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1.  Perception of Social Cues of Danger in Autism Spectrum Disorders 
PLoS ONE  2013;8(12):e81206.
Intuitive grasping of the meaning of subtle social cues is particularly affected in autism spectrum disorders (ASD). Despite their relevance in social communication, the effect of averted gaze in fearful faces in conveying a signal of environmental threat has not been investigated using real face stimuli in adults with ASD. Here, using functional MRI, we show that briefly presented fearful faces with averted gaze, previously shown to be a strong communicative signal of environmental danger, produce different patterns of brain activation than fearful faces with direct gaze in a group of 26 normally intelligent adults with ASD compared with 26 matched controls. While implicit cue of threat produces brain activation in attention, emotion processing and mental state attribution networks in controls, this effect is absent in individuals with ASD. Instead, individuals with ASD show activation in the subcortical face-processing system in response to direct eye contact. An effect of differences in looking behavior was excluded in a separate eye tracking experiment. Our data suggest that individuals with ASD are more sensitive to direct eye contact than to social signals of danger conveyed by averted fearful gaze.
PMCID: PMC3852523  PMID: 24324679
2.  Neural correlates of “social gaze” processing in high-functioning autism under systematic variation of gaze duration☆ 
NeuroImage : Clinical  2013;3:340-351.
Direct gaze is a salient nonverbal signal for social interest and the intention to communicate. In particular, the duration of another's direct gaze can modulate our perception of the social meaning of gaze cues. However, both poor eye contact and deficits in social cognitive processing of gaze are specific diagnostic features of autism. Therefore, investigating neural mechanisms of gaze may provide key insights into the neural mechanisms related to autistic symptoms. Employing functional magnetic resonance imaging (fMRI) and a parametric design, we investigated the neural correlates of the influence of gaze direction and gaze duration on person perception in individuals with high-functioning autism (HFA) and a matched control group. For this purpose, dynamically animated faces of virtual characters, displaying averted or direct gaze of different durations (1 s, 2.5 s and 4 s) were evaluated on a four-point likeability scale. Behavioral results revealed that HFA participants showed no significant difference in likeability ratings depending on gaze duration, while the control group rated the virtual characters as increasingly likeable with increasing gaze duration. On the neural level, direct gaze and increasing direct gaze duration recruit regions of the social neural network (SNN) in control participants, indicating the processing of social salience and a perceived communicative intent. In participants with HFA however, regions of the social neural network were more engaged by averted and decreasing amounts of gaze, while the neural response for processing direct gaze in HFA was not suggestive of any social information processing.
•We investigate the neural processing of gaze direction and duration in HFA.•We use a combined categorical and parametric approach to analyze fMRI data.•The social neural network is not modulated by direct gaze cues in HFA.•Persons with HFA are impaired in using subtle aspects of gaze to understand others.
PMCID: PMC3815020  PMID: 24273718
Social gaze; Gaze duration; High-functioning autism; FMRI
3.  Abnormal social reward processing in autism as indexed by pupillary responses to happy faces 
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.
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.
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.
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.
PMCID: PMC3461481  PMID: 22958650
Autism; Pupillary response; Reward processing
4.  Atypical Functional Connectivity of the Amygdala in Childhood Autism Spectrum Disorders during Spontaneous Attention to Eye-Gaze 
Autism Research and Treatment  2012;2012:652408.
We examined functional connectivity of the amygdala in preadolescent children with Autism Spectrum Disorders (ASDs) during spontaneous attention to eye-gaze in emotional faces. Children responded to a target word (“LEFT/RIGHT”) printed on angry or fearful faces looking in a direction that was congruent, incongruent, or neutral with the target word. Despite being irrelevant to the task, gaze-direction facilitated (Congruent > Neutral) or interfered with (Incongruent > Congruent) performance in both groups. Despite similar behavioral performance, amygdala-connectivity was atypical and more widespread in children with ASD. In control children, the amygdala was more strongly connected with an emotional cognitive control region (subgenual cingulate) during interference, while during facilitation, no regions showed greater amygdala connectivity than in ASD children. In contrast, in children with ASD the amygdala was more strongly connected to salience and cognitive control regions (posterior and dorsal cingulate) during facilitation and with regions involved in gaze processing (superior temporal sulcus), cognitive control (inferior frontal gyrus), and processing of viscerally salient information (pregenual cingulate, anterior insula, and thalamus) during interference. These findings showing more widespread connectivity of the amygdala extend past findings of atypical functional anatomy of eye-gaze processing in children with ASD and challenge views of general underconnectivity in ASD.
