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1.  Phonological processing in first-degree relatives of individuals with autism: An fMRI study 
Human brain mapping  2012;34(6):1447-1463.
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders. Twin studies have provided heritability estimates as high as 90% for idiopathic ASD. Further evidence for the spectrum’s heritability is provided by the presence of the broad autism phenotype (BAP) in unaffected first-degree relatives. Language ability, specifically phonological processing, is proposed to be a core BAP trait. To date, however, no functional neuroimaging investigations of phonological processing in relatives of individuals with ASD have been undertaken. We conducted a functional magnetic resonance imaging (fMRI) study in parents of children with ASD utilizing a priming task probing implicit phonological processing. In our condition that placed heavier demands on phonological recoding, parents exhibited greater hemodynamic responses than controls in a network of cortical regions involved in phonological processing. Across conditions, parents exhibited enhanced priming-induced response suppression suggesting compensatory neural processing. A nonword repetition test used in previous studies of relatives was also administered. Correlations between this measure and our functional measures also suggested compensatory processing in parents. Regions exhibiting atypical responses in parents included regions previously implicated in the spectrum’s language impairments and found to exhibit structural abnormalities in a parent study. These results suggest a possible neurobiological substrate of the phonological deficits proposed to be a core BAP trait. However, these results should be considered preliminary. No previous fMRI study has investigated phonological processing in ASD, so replication is required. Furthermore, interpretation of our fMRI results is limited by the fact that the parent group failed to exhibit behavioral evidence of phonological impairments.
PMCID: PMC4136540  PMID: 22419478
functional magnetic resonance imaging (fMRI); autism spectrum disorders (ASD); broad autism phenotype (BAP); phonology; priming; nonword repetition
2.  Autism Spectrum Disorder as Early Neurodevelopmental Disorder: Evidence from the Brain Imaging Abnormalities in 2–3 Years Old Toddlers 
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships in adolescents and adults with ASD, literature is still limited in information about the neurobiology of ASD in the early age of life. Brain images of 50 toddlers with ASD and 28 age, gender, and developmental quotient matched toddlers with developmental delay (DD) (control group) between ages 2 and 3 years were captured using combined magnetic resonance-based structural imaging and diffusion tensor imaging (DTI). Structural magnetic resonance imaging was applied to assess overall gray matter (GM) and white matter (WM) volumes, and regional alterations were assessed by voxel-based morphometry. DTI was used to investigate the white matter tract integrity. Compared with DD, significant increases were observed in ASD, primarily in global GM and WM volumes and in right superior temporal gyrus regional GM and WM volumes. Higher fractional anisotropy value was also observed in the corpus callosum, posterior cingulate cortex, and limbic lobes of ASD. The converging findings of structural and white matter abnormalities in ASD suggest that alterations in neural-anatomy of different brain regions may be involved in behavioral and cognitive deficits associated with ASD, especially in an early age of 2–3 years old toddlers.
PMCID: PMC4057630  PMID: 24419870
Autism spectrum disorder; Toddler; Magnetic resonance imaging; Voxel based morphometry; Diffusion tensor imaging
3.  Linked alterations in gray and white matter morphology in adults with high-functioning autism spectrum disorder: A multimodal brain imaging study 
NeuroImage : Clinical  2014;7:155-169.
Growing evidence suggests that a broad range of behavioral anomalies in people with autism spectrum disorder (ASD) can be linked with morphological and functional alterations in the brain. However, the neuroanatomical underpinnings of ASD have been investigated using either structural magnetic resonance imaging (MRI) or diffusion tensor imaging (DTI), and the relationships between abnormalities revealed by these two modalities remain unclear. This study applied a multimodal data-fusion method, known as linked independent component analysis (ICA), to a set of structural MRI and DTI data acquired from 46 adult males with ASD and 46 matched controls in order to elucidate associations between different aspects of atypical neuroanatomy of ASD. Linked ICA identified two composite components that showed significant between-group differences, one of which was significantly correlated with age. In the other component, participants with ASD showed decreased gray matter (GM) volumes in multiple regions, including the bilateral fusiform gyri, bilateral orbitofrontal cortices, and bilateral pre- and post-central gyri. These GM changes were linked with a pattern of decreased fractional anisotropy (FA) in several white matter tracts, such as the bilateral inferior longitudinal fasciculi, bilateral inferior fronto-occipital fasciculi, and bilateral corticospinal tracts. Furthermore, unimodal analysis for DTI data revealed significant reductions of FA along with increased mean diffusivity in those tracts for ASD, providing further evidence of disrupted anatomical connectivity. Taken together, our findings suggest that, in ASD, alterations in different aspects of brain morphology may co-occur in specific brain networks, providing a comprehensive view for understanding the neuroanatomy of this disorder.
