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1.  Temporal dynamics reveal atypical brain response to social exclusion in autism 
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.
doi:10.1016/j.dcn.2011.02.003
PMCID: PMC3125043  PMID: 21731598
ERP; EEG; autism spectrum disorder; social exclusion; social neuroscience
2.  The Modifier Model of Autism and Social Development in Higher Functioning Children 
The study of phenotypic variability in social impairments and comorbid emotional disorders in autism is important because it provides information on phenotypic differences that currently complicate diagnosis, research, and treatment of this disorder. Currently, though, relatively little is known about the processes that contribute to individual differences in social impairments and comorbidity in autism. In this paper, we present a model that suggests modifier processes (MPs), which are not necessarily specific to the syndrome refractor alter the expression of autism and contribute to fundamental behavioral and psychological differences in children diagnosed with this disorder. One MPs involves the somewhat surprising tendency of some children with higher functioning autism (HFA) to make attributions about other peoples thoughts, although they have social cognitive deficits Just as in other children, the attributions of children with HFA are linked to some of their behavioral problems Another MP involves the influence of differences in motivation associated with the behavioral activation and inhibition systems that can be assessed with measures of anterior EEG asymmetry. This dimension of motivation may be linked to how active but inappropriate and withdrawn children with HFA may appear. Third, differences in the self-monitoring of errors among children with HFA appear to be related to individual differences in IQ and social symptom severity in these children. The possible role of these MPs in diagnostic subgroups and differences in treatment responses among children with HFA are discussed. In addition, the role of MPs in understanding the effects associated with specific genetic functions in autism, such as those associated with the serotonin transporter gene (5-HTTLPR), is discussed. A conclusion of this paper is that the varied expression of autism may require that we understand how autism interacts with other non-syndrome-specific processes that are related to individual differences in all people.
PMCID: PMC2773555  PMID: 19898685
phenotypic variability; comorbity; self-monitoring; motivation and attributional processes; autism
3.  The Interplay between Emotion and Cognition in Autism Spectrum Disorder: Implications for Developmental Theory 
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is clinically defined by abnormalities in reciprocal social and communicative behaviors and an inflexible adherence to routinised patterns of thought and behavior. Laboratory studies repeatedly demonstrate that autistic individuals experience difficulties in recognizing and understanding the emotional expressions of others and naturalistic observations show that they use such expressions infrequently and inappropriately to regulate social exchanges. Dominant theories attribute this facet of the ASD phenotype to abnormalities in a social brain network that mediates social-motivational and social-cognitive processes such as face processing, mental state understanding, and empathy. Such theories imply that only emotion related processes relevant to social cognition are compromised in ASD but accumulating evidence suggests that the disorder may be characterized by more widespread anomalies in the domain of emotions. In this review I summarize the relevant literature and argue that the social-emotional characteristics of ASD may be better understood in terms of a disruption in the domain-general interplay between emotion and cognition. More specifically I will suggest that ASD is the developmental consequence of early emerging anomalies in how emotional responses to the environment modulate a wide range of cognitive processes including those that are relevant to navigating the social world.
doi:10.3389/fnint.2012.00113
PMCID: PMC3540960  PMID: 23316143
autism; emotion; social-motivation; social brain; social cognition
4.  The Creatine Transporter Gene Paralogous at 16p11.2 Is Expressed in Human Brain 
Autism is a complex neurodevelopmental disorder characterized by impairment of social interaction, language, communication, and stereotyped, repetitive behavior. Genetic predisposition to autism has been demonstrated in families and twin studies. About 5–10% of autism cases are associated with chromosomal abnormalities or monogenic disorders. The identification of genes involved in the origin of autism is expected to increase our understanding of the pathogenesis. We report on the clinical, cytogenetic, and molecular findings in a boy with autism carrying a de novo translocation t(7;16)(p22.1;p11.2). The chromosome 16 breakpoint disrupts the paralogous SLC6A8 gene also called SLC6A10 or CT2. Predicted translation of exons and RT-PCR analysis reveal specific expression of the creatine transporter paralogous in testis and brain. Several studies reported on the role of X-linked creatine transporter mutations in individuals with mental retardation, with or without autism. The existence of disruption in SLC6A8 paralogous gene associated with idiopathic autism suggests that this gene may be involved in the autistic phenotype in our patient.
doi:10.1155/2008/609684
PMCID: PMC2396218  PMID: 18509488
5.  Amygdala Enlargement in Toddlers with Autism Related to Severity of Social and Communication Impairments 
Biological psychiatry  2009;66(10):942-949.
