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1.  Enhanced Neural Responses to Rule Violation in Children with Autism: A Comparison to Social Exclusion 
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.
doi:10.1016/j.dcn.2011.02.002
PMCID: PMC3129780  PMID: 21743819
Social Exclusion; Rule Violation; Autism Spectrum Disorder; Right Insula; Functional Magnetic Resonance Imaging
2.  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
3.  Neural correlates of social exclusion during adolescence: understanding the distress of peer rejection 
Developmental research has demonstrated the harmful effects of peer rejection during adolescence; however, the neural mechanisms responsible for this salience remain unexplored. In this study, 23 adolescents were excluded during a ball-tossing game in which they believed they were playing with two other adolescents during an fMRI scan; in reality, participants played with a preset computer program. Afterwards, participants reported their exclusion-related distress and rejection sensitivity, and parents reported participants’ interpersonal competence. Similar to findings in adults, during social exclusion adolescents displayed insular activity that was positively related to self-reported distress, and right ventrolateral prefrontal activity that was negatively related to self-reported distress. Findings unique to adolescents indicated that activity in the subgenual anterior cingulate cortex (subACC) related to greater distress, and that activity in the ventral striatum related to less distress and appeared to play a role in regulating activity in the subACC and other regions involved in emotional distress. Finally, adolescents with higher rejection sensitivity and interpersonal competence scores displayed greater neural evidence of emotional distress, and adolescents with higher interpersonal competence scores also displayed greater neural evidence of regulation, perhaps suggesting that adolescents who are vigilant regarding peer acceptance may be most sensitive to rejection experiences.
doi:10.1093/scan/nsp007
PMCID: PMC2686232  PMID: 19470528
peer rejection; adolescence; functional magnetic resonance imaging
4.  fMRI activation during a language task in adolescents 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.
doi:10.1017/S1355617708081216
PMCID: PMC2747321  PMID: 18954477
Autistic disorder; Functional MRI; Broca's area; Wernicke's area; Semantics; Asymmetry
5.  Neural and Behavioral Responses During Self-Evaluative Processes Differ in Youth With and Without Autism 
This fMRI study investigated neural responses while making appraisals of self and other, across the social and academic domains, in children and adolescents with and without autism spectrum disorders (ASD). Compared to neurotypical youth, those with ASD exhibited hypoactivation of ventromedial prefrontal cortex during self-appraisals. Responses in middle cingulate cortex (MCC) and anterior insula (AI) also distinguished between groups. Stronger activity in MCC and AI during self-appraisals was associated with better social functioning in the ASD group. Although self-appraisals were significantly more positive in the neurotypical group, positivity was unrelated to brain activity in these regions. Together, these results suggest that multiple brain regions support making self-appraisals in neurotypical development, and function atypically in youth with ASD.
doi:10.1007/s10803-012-1563-3
PMCID: PMC3507334  PMID: 22760337
Autism; Self; Ventral mPFC; Anterior insula; Middle cingulate cortex; Development
6.  Subgenual anterior cingulate responses to peer rejection: A marker of adolescents’ risk for depression 
Development and psychopathology  2011;23(1):283-292.
Extensive developmental research has linked peer rejection during adolescence with a host of psychopathological outcomes, including depression. Moreover, recent neuroimaging research has suggested that increased activity in the subgenual region of the anterior cingulate cortex (subACC), which has been consistently linked with depression, is related to heightened sensitivity to peer rejection among adolescents. The goal of the current study was to directly test the hypothesis that adolescents’ subACC responses are predictive of their risk for future depression, by examining the relationship between subACC activity during peer rejection and increases in depressive symptoms during the following year. During a functional magnetic resonance imaging scan, 20 13-year-olds were ostensibly excluded by peers during an online social interaction. Participants’ depressive symptoms were assessed via parental reports at the time of the scan and 1 year later. Region of interest and whole-brain analyses indicated that greater subACC activity during exclusion was associated with increases in parent-reported depressive symptoms during the following year. These findings suggest that subACC responsivity to social exclusion may serve as a neural marker of adolescents’ risk for future depression and have implications for understanding the relationship between sensitivity to peer rejection and the increased risk of depression that occurs during adolescence.
doi:10.1017/S0954579410000799
PMCID: PMC3229829  PMID: 21262054
7.  The Neural Substrates of Cognitive Control Deficits in Autism Spectrum Disorders 
Neuropsychologia  2009;47(12):2515-2526.
