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1.  In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism 
Brain research  2010;1380:198-205.
Attentional dysfunction is one of the most consistent findings in individuals with autism spectrum disorders (ASD). However, the significance of such findings for the pathophysiology of autism is unclear. In this study, we investigated cellular neurochemistry with proton magnetic resonance spectroscopy imaging (1H-MRS) in brain regions associated with networks subserving alerting, orienting, and executive control of attention in patients with ASD. Concentrations of cerebral N-acetyl-aspartate (NAA), creatinine + phosphocreatinine, choline-containing compounds, myo-inositol (Ins) and glutamate + glutamine (Glx) were determined by 3 T 1H-MRS examinations in 14 high-functioning medication-free adults with a diagnosis of ASD and 14 age- and IQ-matched healthy controls (HC) in the anterior cingulate cortex (ACC), thalamus, temporoparietal junction (TPJ), and areas near or along the intraparietal sulcus (IPS). Compared to HC group, the ASD group showed significantly lower Glx concentrations in right ACC and reduced Ins in left TPJ. This study provides evidence of abnormalities in neurotransmission related to networks subserving executive control and alerting of attention, functions which have been previously implicated in ASD pathogenesis.
doi:10.1016/j.brainres.2010.12.057
PMCID: PMC3073642  PMID: 21185269
autism; spectroscopy; glutamate; anterior cingulate cortex; intraparietal sulcus; myo-inositol
2.  Atypical Attentional Networks and the Emergence of Autism 
The sociocommunicative impairments that define autism spectrum disorder (ASD) are not present at birth but emerge gradually over the first two years of life. In typical development, basic attentional processes may provide a critical foundation for sociocommunicative abilities. Therefore early attentional dysfunction in ASD may result in atypical development of social communication. Prior research has demonstrated that persons with ASD exhibit early and lifelong impairments in attention. The primary aim of this paper is to provide a review of the extant research on attention in ASD using a framework of functionally independent attentional networks as conceptualized by Posner and colleagues: the alerting, orienting and executive control networks (Posner and Petersen, 1990; Petersen & Posner, 2012). The neural substrates and typical development of each attentional network is briefly discussed, a review of the ASD attention literature is presented, and a hypothesis is proposed that links aberrant attentional mechanisms, specifically impaired disengagement of attention, with the emergence of core ASD symptoms.
doi:10.1016/j.neubiorev.2012.11.014
PMCID: PMC3563720  PMID: 23206665
autism; attention; development; alerting; arousal; orienting; disengagement; executive control
3.  Attentional networks in children and adolescents with autism spectrum disorder 
Background
Individuals diagnosed with autism spectrum disorder (ASD) exhibit lifelong abnormalities in the adaptive allocation of visual attention. The ubiquitous nature of attentional impairments in ASD has led some authors to hypothesize that atypical attentional modulation may be a factor in the development of higher-level sociocommunicative deficits.
Method
Participants were 20 children with ASD and 20 age- and Nonverbal IQ-matched typically developing (TD) children. We used the Attention Network Test (ANT) to investigate the efficiency and independence of three discrete attentional networks: alerting, orienting, and executive control. Additionally, we sought to investigate the relationship between each attentional network and measures of sociocommunicative symptom severity in children with ASD.
Results
Results indicate that the orienting, but not alerting or executive control, networks may be impaired in children with ASD. In contrast to TD children, correlational analyses suggest that the alerting and executive control networks may not function as independently in children with ASD. Additionally, an association was found between the alerting network and social impairment and between the executive control network and IQ in children with ASD.
Conclusions
The results provide further evidence of an impairment in the visuospatial orienting network in ASD and suggest that there may be greater interdependence of alerting and executive control networks in ASD. Furthermore, decreased ability to efficiently modulate levels of alertness was related to increased sociocommunicative deficits, suggesting that domain-general attentional function may be associated with ASD symptomatology.
doi:10.1111/j.1469-7610.2010.02257.x
PMCID: PMC3145814  PMID: 20456535
Autism; reaction time; visual attention; alerting; orienting; executive control
4.  Caudate Nucleus Volume and Cognitive Performance: Are they related in Childhood Psychopathology?1 
Biological psychiatry  2006;60(9):942-950.