•Structural alterations of gray (GM) and white matter (WM) in ASD were investigated.•Linked independent component analysis was used for multimodal data analysis.•Alterations of GM and WM in ASD co-occurred in cognitive and affective networks.•Results reveal an integrative view of multiple aspects of structural changes in ASD.
PMCID: PMC4299973  PMID: 25610777
Autism spectrum disorder; Multimodal brain imaging; Linked independent component analysis; Voxel-based morphometry; Tract-based spatial statistics
4.  Brain function and gaze-fixation during facial emotion processing in fragile-X and autism 
This research focuses on the relationship between fragile X syndrome (FXS) and autism spectrum disorders (ASD). Both of these populations have a tendency to avoid looking others in the eye, along with difficulties in communication with others and tend to be socially withdrawn. While it is clear that FXS and ASD share some common abnormal behaviors, the underlying brain mechanisms associated with the social and emotional deficits in these groups remain unclear. We showed pictures of emotional and non-emotional human faces to these groups while in a magnetic resonance scanner (MRI). We collected images of brain function along with measures of where on the faces the individuals were looking (e.g. eyes or mouth). The FXS group showed a similar yet less abnormal pattern of where they were looking on the face compared to the ASD group. The FXS group also showed a similar pattern of decreased brain function in the area of the brain typically used when looking at faces, the fusiform gyrus (FG). The amount of activation in the FG was associated with how much time the FXS and ASD individuals looked at the eyes, the more they looked at the eyes, the greater the FG activation. The FXS group also displayed more brain activation than both the ASD group and a group of typically developing control subjects in brain areas that might suggest increased task difficulty for the FXS group. These group differences in brain activation are important as they suggest there is some overlap in areas of brain function in FXS and ASD when looking at faces, but that these two groups also have unique activation in other brain areas. These findings largely support the idea that ASD characteristics in FXS are associated with partially different patterns of brain activation when looking at human faces compared to individuals with ASD.
Fragile X syndrome (FXS) is the most commonly known genetic disorder associated with autism spectrum disorder (ASD). Overlapping features in these populations include gaze aversion, communication deficits, and social withdrawal. Although the association between FXS and ASD has been well documented at the behavioral level, the underlying neural mechanisms associated with the social/emotional deficits in these groups remain unclear.
We collected functional brain images and eye-gaze fixations from 9 individuals with FXS and 14 individuals with idiopathic ASD, as well as 15 typically developing (TD) individuals, while they performed a facial-emotion discrimination task.
The FXS group showed a similar yet less aberrant pattern of gaze-fixations compared to the ASD group. The FXS group also showed fusiform gyrus (FG) hypoactivation compared to the TD control group. Activation in FG was strongly and positively associated with average eye fixation and negatively associated with ASD characteristics in the FXS group. The FXS group displayed significantly greater activation than both the TD control and ASD groups in the left hippocampus (HIPP), left superior temporal gyrus (STG), right insula (INS), and left post-central gyrus (PCG).
These group differences in brain activation are important as they suggest unique underlying face-processing neural circuitry in FXS versus idiopathic ASD, largely supporting the hypothesis that ASD characteristics in FXS and idiopathic ASD reflect partially divergent impairments at the neural level, at least in FXS individuals without a co-morbid diagnosis of ASD.
PMCID: PMC2679695  PMID: 19360673
fragile X syndrome; autism; face processing; brain function; fMRI
5.  Structural and functional magnetic resonance imaging of autism spectrum disorders 
Brain research  2010;1380:146-161.
The neurobiology of autism spectrum disorders (ASDs) has become increasingly understood since the advent of magnetic resonance imaging (MRI). Initial observations of an above-average head circumference were supported by structural MRI studies that found evidence of increased total brain volume and early rapid brain overgrowth in affected individuals. Subsequent research revealed consistent abnormalities in cortical gray and white matter volume in ASDs. The structural integrity and orientation of white matter have been further elucidated via diffusion tensor imaging methods. The emergence of functional MRI techniques led to an enhanced understanding of the neural circuitry of ASDs, demonstrating areas of dysfunctional cortical activation and atypical cortical specialization. These studies have provided evidence of underconnectivity in distributed cortical networks integral to the core impairments associated with ASDs. Abnormalities in the default-mode network during the resting state have also been identified. Overall, structural and functional MRI research has generated important insights into the neurobiology of ASDs. Additional research is needed to further delineate the underlying brain basis of this constellation of disorders.