PMCID: PMC3544253  PMID: 23326662
5.  Hard to “tune in”: neural mechanisms of live face-to-face interaction with high-functioning autistic spectrum disorder 
Persons with autism spectrum disorders (ASD) are known to have difficulty in eye contact (EC). This may make it difficult for their partners during face to face communication with them. To elucidate the neural substrates of live inter-subject interaction of ASD patients and normal subjects, we conducted hyper-scanning functional MRI with 21 subjects with autistic spectrum disorder (ASD) paired with typically-developed (normal) subjects, and with 19 pairs of normal subjects as a control. Baseline EC was maintained while subjects performed real-time joint-attention task. The task-related effects were modeled out, and inter-individual correlation analysis was performed on the residual time-course data. ASD–Normal pairs were less accurate at detecting gaze direction than Normal–Normal pairs. Performance was impaired both in ASD subjects and in their normal partners. The left occipital pole (OP) activation by gaze processing was reduced in ASD subjects, suggesting that deterioration of eye-cue detection in ASD is related to impairment of early visual processing of gaze. On the other hand, their normal partners showed greater activity in the bilateral occipital cortex and the right prefrontal area, indicating a compensatory workload. Inter-brain coherence in the right IFG that was observed in the Normal-Normal pairs (Saito et al., 2010) during EC diminished in ASD–Normal pairs. Intra-brain functional connectivity between the right IFG and right superior temporal sulcus (STS) in normal subjects paired with ASD subjects was reduced compared with in Normal–Normal pairs. This functional connectivity was positively correlated with performance of the normal partners on the eye-cue detection. Considering the integrative role of the right STS in gaze processing, inter-subject synchronization during EC may be a prerequisite for eye cue detection by the normal partner.
PMCID: PMC3459004  PMID: 23060772
functional connectivity; hyperscanning; inter-subject coherence; joint attention; mutual gaze; autistic spectrum disorder; functional magnetic resonance imaging
6.  Atypical Neural Networks for Social Orienting in Autism Spectrum Disorders 
NeuroImage  2011;56(1):354-362.
Autism spectrum disorders (ASD) are characterized by significant social impairments, including deficits in orienting attention following social cues. Behavioral studies investigating social orienting in ASD, however, have yielded mixed results, as the use of naturalistic paradigms typically reveals clear deficits whereas computerized laboratory experiments often report normative behavior. The present study is the first to examine the neural mechanisms underlying social orienting in ASD in order to provide new insight into the social attention impairments that characterize this disorder. Using fMRI, we examined the neural correlates of social orienting in children and adolescents with ASD and in a matched sample of typically developing (TD) controls while they performed a spatial cueing paradigm with social (eye gaze) and nonsocial (arrow) cues. Cues were either directional (indicating left or right) or neutral (indicating no direction), and directional cues were uninformative of the upcoming target location in order to engage automatic processes by minimizing expectations. Behavioral results demonstrated intact orienting effects for social and nonsocial cues, with no differences between groups. The imaging results, however, revealed clear group differences in brain activity. When attention was directed by social cues compared to nonsocial cues, the TD group showed increased activity in frontoparietal attention networks, visual processing regions, and the striatum, whereas the ASD group only showed increased activity in the superior parietal lobule. Significant group × cue type interactions confirmed greater responsivity in task-relevant networks for social cues than nonsocial cues in TD as compared to ASD, despite similar behavioral performance. These results indicate that, in the autistic brain, social cues are not assigned the same privileged status as they are in the typically developing brain. These findings provide the first empirical evidence that the neural circuitry involved in social orienting is disrupted in ASD and highlight that normative behavioral performance in a laboratory setting may reflect compensatory mechanisms rather than intact social attention.