BACKGROUND
Autism is a heterogeneous neurodevelopmental disorder of unknown etiology. The amygdala has long been a site of intense interest in the search for neuropathology in autism, given its role in emotional and social behavior. An interesting hypothesis has emerged that the amygdala undergoes an abnormal developmental trajectory with a period of early overgrowth in autism; however this finding has not been well established at young ages nor analyzed with boys and girls independently.
METHODS
We measured amygdala volumes on MRI scans from eighty-nine toddlers at 1 to 5 years of age (mean 3 yrs). Each child returned at ~5 years of age for final clinical evaluation.
RESULTS
Toddlers who later received a confirmed autism diagnosis (32 males, 9 females) had a larger right (p<.01) and left (p<.05) amygdala compared to typically-developing toddlers (28 males, 11 females) with and without covarying for total cerebral volume. Amygdala size in toddlers with autism spectrum disorder correlated with the severity of their social and communication impairments as measured on the ADI-R and Vineland. Strikingly, females more robustly differed from typical in amygdala volume whereas males accounted for the significant relationship of amygdala size with severity of their clinical impairments.
CONCLUSIONS
This study provides evidence that the amygdala is enlarged in young children with autism; the overgrowth must begin before 3 years of age and is associated with the severity of clinical impairments. However, neuroanatomical phenotypic profiles differ between males and females, which critically impacts future studies on the genetics and etiology of autism.
doi:10.1016/j.biopsych.2009.07.007
PMCID: PMC2795360  PMID: 19726029
MRI; temporal; volume; neuroanatomy; development; brain growth
6.  Neuropathology and Animal Models of Autism: Genetic and Environmental Factors 
Autism Research and Treatment  2013;2013:731935.
Autism is a heterogeneous behaviorally defined neurodevelopmental disorder. It is defined by the presence of marked social deficits, specific language abnormalities, and stereotyped repetitive patterns of behavior. Because of the variability in the behavioral phenotype of the disorder among patients, the term autism spectrum disorder has been established. In the first part of this review, we provide an overview of neuropathological findings from studies of autism postmortem brains and identify the cerebellum as one of the key brain regions that can play a role in the autism phenotype. We review research findings that indicate possible links between the environment and autism including the role of mercury and immune-related factors. Because both genes and environment can alter the structure of the developing brain in different ways, it is not surprising that there is heterogeneity in the behavioral and neuropathological phenotypes of autism spectrum disorders. Finally, we describe animal models of autism that occur following insertion of different autism-related genes and exposure to environmental factors, highlighting those models which exhibit both autism-like behavior and neuropathology.
doi:10.1155/2013/731935
PMCID: PMC3787615  PMID: 24151553
7.  Brain Region–Specific Decrease in the Activity and Expression of Protein Kinase A in the Frontal Cortex of Regressive Autism 
PLoS ONE  2011;6(8):e23751.
Autism is a severe neurodevelopmental disorder that is characterized by impaired language, communication, and social skills. In regressive autism, affected children first show signs of normal social and language development but eventually lose these skills and develop autistic behavior. Protein kinases are essential in G-protein-coupled, receptor-mediated signal transduction and are involved in neuronal functions, gene expression, memory, and cell differentiation. We studied the activity and expression of protein kinase A (PKA), a cyclic AMP–dependent protein kinase, in postmortem brain tissue samples from the frontal, temporal, parietal, and occipital cortices, and the cerebellum of individuals with regressive autism; autistic subjects without a clinical history of regression; and age-matched developmentally normal control subjects. The activity of PKA and the expression of PKA (C-α), a catalytic subunit of PKA, were significantly decreased in the frontal cortex of individuals with regressive autism compared to control subjects and individuals with non-regressive autism. Such changes were not observed in the cerebellum, or the cortices from the temporal, parietal, and occipital regions of the brain in subjects with regressive autism. In addition, there was no significant difference in PKA activity or expression of PKA (C-α) between non-regressive autism and control groups. These results suggest that regression in autism may be associated, in part, with decreased PKA-mediated phosphorylation of proteins and abnormalities in cellular signaling.
doi:10.1371/journal.pone.0023751
PMCID: PMC3166116  PMID: 21909354
8.  Expression of non-protein-coding antisense RNAs in genomic regions related to autism spectrum disorders 
Molecular Autism  2013;4:32.