PMCID: PMC3465665  PMID: 21130750
Autism; Autism spectrum disorder; Magnetic resonance imaging; Neurobiology; Review
6.  Abnormal functional connectivity during visuospatial processing is associated with disrupted organisation of white matter in autism 
Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD) but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were (1) to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM) in ASD and (2) to examine the relationships between aberrant neural connectivity and behavior in ASD. Twenty-two individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD) based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19) and five paired regions: left caudate head, left caudate body, left uncus, left thalamus, and left cuneus. Measures of WM microstructural organization were extracted from these tracts. Fractional anisotropy (FA) reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant WM microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute (1) to abnormal functional connectivity and (2) to atypical visuospatial processing in ASD.
PMCID: PMC3783945  PMID: 24133425
neuroimaging; autism spectrum disorders; functional connectivity; diffusion tractography; constrained spherical deconvolution; visuospatial processing; structural connectivity; mental rotation
7.  White matter correlates of sensory processing in autism spectrum disorders 
NeuroImage : Clinical  2014;6:379-387.
Autism spectrum disorder (ASD) has been characterized by atypical socio-communicative behavior, sensorimotor impairment and abnormal neurodevelopmental trajectories. DTI has been used to determine the presence and nature of abnormality in white matter integrity that may contribute to the behavioral phenomena that characterize ASD. Although atypical patterns of sensory responding in ASD are well documented in the behavioral literature, much less is known about the neural networks associated with aberrant sensory processing. To address the roles of basic sensory, sensory association and early attentional processes in sensory responsiveness in ASD, our investigation focused on five white matter fiber tracts known to be involved in these various stages of sensory processing: superior corona radiata, centrum semiovale, inferior longitudinal fasciculus, posterior limb of the internal capsule, and splenium. We acquired high angular resolution diffusion images from 32 children with ASD and 26 typically developing children between the ages of 5 and 8. We also administered sensory assessments to examine brain-behavior relationships between white matter integrity and sensory variables. Our findings suggest a modulatory role of the inferior longitudinal fasciculus and splenium in atypical sensorimotor and early attention processes in ASD. Increased tactile defensiveness was found to be related to reduced fractional anisotropy in the inferior longitudinal fasciculus, which may reflect an aberrant connection between limbic structures in the temporal lobe and the inferior parietal cortex. Our findings also corroborate the modulatory role of the splenium in attentional orienting, but suggest the possibility of a more diffuse or separable network for social orienting in ASD. Future investigation should consider the use of whole brain analyses for a more robust assessment of white matter microstructure.
•First study of ASD to link observed sensory behaviors to white matter integrity•Findings suggest that aberrant limbic connectivity is related to tactile defensiveness.•Findings corroborate modulatory role of splenium in orienting.•Findings suggest a more diffuse or separable network for social orienting in ASD.
PMCID: PMC4218938  PMID: 25379451
8.  Constraining Heterogeneity: The Social Brain and its Development in Autism Spectrum Disorder 
The expression of autism spectrum disorder (ASD) is highly heterogeneous, owing to the complex interactions between genes, the brain, and behavior throughout development. Here we present a model of ASD that implicates an early and initial failure to develop the specialized functions of one or more of the set of neuroanatomical structures involved in social information processing (i.e., the “social brain”). From this early and primary disruption, abnormal brain development is canalized because the individual with an ASD must develop in a highly social world without the specialized neural systems that would ordinarily allow him or her to partake in the fabric of social life, which is woven from the thread of opportunities for social reciprocity and the tools of social engagement. This brain canalization gives rise to other characteristic behavioral deficits in ASD including deficits in communication, restricted interests, and repetitive behaviors. We propose that focused efforts to explore the brain mechanisms underlying the core, pathognomic deficits in the development of mechanisms for social engagement in ASD will greatly elucidate our understanding and treatment of this complex, devastating family of neurodevelopmental disorders. In particular, developmental studies (i.e., longitudinal studies of young children with and without ASD, as well as infants at increased risk for being identified with ASD) of the neural circuitry supporting key aspects of social information processing are likely to provide important insights into the underlying components of the full-syndrome of ASD. These studies could also contribute to the identification of developmental brain endophenotypes to facilitate genetic studies. The potential for this kind of approach is illustrated via examples of functional neuroimaging research from our own laboratory implicating the posterior superior temporal sulcus (STS) as a key player in the set of neural structures giving rise to ASD.
PMCID: PMC3096715  PMID: 21244421
9.  Differences in global and local level information processing in autism: an fMRI investigation 
Psychiatry research  2013;213(2):115-121.