PMCID: PMC3091391  PMID: 21334443
autism; attention; functional magnetic resonance imaging; gaze; social cue
7.  Visual disengagement in the infant siblings of children with an Autism Spectrum Disorder (ASD) 
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.
PMCID: PMC2860749  PMID: 18805943
autism spectrum disorders; siblings; at-risk; disengagement; early deficits
Three experiments explored attention to eye gaze, which is incompletely understood in typical development and is hypothesized to be disrupted in autism. Experiment 1 (n=26 typical adults) involved covert orienting to box, arrow, and gaze cues at two probabilities and cue-target times to test whether reorienting for gaze is endogenous, exogenous, or unique; experiment 2 (total n=80: male and female children and adults) studied age and sex effects on gaze cueing. Gaze cueing appears endogenous and may strengthen in typical development. Experiment 3 tested exogenous, endogenous, and/or gaze-based orienting in 25 typical and 27 Autistic Spectrum Disorder (ASD) children. ASD children made more saccades, slowing their reaction times; however, exogenous and endogenous orienting, including gaze cueing, appear intact in ASD.
PMCID: PMC3660145  PMID: 20809377
gaze; box; arrow; vision; oculomotor; child
9.  ERP responses differentiate inverted but not upright face processing in adults with ASD 
Individuals with autism spectrum disorders (ASD) have documented deficits in face processing, face memory and abnormal activation of the neural circuitry that supports these functions. To examine speed of processing of faces in ASD, high density event-related brain potentials were recorded to images of faces, inverted faces and non-face objects from 32 high-functioning adults with ASD and controls. Participants were instructed to focus on a cross hair prior to stimulus onset; the cross-hair location directed the participant's eye gaze to the eye region at stimulus onset. Although the ASD group preformed more poorly on behavioral tests of face and object memory, both groups demonstrated similar ERP responses, characterized by greater (positive) P1 and (negative) N170 amplitude to faces vs houses. N170 speed of processing to faces did not differ between groups. However, only the control group demonstrated differential responses to upright vs inverted faces. For the ASD group, the differential response to inverted vs upright faces was associated with better performance on face memory and self-reported social skills. It is possible that the use of attention cues may facilitate face processing in high-functioning adults with ASD, suggesting that the underlying neural circuitry can be activated in adults with ASD under specific demands.
PMCID: PMC3375882  PMID: 19454620
event-related potential; P100; N170; autism; face processing
10.  Association between amygdala response to emotional faces and social anxiety in autism spectrum disorders 
Neuropsychologia  2010;48(12):3665-3670.
Difficulty interpreting facial expressions has been reported in autism spectrum disorders (ASD) and is thought to be associated with amygdala abnormalities. To further explore the neural basis of abnormal emotional face processing in ASD, we conducted an fMRI study of emotional face matching in high-functioning adults with ASD and age, IQ, and gender matched controls. In addition, we investigated whether there was a relationship between self-reported social anxiety and fMRI activation. During fMRI scanning, study participants were instructed to match facial expressions depicting fear or anger. The control condition was a comparable shape - matching task. The control group evidenced significantly increased left prefrontal activation and decreased activation in the occipital lobes compared to the ASD group during emotional face matching. Further, within the ASD group, greater social anxiety was associated with increased activation in right amygdala and left middle temporal gyrus, and decreased activation in the fusiform face area. These results indicate that level of social anxiety mediates the neural response to emotional face perception in ASD.
