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1.  Time reproduction performance is associated with age and working memory in high functioning youth with autism spectrum disorder 
Lay Abstract
Temporal processing refers to our ability to “sense” or register the passage of time and to use that information to guide behavior. There is evidence that children with autism spectrum disorders (ASD) differ from children without ASD in their ability to process temporal information. Prior research has shown that age and working memory (the ability to hold and manipulate information in short-term memory storage) impact performance on temporal processing tasks in typically developing children, but it is not known whether there are similar associations in youth with ASD. It is also known that children with high levels of inattention and hyperactivity/impulsivity, who do not have ASD, tend to perform more poorly on measures of temporal processing. Our study examined the effects of working memory, age, and inattention/hyperactivity on the accuracy and consistency of temporal processing in 27 high-functioning youth with ASD and 25 youth without ASD. Our results show that youth with ASD are less accurate and less consistent in their ability to estimate time intervals, relative to typically developing youth. The difference in accuracy between the groups is more pronounced at younger ages, while working memory has a differential effect on consistency. Within the ASD group, inattention/hyperactivity was not associated with either accuracy or consistency. This study shows for the first time that both age and working memory affect how youth with and without ASD perceive and represent the passage of time.
Scientific Abstract
Impaired temporal processing has historically been viewed as a hallmark feature of attention-deficit/hyperactivity disorder (ADHD). Recent evidence suggests temporal processing deficits may also be characteristic of autism spectrum disorder (ASD). However, little is known about the factors that impact temporal processing in children with ASD. The purpose of this study was to assess the effects of co-morbid attention problems, working memory (WM), age, and their interactions, on time reproduction in youth with and without ASD.
Twenty-seven high functioning individuals with ASD and 25 demographically comparable typically developing individuals (ages 9–17; 85% male) were assessed on measures of time reproduction, auditory WM, and inattention/hyperactivity. The time reproduction task required depression of a computer key to mimic interval durations of 4, 8, 12, 16, or 20 seconds. Mixed effects regression analyses were used to model accuracy and variability of time reproduction as functions of diagnostic group, interval duration, age, WM, and inattention/hyperactivity.
A significant group by age interaction was detected for accuracy, with the deficit in the ASD group being greater in younger children. There was a significant group by WM interaction for consistency, with the effects of poor WM on performance consistency being more pronounced in youth with ASD. All participants tended to underestimate longer interval durations and to be less consistent for shorter interval durations; these effects appeared more pronounced in those who were younger or who had poorer working memory performance. Inattention/hyperactivity symptoms in the ASD group were not related to either accuracy or consistency.
This study highlights the potential value of temporal processing as an intermediate trait of relevance to multiple neurodevelopmental disorders.
doi:10.1002/aur.1401
PMCID: PMC4312276  PMID: 25078724
2.  Neural Signatures of Autism Spectrum Disorders: Insights into Brain Network Dynamics 
Neuropsychopharmacology  2014;40(1):171-189.
Neuroimaging investigations of autism spectrum disorders (ASDs) have advanced our understanding of atypical brain function and structure, and have recently converged on a model of altered network-level connectivity. Traditional task-based functional magnetic resonance imaging (MRI) and volume-based structural MRI studies have identified widespread atypicalities in brain regions involved in social behavior and other core ASD-related behavioral deficits. More recent advances in MR-neuroimaging methods allow for quantification of brain connectivity using diffusion tensor imaging, functional connectivity, and graph theoretic methods. These newer techniques have moved the field toward a systems-level understanding of ASD etiology, integrating functional and structural measures across distal brain regions. Neuroimaging findings in ASD as a whole have been mixed and at times contradictory, likely due to the vast genetic and phenotypic heterogeneity characteristic of the disorder. Future longitudinal studies of brain development will be crucial to yield insights into mechanisms of disease etiology in ASD sub-populations. Advances in neuroimaging methods and large-scale collaborations will also allow for an integrated approach linking neuroimaging, genetics, and phenotypic data.
doi:10.1038/npp.2014.172
PMCID: PMC4262896  PMID: 25011468
3.  Altered resting perfusion and functional connectivity of default mode network in youth with autism spectrum disorder 
Brain and Behavior  2015;5(9):e00358.