Executive functions deficits are among the most frequently reported symptoms of autism spectrum disorders (ASDs), however, there have been few functional magnetic resonance imaging (fMRI) studies that investigate the neural substrates of executive functions deficits in ASDs, and only one in adolescents. The current study examined cognitive control –the ability to maintain task context online to support adaptive functioning in the face of response competition—in 22 adolescents aged 12–18 with autism spectrum disorders and 23 age, gender, and IQ matched typically developing subjects. During the cue phase of the task, where subjects must maintain information online to overcome a prepotent response tendency, typically developing subjects recruited significantly more anterior frontal (BA 10), parietal (BA 7, 40), and occipital regions (BA 18) for high control trials (25% of trials) versus low control trials (75% of trials). Both groups showed similar activation for low control cues, however the ASD group exhibited significantly less activation for high control cues. Functional connectivity analysis using time series correlation, factor analysis, and beta series correlation methods provided convergent evidence that the ASD group exhibited lower levels of functional connectivity and less network integration between frontal, parietal, and occipital regions. In the typically developing group, fronto-parietal connectivity was related to lower error rates on high control trials. In the autism group, reduced fronto-parietal connectivity was related to attention deficit hyperactivity disorder symptoms.
doi:10.1016/j.neuropsychologia.2009.04.019
PMCID: PMC2766616  PMID: 19410583
autism spectrum disorders; cognitive control; executive functions; fMRI; functional connectivity; attention deficit disorder
8.  Neural bases of gaze and emotion processing in children with autism spectrum disorders 
Brain and Behavior  2011;1(1):1-11.
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.
doi:10.1002/brb3.6
PMCID: PMC3217668  PMID: 22398976
Autism; facial expression; functional magnetic resonance imaging; gaze; developmental neuroimaging
9.  Social Involvement of Children with Autism Spectrum Disorders in Elementary School Classrooms 
Background
Children with autism spectrum disorders (ASD) are increasingly included in general education classrooms in an effort to improve their social involvement.
Methods
Seventy-nine children with ASD and 79 randomly-selected, gender-matched peers (88.6% male) in 75 early (K-1), middle (2nd–3rd), and late (4th–5th) elementary classrooms across 30 schools completed social network surveys examining each child’s reciprocal friendships, peer rejection, acceptance, and social involvement.
Results
Across grade levels, peers less frequently reciprocated friendships with children with ASD than students in the matched sample. While children with ASD were not more likely to be rejected by peers, they were less accepted and had fewer reciprocal friendships than matched peers at each grade level. Although 48.1% of children with ASD were involved in the social networks of their classrooms, children with ASD were more likely to be isolated or peripheral to social relationships within the classroom across all grade levels, and this difference is even more dramatic in later elementary grades.
Conclusions
In inclusive classrooms, children with ASD are only involved in peers’ social relationships about half of the time, and appear to be even less connected with increasing grade level. Promoting children with ASD’s skills in popular activities to share with peers in early childhood may be a key preventive intervention to protect social relationships in late elementary school grades.
doi:10.1111/j.1469-7610.2010.02289.x
PMCID: PMC2970745  PMID: 20673234
Autism; Social involvement; Inclusive education; Social networks
10.  The neural underpinnings of prosody in autism 
This study examines the processing of prosodic cues to linguistic structure and to affect, drawing on fMRI and behavioral data from 16 high-functioning adolescents with autism spectrum disorders (ASD) and 11 typically-developing controls. Stimuli were carefully matched on pitch, intensity, and duration, while varying systematically in conditions of affective prosody (angry versus neutral speech) and grammatical prosody (questions versus statement). To avoid conscious attention to prosody, which normalizes responses in young people with ASD, the implicit comprehension task directed attention to semantic aspects of the stimuli. Results showed that when perceiving prosodic cues, both affective and grammatical, activation of neural regions was more generalized in ASD than in typical development, and areas recruited reflect heightened reliance on cognitive control, reading of intentions, attentional management, and visualization. This broader recruitment of executive and “mind-reading” brain areas for a relative simple language processing task may be interpreted to suggest that speakers with HFA have developed less automaticity in language processing, and may also suggest that “mind-reading” or theory of mind deficits are intricately bound up in language processing. Data provide support for both a right-lateralized as well as a bilateral model of prosodic processing in typical individuals, depending upon the function of the prosodic information.
