Objective

Brain enlargement has been observed in 2 year old children with autism but the underlying mechanisms are unknown. This longitudinal MRI study investigated early growth trajectories in brain volume and cortical thickness.

Method

Cerebral gray and white matter volumes and cortical thickness in children with autism spectrum disorder and controls were examined. Subjects were seen at approximately 2 years of age (autism = 59, controls = 38) and were rescanned approximately 24 months later at age 4–5 years (autism = 38, controls = 21).

Results

We observed generalized cerebral cortical enlargement in individuals with ASD at both 2 and 4 – 5 years of age. Rate of cerebral cortical growth across multiple brain regions and tissue compartments, in individuals with ASD, was parallel to that seen in controls, indicating that there was no increase in rate of cerebral cortical growth during this interval. No cerebellar differences were observed in ASD. After controlling for TBV, a disproportionate enlargement in temporal lobe white matter was observed in the ASD group. We found no differences in cortical thickness, but an increase in an estimate of surface area in the ASD group compared to controls for all cortical regions measured (temporal, frontal, and parietal-occipital).

Conclusions

Our longitudinal MRI study found generalized cerebral cortical enlargement in children with ASD, with a disproportionate enlargement in temporal lobe white matter. There was no difference from controls in the rate of brain growth for this age interval, indicating brain enlargement in ASD results from an increased rate of brain growth prior to age 2. The presence of increased cortical volume, but not cortical thickness, suggests that early brain enlargement may be associated with increased cortical surface area. Cortical surface area overgrowth in ASD may underlie brain enlargement and implicates a distinct set of pathogenic mechanisms.

Context

Cerebral cortical volume enlargement has been reported in 2- to 4-year-olds with autism. Little is known about the volume of sub-regions during this period of development. The amygdala is hypothesized to be abnormal in volume and related to core clinical features in autism.

Objective

To examine amygdala volume at 2 years with follow-up at 4 years of age in children with autism and to explore the relationship between amygdala volume and selected behavioral features of autism.

Design

Longitudinal magnetic resonance imaging study.

Setting

University medical setting.

Participants

Fifty-two autistic and 33 control (11 developmentally delayed, 22 typically developing) children between 18 and 35 months (2 years) of age followed up at 42 to 59 months (4 years) of age.

Main Outcome Measures

Amygdala volumes in relation to joint attention ability measured with a new observational coding system, the Social Orienting Continuum and Response scale; group comparisons including total tissue volume, sex, IQ and age as covariates.

Results

Amygdala enlargement was observed in subjects with autism at both 2 and 4 years of age. Significant change over time in volume was observed, though the rate of change did not differ between groups. Amygdala volume was associated with joint attention ability at age 4 years in subjects with autism.

Conclusions

The amygdala is enlarged in autism relative to controls by age 2 years but shows no relative increase in magnitude between 2 and 4 years of age. A significant association between amygdala volume and joint attention suggests that alterations to this structure may be linked to a core deficit of autism.

One goal of statistical shape analysis is the discrimination between two populations of objects. Whereas traditional shape analysis was mostly concerned with studying single objects, analysis of multi-object complexes presents new challenges related to alignment and relative object pose. In this paper, we present a methodology for discriminant analysis of sets multiple shapes. Shapes are represented by sampled medial manifolds including normals to the boundary. Non-Euclidean metrics that describe geodesic distance between sets of sampled representations are used for shape alignment and discrimination. Our choice of discriminant method is the distance weighted discriminant (DWD) because of its generalization ability in high dimensional, low sample size settings. Using an unbiased, soft discrimination score we can associate a statistical hypothesis test with the discrimination results. Furthermore, localization and nature significant differences between populations can be visualized via the average best discriminating axis.

We explore the effectiveness of different choices of features as input to the discriminant analysis, using morphologic measures like volume, pose, shape and the combination of pose and shape. Our method is applied to a longitudinal pediatric autism study with object sets of 10 subcortical brain structures in a population of 70 samples. The results compare group discrimination by volume, pure shape or pose, and combinations thereof. It is shown that the choices of type of global alignment and of intrinsic versus extrinsic shape features, the latter being sensitive to relative pose, are crucial factors for group discrimination and also for explaining the nature of shape change in terms of the application domain.

This study investigated rapid automatized naming (RAN) ability in high functioning individuals with autism and parents of individuals with autism. Findings revealed parallel patterns of performance in parents and individuals with autism, where both groups had longer naming times than controls. Significant parent-child correlations were also detected, along with associations with language and personality features of the broad autism phenotype (retrospective reports of early language delay, socially reticent personality). Together, findings point towards RAN as a potential marker of genetic liability to autism.