Background
Autism spectrum disorders (ASD) manifest with neurodevelopmental phenotypes including communicative, social and behavioral impairments that affect as many as 1 in 88 children. The majority of autism cases have no known genetic cause, suggesting complex genetics of the disorder, but a few genes of large effect have been identified.
Methods
In order to identify novel ASD genetic correlates, we investigated non-protein coding RNAs (ncRNAs) which are abundantly transcribed from the human genome, enriched in the brain, and have been implicated in neurodevelopmental disorders. Using an algorithm that we developed, we examined a publicly available transcriptomics database, AceView, to identify the natural antisense transcripts (NATs) that overlap with known autism-related genes. We validated the presence and differential expression of NATs in different brain regions of ASD and control brains using qRT-PCR. Additionally, we investigated the subcellular localization of these transcripts in a neuronal cell line using RNA-sequencing (RNA-seq).
Results
We found noncoding antisense RNA transcripts at approximately 40% of loci previously implicated in ASD. We confirmed the expression of 10 antisense RNAs in different postmortem human brain tissues. The expression of five antisense transcripts was found to be region-specific, suggesting a role for these ncRNAs in the development and function of specific brain regions. Some antisense RNAs overlapping suspected ASD genes exhibited concordant expression relative to their sense protein-coding genes, while other sense-antisense pairs demonstrate a discordant relationship. Interestingly, the antisense RNA corresponding to the SYNGAP1 locus (SYNGAP1-AS) was found to be differentially expressed in brain regions of patients with ASD compared to control individuals. RNA-seq analysis of subcellular compartments from SH-SY5Y human neuroblastoma cells demonstrated that antisense RNAs to ASD candidate genes are predominantly expressed in the nucleoplasmic or chromatin compartments, implying their involvement in nuclear-associated processes.
Conclusions
Our data suggests that NATs are abundantly expressed from ASD-related loci and provide evidence for their roles in target gene regulation, neurodevelopment and autism pathogenesis. This class of RNA should therefore be considered in functional studies aimed at understanding genetic risk factors for ASD.
doi:10.1186/2040-2392-4-32
PMCID: PMC3851999  PMID: 24007600
Autism; ASDs; Epigenetics; lncRNAs; NATs; ncRNAs
9.  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.
doi:10.3389/fnhum.2013.00894
PMCID: PMC3874476  PMID: 24416006
autism spectrum disorders; amygdala; ventromedial prefrontal cortex; self-relevance; social brain
10.  Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway 
Autism is a neurodevelopmental disorder marked by social skills and communication deficits and interfering repetitive behavior. Intellectual disability often accompanies autism. In addition to behavioral deficits, autism is characterized by neuropathology and brain overgrowth. Increased intracranial volume often accompanies this brain growth. We have found that the Alzheimer’s disease (AD) associated amyloid-β precursor protein (APP), especially its neuroprotective processing product, secreted APP α, is elevated in persons with autism. This has led to the “anabolic hypothesis” of autism etiology, in which neuronal overgrowth in the brain results in interneuronal misconnections that may underlie multiple autism symptoms. We review the contribution of research in brain volume and of APP to the anabolic hypothesis, and relate APP to other proteins and pathways that have already been directly associated with autism, such as fragile X mental retardation protein, Ras small GTPase/extracellular signal-regulated kinase, and phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin. We also present additional evidence of magnetic resonance imaging intracranial measurements in favor of the anabolic hypothesis. Finally, since it appears that APP’s involvement in autism is part of a multi-partner network, we extend this concept into the inherently interactive realm of epigenetics. We speculate that the underlying molecular abnormalities that influence APP’s contribution to autism are epigenetic markers overlaid onto potentially vulnerable gene sequences due to environmental influence.