doi:10.1080/09297049.2011.639757
PMCID: PMC3461129  PMID: 22176162
11.  Alterations of Resting State Functional Connectivity in the Default Network in Adolescents with Autism Spectrum Disorders 
Brain research  2009;1313:202.
Autism spectrum disorders (ASD) are associated with disturbances of neural connectivity. Functional connectivity between neural structures is typically examined within the context of a cognitive task, but also exists in the absence of a task (i.e., “rest”). Connectivity during rest is particularly active in a set of structures called the default network, which includes the posterior cingulate cortex (PCC), retrosplenial cortex, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus. We previously reported that adults with ASD relative to controls show areas of stronger and weaker connectivity within the default network. The objective of the present study was to examine the default network in adolescents with ASD. Sixteen adolescents with ASD and 15 controls participated in a functional MRI study. Functional connectivity was examined between a PCC seed and other areas of the default network. Both groups showed connectivity in the default network. Relative to controls, adolescents with ASD showed widespread weaker connectivity in nine of the eleven areas of the default network. Moreover, an analysis of symptom severity indicated that poorer social skills and increases in restricted and repetitive behaviors and interests correlated with weaker connectivity, whereas poorer verbal and non-verbal communication correlated with stronger connectivity in multiple areas of the default network. These findings indicate that adolescents with ASD show weaker connectivity in the default network than previously reported in adults with ASD. The findings also show that weaker connectivity within the default network is associated with specific impairments in ASD.
doi:10.1016/j.brainres.2009.11.057
PMCID: PMC2818723  PMID: 20004180
Functional Magnetic Resonance Imaging; development; symptom severity; Asperger’s syndrome; pervasive developmental disorder not otherwise specified
12.  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.
doi:10.1016/j.neuroimage.2011.02.031
PMCID: PMC3091391  PMID: 21334443
autism; attention; functional magnetic resonance imaging; gaze; social cue
13.  Sources of group differences in functional connectivity: an investigation applied to autism spectrum disorder 
NeuroImage  2009;49(1):401-414.
An increasing number of fMRI studies are using the correlation of low-frequency fluctuations between brain regions, believed to reflect synchronized variations in neuronal activity, to infer “functional connectivity”. In studies of autism spectrum disorder (ASD), decreases in this measure of connectivity have been found by focusing on the response to task modulation, by using only the rest periods, or by analyzing purely resting-state data. This difference in connectivity, however, could result from a number of different mechanisms – differences in noise, task-related fluctuations, task performance, or spontaneous neuronal activity. In this study, we investigate the difference in functional connectivity between adolescents with high-functioning ASD and typically developing control subjects by examining the residual fluctuations occurring on top of the fMRI response to an overt verbal fluency task. We find decreased correlations of these residuals (a decreased “connectivity”) in ASD subjects. Furthermore, we find that this decrease was not due to task-related effects, block-to-block variations in task performance, or increased noise, and the difference was greatest when primarily rest periods are considered. These findings suggest that the estimate of disrupted functional connectivity in ASD is likely driven by differences in task-unrelated neuronal fluctuations.
doi:10.1016/j.neuroimage.2009.07.051
PMCID: PMC2832835  PMID: 19646533
14.  Lack of developmental improvement on a face memory task during adolescence in autism 
Neuropsychologia  2010;48(13):3955-3960.