Data sharing in autism neuroimaging presents scientific, technical, and social obstacles. We outline the desiderata for a data-sharing scheme that combines imaging with other measures of phenotype and with genetics, defines requirements for comparability of derived data and recommendations for raw data, outlines a core protocol including multispectral structural and diffusion-tensor imaging and optional extensions, provides for the collection of prospective, confound-free normative data, and extends sharing and collaborative development not only to data but to the analytical tools and methods applied to these data. A theme in these requirements is the need to preserve creative approaches and risk-taking within individual laboratories at the same time as common standards are provided for these laboratories to build on.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)—two genes encoding neuronal cell-adhesion molecules—revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 × 10−8, odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 × 10−8 to 2.1 × 10−10. Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Autism spectrum disorders (ASDs) are childhood neurodevelopmental disorders with complex genetic origins1–4. Previous studies focusing on candidate genes or genomic regions have identified several copy number variations (CNVs) that are associated with an increased risk of ASDs5–9. Here we present the results from a whole-genome CNV study on a cohort of 859 ASD cases and 1,409 healthy children of European ancestry who were genotyped with ~550,000 single nucleotide polymorphism markers, in an attempt to comprehensively identify CNVs conferring susceptibility to ASDs. Positive findings were evaluated in an independent cohort of 1,336 ASD cases and 1,110 controls of European ancestry. Besides previously reported ASD candidate genes, such as NRXN1 (ref. 10) and CNTN4 (refs 11, 12), several new susceptibility genes encoding neuronal cell-adhesion molecules, including NLGN1 and ASTN2, were enriched with CNVs in ASD cases compared to controls (P = 9.5 × 10−3). Furthermore, CNVs within or surrounding genes involved in the ubiquitin pathways, including UBE3A, PARK2, RFWD2 and FBXO40, were affected by CNVs not observed in controls (P = 3.3 × 10−3). We also identified duplications 55 kilobases upstream of complementary DNA AK123120 (P = 3.6 × 10−6). Although these variants may be individually rare, they target genes involved in neuronal cell-adhesion or ubiquitin degradation, indicating that these two important gene networks expressed within the central nervous system may contribute to the genetic susceptibility of ASD.

To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18–42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior.

This study investigated rapid automatized naming (RAN) ability in high functioning individuals with autism and parents of individuals with autism. Findings revealed parallel patterns of performance in parents and individuals with autism, where both groups had longer naming times than controls. Significant parent-child correlations were also detected, along with associations with language and personality features of the broad autism phenotype (retrospective reports of early language delay, socially reticent personality). Together, findings point towards RAN as a potential marker of genetic liability to autism.

Context

Brain maturation starts well before birth and occurs as a unified process with developmental interaction among different brain regions. Gene and environment play large roles in such process. Studies of genetic disorders such as fragile X syndrome (FXS) which is a disorder caused by a single gene mutation resulting in abnormal dendritic and synaptic pruning, together with healthy individuals may provide valuable information.

Objective

To examine morphometric spatial patterns that differentiate between FXS from controls in early childhood.

Design

A cross-sectional in-vivo neuroimaging study

Setting

Academic medical centers

Participants

A total of 101 children of ages 1 to 3; 51 boys with FXS, 32 typically developing (TD) boys and 18 boys with idiopathic developmental delay (DD)

Main Outcome Measures

Regional gray matter volume as measured by voxel-based morphometry and manual tracing, supplemented by permutation analyses. Regression analyses between gray and white matter volumes and IQ and fragile X mental retardation protein (FMRP). Linear support vector machine analyses to classify group membership.

Results

In addition to aberrant brain structures reported previously in older individuals with FXS, we found reduced gray matter volumes in regions such as the hypothalamus, insula and medial and lateral prefrontal cortices. These findings are consistent with the cognitive and behavioral phenotypes of FXS. Further, multivariate pattern classification analyses discriminated FXS from TD and DD controls with over 90 % prediction accuracy. The spatial patterns that classified FXS from controls included those that may have been difficult to identify previously using other methods. These included medial to lateral gradient of increased and decreased regional brain volumes in the posterior vermis, amygdala and hippocampus.

Conclusions

These findings are critical in understanding interplay among gene, environment, brain and behavior, and signify the importance of examining detailed spatial patterns of healthy and perturbed brain development.

Objective

To determine how neuroanatomic variation in children and adolescents with fragile X syndrome is linked to reduced levels of the fragile X mental retardation-1 protein and to aberrant cognition and behavior.

Methods

This study included 84 children and adolescents with the fragile X full mutation and 72 typically developing control subjects matched for age and sex. Brain morphology was assessed with volumetric, voxel-based, and surface-based modeling approaches. Intelligence quotient was evaluated with standard cognitive testing, whereas abnormal behaviors were measured with the Autism Behavior Checklist and the Aberrant Behavior Checklist.