Background
Neuroimaging studies can shed light on the neurobiological underpinnings of autism spectrum disorders (ASD). Studies of the resting brain have shown both altered baseline metabolism from PET/SPECT and altered functional connectivity (FC) of intrinsic brain networks based on resting-state fMRI. To date, however, no study has investigated these two physiological parameters of resting brain function jointly, or explored the relationship between these measures and ASD symptom severity.
Methods
Here, we used pseudo-continuous arterial spin labeling with 3D background-suppressed GRASE to assess resting cerebral blood flow (CBF) and FC in 17 youth with ASD and 22 matched typically developing (TD) children.
Results
A pattern of altered resting perfusion was found in ASD versus TD children including frontotemporal hyperperfusion and hypoperfusion in the dorsal anterior cingulate cortex. We found increased local FC in the anterior module of the default mode network (DMN) accompanied by decreased CBF in the same area. In our cohort, both alterations were associated with greater social impairments as assessed with the Social Responsiveness Scale (SRS-total T scores). While FC was correlated with CBF in TD children, this association between FC and baseline perfusion was disrupted in children with ASD. Furthermore, there was reduced long-range FC between anterior and posterior modules of the DMN in children with ASD.
Conclusion
Taken together, the findings of this study – the first to jointly assess resting CBF and FC in ASD – highlight new avenues for identifying novel imaging markers of ASD symptomatology.
doi:10.1002/brb3.358
PMCID: PMC4589806  PMID: 26445698
arterial spin labeling; autism spectrum disorder; cerebral blood flow; default mode network; dorsal ACC; functional connectivity
4.  The pediatric template of brain perfusion 
Scientific Data  2015;2:150003.
Magnetic resonance imaging (MRI) captures the dynamics of brain development with multiple modalities that quantify both structure and function. These measurements may yield valuable insights into the neural patterns that mark healthy maturation or that identify early risk for psychiatric disorder. The Pediatric Template of Brain Perfusion (PTBP) is a free and public neuroimaging resource that will help accelerate the understanding of childhood brain development as seen through the lens of multiple modality neuroimaging and in relation to cognitive and environmental factors. The PTBP uses cross-sectional and longitudinal MRI to quantify cortex, white matter, resting state functional connectivity and brain perfusion, as measured by Arterial Spin Labeling (ASL), in 120 children 7–18 years of age. We describe the PTBP and show, as a demonstration of validity, that global summary measurements capture the trajectories that demarcate critical turning points in brain maturation. This novel resource will allow a more detailed understanding of the network-level, structural and functional landmarks that are obtained during normal adolescent brain development.
doi:10.1038/sdata.2015.3
PMCID: PMC4413243  PMID: 25977810
Paediatrics; Network models; Brain imaging; Magnetic resonance imaging
5.  The Autism Brain Imaging Data Exchange: Towards Large-Scale Evaluation of the Intrinsic Brain Architecture in Autism 
Molecular psychiatry  2013;19(6):659-667.
Autism spectrum disorders (ASD) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, life-long nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. While the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE) – a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) datasets with corresponding structural MRI and phenotypic information from 539 individuals with ASD and 573 age-matched typical controls (TC; 7–64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 males with ASD and 403 male age-matched TC. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo and hyperconnectivity in the ASD literature; both were detected, though hypoconnectivity dominated, particularly for cortico-cortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASD (mid and posterior insula, posterior cingulate cortex), and highlighted less commonly explored regions such as thalamus. The survey of the ABIDE R-fMRI datasets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international datasets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
doi:10.1038/mp.2013.78
PMCID: PMC4162310  PMID: 23774715
Resting state fMRI; Intrinsic functional connectivity; Data sharing; Large-scale networks; Default network; Interhemispheric connectivity; Thalamus
6.  Over-Reactive Brain Responses to Sensory Stimuli in Youth With Autism Spectrum Disorders RH: fMRI Response to Sensory Stimuli in ASD 
Objectives:
Sensory over-responsivity (SOR), defined as a negative response to or avoidance of sensory stimuli, is both highly prevalent and extremely impairing in youth with autism spectrum disorders (ASD), yet little is known about the neurological bases of SOR. This study aimed to examine the functional neural correlates of SOR by comparing brain responses to sensory stimuli in youth with and without ASD.