doi:10.3389/fncel.2013.00094
PMCID: PMC3689023  PMID: 23801940
Alzheimer’s-autism continuum; anabolic hypothesis; neurite overgrowth; cranial volume
11.  Inter-Regional Brain Communication and Its Disturbance in Autism 
In this review article, we summarize recent progress toward understanding disturbances in functional and anatomical brain connectivity in autism. Autism is a neurodevelopmental disorder affecting language, social interaction, and repetitive behaviors. Recent studies have suggested that limitations of frontal–posterior brain connectivity in autism underlie the varied set of deficits associated with this disorder. Specifically, the underconnectivity theory of autism postulates that individuals with autism have a reduced communication bandwidth between frontal and posterior cortical areas, which constrains the psychological processes that rely on the integrated functioning of frontal and posterior brain networks. This review summarizes the recent findings of reduced frontal–posterior functional connectivity (synchronization) in autism in a wide variety of high-level tasks, focusing on data from functional magnetic resonance imaging studies. It also summarizes the findings of disordered anatomical connectivity in autism, as measured by a variety of techniques, including distribution of white matter volumes and diffusion tensor imaging. We conclude with a discussion of the implications of these findings for autism and future directions for this line of research.
doi:10.3389/fnsys.2011.00010
PMCID: PMC3046360  PMID: 21390284
autism; brain connectivity; fMRI; DTI
12.  Autism and exergaming: effects on repetitive behaviors and cognition 
Autism is a neurodevelopmental disorder that leads to impairment in social skills and delay in language development, and results in repetitive behaviors and restricted interests that impede academic and social involvement. Physical exercise has been shown to decrease repetitive behaviors in autistic children and improve cognitive function across the life-span. Exergaming combines physical and mental exercise simultaneously by linking physical activity movements to video game control and may yield better compliance with exercise. In this investigation, two pilot studies explored the potential behavioral and cognitive benefits of exergaming. In Pilot I, twelve children with autism spectrum disorders completed a control task and an acute bout of Dance Dance Revolution (DDR); in Pilot II, ten additional youths completed an acute bout of cyber cycling. Repetitive behaviors and executive function were measured before and after each activity. Repetitive behaviors significantly decreased, while performance on Digits Backwards improved following the exergaming conditions compared with the control condition. Additional research is needed to replicate these findings, and to explore the application of exergaming for the management of behavioral disturbance and to increase cognitive control in children on the autism spectrum.
doi:10.2147/PRBM.S24016
PMCID: PMC3218790  PMID: 22114543
autism; repetitive behaviors; exergaming; exercise; executive function
13.  Further characterization of autoantibodies to GABAergic neurons in the central nervous system produced by a subset of children with autism 
Molecular Autism  2011;2:5.
Background
Autism is a neurodevelopmental disorder characterized by impairments in social interaction and deficits in verbal and nonverbal communication, together with the presence of repetitive behaviors or a limited repertoire of activities and interests. The causes of autism are currently unclear. In a previous study, we determined that 21% of children with autism have plasma autoantibodies that are immunoreactive with a population of neurons in the cerebellum that appear to be Golgi cells, which are GABAergic interneurons.
Methods
We have extended this analysis by examining plasma immunoreactivity in the remainder of the brain. To determine cell specificity, double-labeling studies that included one of the calcium-binding proteins that are commonly colocalized in GABAergic neurons (calbindin, parvalbumin or calretinin) were also carried out to determine which GABAergic neurons are immunoreactive. Coronal sections through the rostrocaudal extent of the macaque monkey brain were reacted with plasma from each of seven individuals with autism who had previously demonstrated positive Golgi cell staining, as well as six negative controls. In addition, brain sections from adult male mice were similarly examined.
Results
In each case, specific staining was observed for neurons that had the morphological appearance of interneurons. By double-labeling sections with plasma and with antibodies directed against γ-aminobutyric acid (GABA), we determined that all autoantibody-positive neurons were GABAergic. However, not all GABAergic neurons were autoantibody-positive. Calbindin was colabeled in several of the autoantibody-labeled cells, while parvalbumin colabeling was less frequently observed. Autoantibody-positive cells rarely expressed calretinin. Sections from the mouse brain processed similarly to the primate sections also demonstrated immunoreactivity to interneurons distributed throughout the neocortex and many subcortical regions. Some cell populations stained in the primate (such as the Golgi neurons in the cerebellum) were not as robustly immunoreactive in the mouse brain.