Results

Significantly increased size of the caudate nucleus and decreased size of the posterior cerebellar vermis, amygdala, and superior temporal gyrus were present in the fragile X group. Subjects with fragile X also demonstrated an abnormal profile of cortical lobe volumes. A receiver operating characteristic analysis identified the combination of a large caudate with small posterior cerebellar vermis, amygdala, and superior temporal gyrus as distinguishing children with fragile X from control subjects with a high level of sensitivity and specificity. Large caudate and small posterior cerebellar vermis were associated with lower fragile X mental retardation protein levels and more pronounced cognitive deficits and aberrant behaviors.

Interpretation

Abnormal development of specific brain regions characterizes a neuroanatomic phenotype associated with fragile X syndrome and may mediate the effects of FMR1 gene mutations on the cognitive and behavioral features of the disorder. Fragile X syndrome provides a model for elucidating critical linkages among gene, brain, and cognition in children with serious neurodevelopmental disorders.

This paper describes a framework for quantitative analysis of neuroimaging data of traveling human phantoms used for cross-site validation. We focus on the analysis of magnetic resonance image data including intra- and inter-site comparison. Locations and magnitude of geometric deformation is studied via unbiased atlas building and metrics on deformation fields. Variability of tissue segmentation is analyzed by comparison of volumes, overlap of tissue maps, and a new Kullback-Leibler divergence on tissue probabilities, with emphasis on comparing probabilistic rather than binary segmentations. We show that results from this information theoretic measure are highly correlated with overlap. Reproducibility of automatic, atlas-based segmentation of subcortical structures is examined by comparison of volumes, shape overlap and surface distances. Variability among scanners of the same type but also differences to a different scanner type are discussed. The results demonstrate excellent reliability across multiple sites that can be achieved by the use of the today’s scanner generation and powerful automatic analysis software. Knowledge about such variability is crucial for study design and power analysis in new multi-site clinical studies.

This study examined the frequency of personality, language, and social-behavioral characteristics believed to comprise the broad autism phenotype (BAP), across families differing in genetic liability to autism. We hypothesized that within this unique sample comprised of multiple-incidence autism families (MIAF), single-incidence autism families (SIAF), and control Down syndrome families (DWNS), a graded expression would be observed for the principal characteristics conferring genetic susceptibility to autism, in which such features would express most profoundly among parents from MIAFs, less strongly among SIAFs, and least of all among comparison parents from DWNS families, who should display population base rates. Analyses detected linear expression of traits in line with hypotheses, and further suggested differential intrafamilial expression across family types. In the vast majority of MIAFs both parents displayed BAP characteristics, whereas within SIAFs, it was equally likely that one, both, or neither parent show BAP features. The significance of these findings is discussed in relation to etiologic mechanisms in autism and relevance to molecular genetic studies.

Schizophrenia and autism both feature significant impairments in social cognition and social functioning, but the specificity and mechanisms of these deficits remain unknown. Recent research suggests that social cognitive deficits in both disorders may arise from dysfunctions in the neural systems that underlie social cognition. We explored the neural activation of discrete brain regions implicated in social cognitive and face processing in schizophrenia subgroups and autism spectrum disorders during complex social judgments of faces. Twelve individuals with autism spectrum disorders (ASD), 12 paranoid individuals with schizophrenia (P-SCZ), 12 non-paranoid individuals with schizophrenia (NP-SCZ), and 12 non-clinical healthy controls participated in this cross sectional study. Neural activation, as indexed by blood oxygenation level dependent (BOLD) contrast, was measured in a priori regions of interest while individuals rated faces for trustworthiness. All groups showed significant activation of a social cognitive network including the amygdala, fusiform face area (FFA), superior temporal sulcus (STS), and ventrolateral prefrontal cortex (VLPFC) while completing a task of complex social cognition (i.e. trustworthiness judgments). ASD and P-SCZ individuals showed significantly reduced neural activation in the right amygdala, FFA, and left VLPFC as compared to controls and in the left VLPFC as compared to NP-SCZ individuals during this task. These findings lend support to models hypothesizing well-defined neural substrates of social cognition and suggest a specific neural mechanism that may underlie social cognitive impairments in both autism and paranoid schizophrenia.

AIM

Fragile X syndrome is associated with cognitive deficits in inhibitory control and with abnormal neuronal morphology and development.

METHOD

In this study, we used a diffusion tensor imaging (DTI) tractography approach to reconstruct white-matter fibers in the ventral frontostriatal pathway in young males with fragile X syndrome (n=17; mean age 2y 9mo, SD 7mo, range 1y 7mo–3y 10mo), and two age-matched comparison groups: (1) typically developing (n=13; mean age 2y 3mo, SD 7mo, range 1y 7mo–3y 6mo) and (2) developmentally delayed (n=8; mean age 3y, SD 4mo, range 2y 9mo–3y 8mo).