PMCID: PMC3426451  PMID: 20655320
Autism; Asperger’s disorder; amygdala; anxiety; emotional face processing; fusiform face area
11.  Atypical gaze patterns in children and adults with autism spectrum disorders dissociated from developmental changes in gaze behaviour 
Eye tracking has been used to investigate gaze behaviours in individuals with autism spectrum disorder (ASD). However, traditional analysis has yet to find behavioural characteristics shared by both children and adults with ASD. To distinguish core ASD gaze behaviours from those that change with development, we examined temporo-spatial gaze patterns in children and adults with and without ASD while they viewed video clips. We summarized the gaze patterns of 104 participants using multidimensional scaling so that participants with similar gaze patterns would cluster together in a two-dimensional plane. Control participants clustered in the centre, reflecting a standard gaze behaviour, whereas participants with ASD were distributed around the periphery. Moreover, children and adults were separated on the plane, thereby showing a clear effect of development on gaze behaviours. Post hoc frame-by-frame analyses revealed the following findings: (i) both ASD groups shifted their gaze away from a speaker earlier than the control groups; (ii) both ASD groups showed a particular preference for letters; and (iii) typical infants preferred to watch the mouth rather than the eyes during speech, a preference that reversed with development. These results highlight the importance of taking the effect of development into account when addressing gaze behaviours characteristic of ASD.
PMCID: PMC2982027  PMID: 20484237
eye tracking; eye movements; autism; development; mouth viewing; turn taking
12.  Normal Gaze Cueing in Children with Autism Is Disrupted by Simultaneous Speech Utterances in “Live” Face-to-Face Interactions 
Autism Research and Treatment  2011;2011:545964.
Gaze cueing was assessed in children with autism and in typically developing children, using a computer-controlled “live” face-to-face procedure. Sensitivity to gaze direction was assessed using a Posner cuing paradigm. Both static and dynamic directional gaze cues were used. Consistent with many previous studies, using photographic and cartoon faces, gaze cueing was present in children with autism and was not developmentally delayed. However, in the same children, gaze cueing was abolished when a mouth movement occurred at the same time as the gaze cue. In contrast, typical children were able to use gaze cues in all conditions. The findings indicate that gaze cueing develops successfully in some children with autism but that their attention is disrupted by speech utterances. Their ability to learn to read nonverbal emotional and intentional signals provided by the eyes may therefore be significantly impaired. This may indicate a problem with cross-modal attention control or an abnormal sensitivity to peripheral motion in general or the mouth region in particular.
PMCID: PMC3420531  PMID: 22937251
13.  Face-to-face interference in typical and atypical development 
Developmental Science  2012;15(2):281-291.
Visual communication cues facilitate interpersonal communication. It is important that we look at faces to retrieve and subsequently process such cues. It is also important that we sometimes look away from faces as they increase cognitive load that may interfere with online processing. Indeed, when typically developing individuals hold face gaze it interferes with task completion. In this novel study we quantify face interference for the first time in Williams syndrome (WS) and Autism Spectrum Disorder (ASD). These disorders of development impact on cognition and social attention, but how do faces interfere with cognitive processing? Individuals developing typically as well as those with ASD (n = 19) and WS (n = 16) were recorded during a question and answer session that involved mathematics questions. In phase 1 gaze behaviour was not manipulated, but in phase 2 participants were required to maintain eye contact with the experimenter at all times. Looking at faces decreased task accuracy for individuals who were developing typically. Critically, the same pattern was seen in WS and ASD, whereby task performance decreased when participants were required to hold face gaze. The results show that looking at faces interferes with task performance in all groups. This finding requires the caveat that individuals with WS and ASD found it harder than individuals who were developing typically to maintain eye contact throughout the interaction. Individuals with ASD struggled to hold eye contact at all points of the interaction while those with WS found it especially difficult when thinking.
PMCID: PMC3627295  PMID: 22356183
14.  Eye contact influences neural processing of emotional expressions in 4-month-old infants 
Eye gaze is a fundamental component of human communication. During the first post-natal year, infants rapidly learn that the gaze of others provides socially significant information. In addition, infants are sensitive to several emotional expressions. However, little is known regarding how eye contact influences the way the infant brain processes emotional expressions. We measured 4-month-old infants’ brain electric activity to assess neural processing of faces displaying neutral, happy and angry emotional expressions when accompanied by direct and averted eye gaze. The results show that processing of angry facial expressions was influenced by eye gaze. In particular, infants showed enhanced neural processing of angry expressions when these expressions were accompanied by direct eye gaze. These results show that by 4 months of age, the infant detects angry emotional expressions, and the infant brain processes their relevance to the self.