Background
Impaired neuropsychological test performance, especially on tests of executive function and attention, is often seen in children diagnosed with autism spectrum disorders (ASD). Structures involved in fronto-striatal circuitry, such as the caudate nucleus, may support these cognitive abilities. However, few studies have examined caudate volumes specifically in children with ASD, or correlated caudate volumes to cognitive ability.
Methods
Neuropsychological test scores and caudate volumes of children with ASD were compared to those of children with bipolar disorder (BD) and of typically developing (TD) children. The relationship between test performance and caudate volumes was analyzed.
Results
The ASD group displayed larger right and left caudate volumes, and modest executive deficits, compared to TD controls. While caudate volume inversely predicted performance on the Wisconsin Card Sorting Test in all participants, it differentially predicted performance on measures of attention across the ASD, BD and TD groups.
Conclusions
Larger caudate volumes were related to impaired problem solving. On a test of attention, larger left caudate volumes predicted increased impulsivity and more omission errors in the ASD group as compared to the TD group, however smaller volume predicted poorer discriminant responding as compared to the BD group.
doi:10.1016/j.biopsych.2006.03.071
PMCID: PMC2947855  PMID: 16950212
executive function; attention; bipolar disorder; autism spectrum disorders; caudate volume; neuroimaging
5.  Atypical recruitment of medial prefrontal cortex in autism spectrum disorders: An fMRI study of two executive function tasks 
Neuropsychologia  2008;46(9):2281-2291.
Recent studies have suggested an uneven profile of executive dysfunction in autism spectrum disorders (ASD). For example, some authors have reported deficits on newly developed tests of executive function sensitive to rostral prefrontal function, despite spared, or even superior, performance on other tests. We investigated the performance of a group of high-functioning participants with ASD (N = 15) and an age- and IQ-matched control group (N = 18) on two executive function tests, whilst undergoing functional magnetic resonance imaging (fMRI). Behaviourally, there were no significant differences between the two groups. In a classical test of executive function (random response generation), BOLD signal differed between the groups in the cerebellum but not in the frontal lobes. However, on a new test of executive function (selection between stimulus-oriented and stimulus-independent thought), the ASD group exhibited significantly greater signal-change in medial rostral prefrontal cortex (especially Brodmann Area 10) in the comparison of stimulus-oriented versus stimulus-independent attention. In addition, the new test (but not the classical test) provided evidence for abnormal functional organisation of medial prefrontal cortex in ASD. These results underline the heterogeneity of different tests of executive function, and suggest that executive functioning in ASD is associated with task-specific functional change.
doi:10.1016/j.neuropsychologia.2008.03.025
PMCID: PMC2648877  PMID: 18485420
Autism; Asperger syndrome; Executive function; fMRI; Prefrontal cortex
6.  Working memory deficits in high-functioning adolescents with autism spectrum disorders: neuropsychological and neuroimaging correlates 
Working memory is a temporary storage system under attentional control. It is believed to play a central role in online processing of complex cognitive information and may also play a role in social cognition and interpersonal interactions. Adolescents with a disorder on the autism spectrum display problems in precisely these domains. Social impairments, communication difficulties, and repetitive interests and activities are core domains of autism spectrum disorders (ASD), and executive function problems are often seen throughout the spectrum. As the main cognitive theories of ASD, including the theory of mind deficit hypotheses, weak central coherence account, and the executive dysfunction theory, still fail to explain the broad spectrum of symptoms, a new perspective on the etiology of ASD is needed. Deficits in working memory are central to many theories of psychopathology, and are generally linked to frontal-lobe dysfunction. This article will review neuropsychological and (functional) brain imaging studies on working memory in adolescents with ASD. Although still disputed, it is concluded that within the working memory system specific problems of spatial working memory are often seen in adolescents with ASD. These problems increase when information is more complex and greater demands on working memory are made. Neuroimaging studies indicate a more global working memory processing or connectivity deficiency, rather than a focused deficit in the prefrontal cortex. More research is needed to relate these working memory difficulties and neuroimaging results in ASD to the behavioral difficulties as seen in individuals with a disorder on the autism spectrum.
doi:10.1186/1866-1955-5-14
PMCID: PMC3674927  PMID: 23731472
Working memory; Adolescents; Autism; Neuropsychology; Neuroimaging
7.  The brains of high functioning autistic individuals do not synchronize with those of others☆ 
NeuroImage : Clinical  2013;3:489-497.