People with autism spectrum disorders (ASD) have atypical visual perception of global and local information. Previous neuroimaging studies have examined the functional anatomy of locally-directed attention during visual processing in ASD, but few have examined differences in both globally-and locally-directed attention. We performed functional magnetic resonance imaging (fMRI) in 17 adults with ASD and 16 typically developing (TD) subjects to examine the neurobiology of both global- and local- level information processing in ASD using an abstract hierarchical design task. TD subjects showed no regions of increased brain activation relative to subjects with ASD using whole brain analysis. Subjects with ASD exhibited greater activation in right superior frontal gyrus during locally directed attention. During globally directed attention, the ASD group showed greater right lateral occipital activation. Additionally, subjects with ASD showed less deactivation in medial prefrontal cortex (part of the default mode network) in the globally directed attention condition. Our findings help elucidate networks of brain activation related to atyipcal global and local feature processing in ASD.
PMCID: PMC4012718  PMID: 23768913
(from Index Medicus): Autistic disorder; Magnetic resonance imaging; Child developmental disorders; pervasive; Asperger syndrome; Attention
10.  Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder 
Autism spectrum disorder (ASD) is very heterogeneous and multiple subtypes and etiologies likely exist. The maternal immune system has been implicated in the pathogenesis of some forms of ASD. Previous studies have identified the presence of specific maternal IgG autoantibodies with reactivity to fetal brain proteins at 37 and 73KDa in up to 12% of mothers of children with ASD. The current study evaluates the presence of these autoantibodies in an independent cohort of mothers of 181 preschool-aged male children (131 ASD, 50 typically developing [TD] controls). We also investigated whether ASD children born to mothers with these autism-specific maternal IgG autoantibodies exhibit a distinct neural phenotype by evaluating total brain volume using structural magnetic resonance imaging (MRI). Of the 131 ASD children, 10 (7.6%) were born to mothers with the 37/73Kda IgG autoantibodies (ASD-IgG). The mothers of the remaining ASD children and all TD controls were negative for these paired autoantibodies. While both ASD groups exhibited abnormal brain enlargement that is commonly observed in this age range, the ASD-IgG group exhibited a more extreme 12.1% abnormal brain enlargement relative to the TD controls. In contrast, the remaining ASD children exhibited a smaller 4.4% abnormal brain enlargement relative to TD controls. Lobar and tissue type analyses revealed that the frontal lobe is selectively enlarged in the ASD-IgG group and that both gray and white matter are similarly affected. These results suggest that maternal autoantibodies associated with autism spectrum disorder may impact brain development leading to abnormal enlargement.
PMCID: PMC3641177  PMID: 23395715
Autism spectrum disorder; MRI; structural neuroimaging; maternal antibody; autoantibody
11.  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.
PMCID: PMC3129780  PMID: 21743819
Social Exclusion; Rule Violation; Autism Spectrum Disorder; Right Insula; Functional Magnetic Resonance Imaging
12.  Allelic Variation within the Putative Autism Spectrum Disorder Risk Gene Homeobox-A-1 (HOXA1) and Cerebellar Maturation in Typically Developing Children and Adolescents 
Autism Research  2012;5(2):93-100.
Autism is known to be highly heritable, and has been associated with abnormalities in the development of several brain structures, including the cerebellum. Previous research has hinted that a gene controlling the development of posterior brain regions such as the cerebellum, may influence risk for autism. This gene is called Homeobox Domain A1 (HOXA1), and the variant within HOXA1 that has been most studied in relation to autism (A218G) falls within a gene region that is important for HOXA1 protein functioning. Although we know that autism appear to influence the dynamics of brain development, and that cerebellar anatomy continues to change over the lifespan – we do not know if A218G genotype influences cerebellar development over time. We studied this issue in typically developing controls who had a total of 296 repeat structural brain scans taken between ages 5 and 23 years of age. The volume of multiple cerebellar components was measures by hand in each scan, and we related developmental changes in these volumes to A218G genotype. We found that, in a part of the cerebellum implicated in autism, A218G genotype modified the rate of cerebellar growth. This suggests for the first time that the putative ASD risk gene HOXA1 has the capacity to modify the longitudinal development of cerebellar systems implicated in ASD neurobiology.
Homeobox-A-1 (HOXA1) has been proposed as a candidate gene for autism spectrum disorder (ASD) as it regulates embryological patterning of hind-brain structures implicated in autism neurobiology. In line with this notion, a non-synonymous single nucleotide polymorphism within a highly conserved domain of HOXA1 - A218G (rs10951154) - has been linked to both ASD risk, and cross-sectional differences in superior posterior lobar cerebellar anatomy in late adulthood. Despite evidence for early onset and developmentally dynamic cerebellar involvement in ASD, little is known of the relationship between A218G genotype and maturation of the cerebellum over early development. We addressed this issue using 296 longitudinally acquired structural magnetic resonance imaging brain scans from 116 healthy individuals between 5 and 23 years of age. Mixed models were used to compare the relationship between age and semi-automated measures of cerebellar volume in A-homozygotes (AA) and carriers of the G allele (Gcar). Total cerebellar volume increased between ages 5 and 23 years in both groups. However, this was accelerated in the Gcar relative to the AA group (Genotype-by-age interaction term, p=0.03), and driven by genotype-dependent differences in the rate of bilateral superior posterior lobar volume change with age (p=0.002). Resultantly, although superior posterior lobar volume did not differ significantly between genotype groups at age 5 (p=0.9), by age 23 it was 12% greater in Gcar than AA (p=0.002). Our results suggest that common genetic variation within this putative ASD risk gene has the capacity to modify the development of cerebellar systems implicated in ASD neurobiology.