Autism Spectrum Disorders (ASD) are associated with abnormalities in face memory, which evidence suggests has a protracted development through adolescence. The development of face memory in people with and without ASD, from 9 to 29 years old, was examined using the Cambridge Face Memory Test (CFMT). Results indicate that the developmental improvement evident from adolescence to adulthood typically was not apparent in individuals with ASD. While children and adolescents with ASD performed similarly to typically developing individuals comparable in age and IQ, adults with ASD displayed limitations on the CFMT. The pattern of performance was constant across conditions despite differences in the timing of the presentation and delay. This atypical development in ASD is consistent with the view that the processing of complex visual stimuli continues to develop through adolescence, along with the function and structure of the temporal lobes, but that this process is disrupted in ASD. This result underscores the importance of characterizing adolescent development for understanding ASD, and suggests additional opportunities for intervention.
doi:10.1016/j.neuropsychologia.2010.08.024
PMCID: PMC2975893  PMID: 20813119
development; developmental disorders; frontal; temporal; social cognition
15.  Diminished Sensitivity to Sad Facial Expressions in High Functioning Autism Spectrum Disorders is Associated with Symptomatology and Adaptive Functioning 
Prior studies implicate facial emotion recognition (FER) difficulties among individuals with autism spectrum disorders (ASD); however, many investigations focus on FER accuracy alone and few examine ecological validity through links with everyday functioning. We compared FER accuracy and perceptual sensitivity (from neutral to full expression) between 42 adolescents with high functioning (IQ>80) ASD and 31 typically developing adolescents (matched on age, IQ, sex ratio) across six basic emotions and examined links between FER and symptomatology/adaptive functioning within the ASD group. Adolescents with ASD required more intense facial expressions for accurate emotion identification. Controlling for this overall group difference revealed particularly diminished sensitivity to sad facial expressions in ASD, which was uniquely correlated with ratings of autism-related behavior and adaptive functioning.
doi:10.1007/s10803-010-1170-0
PMCID: PMC3448486  PMID: 21347615
autism; emotion; face; symptomatology; adaptive functioning
16.  Neural circuitry underlying affective response to peer feedback in adolescence 
Peer feedback affects adolescents’ behaviors, cognitions and emotions. We examined neural circuitry underlying adolescents’ emotional response to peer feedback using a functional neuroimaging paradigm whereby, 36 adolescents (aged 9–17 years) believed they would interact with unknown peers postscan. Neural activity was expected to vary based on adolescents’ perceptions of peers and feedback type. Ventrolateral prefrontal cortex (vlPFC) activity was found when adolescents indicated how they felt following feedback (acceptance or rejection) from peers of low vs high interest. Greater activation in both cortical (e.g. superior temporal gyrus, insula, anterior cingulate) and subcortical (e.g. striatum, thalamus) regions emerged in response to acceptance vs rejection feedback. Response to acceptance also varied by age and gender in similar regions (e.g. superior temporal gyrus, fusiform, insula), with greater age-related increases in activation to acceptance vs rejection for females than males. Affective response to rejection vs acceptance did not yield significantly greater neural activity in any region. vlPFC response suggests cognitive flexibility in reappraising initial perceptions of peers following feedback. Striatal response suggests that acceptance is a potent social reward for adolescents, an interpretation supported by more positive self-reported affective response to acceptance than rejection from high- but not low-interest peers.
doi:10.1093/scan/nsr043
PMCID: PMC3252630  PMID: 21828112
adolescence; cognitive flexibility; peer feedback; social reward
17.  Is Emotion Recognition Impaired in Individuals with Autism Spectrum Disorders? 
Researchers have argued that individuals with autism spectrum disorders (ASDs) use an effortful “systematizing” process to recognize emotion expressions, whereas typically developing (TD) individuals use a more holistic process. If this is the case, individuals with ASDs should show slower and less efficient emotion recognition, particularly for socially complex emotions. We tested this account by assessing the speed and accuracy of emotion recognition while limiting exposure time and response window. Children and adolescents with ASDs showed quick and accurate recognition for most emotions, including pride, a socially complex emotion, and no differences emerged between ASD and TD groups. Furthermore, both groups trended toward higher accuracy when responding quickly, even though systematizing should promote a speed-accuracy trade-off for individuals with ASDs.