Multifaceted and idiosyncratic aberrancies in social cognition characterize autism spectrum disorders (ASDs). To advance understanding of underlying neural mechanisms, we measured brain hemodynamic activity with functional magnetic resonance imaging (fMRI) in individuals with ASD and matched-pair neurotypical (NT) controls while they were viewing a feature film portraying social interactions. Pearson's correlation coefficient was used as a measure of voxelwise similarity of brain activity (InterSubject Correlations—ISCs). Individuals with ASD showed lower ISC than NT controls in brain regions implicated in processing social information including the insula, posterior and anterior cingulate cortex, caudate nucleus, precuneus, lateral occipital cortex, and supramarginal gyrus. Curiously, also within NT group, autism-quotient scores predicted ISC in overlapping areas, including, e.g., supramarginal gyrus and precuneus. In ASD participants, functional connectivity was decreased between the frontal pole and the superior frontal gyrus, angular gyrus, superior parietal lobule, precentral gyrus, precuneus, and anterior/posterior cingulate gyrus. Taken together these results suggest that ISC and functional connectivity measure distinct features of atypical brain function in high-functioning autistic individuals during free viewing of acted social interactions. Our ISC results suggest that the minds of ASD individuals do not ‘tick together’ with others while perceiving identical dynamic social interactions.
Highlights
•We studied brain function in autism during free viewing of social interactions.•The brains of individuals with autism do not ‘tick together’ with others.•Long-range functional connectivity is altered in individuals with autism.•Link between autistic traits and social brain synchrony extends to normal population.
doi:10.1016/j.nicl.2013.10.011
PMCID: PMC3830058  PMID: 24273731
Asperger syndrome; fMRI; Intersubject correlation; Movie; Social brain
8.  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
9.  Reduced Theta Connectivity during Set-Shifting in Children with Autism 
Autism spectrum disorder (ASD) is a characterized by deficits in social cognition and executive function. An area of particular difficulty for children with ASD is cognitive flexibility, such as the ability to shift between attentional or response sets. The biological basis of such deficits remains poorly understood, although atypical development of structural and functional brain connectivity have been reported in ASD, suggesting that disruptions of normal patterns of inter-regional communication may contribute to cognitive problems in this group. The present magnetoencephalography study measured inter-regional phase synchronization while children with ASD and typically developing matched controls (6–14 years of age) performed a set-shifting task. Reduced theta-band phase synchronization was observed in children with ASD during extradimensional set-shifting. This reduction in task-dependent inter-regional connectivity encompassed numerous areas including multiple frontal lobe regions, and indicates that problems with communication among brain areas may contribute to difficulties with executive function in ASD.
doi:10.3389/fnhum.2013.00785
PMCID: PMC3827625  PMID: 24294201
ASD; autism; neural synchrony; neural oscillation; magnetoencephalography; set-shifting; executive function; functional connectivity
10.  The effects of a DTNBP1 gene variant on attention networks: an fMRI study 
Background
Attention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers.
Methods
The present event-related fMRI study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 of the DTNBP1 (dystrobrevin-binding protein 1) gene on brain activity in 80 subjects while performing the attention network test (ANT). In this reaction time task three domains of attention are probed simultaneously: alerting, orienting and executive control of attention.
Results
Risk allele carriers showed impaired performance in the executive control condition associated with reduced neural activity in the left superior frontal gyrus [Brodmann area (BA) 9]. Risk allele carriers did not show alterations in the alerting and orienting networks.