Method:
Twenty-five high-functioning youth with ASD and 25 age- and IQ-equivalent typically developing (TD) youth were presented with mildly aversive auditory and visual stimuli during a functional magnetic resonance imaging (fMRI) scan. Parents provided ratings of children's SOR and anxiety symptom severity.
Results:
Compared to TD participants, ASD participants displayed greater activation in primary sensory cortical areas as well as amygdala, hippocampus, and orbital-frontal cortex. In both groups, the level of activity in these areas was positively correlated with level of SOR severity as rated by parents, over and above behavioral ratings of anxiety.
Conclusions:
This study demonstrates that youth with ASD show neural hyper-responsivity to sensory stimuli, and that behavioral symptoms of SOR may be related to both heightened responsivity in primary sensory regions as well as areas related to emotion processing, and regulation.
doi:10.1016/j.jaac.2013.08.004
PMCID: PMC3820504  PMID: 24157390
amygdala; anxiety; autism spectrum disorders; functional magnetic resonance; imaging (fMRI); sensory over-responsivity
7.  Neural responses to witnessing peer rejection after being socially excluded: fMRI as a window into adolescents’ emotional processing 
Developmental science  2013;16(5):743-759.
During adolescence, concerns about peer rejection and acceptance become increasingly common. Adolescents regularly experience peer rejection firsthand and witness these behaviors among their peers. In the current study, neuroimaging techniques were employed to conduct a preliminary investigation of the affective and cognitive processes involved in witnessing peer acceptance and rejection—specifically when these witnessed events occur in the immediate aftermath of a firsthand experience with rejection. During an fMRI scan, twenty-three adolescents underwent a simulated experience of firsthand peer rejection. Then, immediately following this experience they watched as another adolescent was ostensibly first accepted and then rejected. Findings indicated that in the immediate aftermath of being rejected by peers, adolescents displayed neural activity consistent with distress when they saw another peer being accepted, and neural activity consistent with emotion regulation and mentalizing (e.g., perspective-taking) processes when they saw another peer being rejected. Furthermore, individuals displaying a heightened sensitivity to firsthand rejection were more likely to show neural activity consistent with distress when observing a peer being accepted. Findings are discussed in terms of how witnessing others being accepted or rejected relates to adolescents’ interpretations of both firsthand and observed experiences with peers. Additionally, the potential impact that witnessed events might have on the broader perpetuation of bullying at this age is also considered.
doi:10.1111/desc.12056
PMCID: PMC3775008  PMID: 24033579
peer rejection; peer acceptance; adolescence; functional magnetic resonance imaging; bullying
8.  Associations Among Pubertal Development, Empathic Ability, and Neural Responses While Witnessing Peer Rejection in Adolescence 
Child development  2013;84(4):1338-1354.
Links among concurrent and longitudinal changes in pubertal development and empathic ability from age 10 to 13 and neural responses while witnessing peer rejection at age 13 were examined in 16 participants. More advanced pubertal development at age 13, and greater longitudinal increases in pubertal development, related to increased activity in regions underlying cognitive aspects of empathy. Likewise, at age 13 greater perspective taking related to activity in cognitive empathy-related regions; however, affective components of empathy (empathic concern and personal distress) were additionally associated with activity in affective pain-related regions. Longitudinal increases in empathic ability related to cognitive and affective empathy-related circuitry. Findings provide preliminary evidence that physical and cognitive-emotional development relate to adolescents’ neural responses when witnessing peer rejection.
doi:10.1111/cdev.12056
PMCID: PMC3659192  PMID: 23379360
9.  Race modulates neural activity during imitation 
NeuroImage  2011;59(4):3594-3603.