PMCID: PMC3329569  PMID: 22359339
Autism; HOXA1; Cerebellum; Gene; Brain; MRI
13.  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) ( 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.
PMCID: PMC4162310  PMID: 23774715
Resting state fMRI; Intrinsic functional connectivity; Data sharing; Large-scale networks; Default network; Interhemispheric connectivity; Thalamus
14.  Increased Rate of Amygdala Growth in Children Aged 2 to 4 Years With Autism Spectrum Disorders 
Archives of general psychiatry  2012;69(1):53-61.
Precocious amygdala enlargement is commonly observed in young children with autism. However, the age at which abnormal amygdala enlargement begins and the relative growth trajectories of the amygdala and total brain remain unclear.
To determine whether the rate of amygdala growth is abnormal and disproportionate to total brain growth in very young children with autism spectrum disorders (ASDs).
Longitudinal structural magnetic resonance imaging study.
Neuroimaging and diagnostic assessments were performed at an academic medical center. Participants were recruited from the community.
Baseline scans were acquired in 132 boys (85 with ASD and 47 control subjects with typical development [TD]; mean age, 37 months). Longitudinal magnetic resonance images were acquired in 70 participants (45 with ASD and 25 TD controls) 1 year later.
Main Outcome Measure
Amygdala volumes and total cerebral volumes (TCVs) were evaluated at both time points, and 1-year growth rates were calculated.
The amygdala was larger in children with ASD at both time points, but the magnitude of enlargement was greater at time 2. The TCV was also enlarged in the children with ASD by the same magnitude at both time points. When we controlled for TCV, amygdala enlargement remained significant at both time points. The rate of amygdala growth during this 1-year interval was faster in children with ASD than in TD controls. The rate of TCV growth did not differ between groups. Post hoc exploratory analyses revealed 3 patterns of amygdala and TCV growth rates in the ASD group.
Disproportionate amygdala enlargement is present by 37 months of age in ASD. The amygdala continues to grow at an increased rate, but substantial heterogeneity exists in amygdala and TCV growth patterns. Future studies aimed at clinical characterization of different growth patterns could have implications for choice and outcomes of treatment and behavioral therapy.
PMCID: PMC3632313  PMID: 22213789
15.  Neural circuitry of emotional face processing in autism spectrum disorders 
Autism spectrum disorders (ASD) are associated with severe impairments in social functioning. Because faces provide nonverbal cues that support social interactions, many studies of ASD have examined neural structures that process faces, including the amygdala, ventromedial prefrontal cortex and superior and middle temporal gyri. However, increases or decreases in activation are often contingent on the cognitive task. Specifically, the cognitive domain of attention influences group differences in brain activation. We investigated brain function abnormalities in participants with ASD using a task that monitored attention bias to emotional faces.
Twenty-four participants (12 with ASD, 12 controls) completed a functional magnetic resonance imaging study while performing an attention cuing task with emotional (happy, sad, angry) and neutral faces.
In response to emotional faces, those in the ASD group showed greater right amygdala activation than those in the control group. A preliminary psychophysiological connectivity analysis showed that ASD participants had stronger positive right amygdala and ventromedial prefrontal cortex coupling and weaker positive right amygdala and temporal lobe coupling than controls. There were no group differences in the behavioural measure of attention bias to the emotional faces.
The small sample size may have affected our ability to detect additional group differences.
When attention bias to emotional faces was equivalent between ASD and control groups, ASD was associated with greater amygdala activation. Preliminary analyses showed that ASD participants had stronger connectivity between the amygdala ventromedial prefrontal cortex (a network implicated in emotional modulation) and weaker connectivity between the amygdala and temporal lobe (a pathway involved in the identification of facial expressions, although areas of group differences were generally in a more anterior region of the temporal lobe than what is typically reported for emotional face processing). These alterations in connectivity are consistent with emotion and face processing disturbances in ASD.