doi:10.1007/s10803-010-1030-y
PMCID: PMC3005106  PMID: 20464465
Autism; Emotion recognition; Systematizing; Pride expression
18.  Reading Faces for Information about Words and Emotions in Adolescents with Autism 
Studies of explicit processing of facial expressions by individuals with autism spectrum disorder (ASD) have found a variety of deficits and preserved abilities compared to their typically developing (TD) peers. However, little attention has been paid to their implicit processing abilities for emotional facial expressions. The question has also been raised whether preferential attention to the mouth region of a speaker’s face by ASD individuals has resulted in a relative lipreading expertise. We present data on implicit processing of pseudo-dynamic facial emotions and visual speech in adolescents with autism. We compared 25 ASD and 25 TD participants on their ability to recreate the sequences of four dynamic emotional facial expressions (happy, sad, disgust, fear) as well as four spoken words (with, bath, thumb, watch) using six still images taken from a video sequence. Typical adolescents were significantly better at recreating the dynamic properties of emotional expressions than those of facial speech, while the autism group showed the reverse accuracy pattern. For Experiment 2 we obscured the eye region of the stimuli and found no significant difference between the 22 adolescents with ASD and 22 TD controls. Fearful faces achieved the highest accuracy results among the emotions in both groups.
doi:10.1016/j.rasd.2008.02.004
PMCID: PMC2756601  PMID: 19809572
19.  Amygdala Habituation and Prefrontal Functional Connectivity in Youth With Autism Spectrum Disorders 
Objective
Amygdala habituation, the rapid decrease in amygdala responsiveness to repeated presentation of stimuli, is fundamental to the nervous system. Habituation is important for maintaining adaptive levels of arousal to predictable social stimuli and reduced habituation is associated with heightened anxiety. Input from the ventromedial prefrontal cortex (vmPFC) regulates amygdala activity. Although previous research demonstrated abnormal amygdala function in youth with autism spectrum disorders (ASD), no study had examined amygdala habituation in a young sample or whether habituation related to amygdala connectivity with the vmPFC.
Method
Data were analyzed from 32 children and adolescents with ASD and 56 typically developing controls who underwent functional magnetic resonance imaging (fMRI) scanning while performing a gender identification task for faces that were fearful, happy, sad, or neutral. Habituation was tested by comparing amygdala activation to faces during the first half versus the second half of the session. VmPFC–amygdala connectivity was examined through psychophysiological interaction analysis.
Results
Youth with ASD had decreased amygdala habituation to sad and neutral faces relative to controls. Moreover, reduced amygdala habituation correlated with autism severity as measured by the Social Responsiveness Scale. There was a group difference in vmPFC–amygdala connectivity while viewing sad faces, and connectivity predicted amygdala habituation to sad faces within controls.
Conclusions
Sustained amygdala activation to faces suggests that repeated faces are processed differently in individuals with ASD, which could contribute to social impairments. Abnormal modulation of the amygdala by the vmPFC may play a role in reduced habituation.
doi:10.1016/j.jaac.2012.10.012
PMCID: PMC3530144  PMID: 23265636
fMRI; habituation; autism; adolescent; emotion
20.  A potentiated startle study of uncertainty and contextual anxiety in adolescents diagnosed with autism spectrum disorder 
Molecular Autism  2013;4:31.
Background
Beyond the core symptoms of autism spectrum disorder (ASD), associated symptoms of anxiety can cause substantial impairment for individuals affected by ASD and those who care for them.
Methods
We utilized a potentiated startle paradigm with a puff of air to the neck as the unconditioned stimulus in order to investigate differences between response to cued fear and contextual anxiety among cognitively able adolescents diagnosed with ASD and an age- and IQ-matched typically developing group.
Results
In a threat-modulated startle paradigm, response patterns to neutral, predictable, and unpredictable conditions were comparable across typically developing and ASD youth in terms of startle response magnitude and latency. However, the ASD group showed significantly greater absolute startle responsivity at baseline and throughout the experiment, suggesting possibly enhanced general sensitivity to threatening contexts. The ASD group, but not the control group, demonstrated moderate to strong negative correlations between psychophysiological response to unpredictable threats (uncertainty) and questionnaire measures of generalized anxiety, intolerance of uncertainty, and repetitive behavior.