Conclusions
BA 9 is a key region of schizophrenia pathology and belongs to a network that has been shown previously to be involved in impaired executive control mechanisms in schizophrenia. Our results identified the impact of DTNBP1 on the development of a specific attention deficit via modulation of a left prefrontal network.
doi:10.1186/1744-9081-6-54
PMCID: PMC2949706  PMID: 20846375
11.  Autism is characterized by dorsal anterior cingulate hyperactivation during social target detection 
Though the functional neural correlates of impaired cognitive control and social dysfunction in autism spectrum disorders (ASD) have been delineated, brain regions implicated in poor cognitive control of social information is a novel area of autism research. We recently reported in a non-clinical sample that detection of ‘social oddball’ targets activated a portion of the dorsal anterior cingulate gyrus and the supracalcarine cortex (Dichter, Felder, Bodfish, Sikich, and Belger, 2009). In the present investigation, we report functional magnetic resonance imaging results from individuals with ASD who completed the same social oddball task. Between-group comparisons revealed generally greater activation in the ASD group to both social and non-social targets. When responses to social and non-social targets were contrasted, the ASD group showed relatively greater activation in the right and middle inferior frontal gyri and a region in dorsomedial prefrontal cortex that abuts the dorsal anterior cingulate (Brodmann's Area 32). Further, dorsal anterior cingulate activation to social targets predicted the severity of social impairments in a subset of the ASD sample. These data suggest that the dorsal anterior cingulate mediates social target detection in neurotypical individuals and is implicated in deficits of cognitive control of social information in ASD.
doi:10.1093/scan/nsp017
PMCID: PMC2728636  PMID: 19574440
autism; fMRI; target detection; face processing; cingulate gyrus
12.  N-acetyl aspartate in autism spectrum disorders: Regional effects and relationship to FMRI activation 
Brain research  2007;1162:85-97.
Rapid progress in our understanding of macrostructural abnormalities in autism spectrum disorders (ASD) has occurred in recent years. However, the relationship between the integrity of neural tissue and neural function has not been previously investigated. Single-voxel proton magnetic resonance spectroscopy and functional magnetic resonance imaging of an executive functioning task was obtained in 13 high functioning adolescents and adults with ASD and 13 age-matched controls. The ASD group showed significant reductions in N-acetyl aspartate (NAA) in all brain regions combined and a specific reduction in left frontal cortex compared to controls. Regression analyses revealed a significant group interaction effect between frontal and cerebellar NAA. In addition, a significant positive semi-partial correlation between left frontal lobe NAA and frontal lobe functional activation was found in the ASD group. These findings suggest that widespread neuronal dysfunction is present in high functioning individuals with ASD. Hypothesized developmental links between frontal and cerebellar vermis neural abnormalities were supported, in that impaired neuronal functioning in the vermis was associated with impaired neuronal functioning in the frontal lobes in the ASD group. Furthermore, this study provided the first direct evidence of the relationship between abnormal functional activation in prefrontal cortex and neuronal dysfunction in ASD.
doi:10.1016/j.brainres.2007.04.081
PMCID: PMC3477551  PMID: 17612510
autism; FMRI; magnetic resonance spectroscopy; verbal fluency; cerebellum; frontal lobe; NAA
13.  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
14.  Reduced cognitive control of response inhibition by the anterior cingulate cortex in autism spectrum disorders 
NeuroImage  2010;52(1):336-347.
Response inhibition, or the suppression of prepotent, but contextually inappropriate behaviors, is essential to adaptive, flexible responding. In autism spectrum disorders (ASD), difficulty inhibiting prepotent behaviors may contribute to restricted, repetitive behavior (RRB). Individuals with ASD consistently show deficient response inhibition while performing antisaccades, which require one to inhibit the prepotent response of looking towards a suddenly appearing stimulus (i.e., a prosaccade), and to substitute a gaze in the opposite direction. Here, we used fMRI to identify the neural correlates of this deficit. We focused on two regions that are critical for saccadic inhibition: the frontal eye field (FEF), the key cortical region for generating volitional saccades, and the dorsal anterior cingulate cortex (dACC), which is thought to exert top-down control on FEF. We also compared ASD and control groups on the functional connectivity of the dACC and FEF during saccadic performance. In the context of an increased antisaccade error rate, ASD participants showed decreased functional connectivity of the FEF and dACC and decreased inhibition-related activation (based on the contrast of antisaccades and prosaccades) in both regions. Decreased dACC activation correlated with a higher error rate in both groups, consistent with a role in top-down control. Within the ASD group, increased FEF activation and dACC/FEF functional connectivity were associated with more severe RRB. These findings demonstrate functional abnormalities in a circuit critical for volitional ocular motor control in ASD that may contribute to deficient response inhibition and to RRB. More generally, our findings suggest reduced cognitive control over behavior by the dACC in ASD.
doi:10.1016/j.neuroimage.2010.04.010
PMCID: PMC2883672  PMID: 20394829
15.  Decreased Coherent Motion Discrimination in Autism Spectrum Disorder: The Role of Attentional Zoom-Out Deficit 
PLoS ONE  2012;7(11):e49019.