PMCID: PMC2555439  PMID: 18985122
infants; EEG; eye gaze; social cognition; ERP
15.  Brain Mechanisms for Processing Direct and Averted Gaze in Individuals with Autism 
Prior studies have indicated brain abnormalities underlying social processing in autism, but no fMRI study has specifically addressed the differential processing of direct and averted gaze, a critical social cue. Fifteen adolescents and adults with autism and 14 typically developing comparison participants viewed dynamic virtual-reality videos depicting a simple but realistic social scenario, in which an approaching male figure maintained either direct or averted gaze. Significant group by condition interactions reflecting differential responses to direct versus averted gaze in people with autism relative to typically developing individuals were identified in the right temporoparietal junction, right anterior insula, left lateral occipital cortex, and left dorsolateral prefrontal cortex. Our results provide initial evidence regarding brain mechanisms underlying the processing of gaze direction during simple social encounters, providing new insight into the social deficits in individuals with autism.
PMCID: PMC3337548  PMID: 21484518
Autism; direct gaze; averted gaze; gaze processing; functional magnetic resonance imaging
16.  Culture, gaze and the neural processing of fear expressions 
The direction of others’ eye gaze has important influences on how we perceive their emotional expressions. Here, we examined differences in neural activation to direct- versus averted-gaze fear faces as a function of culture of the participant (Japanese versus US Caucasian), culture of the stimulus face (Japanese versus US Caucasian), and the relation between the two. We employed a previously validated paradigm to examine differences in neural activation in response to rapidly presented direct- versus averted-fear expressions, finding clear evidence for a culturally determined role of gaze in the processing of fear. Greater neural responsivity was apparent to averted- versus direct-gaze fear in several regions related to face and emotion processing, including bilateral amygdalae, when posed on same-culture faces, whereas greater response to direct- versus averted-gaze fear was apparent in these same regions when posed on other-culture faces. We also found preliminary evidence for intercultural variation including differential responses across participants to Japanese versus US Caucasian stimuli, and to a lesser degree differences in how Japanese and US Caucasian participants responded to these stimuli. These findings reveal a meaningful role of culture in the processing of eye gaze and emotion, and highlight their interactive influences in neural processing.
PMCID: PMC2894663  PMID: 20019073
eye gaze; facial expression; face perception; cross-cultural psychology; amygdala
17.  Autism spectrum traits predict the neural response to eye gaze in typical individuals 
Neuroimage  2012;59(4-4):3356-3363.
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.
► 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.
PMCID: PMC3315678  PMID: 22062191
Eye gaze; fMRI; Autism spectrum; Attention; Face perception
18.  Visual attention to dynamic faces and objects is linked to face processing skills: a combined study of children with autism and controls 
Although the extant literature on face recognition skills in Autism Spectrum Disorder (ASD) shows clear impairments compared to typically developing controls (TDC) at the group level, the distribution of scores within ASD is broad. In the present research, we take a dimensional approach and explore how differences in social attention during an eye tracking experiment correlate with face recognition skills across ASD and TDC. Emotional discrimination and person identity perception face processing skills were assessed using the Let's Face It! Skills Battery in 110 children with and without ASD. Social attention was assessed using infrared eye gaze tracking during passive viewing of movies of facial expressions and objects displayed together on a computer screen. Face processing skills were significantly correlated with measures of attention to faces and with social skills as measured by the Social Communication Questionnaire (SCQ). Consistent with prior research, children with ASD scored significantly lower on face processing skills tests but, unexpectedly, group differences in amount of attention to faces (vs. objects) were not found. We discuss possible methodological contributions to this null finding. We also highlight the importance of a dimensional approach for understanding the developmental origins of reduced face perception skills, and emphasize the need for longitudinal research to truly understand how social motivation and social attention influence the development of social perceptual skills.