Imitation plays a central role in the acquisition of culture. People preferentially imitate others who are self-similar, prestigious or successful. Because race can indicate a person's self-similarity or status, race influences whom people imitate. Prior studies of the neural underpinnings of imitation have not considered the effects of race. Here we measured neural activity with fMRI while European American participants imitated meaningless gestures performed by actors of their own race, and two racial outgroups, African American, and Chinese American. Participants also passively observed the actions of these actors and their portraits. Frontal, parietal and occipital areas were differentially activated while participants imitated actors of different races. More activity was present when imitating African Americans than the other racial groups, perhaps reflecting participants' reported lack of experience with and negative attitudes towards this group, or the group's lower perceived social status. This pattern of neural activity was not found when participants passively observed the gestures of the actors or simply looked at their faces. Instead, during face-viewing neural responses were overall greater for own-race individuals, consistent with prior race perception studies not involving imitation. Our findings represent a first step in elucidating neural mechanisms involved in cultural learning, a process that influences almost every aspect of our lives but has thus far received little neuroscientific study.
doi:10.1016/j.neuroimage.2011.10.074
PMCID: PMC3909702  PMID: 22062193
Race; Imitation; Mirror neuron system; Neuroimaging; Cultural learning
10.  Social status modulates neural activity in the mentalizing network 
NeuroImage  2012;60(3):1771-1777.
The current research explored the neural mechanisms linking social status to perceptions of the social world. Two fMRI studies provide converging evidence that individuals lower in social status are more likely to engage neural circuitry often involved in ‘mentalizing’ or thinking about others' thoughts and feelings. Study 1 found that college students' perception of their social status in the university community was related to neural activity in the mentalizing network (e.g., DMPFC, MPFC, precuneus/PCC) while encoding social information, with lower social status predicting greater neural activity in this network. Study 2 demonstrated that socioeconomic status, an objective indicator of global standing, predicted adolescents' neural activity during the processing of threatening faces, with individuals lower in social status displaying greater activity in the DMPFC, previously associated with mentalizing, and the amygdala, previously associated with emotion/salience processing. These studies demonstrate that social status is fundamentally and neurocognitively linked to how people process and navigate their social worlds.
doi:10.1016/j.neuroimage.2012.01.080
PMCID: PMC3909703  PMID: 22289808
Social status; SES; Mentalizing; fMRI
11.  Atypical Neural Processing of Ironic and Sincere Remarks in Children and Adolescents with Autism Spectrum Disorders 
Metaphor and symbol  2012;27(1):70-92.
Individuals with ASD show consistent impairment in processing pragmatic language when attention to multiple social cues (e.g., facial expression, tone of voice) is often needed to navigate social interactions. Building upon prior fMRI work examining how facial affect and prosodic cues are used to infer a speaker's communicative intent, the authors examined whether children and adolescents with ASD differ from typically developing (TD) controls in their processing of sincere versus ironic remarks. At the behavioral level, children and adolescents with ASD and matched TD controls were able to determine whether a speaker's remark was sincere or ironic equally well, with both groups showing longer response times for ironic remarks. At the neural level, for both sincere and ironic scenarios, an extended cortical network—including canonical language areas in the left hemisphere and their right hemisphere counterparts—was activated in both groups, albeit to a lesser degree in the ASD sample. Despite overall similar patterns of activity observed for the two conditions in both groups, significant modulation of activity was detected when directly comparing sincere and ironic scenarios within and between groups. While both TD and ASD groups showed significantly greater activity in several nodes of this extended network when processing ironic versus sincere remarks, increased activity was largely confined to left language areas in TD controls, whereas the ASD sample showed a more bilateral activation profile which included both language and “theory of mind” areas (i.e., ventromedial prefrontal cortex). These findings suggest that, for high-functioning individuals with ASD, increased activity in right hemisphere homologues of language areas in the left hemisphere, as well as regions involved in social cognition, may reflect compensatory mechanisms supporting normative behavioral task performance.
doi:10.1080/10926488.2012.638856
PMCID: PMC3909704  PMID: 24497750
12.  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
13.  Entering Adolescence: Resistance to Peer Influence, Risky Behavior, and Neural Changes in Emotion Reactivity 
Neuron  2011;69(5):10.1016/j.neuron.2011.02.019.