Conclusions
Our data suggest enhanced general reactivity among the ASD group, possibly reflecting greater sensitivity to the threatening context of the startle paradigm. Associations with the response to uncertainty may help explain shared neurobehavioral mechanisms in ASD and anxiety. This task can provide useful targets for future neuroimaging and genetics studies as well as specific avenues for intervention. We emphasize the importance of further basic and clinical research into links among these important constructs.
doi:10.1186/2040-2392-4-31
PMCID: PMC3844321  PMID: 24007557
Autism spectrum disorder; Anxiety; Fear; Potentiated startle; Eye blink; EMG; Intolerance of uncertainty; Psychophysiology; Repetitive behavior
21.  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.
doi:10.1017/S135561770808140X
PMCID: PMC3047502  PMID: 18954473
Functional MRI; Autism; Asperger’s; Face processing; Face inversion; Development
22.  Portable Intermodal Preferential Looking (IPL): Investigating Language Comprehension in Typically Developing Toddlers and Young Children with Autism 
One of the defining characteristics of autism spectrum disorder (ASD) is difficulty with language and communication.1 Children with ASD's onset of speaking is usually delayed, and many children with ASD consistently produce language less frequently and of lower lexical and grammatical complexity than their typically developing (TD) peers.6,8,12,23 However, children with ASD also exhibit a significant social deficit, and researchers and clinicians continue to debate the extent to which the deficits in social interaction account for or contribute to the deficits in language production.5,14,19,25
Standardized assessments of language in children with ASD usually do include a comprehension component; however, many such comprehension tasks assess just one aspect of language (e.g., vocabulary),5 or include a significant motor component (e.g., pointing, act-out), and/or require children to deliberately choose between a number of alternatives. These last two behaviors are known to also be challenging to children with ASD.7,12,13,16
We present a method which can assess the language comprehension of young typically developing children (9-36 months) and children with autism.2,4,9,11,22 This method, Portable Intermodal Preferential Looking (P-IPL), projects side-by-side video images from a laptop onto a portable screen. The video images are paired first with a 'baseline' (nondirecting) audio, and then presented again paired with a 'test' linguistic audio that matches only one of the video images. Children's eye movements while watching the video are filmed and later coded. Children who understand the linguistic audio will look more quickly to, and longer at, the video that matches the linguistic audio.2,4,11,18,22,26
This paradigm includes a number of components that have recently been miniaturized (projector, camcorder, digitizer) to enable portability and easy setup in children's homes. This is a crucial point for assessing young children with ASD, who are frequently uncomfortable in new (e.g., laboratory) settings. Videos can be created to assess a wide range of specific components of linguistic knowledge, such as Subject-Verb-Object word order, wh-questions, and tense/aspect suffixes on verbs; videos can also assess principles of word learning such as a noun bias, a shape bias, and syntactic bootstrapping.10,14,17,21,24 Videos include characters and speech that are visually and acoustically salient and well tolerated by children with ASD.
doi:10.3791/4331
PMCID: PMC3570064  PMID: 23271456
Medicine; Issue 70; Neuroscience; Psychology; Behavior; Intermodal preferential looking; language comprehension; children with autism; child development; autism
23.  Resting state fMRI reveals a default mode dissociation between retrosplenial and medial prefrontal subnetworks in ASD despite motion scrubbing 
In resting state functional magnetic resonance imaging (fMRI) studies of autism spectrum disorders (ASDs) decreased frontal-posterior functional connectivity is a persistent finding. However, the picture of the default mode network (DMN) hypoconnectivity remains incomplete. In addition, the functional connectivity analyses have been shown to be susceptible even to subtle motion. DMN hypoconnectivity in ASD has been specifically called for re-evaluation with stringent motion correction, which we aimed to conduct by so-called scrubbing. A rich set of default mode subnetworks can be obtained with high dimensional group independent component analysis (ICA) which can potentially provide more detailed view of the connectivity alterations. We compared the DMN connectivity in high-functioning adolescents with ASDs to typically developing controls using ICA dual-regression with decompositions from typical to high dimensionality. Dual-regression analysis within DMN subnetworks did not reveal alterations but connectivity between anterior and posterior DMN subnetworks was decreased in ASD. The results were very similar with and without motion scrubbing thus indicating the efficacy of the conventional motion correction methods combined with ICA dual-regression. Specific dissociation between DMN subnetworks was revealed on high ICA dimensionality, where networks centered at the medial prefrontal cortex and retrosplenial cortex showed weakened coupling in adolescents with ASDs compared to typically developing control participants. Generally the results speak for disruption in the anterior-posterior DMN interplay on the network level whereas local functional connectivity in DMN seems relatively unaltered.