PMCID: PMC3622030  PMID: 23596436
autism; eye tracking; face processing; eyetracking; autism spectrum disorder; ASD
19.  A Prospective Study of the Emergence of Early Behavioral Signs of Autism 
To examine prospectively the emergence of behavioral signs of autism in the first years of life in infants at low and high risk for autism.
A prospective longitudinal design was used to compare 25 infants later diagnosed with an autism spectrum disorder (ASD) with 25 gender-matched low-risk children later determined to have typical development. Participants were evaluated at 6, 12, 18, 24, and 36 months of age. Frequencies of gaze to faces, social smiles, and directed vocalizations were coded from video and rated by examiners.
The frequency of gaze to faces, shared smiles, and vocalizations to others were highly comparable between groups at 6 months of age, but significantly declining trajectories over time were apparent in the group later diagnosed with ASD. Group differences were significant by 12 months of age on most variables. Although repeated evaluation documented loss of skills in most infants with ASD, most parents did not report a regression in their child’s development.
These results suggest that behavioral signs of autism are not present at birth, as once suggested by Kanner, but emerge over time through a process of diminishment of key social communication behaviors. More children may present with a regressive course than previously thought, but parent report methods do not capture this phenomenon well. Implications for onset classification systems and clinical screening are also discussed.
PMCID: PMC2923050  PMID: 20410715
Autism; Onset; Infancy; Regression
20.  The amygdala and the relevance detection theory of autism: an evolutionary perspective 
In the last few decades there has been increasing interest in the role of the amygdala in psychiatric disorders and, in particular, in its contribution to the socio-emotional impairments in autism spectrum disorders (ASDs). Given that the amygdala is a component structure of the “social brain,” several theoretical explanations compatible with amygdala dysfunction have been proposed to account for socio-emotional impairments in ASDs, including abnormal eye contact, gaze monitoring, face processing, mental state understanding, and empathy. Nevertheless, many theoretical accounts, based on the Amygdala Theory of Autism, fail to elucidate the complex pattern of impairments observed in this population, which extends beyond the social domain. As posited by the Relevance Detector theory (Sander et al., 2003), the human amygdala is a critical component of a brain circuit involved in the appraisal of self-relevant events that include, but are not restricted to, social stimuli. Here, we propose that the behavioral and social–emotional features of ASDs may be better understood in terms of a disruption in a “Relevance Detector Network” affecting the processing of stimuli that are relevant for the organism’s self-regulating functions. In the present review, we will first summarize the main literature supporting the involvement of the amygdala in socio-emotional disturbances in ASDs. Next, we will present a revised version of the Amygdala Relevance Detector hypothesis and we will show that this theoretical framework can provide a better understanding of the heterogeneity of the impairments and symptomatology of ASDs. Finally, we will discuss some predictions of our model, and suggest new directions in the investigation of the role of the amygdala within the more generally disrupted cortical connectivity framework as a model of neural organization of the autistic brain.
PMCID: PMC3874476  PMID: 24416006
autism spectrum disorders; amygdala; ventromedial prefrontal cortex; self-relevance; social brain
21.  Investigating Gaze of Children with ASD in Naturalistic Settings 
PLoS ONE  2012;7(9):e44144.
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.
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.
PMCID: PMC3454390  PMID: 23028494
22.  Social interaction modifies neural response to gaze shifts 
Monitoring gaze shifts is important for social interactions. The direction of gaze can reveal intentions and help to predict future actions. Here we examined whether behavioural and neural responses to gaze shifts were modulated by the social context of the gaze shift in two linked experiments. Two faces were presented, one gazing directly at the subject (the ‘social’ face) and one with averted gaze (the ’unsocial’ face). One face then made a gaze shift that was either towards a visible target (’correct’) or towards another location in space (’incorrect’). Both behavioural and neural responses to gaze shifts were modulated by the social context and the goal directedness of the gaze shift. Reaction times were significantly faster in response to ’correct’ and ‘social’ compared with ’incorrect’ and ’unsocial’ gaze shifts, respectively. Using functional magnetic resonance imaging, we found significantly greater activation in the parieto-frontal attentional network, and in some parts of the posterior superior temporal sulcus, in response to ‘incorrect’ and ’unsocial’ compared with ’incorrect’ and ‘social’ gaze shifts, respectively. Conversely, we found greater activation in the medial prefrontal cortex and precuneus in response to ’correct’ and ‘social’ compared with ’incorrect’ and ’unsocial’ gaze shifts. This activity may reflect the experience of joint attention associated with these gaze shifts.