SUMMARY
Adolescence is often described as a period of heightened reactivity to emotions paired with reduced regulatory capacities, a combination suggested to contribute to risk-taking and susceptibility to peer influence during puberty. However, no longitudinal research has definitively linked these behavioral changes to underlying neural development. Here, 38 neurotypical participants underwent two fMRI sessions across the transition from late childhood (10 years) to early adolescence (13 years). Responses to affective facial displays exhibited a combination of general and emotion-specific changes in ventral striatum (VS), ventromedial PFC, amygdala, and temporal pole. Furthermore, VS activity increases correlated with decreases in susceptibility to peer influence and risky behavior. VS and amygdala responses were also significantly more negatively coupled in early adolescence than in late childhood while processing sad and happy versus neutral faces. Together, these results suggest that VS responses to viewing emotions may play a regulatory role that is critical to adolescent interpersonal functioning.
doi:10.1016/j.neuron.2011.02.019
PMCID: PMC3840168  PMID: 21382560
14.  Mirroring others’ emotions relates to empathy and interpersonal competence in children 
NeuroImage  2007;39(4):10.1016/j.neuroimage.2007.10.032.
The mirror neuron system (MNS) has been proposed to play an important role in social cognition by providing a neural mechanism by which others’ actions, intentions, and emotions can be understood. Here functional magnetic resonance imaging was used to directly examine the relationship between MNS activity and two distinct indicators of social functioning in typically-developing children (aged 10.1 years±7 months): empathy and interpersonal competence. Reliable activity in pars opercularis, the frontal component of the MNS, was elicited by observation and imitation of emotional expressions. Importantly, activity in this region (as well as in the anterior insula and amygdala) was significantly and positively correlated with established behavioral measures indexing children’s empathic behavior (during both imitation and observation) and interpersonal skills (during imitation only). These findings suggest that simulation mechanisms and the MNS may indeed be relevant to social functioning in everyday life during typical human development.
doi:10.1016/j.neuroimage.2007.10.032
PMCID: PMC3840169  PMID: 18082427
15.  Longitudinal change in the neural bases of adolescent social self-evaluations: Effects of age and pubertal development 
Self-evaluations undergo significant transformation during early adolescence, developing in parallel with the heightened complexity of teenagers’ social worlds. Intuitive theories of adolescent development, based in part on animal work, suggest that puberty is associated with neural-level changes that facilitate a “social reorientation” (Nelson, Leibenluft, McClure, and Pine, 2005). However, direct tests of this hypothesis using neuroimaging are limited in humans. This longitudinal fMRI study examined neurodevelopmental trajectories associated with puberty, self-evaluations, and the presumed social reorientation during the transition from childhood to adolescence. Participants (N = 27, M age = 10.1 and 13.1 years at timepoints one and two, respectively) engaged in trait evaluations of two targets (the self and a familiar fictional other), across two domains of competence (social and academic). Responses in ventromedial PFC increased with both age and pubertal development during self-evaluations in the social domain, but not in the academic domain. These results suggest changes in social self-evaluations are intimately connected with biology, not just peer contexts, and provide important empirical support for the relationship between neurodevelopment, puberty, and social functioning.
doi:10.1523/JNEUROSCI.4074-12.2013
PMCID: PMC3809090  PMID: 23616547
16.  Own-gender imitation activates the brain's reward circuitry 
Imitation is an important component of human social learning throughout life. Theoretical models and empirical data from anthropology and psychology suggest that people tend to imitate self-similar individuals, and that such imitation biases increase the adaptive value (e.g., self-relevance) of learned information. It is unclear, however, what neural mechanisms underlie people's tendency to imitate those similar to themselves. We focused on the own-gender imitation bias, a pervasive bias thought to be important for gender identity development. While undergoing fMRI, participants imitated own- and other-gender actors performing novel, meaningless hand signs; as control conditions, they also simply observed such actions and viewed still portraits of the same actors. Only the ventral and dorsal striatum, orbitofrontal cortex and amygdala were more active when imitating own- compared to other-gender individuals. A Bayesian analysis of the BrainMap neuroimaging database demonstrated that the striatal region preferentially activated by own-gender imitation is selectively activated by classical reward tasks in the literature. Taken together, these findings reveal a neurobiological mechanism associated with the own-gender imitation bias and demonstrate a novel role of reward-processing neural structures in social behavior.
doi:10.1093/scan/nsr055
PMCID: PMC3475355  PMID: 22383803
imitation; neuroimaging; reward; gender; cultural learning
17.  Relationships between Cerebral Blood Flow and IQ in Typically Developing Children and Adolescents 
Journal of cognitive science  2011;12(2):151-170.