Autism spectrum disorder (ASD) has been associated with decreased coherent dot motion (CDM) performance, a task that measures magnocellular sensitivity as well as fronto-parietal attentional integration processing. In order to clarify the role of spatial attention in CDM tasks, we measured the perception of coherently moving dots displayed in the central or peripheral visual field in ASD and typically developing children. A dorsal-stream deficit in children with ASD should predict a generally poorer performance in both conditions. In our study, however, we show that in children with ASD, CDM perception was selectively impaired in the central condition. In addition, in the ASD group, CDM efficiency was correlated to the ability to zoom out the attentional focus. Importantly, autism symptoms severity was related to both the CDM and attentional zooming-out impairment. These findings suggest that a dysfunction in the attentional network might help to explain decreased CDM discrimination as well as the “core” social cognition deficits of ASD.
doi:10.1371/journal.pone.0049019
PMCID: PMC3490913  PMID: 23139831
16.  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
17.  Impaired social brain network for processing dynamic facial expressions in autism spectrum disorders 
BMC Neuroscience  2012;13:99.
Background
Impairment of social interaction via facial expressions represents a core clinical feature of autism spectrum disorders (ASD). However, the neural correlates of this dysfunction remain unidentified. Because this dysfunction is manifested in real-life situations, we hypothesized that the observation of dynamic, compared with static, facial expressions would reveal abnormal brain functioning in individuals with ASD.
We presented dynamic and static facial expressions of fear and happiness to individuals with high-functioning ASD and to age- and sex-matched typically developing controls and recorded their brain activities using functional magnetic resonance imaging (fMRI).
Result
Regional analysis revealed reduced activation of several brain regions in the ASD group compared with controls in response to dynamic versus static facial expressions, including the middle temporal gyrus (MTG), fusiform gyrus, amygdala, medial prefrontal cortex, and inferior frontal gyrus (IFG). Dynamic causal modeling analyses revealed that bi-directional effective connectivity involving the primary visual cortex–MTG–IFG circuit was enhanced in response to dynamic as compared with static facial expressions in the control group. Group comparisons revealed that all these modulatory effects were weaker in the ASD group than in the control group.
Conclusions
These results suggest that weak activity and connectivity of the social brain network underlie the impairment in social interaction involving dynamic facial expressions in individuals with ASD.
doi:10.1186/1471-2202-13-99
PMCID: PMC3459703  PMID: 22889284
Amygdala; Autism spectrum disorders (ASD); Dynamic facial expression; Fusiform gyrus; Inferior frontal gyrus; Medial prefrontal cortex; Middle temporal gyrus/superior temporal sulcus; Mirror neuron system
18.  Atypical neural substrates of Embedded Figures Task performance in children with Autism Spectrum Disorders 
NeuroImage  2007;38(1):184-193.
Superior performance on the Embedded Figures Task (EFT) has been attributed to weak central coherence in perceptual processing in Autism Spectrum Disorders (ASD). The present study used functional magnetic resonance imaging to examine the neural basis of EFT performance in 7-12 year old ASD children and age and IQ matched controls. ASD children activated only a subset of the distributed network of regions activated in controls. In frontal cortex, control children activated left dorsolateral, medial and dorsal premotor regions whereas ASD children only activated the dorsal premotor region. In parietal and occipital cortices, activation was bilateral in control children but unilateral (left superior parietal and right occipital) in ASD children. Further, extensive bilateral ventral temporal activation was observed in control, but not ASD children. ASD children performed the EFT at the same level as controls but with reduced cortical involvement, suggesting that disembedded visual processing is accomplished parsimoniously by ASD relative to typically developing brains.
doi:10.1016/j.neuroimage.2007.07.013
PMCID: PMC2084060  PMID: 17707658
19.  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
20.  Disentangling weak coherence and executive dysfunction: planning drawing in autism and attention-deficit/hyperactivity disorder. 