Conclusions
These results suggest that the earlier report of autoantibody immunoreactivity to specific cells in the cerebellum extend to other regions of the brain. Further, these findings confirm the autoantibody-targeted cells to be a subpopulation of GABAergic interneurons. The potential impact of these autoantibodies on GABAergic disruption with respect to the etiology of autism is discussed herein.
doi:10.1186/2040-2392-2-5
PMCID: PMC3108923  PMID: 21521495
14.  Relational Victimization Predicts Children’s Social-Cognitive and Self-Regulatory Responses in a Challenging Peer Context 
Developmental psychology  2009;45(5):1444-1454.
This study examined whether exposure to relational victimization was associated with children’s thoughts, emotions, and behavior in an unfamiliar, challenging peer context. Children (110 girls, 96 boys; M age = 10.13 years, SD = 1.16) reported on their exposure to relational victimization by peers. Following a challenging interaction with an unfamiliar peer, children reported on their beliefs about their interaction partners and their social goals (i.e., focus on getting to know their partner versus impressing their partner) during the interaction. Coders rated children’s emotion and behavior regulation and the quality of the dyadic context. Results from hierarchical linear modeling analyses revealed that relational victimization predicted maladaptive social-cognitive processes (i.e., more negative peer beliefs and a heightened performance goal orientation) and heightened emotion and behavior dysregulation. Several of these effects were particularly salient in the context of a conflictual dyadic interaction. This research provides insight into impairments associated with relational victimization that may contribute to the emergence and/or perpetuation of peer difficulties.
doi:10.1037/a0014858
PMCID: PMC2780469  PMID: 19702404
15.  Atypical Social Referencing in Infant Siblings of Children with Autism Spectrum Disorders 
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.
doi:10.1007/s10803-012-1518-8
PMCID: PMC3593052  PMID: 22456817
Autism; Social referencing; Joint attention; Behavior regulation
16.  Basal and Adrenocorticotropic Hormone Stimulated Plasma Cortisol Levels Among Egyptian Autistic Children: Relation to Disease Severity 
Background
Autism is a disorder of early childhood characterized by social impairment, communication abnormalities and stereotyped behaviors. The hypothalamic-pituitary-adrenocortical (HPA) axis deserves special attention, since it is the basis for emotions and social interactions that are affected in autism.
Aim
To assess basal and stimulated plasma cortisol, and adrenocorticotropic hormone (ACTH) levels in autistic children and their relationship to disease characteristics.
Methods
Fifty autistic children were studied in comparison to 50 healthy age-, sex- and pubertal stage- matched children. All subjects were subjected to clinical evaluation and measurement of plasma cortisol (basal and stimulated) and ACTH. In addition, electroencephalography (EEG) and intelligence quotient (IQ) assessment were done for all autistic children.
Results
Sixteen% of autistic patients had high ACTH, 10% had low basal cortisol and 10% did not show adequate cortisol response to ACTH stimulation. Autistic patients had lower basal (p = 0.032) and stimulated cortisol (p = 0.04) and higher ACTH (p = 0.01) than controls. Childhood Autism Rating Scale (CARS) score correlated positively with ACTH (r = 0.71, p = 0.02) and negatively with each of basal (r = -0.64, p = 0.04) and stimulated cortisol (r = -0.88, p < 0.001). Hormonal profile did not differ in relation to EEG abnormalities, IQ and self- aggressive symptoms.
Conclusions
The observed hormonal changes may be due to a dysfunction in the HPA axis in autistic individuals. Further studies are warranted regarding the role of HPA axis dysfunction in the pathogenesis of autism.
doi:10.1186/1824-7288-36-71
PMCID: PMC2987909  PMID: 21034507
17.  Amygdala Regulation of Fear and Emotionality in Fragile X Syndrome 
Developmental Neuroscience  2011;33(5):365-378.