The objective of this study was to explore the relationships between IQ and cerebral blood flow (CBF) measured by arterial spin labeling (ASL) in children and adolescents. ASL was used to collect perfusion MRI data on 39 healthy participants aged 7 to 17. The Wechsler Abbreviated Intelligence Scale was administered to determine IQ scores. Multivariate regression was applied to reveal correlations between CBF and IQ scores, accounting for age, sex and global mean CBF. Voxel Based Morphometry (VBM) analysis, which measures regional cortical volume, was performed as a control. Regression analyses were further performed on CBF data with adjustment of regional gray matter density (GMD). A positive correlation between CBF and IQ scores was primarily seen in the subgenual/anterior cingulate, right orbitofrontal, superior temporal and right inferior parietal regions. An inverse relationship between CBF and IQ was mainly observed in bilateral posterior temporal regions. After adjusting for regional GMD, the correlations between CBF and IQ in the subgenual/anterior cingulate cortex, right orbitofrontal, superior temporal regions and left insula remained significant. These findings support the Parieto-Frontal Integration Theory of intelligence, especially the role of the subgenual/anterior cingulate cortex in the neural networks associated with intelligence. The present study also demonstrates the unique value of CBF in assessing brain-behavior relationships, in addition to structural morphometric measures.
PMCID: PMC3749787  PMID: 23976891
Arterial Spin Labeling (ASL); Perfusion; Voxel Based Morphometry (VBM); Cognitive Development; Intelligence quotient (IQ)
18.  Age and experience shape developmental changes in the neural basis of language-related learning 
Developmental science  2011;14(6):1261-1282.
Very little is known about the neural underpinnings of language learning across the lifespan and how these might be modified by maturational and experiential factors. Building on behavioral research highlighting the importance of early word segmentation (i.e. the detection of word boundaries in continuous speech) for subsequent language learning, here we characterize developmental changes in brain activity as this process occurs online, using data collected in a mixed cross-sectional and longitudinal design. One hundred and fifty-six participants, ranging from age 5 to adulthood, underwent functional magnetic resonance imaging (fMRI) while listening to three novel streams of continuous speech, which contained either strong statistical regularities, strong statistical regularities and speech cues, or weak statistical regularities providing minimal cues to word boundaries. All age groups displayed significant signal increases over time in temporal cortices for the streams with high statistical regularities; however, we observed a significant right-to-left shift in the laterality of these learning-related increases with age. Interestingly, only the 5- to 10-year-old children displayed significant signal increases for the stream with low statistical regularities, suggesting an age-related decrease in sensitivity to more subtle statistical cues. Further, in a sample of 78 10-year-olds, we examined the impact of proficiency in a second language and level of pubertal development on learning-related signal increases, showing that the brain regions involved in language learning are influenced by both experiential and maturational factors.
doi:10.1111/j.1467-7687.2011.01075.x
PMCID: PMC3717169  PMID: 22010887
19.  Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders 
Nature neuroscience  2005;9(1):28-30.
To examine mirror neuron abnormalities in autism, high-functioning children with autism and matched controls underwent fMRI while imitating and observing emotional expressions. Although both groups performed the tasks equally well, children with autism showed no mirror neuron activity in the inferior frontal gyrus (pars opercularis). Notably, activity in this area was inversely related to symptom severity in the social domain, suggesting that a dysfunctional ‘mirror neuron system’ may underlie the social deficits observed in autism.
doi:10.1038/nn1611
PMCID: PMC3713227  PMID: 16327784
20.  Cracking the Language Code: Neural Mechanisms Underlying Speech Parsing 
Word segmentation, detecting word boundaries in continuous speech, is a critical aspect of language learning. Previous research in infants and adults demonstrated that a stream of speech can be readily segmented based solely on the statistical and speech cues afforded by the input. Using functional magnetic resonance imaging (fMRI), the neural substrate of word segmentation was examined on-line as participants listened to three streams of concatenated syllables, containing either statistical regularities alone, statistical regularities and speech cues, or no cues. Despite the participants’ inability to explicitly detect differences between the speech streams, neural activity differed significantly across conditions, with left-lateralized signal increases in temporal cortices observed only when participants listened to streams containing statistical regularities, particularly the stream containing speech cues. In a second fMRI study, designed to verify that word segmentation had implicitly taken place, participants listened to trisyllabic combinations that occurred with different frequencies in the streams of speech they just heard (“words,” 45 times; “partwords,” 15 times; “nonwords,” once). Reliably greater activity in left inferior and middle frontal gyri was observed when comparing words with partwords and, to a lesser extent, when comparing partwords with nonwords. Activity in these regions, taken to index the implicit detection of word boundaries, was positively correlated with participants’ rapid auditory processing skills. These findings provide a neural signature of on-line word segmentation in the mature brain and an initial model with which to study developmental changes in the neural architecture involved in processing speech cues during language learning.
