal gyri. However, increases or decreases in activation are often contingent on the cognitive task. Specifically, the cognitive domain of attention influences group differences in brain activation. We investigated brain function abnormalities in participants with ASD using a task that monitored attention bias to emotional faces.

Methods

Twenty-four participants (12 with ASD, 12 controls) completed a functional magnetic resonance imaging study while performing an attention cuing task with emotional (happy, sad, angry) and neutral faces.

Results

In response to emotional faces, those in the ASD group showed greater right amygdala activation than those in the control group. A preliminary psychophysiological connectivity analysis showed that ASD participants had stronger positive right amygdala and ventromedial prefrontal cortex coupling and weaker positive right amygdala and temporal lobe coupling than controls. There were no group differences in the behavioural measure of attention bias to the emotional faces.

Limitations

The small sample size may have affected our ability to detect additional group differences.

Conclusion

When attention bias to emotional faces was equivalent between ASD and control groups, ASD was associated with greater amygdala activation. Preliminary analyses showed that ASD participants had stronger connectivity between the amygdala ventromedial prefrontal cortex (a network implicated in emotional modulation) and weaker connectivity between the amygdala and temporal lobe (a pathway involved in the identification of facial expressions, although areas of group differences were generally in a more anterior region of the temporal lobe than what is typically reported for emotional face processing). These alterations in connectivity are consistent with emotion and face processing disturbances in ASD.

Social referencing was investigated in 18-month-old siblings of children with autism spectrum disorders (ASD; “high-risk infants”). Infants were exposed to novel toys, which were emotionally tagged via adults’ facial and vocal signals. Infants’ information seeking (initiation of joint attention with an adult) and their approach/withdrawal behavior toward the toys before versus after the adults’ emotional signals was measured. Compared to both typically developing infants and high-risk infants without ASD, infants later diagnosed with ASD engaged in slower information seeking, suggesting that this aspect of referencing may be an early indicator of ASD. High-risk infants, both those who were and those who were not later diagnosed with ASD, exhibited impairments in regulating their behavior based on the adults’ emotional signals, suggesting that this aspect of social referencing may reflect an endophenotype for ASD.

Socio-communicative impairments are salient features of autism spectrum disorder (ASD) from a young age. The anterior prefrontal cortex (aPFC), or Brodmann area 10, is a key processing area for social function, and atypical development of this area is thought to play a role in the social deficits in ASD. It is important to understand these brain functions in developing children with ASD. However, these brain functions have not yet been well described under conscious conditions in young children with ASD. In the present study, we focused on the brain hemodynamic functional connectivity between the right and the left aPFC in children with ASD and typically developing (TD) children and investigated whether there was a correlation between this connectivity and social ability. Brain hemodynamic fluctuations were measured non-invasively by near-infrared spectroscopy (NIRS) in 3- to 7-year-old children with ASD (n = 15) and gender- and age-matched TD children (n = 15). The functional connectivity between the right and the left aPFC was assessed by measuring the coherence for low-frequency spontaneous fluctuations (0.01 – 0.10 Hz) during a narrated picture-card show. Coherence analysis demonstrated that children with ASD had a significantly higher inter-hemispheric connectivity with 0.02-Hz fluctuations, whereas a power analysis did not demonstrate significant differences between the two groups in terms of low frequency fluctuations (0.01 – 0.10 Hz). This aberrant higher connectivity in children with ASD was positively correlated with the severity of social deficit, as scored with the Autism Diagnostic Observation Schedule. This is the first study to demonstrate aberrant brain functional connectivity between the right and the left aPFC under conscious conditions in young children with ASD.

Background

Autism is a developmental disorder characterized by decreased interest and engagement in social interactions and by enhanced self-focus. While previous theoretical approaches to understanding autism have emphasized social impairments and altered interpersonal interactions, there is a recent shift towards understanding the nature of the representation of the self in individuals with autism spectrum disorders (ASD). Still, the neural mechanisms subserving self-representations in ASD are relatively unexplored.

Methodology/Principal Findings

We used event-related fMRI to investigate brain responsiveness to images of the subjects' own face and to faces of others. Children with ASD and typically developing (TD) children viewed randomly presented digital morphs between their own face and a gender-matched other face, and made “self/other” judgments. Both groups of children activated a right premotor/prefrontal system when identifying images containing a greater percentage of the self face. However, while TD children showed activation of this system during both self- and other-processing, children with ASD only recruited this system while viewing images containing mostly their own face.

Conclusions/Significance

This functional dissociation between the representation of self versus others points to a potential neural substrate for the characteristic self-focus and decreased social understanding exhibited by these individuals, and suggests that individuals with ASD lack the shared neural representations for self and others that TD children and adults possess and may use to understand others.