Fear is a universal response to a threat to one's body or social status. Disruption in the detection and response of the brain's fear system is commonly observed in a variety of neurodevelopmental disorders, including fragile X syndrome (FXS), a brain disorder characterized by variable cognitive impairment and behavioral disturbances such as social avoidance and anxiety. The amygdala is highly involved in mediating fear processing, and increasing evidence supports the idea that inhibitory circuits play a key role in regulating the flow of information associated with fear conditioning in the amygdala. Here, we review the known and potential importance of amygdala fear circuits in FXS, and how developmental studies are critical to understand the formation and function of neuronal circuits that modulate amygdala-based behaviors.
doi:10.1159/000329424
PMCID: PMC3254036  PMID: 21893939
Amygdala; Animal model; Behavior; Fear conditioning; Fragile X syndrome; GABA; Mental illness; Fear; Emotions; Inhibitory circuits
18.  Children with Autism Show Reduced Somatosensory Response: An MEG Study 
Lay Abstract
Autism spectrum disorders are reported to affect nearly one out of every one hundred children, with over 90% of these children showing behavioral disturbances related to the processing of basic sensory information. Behavioral sensitivity to light touch, such as profound discomfort with clothing tags and physical contact, is a ubiquitous finding in children on the autism spectrum. In this study, we investigate the strength and timing of brain activity in response to simple, light taps to the fingertip. Our results suggest that children with autism show a diminished early response in the primary somatosensory cortex (S1). This finding is most evident in the left hemisphere. In exploratory analysis, we also show that tactile sensory behavior, as measured by the Sensory Profile, may be a better predictor of the intensity and timing of brain activity related to touch than a clinical autism diagnosis. We report that children with atypical tactile behavior have significantly lower amplitude somatosensory cortical responses in both hemispheres. Thus sensory behavioral phenotype appears to be a more powerful strategy for investigating neural activity in this cohort. This study provides evidence for atypical brain activity during sensory processing in autistic children and suggests that our sensory behavior based methodology may be an important approach to investigating brain activity in people with autism and neurodevelopmental disorders.
Scientific Abstract
The neural underpinnings of sensory processing differences in autism remain poorly understood. This prospective magnetoencephalography (MEG) study investigates whether children with autism show atypical cortical activity in the primary somatosensory cortex (S1) in comparison to matched controls. Tactile stimuli were clearly detectable, painless taps applied to the distal phalanx of the second (D2) and third (D3) fingers of the right and left hands. Three tactile paradigms were administered: an oddball paradigm (standard taps to D3 at an inter-stimulus interval (ISI) of 0.33 and deviant taps to D2 with ISI ranging from 1.32–1.64s); a slow-rate paradigm (D2) with an ISI matching the deviant taps in the oddball paradigm; and a fast-rate paradigm (D2) with an ISI matching the standard taps in the oddball. Study subjects were boys (age 7–11 years) with and without autism disorder. Sensory behavior was quantified using the Sensory Profile questionnaire. Boys with autism exhibited smaller amplitude left hemisphere S1 response to slow and deviant stimuli during the right hand paradigms. In post-hoc analysis, tactile behavior directly correlated with the amplitude of cortical response. Consequently, the children were re-categorized by degree of parent-report tactile sensitivity. This regrouping created a more robust distinction between the groups with amplitude diminution in the left and right hemispheres and latency prolongation in the right hemisphere in the deviant and slow-rate paradigms for the affected children. This study suggests that children with autism have early differences in somatosensory processing, which likely influence later stages of cortical activity from integration to motor response.
doi:10.1002/aur.1247
PMCID: PMC3474892  PMID: 22933354
Cognitive Neuroscience; Event Related Potential; School age; Low-level perception; Magnetoencephalography
19.  Perception of dynamic changes in facial affect and identity in autism 
Despite elegant behavioral descriptions of abnormalities for processing emotional facial expressions and biological motion in autism, identification of the neural mechanisms underlying these abnormalities remains a critical and largely unmet challenge. We compared brain activity with dynamic and static facial expressions in participants with and without high-functioning autism using event-related functional magnetic resonance imaging (fMRI) and three classes of face stimuli—emotion morphs (fearful and angry), identity morphs and static images (fearful, angry and neutral). We observed reduced activity in the amygdala (AMY) and fusiform gyrus (FFG) to dynamic emotional expressions in people with autism. There was also a lack of modulation by dynamic compared with static emotional expressions of social brain regions including the AMY, posterior superior temporal sulcus (STS) region and FFG. We observed equivalent emotion and identity morph-evoked activity in participants with and without autism in a region corresponding to the expected location of the more generally motion-sensitive area MT or V5. We conclude that dysfunctions in key components of the human face processing system including the AMY, FFG and posterior STS region are present in individuals with high-functioning autism, and this dysfunction might contribute to the deficits in processing emotional facial expressions.