A tendency to focus on details at the expense of configural information, 'weak coherence', has been proposed as a cognitive style in autism. In the present study we tested whether weak coherence might be the result of executive dysfunction, by testing clinical groups known to show deficits on tests of executive control. Boys with autism spectrum disorders (ASD) were compared with age- and intelligence quotient (IQ)-matched boys with attention-deficit/hyperactivity disorder (ADHD), and typically developing (TD) boys, on a drawing task requiring planning for the inclusion of a new element. Weak coherence was measured through analysis of drawing style. In line with the predictions made, the ASD group was more detail-focused in their drawings than were either ADHD or TD boys. The ASD and ADHD groups both showed planning impairments, which were more severe in the former group. Poor planning did not, however, predict detail-focus, and scores on the two aspects of the task were unrelated in the clinical groups. These findings indicate that weak coherence may indeed be a cognitive style specific to autism and unrelated to cognitive deficits in frontal functions.
doi:10.1098/rstb.2002.1204
PMCID: PMC1693126  PMID: 12639335
21.  Abnormalities of Intrinsic Functional Connectivity in Autism Spectrum Disorders 
NeuroImage  2009;47(2):764-772.
Autism spectrum disorders (ASD) impact social functioning and communication, and individuals with these disorders often have restrictive and repetitive behaviors. Accumulating data indicate that ASD is associated with alterations of neural circuitry. Functional MRI (FMRI) studies have focused on connectivity in the context of psychological tasks. However, even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic or resting connectivity. Notably, the default network, which includes the posterior cingulate cortex, retro-splenial, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus, is strongly active when there is no task. Altered intrinsic connectivity within the default network may underlie offline processing that may actuate ASD impairments. Using FMRI, we sought to evaluate intrinsic connectivity within the default network in ASD. Relative to controls, the ASD group showed weaker connectivity between the posterior cingulate cortex and superior frontal gyrus and stronger connectivity between the posterior cingulate cortex and both the right temporal lobe and right parahippocampal gyrus. Moreover, poorer social functioning in the ASD group was correlated with weaker connectivity between the posterior cingulate cortex and the superior frontal gyrus. In addition, more severe restricted and repetitive behaviors in ASD were correlated with stronger connectivity between the posterior cingulate cortex and right parahippocampal gyrus. These findings indicate that ASD subjects show altered intrinsic connectivity within the default network, and connectivity between these structures is associated with specific ASD symptoms.
doi:10.1016/j.neuroimage.2009.04.069
PMCID: PMC2731579  PMID: 19409498
22.  Attentional networks in developmental dyscalculia 
Background
Very little is known about attention deficits in developmental dyscalculia, hence, this study was designed to provide the missing information. We examined attention abilities of participants suffering from developmental dyscalculia using the attention networks test - interactions. This test was designed to examine three different attention networks--executive function, orienting and alerting--and the interactions between them.
Methods
Fourteen university students that were diagnosed as suffering from developmental dyscalculia--intelligence and reading abilities in the normal range and no indication of attention-deficit hyperactivity disorder--and 14 matched controls were tested using the attention networks test - interactions. All participants were given preliminary tests to measure mathematical abilities, reading, attention and intelligence.
Results
The results revealed deficits in the alerting network--a larger alerting effect--and in the executive function networks--a larger congruity effect in developmental dyscalculia participants. The interaction between the alerting and executive function networks was also modulated by group. In addition, developmental dyscalculia participants were slower to respond in the non-cued conditions.
Conclusions
These results imply specific attentional deficits in pure developmental dyscalculia. Namely, those with developmental dyscalculia seem to be deficient in the executive function and alertness networks. They suffer from difficulty in recruiting attention, in addition to the deficits in numerical processing.
doi:10.1186/1744-9081-6-2
PMCID: PMC2821357  PMID: 20157427
23.  Atypical Network Connectivity for Imitation in Autism Spectrum Disorder 
Neuropsychologia  2010;48(10):2931-2939.