Background

Individuals with Autism Spectrum Disorders (ASD) typically show impaired eye contact during social interactions. From a young age, they look less at faces than typically developing (TD) children and tend to avoid direct gaze. However, the reason for this behavior remains controversial; ASD children might avoid eye contact because they perceive the eyes as aversive or because they do not find social engagement through mutual gaze rewarding.

Methods

We monitored pupillary diameter as a measure of autonomic response in children with ASD (n = 20, mean age = 12.4) and TD controls (n = 18, mean age = 13.7) while they looked at faces displaying different emotions. Each face displayed happy, fearful, angry or neutral emotions with the gaze either directed to or averted from the subjects.

Results

Overall, children with ASD and TD controls showed similar pupillary responses; however, they differed significantly in their sensitivity to gaze direction for happy faces. Specifically, pupillary diameter increased among TD children when viewing happy faces with direct gaze as compared to those with averted gaze, whereas children with ASD did not show such sensitivity to gaze direction. We found no group differences in fixation that could explain the differential pupillary responses. There was no effect of gaze direction on pupil diameter for negative affect or neutral faces among either the TD or ASD group.

Conclusions

We interpret the increased pupillary diameter to happy faces with direct gaze in TD children to reflect the intrinsic reward value of a smiling face looking directly at an individual. The lack of this effect in children with ASD is consistent with the hypothesis that individuals with ASD may have reduced sensitivity to the reward value of social stimuli.

Caregiver report on the Adaptive Behavior Assessment System-II (ABAS) for 40 high-functioning individuals with autism spectrum disorders (ASD) and 30 typically developing (TD) individuals matched for age, IQ, and sex ratio revealed global adaptive behavior deficits in ASD, with social skills impairments particularly prominent. Within the ASD group, adaptive communication skills were positively related to IQ while global adaptive functioning was negatively associated with autism symptomatology. Autistic behavior ratings related negatively to ABAS scores in the TD but not the ASD group. This investigation demonstrates: the utility of an adaptive functioning checklist for capturing impairments, even in high-functioning individuals with ASD; and that a relationship between social abilities and autism exists independently of intelligence.

Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. A potential etiologic role for immune dysfunction in ASD has been suggested. Dynamic adaptive cellular immune function was investigated in 66 children with a confirmed diagnosis of ASD and 73 confirmed typically developing (TD) controls 2–5 years-of-age. In vitro stimulation of peripheral blood mononuclear cells with PHA and tetanus was used to compare group-associated cellular responses. The production of GM-CSF, TNFα, and IL-13 were significantly increased whereas IL-12p40 was decreased following PHA stimulation in ASD relative to TD controls. Induced cytokine production was associated with altered behaviors in ASD children such that increased pro-inflammatory or TH1 cytokines were associated with greater impairments in core features of ASD as well as aberrant behaviors. In contrast, production of GM-CSF and TH2 cytokines were associated with better cognitive and adaptive function. Following stimulation, the frequency of CD3+, CD4+ and CD8+ T cells expressing activation markers CD134 and CD25 but not CD69, HLA-DR or CD137 were significantly reduced in ASD, and suggests an altered activation profile for T cells in ASD. Overall these data indicate significantly altered adaptive cellular immune function in children with ASD that may reflect dysfunctional immune activation, along with evidence that these perturbations may be linked to disturbances in behavior and developmental functioning. Further longitudinal analyzes of cellular immunity profiles would delineate the relationship between immune dysfunction and the progression of behavioral and developmental changes throughout the course of this disorder.

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P=0.043), rs1042778 (P=0.037), and rs7632287 (P=0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.

Background

Autism spectrum disorders (ASD) involve a core deficit in social functioning and impairments in the ability to recognize face emotions. In an emotional faces task designed to constrain group differences in attention, the present study used functional MRI to characterize activation in the amygdala, ventral prefrontal cortex (vPFC), and striatum, three structures involved in socio-emotional processing, in adolescents with ASD.

Methods

Twenty-two adolescents with ASD and 20 healthy adolescents viewed facial expressions (happy, fearful, sad and neutral) that were briefly presented (250ms) during functional MRI acquisition. To monitor attention, subjects pressed a button to identify the gender of each face.

Results

The ASD group showed greater activation to the faces relative to the control group in the amygdala, vPFC and striatum. Follow-up analyses indicated that the ASD relative to control group showed greater activation in the amygdala, vPFC and striatum (p<.05 small volume corrected), particularly to sad faces. Moreover, in the ASD group, there was a negative correlation between developmental variables (age and pubertal status) and mean activation from the whole bilateral amygdala; younger adolescents showed greater activation than older adolescents. There were no group differences in accuracy or reaction time in the gender identification task.

Conclusions

When group differences in attention to facial expressions were limited, adolescents with ASD showed greater activation in structures involved in socio-emotional processing.