doi:10.1093/scan/nsm010
PMCID: PMC2174259  PMID: 18174910
autism; amygdala; emotion; face processing; fMRI
20.  Perception of dynamic changes in facial affect and identity in autism 
Despite elegant behavioral descriptions of abnormalities for processing emotional facial expressions and biological motion in autism, identification of the neural mechanisms underlying these abnormalities remains a critical and largely unmet challenge. We compared brain activity with dynamic and static facial expressions in participants with and without high-functioning autism using event-related functional magnetic resonance imaging (fMRI) and three classes of face stimuli—emotion morphs (fearful and angry), identity morphs and static images (fearful, angry and neutral). We observed reduced activity in the amygdala (AMY) and fusiform gyrus (FFG) to dynamic emotional expressions in people with autism. There was also a lack of modulation by dynamic compared with static emotional expressions of social brain regions including the AMY, posterior superior temporal sulcus (STS) region and FFG. We observed equivalent emotion and identity morph-evoked activity in participants with and without autism in a region corresponding to the expected location of the more generally motion-sensitive area MT or V5. We conclude that dysfunctions in key components of the human face processing system including the AMY, FFG and posterior STS region are present in individuals with high-functioning autism, and this dysfunction might contribute to the deficits in processing emotional facial expressions.
doi:10.1093/scan/nsm010
PMCID: PMC2174259  PMID: 18174910
autism; amygdala; emotion; face processing; fMRI
21.  Distinct Face Processing Strategies in Parents of Autistic Children 
Current biology : CB  2008;18(14):1090-1093.
Summary
In his original description of autism, Kanner [1] noted that the parents of autistic children often exhibited unusual social behavior themselves, consistent with what we now know about the high heritability of autism [2]. We investigated this so-called “Broad Autism Phenotype” in the parents of children with autism, who themselves did not have a diagnosis of any psychiatric illness. Building on recent quantifications of social cognition in autism [3], we investigated face processing using the “Bubbles” method [4] to measure how viewers make use of information from specific facial features in order to judge emotions. Parents of autistic children who were assessed as socially aloof (N=15), a key component of the phenotype [5], showed a remarkable reduction in processing the eye region in faces, together with enhanced processing of the mouth, compared to a control group of parents of neurotypical children (N=20), as well as to non-aloof parents of autistic children (N=27, whose pattern of face processing was intermediate). The pattern of face processing seen in the Broad Autism Phenotype showed striking similarities to that previously reported to occur in autism [3], and for the first time provides a window into the endophenotype that may result from a subset of the genes that contribute to social cognition.
doi:10.1016/j.cub.2008.06.073
PMCID: PMC2504759  PMID: 18635351
22.  Photoanthropometric Study of Dysmorphic Features of the Face in Children with Autism and Asperger Syndrome 
Iranian Journal of Psychiatry  2012;7(1):41-46.
Objective
Childhood autism is a neurodevelopmental disorder characterized by impairments in social interactions, verbal and non-verbal communication and by a pattern of stereotypical behaviors and interests. The aim of this study was to estimate the dysmorphic facial features of children with autism and children with Asperger syndrome.
Methods
The examination was conducted on 60 children (30 with childhood autism and 30 with Asperger syndrome). The photo anthropometric method used in this study followed the protocol established by Stengel-Rutkowski et al.
Results
The performed statistical analysis showed that in patients with childhood autism, the anteriorly rotated ears and the long back of the nose appeared more often. In the group of children with autism, there was a connection between the amount of dysmorphies and the presence of some somatic diseases in the first-degree relatives. There was also a connection between the motor coordination and the age the child began to walk.
Discussion
In patients with childhood autism, there were certain dysmorphies (like the anterior rotated ears and the long back of the nose) which appeared more often. Although the connection was not statistically significant, it seemed to concur with data from the literature.