PMCID: PMC2555432  PMID: 18985119
fMRI; gaze; social; attention
23.  Eye-Tracking, Autonomic, and Electrophysiological Correlates of Emotional Face Processing in Adolescents with Autism Spectrum Disorder 
Individuals with autism spectrum disorder (ASD) often have difficulty with social-emotional cues. This study examined the neural, behavioral, and autonomic correlates of emotional face processing in adolescents with ASD and typical development (TD) using eye-tracking and event-related potentials (ERPs) across two different paradigms. Scanning of faces was similar across groups in the first task, but the second task found that face-sensitive ERPs varied with emotional expressions only in TD. Further, ASD showed enhanced neural responding to non-social stimuli. In TD only, attention to eyes during eye-tracking related to faster face-sensitive ERPs in a separate task; in ASD, a significant positive association was found between autonomic activity and attention to mouths. Overall, ASD showed an atypical pattern of emotional face processing, with reduced neural differentiation between emotions and a reduced relationship between gaze behavior and neural processing of faces.
PMCID: PMC3913826  PMID: 22684525
Autism spectrum disorder; Eye-tracking; Event-related potentials; Pupillometry; Emotional face processing
24.  Watch Out! Magnetoencephalographic Evidence for Early Modulation of Attention Orienting by Fearful Gaze Cueing 
PLoS ONE  2012;7(11):e50499.
Others’ gaze and emotional facial expression are important cues for the process of attention orienting. Here, we investigated with magnetoencephalography (MEG) whether the combination of averted gaze and fearful expression may elicit a selectively early effect of attention orienting on the brain responses to targets. We used the direction of gaze of centrally presented fearful and happy faces as the spatial attention orienting cue in a Posner-like paradigm where the subjects had to detect a target checkerboard presented at gazed-at (valid trials) or non gazed-at (invalid trials) locations of the screen. We showed that the combination of averted gaze and fearful expression resulted in a very early attention orienting effect in the form of additional parietal activity between 55 and 70 ms for the valid versus invalid targets following fearful gaze cues. No such effect was obtained for the targets following happy gaze cues. This early cue-target validity effect selective of fearful gaze cues involved the left superior parietal region and the left lateral middle occipital region. These findings provide the first evidence for an effect of attention orienting induced by fearful gaze in the time range of C1. In doing so, they demonstrate the selective impact of combined gaze and fearful expression cues in the process of attention orienting.
PMCID: PMC3510181  PMID: 23209761
25.  Frontal contributions to face processing differences in autism: Evidence from fMRI of inverted face processing 
Functional neuroimaging studies of face processing deficits in autism have typically focused on visual processing regions, such as the fusiform face area (FFA), which have shown reduced activity in autism spectrum disorders (ASD), though inconsistently. We recently reported reduced activity in the inferior frontal region in ASD, implicating impaired mirror-neuron systems during face processing. In the present study, we used fMRI during a face processing task in which subjects had to match faces presented in the upright versus inverted position. Typically developing (TD) children showed a classic behavioral inversion effect, increased reaction time for inverted faces, while this effect was significantly reduced in ASD subjects. The fMRI data showed similar responses in the fusiform face area for ASD and TD children, with both groups demonstrating increased activation for inverted faces. However, the groups did differ in several brain regions implicated in social cognition, particularly prefrontal cortex and amygdala. These data suggest that the behavioral differences in processing upright versus inverted faces for TD children are related not to visual information processing but to the social significance of the stimuli. Our results are consistent with other recent studies implicating frontal and limbic dysfunction during face processing in autism.
PMCID: PMC3047502  PMID: 18954473
Functional MRI; Autism; Asperger’s; Face processing; Face inversion; Development

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