PMCID: PMC2834792  PMID: 20184808
16.  Precentral gyrus functional connectivity signatures of autism 
Motor impairments are prevalent in children with autism spectrum disorders (ASD) and are perhaps the earliest symptoms to develop. In addition, motor skills relate to the communicative/social deficits at the core of ASD diagnosis, and these behavioral deficits may reflect abnormal connectivity within brain networks underlying motor control and learning. Despite the fact that motor abnormalities in ASD are well-characterized, there remains a fundamental disconnect between the complexity of the clinical presentation of ASD and the underlying neurobiological mechanisms. In this study, we examined connectivity within and between functional subregions of a key component of the motor control network, the precentral gyrus, using resting state functional Magnetic Resonance Imaging data collected from a large, heterogeneous sample of individuals with ASD as well as neurotypical controls. We found that the strength of connectivity within and between distinct functional subregions of the precentral gyrus was related to ASD diagnosis and to the severity of ASD traits. In particular, connectivity involving the dorsomedial (lower limb/trunk) subregion was abnormal in ASD individuals as predicted by models using a dichotomous variable coding for the presence of ASD, as well as models using symptom severity ratings. These findings provide further support for a link between motor and social/communicative abilities in ASD.
PMCID: PMC4030180  PMID: 24860442
autism; functional connectivity; motor cortex; multi-center studies; logistic regression; resting state fMRI
17.  Heterogeneity within Autism Spectrum Disorders: What have We Learned from Neuroimaging Studies? 
Autism spectrum disorders (ASD) display significant heterogeneity. Although most neuroimaging studies in ASD have been designed to identify commonalities among affected individuals, rather than differences, some studies have explored variation within ASD. There have been two general types of approaches used for this in the neuroimaging literature to date: comparison of subgroups within ASD, and analyses using dimensional measures to link clinical variation to brain differences. This review focuses on structural and functional magnetic resonance imaging studies that have used these approaches to begin to explore heterogeneity between individuals with ASD. Although this type of data is yet sparse, recognition is growing of the limitations of behaviorally defined categorical diagnoses for understanding neurobiology. Study designs that are more informative regarding the sources of heterogeneity in ASD have the potential to improve our understanding of the neurobiological processes underlying ASD.
PMCID: PMC3812662  PMID: 24198778
autism; psychiatry and developmental disabilities; intellectual disability; functional magnetic resonance imaging; structural magnetic resonance imaging
18.  ANS: Aberrant Neurodevelopment of the Social Cognition Network in Adolescents with Autism Spectrum Disorders 
PLoS ONE  2011;6(4):e18905.
Autism spectrum disorders (ASD) are characterized by aberrant neurodevelopment. Although the ASD brain undergoes precocious growth followed by decelerated maturation during early postnatal period of childhood, the neuroimaging approach has not been empirically applied to investigate how the ASD brain develops during adolescence.
Methodology/Principal Findings
We enrolled 25 male adolescents with high functioning ASD and 25 typically developing controls for voxel-based morphometric analysis of structural magnetic resonance image. Results indicate that there is an imbalance of regional gray matter volumes and concentrations along with no global brain enlargement in adolescents with high functioning ASD relative to controls. Notably, the right inferior parietal lobule, a role in social cognition, have a significant interaction of age by groups as indicated by absence of an age-related gain of regional gray matter volume and concentration for neurodevelopmental maturation during adolescence.
The findings indicate the neural correlates of social cognition exhibits aberrant neurodevelopment during adolescence in ASD, which may cast some light on the brain growth dysregulation hypothesis. The period of abnormal brain growth during adolescence may be characteristic of ASD. Age effects must be taken into account while measures of structural neuroimaging have been clinically put forward as potential phenotypes for ASD.
PMCID: PMC3082537  PMID: 21541322
19.  A functional polymorphism of the brain derived neurotrophic factor gene and cortical anatomy in autism spectrum disorder 
Autism Spectrum Disorder (ASD) is associated with both (i) post-mortem and neuroimaging evidence of abnormal cortical development, and (ii) altered signalling in Brain Derived Neurotrophic Factor (BDNF) pathways - which regulate neuroproliferative and neuroplastic processes. In healthy controls genotype at a single nucleotide polymorphism that alters BDNF signalling (Val66met) has been related to regional cortical volume. It is not known however if this influence on brain development is intact in ASD. Therefore we compared the relationship between genotype and cortical anatomy (as measured using in vivo Magnetic Resonance Imaging) in 41 people with ASD and 30 healthy controls. We measured cortical volume, and its two sole determinants - cortical thickness and surface area - which reflect differing neurodevelopmental processes. We found “Group-by-Genotype” interactions for cortical volume in medial (caudal anterior cingulate, posterior cingulate) and lateral (rostral middle, lateral orbitofrontal, pars orbitalis and pars triangularis) frontal cortices. Furthermore, within (only) these regions “Group-by-Genotype” interactions were also found for surface area. No effects were found for cortical thickness in any region. Our preliminary findings suggest that people with ASD have differences from controls in the relationship between BDNF val66met genotype and regional (especially frontal) cortical volume and surface area, but not cortical thickness. Therefore alterations in the relationship between BDNF val66met genotype and surface area in ASD may drive the findings for volume. If correct, this suggests ASD is associated with a distorted relationship between BDNF val66met genotype and the determinants of regional cortical surface area – gyrification and/or sulcal positioning.