RESULTS

We observed that young males with fragile X syndrome exhibited increased density of DTI reconstructed fibers than those in the typically developing (p=0.001) and developmentally delayed (p=0.001) groups. Aberrant white-matter structure was localized in the left ventral frontostriatal pathway. Greater relative fiber density was found to be associated with lower IQ (Mullen composite scores) in the typically developing group (p=0.008).

INTERPRETATION

These data suggest that diminished or absent fragile X mental retardation 1 protein expression can selectively alter white-matter anatomy during early brain development and, in particular, neural pathways. The results also point to an early neurobiological marker for an important component of cognitive dysfunction associated with fragile X syndrome.

Summary

In his original description of autism, Kanner [1] noted that the parents of autistic children often exhibited unusual social behavior themselves, consistent with what we now know about the high heritability of autism [2]. We investigated this so-called “Broad Autism Phenotype” in the parents of children with autism, who themselves did not have a diagnosis of any psychiatric illness. Building on recent quantifications of social cognition in autism [3], we investigated face processing using the “Bubbles” method [4] to measure how viewers make use of information from specific facial features in order to judge emotions. Parents of autistic children who were assessed as socially aloof (N=15), a key component of the phenotype [5], showed a remarkable reduction in processing the eye region in faces, together with enhanced processing of the mouth, compared to a control group of parents of neurotypical children (N=20), as well as to non-aloof parents of autistic children (N=27, whose pattern of face processing was intermediate). The pattern of face processing seen in the Broad Autism Phenotype showed striking similarities to that previously reported to occur in autism [3], and for the first time provides a window into the endophenotype that may result from a subset of the genes that contribute to social cognition.

Context

There now exist multiple reports of a constellation of language, personality, and social-behavioral features present among relatives that mirror the symptom domains of autism, but much milder in expression. Studies of this ‘broad autism phenotype’ (BAP) may provide a potentially important, complementary approach for detecting the genes causing autism and defining associated neural circuitry, by identifying more refined phenotypes which can be measured quantitatively in both affected and unaffected individuals, and which are tied to functioning in particular regions of the brain.

Objective

To gain insights into neuropsychological features that index genetic liability to autism.

Design

Case-control.

Setting

General community.

Participants

Thirty-eight high-functioning individuals with autism and parents of autistic individuals, both with and without the BAP (N=83), as well as control groups.

Main Outcome Measures

A comprehensive battery of neuropsychological tasks tapping social cognition, executive function, and global/local processing strategies (central coherence).

Results

Both individuals with autism and parents with the BAP differed from controls on measures of social cognition, with performance in the other two domains more similar to controls.

Conclusions

Data suggest that the social cognitive domain may be an important target for linking phenotype to cognitive process to brain structure in autism, and may ultimately provide insights into genes involved in autism.

Despite compelling evidence from twin and family studies indicating a strong genetic involvement in the etiology of autism, the unequivocal detection of autism susceptibility genes remains an elusive goal. The purpose of this review is to evaluate the current state of autism genetics research, with attention focused on new techniques and analytic approaches. We first present a brief overview of evidence for the genetic basis of autism, followed by an appraisal of linkage and candidate gene study findings and consideration of new analytic approaches to the study of complex psychiatric conditions, namely, genome-wide association studies, assessment of structural variation within the genome, and the incorporation of endophenotypes in genetic analysis.

To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18–42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior.

Both autism and schizophrenia feature deficits in aspects of social cognition that may be related to amygdala dysfunction, but it is unclear whether these are similar or different patterns of impairment. We compared the visual scanning patterns and emotion judgments of individuals with autism, individuals with schizophrenia and controls on a task well characterized with respect to amygdala functioning. On this task, eye movements of participants are recorded as they assess emotional content within a series of complex social scenes where faces are either included or digitally erased. Results indicated marked abnormalities in visual scanning for both disorders. Controls increased their gaze on face regions when faces were present to a significantly greater degree than both the autism or schizophrenia groups. While the control and the schizophrenia groups oriented to face regions faster when faces were present compared to when they were absent, the autism group oriented at the same rate in both conditions. The schizophrenia group, meanwhile, exhibited a delay in orienting to face regions across both conditions, although whether anti-psychotic medication contributed to this effect is unclear. These findings suggest that while processing emotional information in social scenes, both individuals with autism and individuals with schizophrenia fixate faces less than controls, although only those with autism fail to orient to faces more rapidly based on the presence of facial information. Autism and schizophrenia may therefore share an abnormality in utilizing facial information for assessing emotional content in social scenes, but differ in the ability to seek out socially relevant cues from complex stimuli. Impairments in social orienting are discussed within the context of evidence suggesting the role of the amygdala in orienting to emotionally meaningful information.