doi:10.1523/JNEUROSCI.5501-05.2006
PMCID: PMC3713232  PMID: 16855090
fMRI; language; speech perception; word segmentation; statistical learning; auditory cortex; inferior frontal gyrus
21.  Reading Affect in the Face and Voice 
Archives of general psychiatry  2007;64(6):698-708.
Context
Understanding a speaker’s communicative intent in everyday interactions is likely to draw on cues such as facial expression and tone of voice. Prior research has shown that individuals with autism spectrum disorders (ASD) show reduced activity in brain regions that respond selectively to the face and voice. However, there is also evidence that activity in key regions can be increased if task demands allow for explicit processing of emotion.
Objectives
To examine the neural circuitry underlying impairments in interpreting communicative intentions in ASD using irony comprehension as a test case, and to determine whether explicit instructions to attend to facial expression and tone of voice will elicit more normative patterns of brain activity.
Design, Setting, and Participants
Eighteen boys with ASD (aged 7–17 years, full-scale IQ >70) and 18 typically developing (TD) boys underwent functional magnetic resonance imaging at the Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles.
Main Outcome Measures
Blood oxygenation level– dependent brain activity during the presentation of short scenarios involving irony. Behavioral performance (accuracy and response time) was also recorded.
Results
Reduced activity in the medial prefrontal cortex and right superior temporal gyrus was observed in children with ASD relative to TD children during the perception of potentially ironic vs control scenarios. Importantly, a significant group X condition interaction in the medial prefrontal cortex showed that activity was modulated by explicit instructions to attend to facial expression and tone of voice only in the ASD group. Finally, medial prefrontal cortex activity was inversely related to symptom severity in children with ASD such that children with greater social impairment showed less activity in this region.
Conclusions
Explicit instructions to attend to facial expression and tone of voice can elicit increased activity in the medial prefrontal cortex, part of a network important for understanding the intentions of others, in children with ASD. These findings suggest a strategy for future intervention research.
doi:10.1001/archpsyc.64.6.698
PMCID: PMC3713233  PMID: 17548751
22.  Neural basis of irony comprehension in children with autism: the role of prosody and context 
Brain : a journal of neurology  2006;129(0 4):932-943.
While individuals with autism spectrum disorders (ASD) are typically impaired in interpreting the communicative intent of others, little is known about the neural bases of higher-level pragmatic impairments. Here, we used functional MRI (fMRI) to examine the neural circuitry underlying deficits in understanding irony in high-functioning children with ASD. Participants listened to short scenarios and decided whether the speaker was sincere or ironic. Three types of scenarios were used in which we varied the information available to guide this decision. Scenarios included (i) both knowledge of the event outcome and strong prosodic cues (sincere or sarcastic intonation), (ii) prosodic cues only or (iii) knowledge of the event outcome only. Although children with ASD performed well above chance, they were less accurate than typically developing (TD) children at interpreting the communicative intent behind a potentially ironic remark, particularly with regard to taking advantage of available contextual information. In contrast to prior research showing hypoactivation of regions involved in understanding the mental states of others, children with ASD showed significantly greater activity than TD children in the right inferior frontal gyrus (IFG) as well as in bilateral temporal regions. Increased activity in the ASD group fell within the network recruited in the TD group and may reflect more effortful processing needed to interpret the intended meaning of an utterance. These results confirm that children with ASD have difficulty interpreting the communicative intent of others and suggest that these individuals can recruit regions activated as part of the normative neural circuitry when task demands require explicit attention to socially relevant cues.
doi:10.1093/brain/awl032
PMCID: PMC3713234  PMID: 16481375
autism; brain development; fMRI; language pragmatics; social cognition
23.  Infants’ Pre-Empathic Behaviors are Associated with Language Skills 
Infant behavior & development  2012;35(3):561-569.