PMCID: PMC3196317  PMID: 21547716
Autism; Brain; Brain derived neurotrophic factor; MRI
20.  Abnormalities in fronto-striatal connectivity within language networks relate to differences in grey-matter heterogeneity in Asperger syndrome☆ 
NeuroImage : Clinical  2013;2:716-726.
Asperger syndrome (AS) is an Autism Spectrum Disorder (ASD) characterised by qualitative impairment in the development of emotional and social skills with relative preservation of general intellectual abilities, including verbal language. People with AS may nevertheless show atypical language, including rate and frequency of speech production. We previously observed that abnormalities in grey matter homogeneity (measured with texture analysis of structural MR images) in AS individuals when compared with controls are also correlated with the volume of caudate nucleus. Here, we tested a prediction that these distributed abnormalities in grey matter compromise the functional integrity of brain networks supporting verbal communication skills. We therefore measured the functional connectivity between caudate nucleus and cortex during a functional neuroimaging study of language generation (verbal fluency), applying psycho-physiological interaction (PPI) methods to test specifically for differences attributable to grey matter heterogeneity in AS participants. Furthermore, we used dynamic causal modelling (DCM) to characterise the causal directionality of these differences in interregional connectivity during word production. Our results revealed a diagnosis-dependent influence of grey matter heterogeneity on the functional connectivity of the caudate nuclei with right insula/inferior frontal gyrus and anterior cingulate, respectively with the left superior frontal gyrus and right precuneus. Moreover, causal modelling of interactions between inferior frontal gyri, caudate and precuneus, revealed a reliance on bottom-up (stimulus-driven) connections in AS participants that contrasted with a dominance of top-down (cognitive control) connections from prefrontal cortex observed in control participants. These results provide detailed support for previously hypothesised central disconnectivity in ASD and specify discrete brain network targets for diagnosis and therapy in ASD.
•We used MRI techniques to assess the connectivity in language networks in AS.•Grey-matter heterogeneity of MR images correlated with volume of caudate in AS.•Hence, caudate nuclei were used as seed ROIs in connectivity analyses: PPI, DCM.•Grey-matter heterogeneity differently tuned caudate connectivity in AS, controls.•DCM of language circuitry featured bottom-up models in AS and top-down in controls.
PMCID: PMC3777793  PMID: 24179823
Autism Spectrum Disorder (ASD); Texture analysis (TA); Psycho-physiological interaction (PPI); Dynamic causal modelling (DCM); Caudate
21.  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.
•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.
PMCID: PMC3830058  PMID: 24273731
Asperger syndrome; fMRI; Intersubject correlation; Movie; Social brain
22.  fMRI investigation of visual change detection in adults with autism☆ 
NeuroImage : Clinical  2013;2:303-312.
People with autism spectrum disorders (ASD) may show unusual reactions to unexpected changes that appear in their environment. Although several studies have highlighted atypical auditory change processing in ASD, little is known in this disorder about the brain processes involved in visual automatic change detection. The present fMRI study was designed to localize brain activity elicited by unexpected visual changing stimuli in adults with ASD compared to controls. Twelve patients with ASD and 17 healthy adults participated in the experiment in which subjects were presented with a visual oddball sequence while performing a concurrent target detection task. Combined results across participants highlight the involvement of both occipital (BA 18/19) and frontal (BA 6/8) regions during visual change detection. However, adults with ASD display greater activity in the bilateral occipital cortex and in the anterior cingulate cortex (ACC) associated with smaller activation in the superior and middle frontal gyri than controls. A psychophysiological interaction (PPI) analysis was performed with ACC as the seed region and revealed greater functionally connectivity to sensory regions in ASD than in controls, but less connectivity to prefrontal and orbito-frontal cortices. Thus, compared to controls, larger sensory activation associated with reduced frontal activation was seen in ASD during automatic visual change detection. Atypical psychophysiological interactions between frontal and occipital regions were also found, congruent with the idea of atypical connectivity between these regions in ASD. The atypical involvement of the ACC in visual change detection can be related to abnormalities previously observed in the auditory modality, thus supporting the hypothesis of an altered general mechanism of change detection in patients with ASD that would underlie their unusual reaction to change.
► Brain processes involved in visual change detection in ASD remain unknown. ► This fMRI study was designed to localize brain activity elicited by visual changes. ► Larger activity in modality-specific sensory cortex and ACC in ASD ► Atypical functional connectivity between ACC and visual cortex in ASD ► Findings suggest an abnormal “amodal” change detection process in ASD.