Imitation has been considered as one of the precursors for sociocommunicative development. Impairments of imitation in autism spectrum disorder (ASD) could be indicative of dysfunctional underlying neural processes. Neuroimaging studies have found reduced activation in areas associated with imitation, but a functional connectivity MRI network perspective of these regions in autism is unavailable. Functional and effective connectivity was examined in 14 male participants with ASD and 14 matched typically developing (TD) participants. We analyzed intrinsic, low-frequency blood oxygen level dependent (BOLD) fluctuations of three regions in literature found to be associated with imitation (inferior frontal gyrus [IFG], inferior parietal lobule [IPL], superior temporal sulcus [STS]). Direct group comparisons did not show significantly reduced functional connectivity within the imitation network in ASD. Conversely, we observed greater connectivity with frontal regions, particularly superior frontal and anterior cingulate gyri, in the ASD compared to TD group. Structural equation modeling of effective connectivity revealed a significantly reduced effect of IPL on IFG together with an increased influence of a region in dorsal prefrontal cortex (dPFC) on IFG in the ASD group. Our results suggest atypical connectivity of the imitation network with an enhanced role of dPFC, which may relate to behavioral impairments.
doi:10.1016/j.neuropsychologia.2010.05.035
PMCID: PMC3315839  PMID: 20558187
Asperger's disorder; fcMRI; intrinsic functional connectivity; effective connectivity; structural equation modeling; prefrontal cortex
24.  Alertness can be improved by an interaction between orienting attention and alerting attention in schizophrenia 
Background
Attention is impaired in schizophrenia. Early attention components include orienting and alerting, as well as executive control networks. Previous studies have shown mainly executive control deficits, while few of them found orienting and alerting abnormalities. Here we explore the different attentive networks, their modulation and interactions in patients with schizophrenia.
Methods
Twenty-one schizophrenic patients (DSMIV), compared to 21 controls, performed a modified version of the Attention Network Task, in which an orienting paradigm (with valid, invalid and no cues) was combined with a flanker task (congruent/incongruent) and an alerting signal (tone/no tone), to assess orienting, executive control and alerting networks independently.
Results
Patients showed an abnormal alerting effect and slower overall reaction time compared to controls. Moreover, there was an interaction between orienting and alerting: patients are helped more than controls by the alerting signal in a valid orientation to solve the incongruent condition.
Conclusion
These results suggest that patients with schizophrenia have altered alerting abilities. However, the orienting and alerting cues interact to improve their attention performance in the resolution of conflict, creating possibilities for cognitive remediation strategies.
doi:10.1186/1744-9081-7-24
PMCID: PMC3156722  PMID: 21729299
25.  Inhibition, flexibility, working memory and planning in autism spectrum disorders with and without comorbid ADHD-symptoms 
Background
Recent studies have not paid a great deal of attention to comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms in autistic children even though it is well known that almost half of children with autism spectrum disorder (ASD) suffer from hyperactivity, inattention and impulsivity. The goal of this study was to evaluate and compare executive functioning (EF) profiles in children with ADHD and in children with ASD with and without comorbid ADHD.
Methods
Children aged 6 to 18 years old with ADHD (n = 20) or ASD (High-Functioning autism or Asperger syndrome) with (n = 20) and without (n = 20) comorbid ADHD and a typically developing group (n = 20) were compared on a battery of EF tasks comprising inhibition, flexibility, working memory and planning tasks. A MANOVA, effect sizes as well as correlations between ADHD-symptomatology and EF performance were calculated. Age- and IQ-corrected z scores were used.
Results
There was a significant effect for the factor group (F = 1.55; dF = 42; p = .02). Post-hoc analysis revealed significant differences between the ADHD and the TD group on the inhibition task for false alarms (p = .01) and between the ADHD group, the ASD+ group (p = .03), the ASD- group (p = .02) and the TD group (p = .01) for omissions. Effect sizes showed clear deficits of ADHD children in inhibition and working memory tasks. Participants with ASD were impaired in planning and flexibility abilities. The ASD+ group showed compared to the ASD- group more problems in inhibitory performance but not in the working memory task.
Conclusion
Our findings replicate previous results reporting impairment of ADHD children in inhibition and working memory tasks and of ASD children in planning and flexibility abilities. The ASD + group showed similarities to the ADHD group with regard to inhibitory but not to working memory deficits. Nevertheless the heterogeneity of these and previous results shows that EF assessment is not useful for differential diagnosis between ADHD and ASD. It might be useful for evaluating strengths and weaknesses in individual children.
doi:10.1186/1753-2000-2-4
PMCID: PMC2276205  PMID: 18237439

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