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The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders.

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Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although 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) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. 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, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.

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Cognitive processing in autism has been characterized by a difficulty with the abstraction of information across multiple stimuli or situations and subsequent generalization to new stimuli or situations. This apparent difficulty leads to the suggestion that prototype formation, a process of creating a mental summary representation of multiple experienced stimuli that go together in a category, may be impaired in autism. Adults with high functioning autism and a typically developing comparison group matched on age and IQ completed a random dot pattern categorization task. Participants with autism demonstrated intact prototype formation in all four ways it was operationally defined, and this performance was not significantly different from that of control participants. However, participants with autism categorized dot patterns that were more highly distorted from the category prototypes less accurately than did control participants. These findings suggest, at least within the constraints of the random dot pattern task, that although prototype formation may not be impaired in autism, difficulties may exist with the generalization of what has been learned about a category to novel stimuli, particularly as they become less similar to the category's prototype.

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BACKGROUND AND PURPOSE: Individuals with autism spectrum disorders often exhibit atypical language patterns, including delay of speech onset, literal speech interpretation, and poor recognition of social and emotional cues in speech. We acquired functional MR images during an auditory language task to evaluate systematic differences in language-network activation between control and high-functioning autistic populations. MATERIALS AND METHODS: Forty-one right-handed male subjects (26 high-functioning autistic subjects, 15 controls) were studied by using an auditory phrase-recognition task, and areas of differential activation between groups were identified. Hand preference, verbal intelligence quotient (IQ), age, and language-function testing were included as covariables in the analysis. RESULTS: Control and autistic subjects showed similar language-activation networks, with 2 notable differences. Control subjects showed significantly increased activation in the left posterior insula compared with autistic subjects (P < .05, false discovery rate), and autistic subjects showed increased bilaterality of receptive language compared with control subjects. Higher receptive-language scores on standardized testing were associated with greater activation of the posterior aspect of the left Wernicke area. A higher verbal IQ was associated with greater activation of the bilateral Broca area and involvement of the prefrontal cortex and lateral premotor cortex. CONCLUSIONS: Control subjects showed greater activation of the posterior insula during receptive language, which may correlate with impaired emotive processing of language in autism. Subjects with autism showed greater bilateral activation of receptive-language areas, which was out of proportion to the differences in hand preference in autism and control populations.

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We performed a high-density, single nucleotide polymorphism (SNP), genome-wide scan on a six-generation pedigree from Utah with seven affected males, diagnosed with autism spectrum disorder. Using a two-stage linkage design, we first performed a nonparametric analysis on the entire genome using a 10K SNP chip to identify potential regions of interest. To confirm potentially interesting regions, we eliminated SNPs in high linkage disequilibrium (LD) using a principal components analysis (PCA) method and repeated the linkage results. Three regions met genome-wide significance criteria after controlling for LD: 3q13.2-q13.31 (nonparametric linkage (NPL), 5.58), 3q26.31-q27.3 (NPL, 4.85) and 20q11.21-q13.12 (NPL, 5.56). Two regions met suggestive criteria for significance 7p14.1-p11.22 (NPL, 3.18) and 9p24.3 (NPL, 3.44). All five chromosomal regions are consistent with other published findings. Haplotype sharing results showed that five of the affected subjects shared more than a single chromosomal region of interest with other affected subjects. Although no common autism susceptibility genes were found for all seven autism cases, these results suggest that multiple genetic loci within these regions may contribute to the autism phenotype in this family, and further follow-up of these chromosomal regions is warranted.

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An increased prevalence of macrocephaly defined by occipital-frontal circumference (OFC) is a consistent finding in autism. Several possible mechanisms have been proposed, the most compelling being early brain overgrowth. However, the proportion of non-neural tissues (NNT) that contribute to OFC has not been reported. Using quantitative magnetic resonance imaging (MRI) methods we analyzed the relationships between OFC and total brain (TBV), ventricular, surface cerebrospinal fluid (CSF)/meningeal, and NNT volumes in subjects with autism. Sixty male subjects (34 autistic; 26 controls) seven years of age and older were used in this study. Compared to other measures, NNT volume was most significantly related to OFC (r values > 0.8, p 0.06). In contrast, the OFC-TBV relationship was less robust in those with autism (r=0.25, p

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OBJECTIVE: To examine the efficacy of intravenous porcine secretin for the treatment of autistic disorder. METHOD: Randomized, double-blind, placebo-controlled, crossover design. Fifty-six subjects with autistic disorder received either a secretin or placebo infusion at baseline and the other substance at week 4. Subjects were given the Autism Diagnostic Observation Schedule (ADOS) and other pertinent developmental measures at baseline and at weeks 4 and 8 to assess drug effects. RESULTS: For the primary efficacy analysis, change of ADOS social-communication total score from week 0 to week 4, no statistically significant difference was obtained between placebo (-0.8 +/- 2.9) and secretin groups (-0.6 +/- 1.4; t54 = 0.346, p < .73). The other measures showed no treatment effect for secretin compared with placebo. CONCLUSION: There was no evidence for efficacy of secretin in this randomized, placebo-controlled, double-blind trial.