PMCID: PMC3777707  PMID: 24179785
Autism spectrum disorders; Visual change detection; fMRI; Functional connectivity; Anterior cingulate cortex
23.  High Resolution Magnetic Resonance Imaging for Characterization of the Neuroligin-3 Knock-in Mouse Model Associated with Autism Spectrum Disorder 
PLoS ONE  2014;9(10):e109872.
Autism spectrum disorders (ASD) comprise an etiologically heterogeneous set of neurodevelopmental disorders. Neuroligin-3 (NL-3) is a cell adhesion protein that mediates synapse development and has been implicated in ASD. We performed ex-vivo high resolution magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) and behavioral (social approach and zero maze) tests at 3 different time points (30, 50 and 70 days-of-age) on NL-3 and wild-type littermates to assess developmental brain abnormalities in NL-3 mice. MRI data were segmented in 39 different gray and white matter regions. Volumetric measurements, along with DTI indices from these segmented regions were also performed. After controlling for age and gender, the NL-3 knock-in animals demonstrated significantly reduced sociability and lower anxiety-related behavior in comparison to their wild type littermates. Significantly reduced volume of several white and gray matter regions in the NL-3 knock-in mice were also observed after considering age, gender and time point as covariates. These findings suggest that structural changes in the brain of NL-3 mice are induced by the mutation in the NL-3 gene. No significant differences in DTI indices were observed, which suggests that the NL-3 mutation may not have a profound effect on water diffusion as detected by DTI. The volumetric and DTI studies aid in understanding the biology of disrupting function on an ASD risk model and may assist in the development of imaging biomarkers for ASD.
PMCID: PMC4192590  PMID: 25299583
24.  Functional Connectivity of the Inferior Frontal Cortex Changes with Age in Children with Autism Spectrum Disorders: A fcMRI Study of Response Inhibition 
Cerebral Cortex (New York, NY)  2008;19(8):1787-1794.
Unmasking the neural basis of neurodevelopmental disorders, such as autism spectrum disorders (ASD), requires studying functional connectivity during childhood when cognitive skills develop. A functional connectivity magnetic resonance imaging (fcMRI) analysis was performed on data collected during Go/NoGo task performance from 24 children ages 8–12 years (12 with ASD; 12 controls matched on age and intellectual functioning). We investigated the connectivity of the left and right inferior frontal cortex (IFC; BA 47), key regions for response inhibition, with other active regions in frontal, striatal, and parietal cortex. Groups did not differ on behavioral measures or functional connectivity of either IFC region. A trend for reduced connectivity in the right IFC for the ASD group was revealed when controlling for age. In the ASD group, there was a significant negative correlation between age and 2 right IFC correlation pairs: right IFC–bilateral presupplementary motor area (BA 6) and right IFC–right caudate. Compared with typical controls, children with ASD may not have gross differences in IFC functional connectivity during response inhibition, which contrasts with an adult study of ASD that reported reduced functional connectivity. This discrepancy suggests an atypical developmental trajectory in ASD for right IFC connectivity with other neural regions supporting response inhibition.
PMCID: PMC2722789  PMID: 19068486
autism; children; cognition; functional connectivity; response inhibition
25.  The role of immune dysfunction in the pathophysiology of autism 
Brain, behavior, and immunity  2011;26(3):383-392.
Autism spectrum disorders (ASD) are a complex group of neurodevelopmental disorders encompassing impairments in communication, social interactions and restricted stereotypical behaviors. Although a link between altered immune responses and ASD was first recognized nearly 40 years ago, only recently has new evidence started to shed light on the complex multifaceted relationship between immune dysfunction and behavior in ASD. Neurobiological research in ASD has highlighted pathways involved in neural development, synapse plasticity, structural brain abnormalities, cognition and behavior. At the same time, several lines of evidence point to altered immune dysfunction in ASD that directly impacts some or all these neurological processes. Extensive alterations in immune function have now been described in both children and adults with ASD, including ongoing inflammation in brain specimens, elevated pro-inflammatory cytokine profiles in the CSF and blood, increased presence of brain-specific auto-antibodies and altered immune cell function. Furthermore, these dysfunctional immune responses are associated with increased impairments in behaviors characteristic of core features of ASD, in particular, deficits in social interactions and communication. This accumulating evidence suggests that immune processes play a key role in the pathophysiology of ASD. This review will discuss the current state of our knowledge of immune dysfunction in ASD, how these findings may impact on underlying neuro-immune mechanisms and implicate potential areas where the manipulation of the immune response could have an impact on behavior and immunity in ASD.
PMCID: PMC3418145  PMID: 21906670

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