Conclusion
Formulation of the other conclusions would require broader studies e.g. dealing with a familial analysis of dysmorphic features.
PMCID: PMC3395970  PMID: 23056117
Autistic Disorder; Asperger syndrome; Etiology; Feature
23.  Mothers’ Reports of Play Dates and Observation of School Playground Behavior of Children Having High-Functioning Autism Spectrum Disorders 
Background
Children with high functioning autism spectrum disorders (ASD) are generally included with typically developing peers at school. They have difficulties interacting with peers on the school play ground. Previous literature suggests that having play dates in the home may be related to better peer acceptance at school.
Methods
This study examines the relationship between mother-reported play date frequency and amount of conflict, and peer interaction observed on the school playground for a sample of 27 boys and 4 girls meeting structured interview and observation criteria for ASD. Measures of intellectual functioning, adaptive behavior, and social skills were included in a stepwise regression analysis to account for their impact on relationships between maternal play date reports, general peer acceptance at school (as rated by the child’s teacher) and observations of school playground behavior.
Results
Results revealed that children with autism spectrum disorders who had more play dates in their home tended to spend a greater amount of time engaged in behaviors such as mutual offering of objects, conversing and other turn taking activities with peers on the school playground. They also received more positive responses to their overtures from peers. These relationships remained highly significant even after accounting for other demographic, general social, and cognitive variables.
Conclusions
The present results suggest that play date frequency is strongly related to school playground behavior. Due to the design of this study, future research must assess whether play dates in the home promote better peer relationships on the playground or the reverse. In either case, the assessment of play dates, as well as observation of spontaneous unsupervised social interactions are important outcome measures to consider in social skills interventions for children with high functioning ASD.
doi:10.1111/j.1469-7610.2010.02318.x
PMCID: PMC3010494  PMID: 20860756
Social Skills; Autism; Asperger’s Disorder; Friendship
24.  Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information 
PLoS ONE  2012;7(6):e39561.
Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information.
doi:10.1371/journal.pone.0039561
PMCID: PMC3382122  PMID: 22745788
25.  Spatiotemporal dipole source localization of face processing ERPs in adolescents: a preliminary study 
Background
Despite extensive investigation of the neural systems for face perception and emotion recognition in adults and young children in the past, the precise temporal activation of brain sources specific to the processing of emotional facial expressions in older children and adolescents is not well known. This preliminary study aims to trace the spatiotemporal dynamics of facial emotion processing during adolescence and provide a basis for future developmental studies and comparisons with patient populations that have social-emotional deficits such as autism.
Methods
We presented pictures showing happy, angry, fearful, or neutral facial expressions to healthy adolescents (aged 10–16 years) and recorded 128-channel event-related potentials (ERPs) while they performed an emotion discrimination task. ERP components were analyzed for effects of age and emotion on amplitude and latency. The underlying cortical sources of scalp ERP activity were modeled as multiple equivalent current dipoles using Brain Electrical Source Analysis (BESA).
Results
Initial global/holistic processing of faces (P1) took place in the visual association cortex (lingual gyrus) around 120 ms post-stimulus. Next, structural encoding of facial features (N170) occurred between 160–200 ms in the inferior temporal/fusiform region, and perhaps early emotion processing (Vertex Positive Potential or VPP) in the amygdala and orbitofrontal cortex. Finally, cognitive analysis of facial expressions (P2) in the prefrontal cortex and emotional reactions in somatosensory areas were observed from about 230 ms onwards. The temporal sequence of cortical source activation in response to facial emotion processing was occipital, prefrontal, fusiform, parietal for young adolescents and occipital, limbic, inferior temporal, and prefrontal for older adolescents.
Conclusion
This is a first report of high-density ERP dipole source analysis in healthy adolescents which traces the sequence of neural activity within the first 500 ms of categorizing emotion from faces. Our spatio-temporal brain source models showed the presence of adult-like cortical networks for face processing in adolescents, whose functional specificity to different emotions appear to be not yet fully mature. Age-related differences in brain activation patterns illustrate the continued development and maturation of distinct neural systems for processing facial expressions during adolescence and possible changes in emotion perception, experience, and reaction with age.
doi:10.1186/1744-9081-5-16
PMCID: PMC2660355  PMID: 19284600

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