Infants’ responses to other people’s distress reflect efforts to make sense of affective information about another person and apply it to oneself. This study sought to determine whether 12-month olds’ responses to another person’s display of negative affect reflect characteristics that support social learning and predict social functioning and language skills at 36 months. Measures of infants’ responsiveness include congruent changes in affect and looking time to the person in distress. Attention to the examiner displaying positive affect, analyzed as a control condition, was not related to social functioning or language skills at 36 months. Neither attention nor affective response to the examiner’s distress at 12 months was related to social functioning at 36 months. However, longer time spent looking at the examiner feigning distress predicted higher language scores. Moreover, infants who demonstrated a congruent affective response to distress had higher receptive language scores at 36 months than children who did not respond affectively. Importantly, these relations were not mediated by maternal education, household income, or 12-month verbal skills. These findings are consistent with the notion that adaptation to changes in a social partner’s affective state supports an infants’ ability to glean useful information from interactions with more experienced social partners. Infants’ sensitivity to affective signals may thus be related to the ability to interpret other people’s behavior and to achieve interpersonal understanding through language.
doi:10.1016/j.infbeh.2012.05.007
PMCID: PMC3428260  PMID: 22728336
Empathy; Infancy; Social Interaction; Language Development; Social Development
24.  Reduced Functional Integration and Segregation of Distributed Neural Systems Underlying Social and Emotional Information Processing in Autism Spectrum Disorders 
Cerebral Cortex (New York, NY)  2011;22(5):1025-1037.
A growing body of evidence suggests that autism spectrum disorders (ASDs) are related to altered communication between brain regions. Here, we present findings showing that ASD is characterized by a pattern of reduced functional integration as well as reduced segregation of large-scale brain networks. Twenty-three children with ASD and 25 typically developing matched controls underwent functional magnetic resonance imaging while passively viewing emotional face expressions. We examined whole-brain functional connectivity of two brain structures previously implicated in emotional face processing in autism: the amygdala bilaterally and the right pars opercularis of the inferior frontal gyrus (rIFGpo). In the ASD group, we observed reduced functional integration (i.e., less long-range connectivity) between amygdala and secondary visual areas, as well as reduced segregation between amygdala and dorsolateral prefrontal cortex. For the rIFGpo seed, we observed reduced functional integration with parietal cortex and increased integration with right frontal cortex as well as right nucleus accumbens. Finally, we observed reduced segregation between rIFGpo and the ventromedial prefrontal cortex. We propose that a systems-level approach—whereby the integration and segregation of large-scale brain networks in ASD is examined in relation to typical development—may provide a more detailed characterization of the neural basis of ASD.
doi:10.1093/cercor/bhr171
PMCID: PMC3328339  PMID: 21784971
amygdala; connectivity; default mode network; face processing; mirror neuron system
25.  Facing puberty: associations between pubertal development and neural responses to affective facial displays 
Adolescence is marked by profound psychosocial and physiological changes. Although investigations into the interactions between these forces have begun to shed light on the neural correlates of affective processing during the transition to adolescence, relatively little is known about the relationship between pubertal development and emotion perception at the neural level. In the current longitudinal study, 45 neurotypical participants were shown affective facial displays while undergoing fMRI, at ages 10 and 13. Neural responses to emotional expressions at both time points were then correlated with a self-report measure of pubertal development, revealing positive associations with activity in amygdala, thalamus and visual cortical areas at age 10 that increased in magnitude and extent by age 13. At the latter time point, pubertal development was additionally correlated with enhanced responses to faces in temporal pole, ventrolateral prefrontal cortex (PFC) and dorsomedial PFC. Longitudinal comparisons revealed that the relationships between pubertal development and activity in the amygdala, hippocampus and temporal pole were significantly stronger during early adolescence than late childhood. These results suggest that pubertal development per se is linked to neural processing of socioemotional stimuli, particularly with respect to the integration of complex perceptual input and higher order cortical processing of affective content.
doi:10.1093/scan/nsr066
PMCID: PMC3252633  PMID: 22228752
adolescence; puberty; emotion; fMRI; amygdala; longitudinal

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