doi:10.3389/fnhum.2013.00802
PMCID: PMC3837226  PMID: 24319422
autism; resting state; fMRI; ICA; default mode; motion
24.  Social Behaviors Increase in Children with Autism in the Presence of Animals Compared to Toys 
PLoS ONE  2013;8(2):e57010.
Background
Previous research has demonstrated the capacity of animal presence to stimulate social interaction among humans. The purpose of this study was to examine the interactions of children with autism spectrum disorder (ASD) with an adult and their typically-developing peers in the presence of animals (two guinea pigs) compared to toys.
Methods
Ninety-nine children from 15 classrooms in 4 schools met the inclusion criteria and participated in groups of three (1 child with ASD and 2 typically-developing peers). Each group was video-recorded during three 10-minute, free-play sessions with toys and three 10-minute, free-play sessions with two guinea pigs. Two blinded observers coded the behavior of children with ASD and their peers. To account for the nested study design, data were analyzed using hierarchical generalized linear modeling.
Results
Participants with ASD demonstrated more social approach behaviors (including talking, looking at faces, and making tactile contact) and received more social approaches from their peers in the presence of animals compared to toys. They also displayed more prosocial behaviors and positive affect (i.e., smiling and laughing) as well as less self-focused behaviors and negative affect (i.e., frowning, crying, and whining) in the presence of animals compared to toys.
Conclusions
These results suggest that the presence of an animal can significantly increase positive social behaviors among children with ASD.
doi:10.1371/journal.pone.0057010
PMCID: PMC3584132  PMID: 23468902
25.  The impact of serotonin transporter genotype on default network connectivity in children and adolescents with autism spectrum disorders☆ 
NeuroImage : Clinical  2012;2:17-24.
Compared to healthy controls, individuals with autism spectrum disorders (ASD) have weaker posterior–anterior connectivity that strengthens less with age within the default network, a set of brain structures connected in the absence of a task and likely involved in social function. The serotonin transporter-linked polymorphic region (5-HTTLPR) genotypes that result in lowered serotonin transporter expression are associated with social impairment in ASD. Additionally, in healthy controls, low expressing 5-HTTLPR genotypes are associated with weaker default network connectivity. However, in ASD, the effect of 5-HTTLPR on the default network is unknown. We hypothesized that 5-HTTLPR's influence on posterior–anterior default network connectivity strength as well as on age-related changes in connectivity differs in the ASD group versus controls. Youth with ASD and healthy controls, ages 8–19, underwent a resting fMRI acquisition. Connectivity was calculated by correlating the posterior hub of the default network with all voxels. Triallelic genotype was assessed via PCR and Sanger sequencing. A genotype-by-diagnosis interaction significantly predicted posterior–anterior connectivity, such that low expressing genotypes (S/S, S/LG, LG/LG) were associated with stronger connectivity than high expressing genotypes (LA/LA, S/LA, LA/LG) in the ASD group, but the converse was true for controls. Also, youth with ASD and low expressing genotypes had greater age-related increases in connectivity values compared to those with high expressing genotypes and controls in either genotype group. Our findings suggest that the cascade of events from genetic variation to brain function differs in ASD. Also, low expressing genotypes may represent a subtype within ASD.
Highlights
► Youth with autism and controls genotyped for 5-HTTLPR ► Posterior–anterior default network connectivity assessed with MRI during rest ► Stronger connectivity in low versus high expressing genotypes in autism ► Weaker connectivity in low versus high expressing genotypes in controls ► Largest age-related increases in connectivity in ASD with low expressing genotypes
doi:10.1016/j.nicl.2012.10.008
PMCID: PMC3777679  PMID: 24179754
Functional MRI; Resting connectivity; Development; Serotonin transporter gene; Autism; Default network

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