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In a case-control study of cognitive performance, tests of intelligence, reading, spelling, and pragmatic language were administered to the parents and siblings of 90 community-ascertained probands with autism (AU group) and to the parents and siblings of 40 similarly ascertained probands with trisomy 21 Down syndrome (DS group). The two samples were comparable for age and parents' education; both groups were well-educated and had above-average intelligence. AU parents scored slightly but significantly lower on the WAIS-R Full Scale and Performance IQ, on two subtests (Picture Arrangement and Picture Completion), and on the Word Attack Test (reading nonsense words) from the Woodcock-Johnson battery. There were no differences between AU and DS siblings. As in earlier studies, AU parents, more often than DS parents, reported a history of early language-related cognitive difficulties; we were not able to replicate this in siblings. AU parents who reported such difficulties scored significantly lower on Verbal IQ, spelling, and the nonsense reading test. AU parents without a history of early language-related cognitive difficulties often had a Verbal IQ that exceeded Performance IQ by more than one standard deviation. AU siblings with early language-related difficulties had similar findings: lower Verbal IQ, poorer spelling, and poorer reading scores, compared to AU siblings without such a history. Parents with a positive history also scored worse on a measure of pragmatic language,the Pragmatic Rating Scale, but not on measures of social-related components of the broader autism phenotype. We propose that cognitive differences in a subset of autism family members are manifestations of the language-related component of the broader autism phenotype, and separate from the social-related component. This is consistent with the hypothesis that there are several genes that may interact to cause autism which segregate independently and have distinguishable manifestations in family members. The hypothesis would be further supported by finding different patterns of genetic loci linked to autism in families where one or both parents has language difficulties.

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OBJECTIVE: To explore the frequency and onset of macrocephaly in autism and its relationship to clinical features. METHOD: Head circumferences at birth, during early childhood, and at the time of examination were studied in a community-based sample of autistic children and adults. The authors investigated whether head circumference at the time of examination was associated with clinical features. RESULTS: Fourteen percent of the autistic subjects had macrocephaly: 11% of males and 24% of females. In most, the macrocephaly was not present at birth; in some it became apparent in early and middle childhood as a result of increased rate of head growth. A small relationship was noted between head circumference percentile and less severe core features of autism. Neither macrocephaly nor head circumference percentile was associated with nonverbal IQ, verbal status, seizure disorder, neurological soft signs or minor physical anomalies in the autistic subjects. CONCLUSION: Macrocephaly is common in autism and usually is not present at birth. Rates of head growth may be abnormal in early and middle childhood in some (37%) children with autism. Macrocephaly does not define a homogeneous subgroup of autistic individuals according to clinical features.

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Autism is a developmental neuropsychiatric disorder defined by the presence of social and communicative deficits, restricted and repetitive behaviors and interests, and a characteristic course. Research suggests that hereditary factors play a principal role in the etiology of most cases. A phenotype broader than autism, including milder social and language-based cognitive deficits, appears to be inherited. Although the pathogenesis is unknown, neurobiologic mechanisms clearly underlie the disorder. Neuropathologic studies have demonstrated abnormalities in limbic structures, the cerebellum, and the cortex. New advances in behavioral therapies and pharmacologic treatment are important components of successful multidisciplinary treatment of this disorder.

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The presentation of affective disorders in people with autism and autistic-like disorders is discussed based upon a review of 17 published cases. Half of the patients were female and almost all of the patients had IQs in the mentally retarded range. 35% of the patients had the onset of affective disorder in childhood. Of the cases mentioning family history, 50% had a family history of affective disorder or suicide. Changes in mood, self-attitude, and vital sense were rarely reported by the patients. A change in mood, attitude toward self and others, and vegetative changes were inferred based on the observations of others. Difficulties in diagnosing affective disorders in autistic people are presented and suggestions are made for diagnosis, treatment, and research.

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Personality characteristics of 87 parents of autistic probands and 38 parents of Down's syndrome probands were examined using a standardized personality interview. Using best-estimate ratings derived from subject and informant interviews, parents of autistic individuals were rated significantly higher than controls on three characteristics: aloof, untactful and undemonstrative. When ratings were based on interviews with subjects only, parents of autistic probands were rated as significantly more aloof, untactful and unresponsive. There were no significant differences between parent groups on ratings based on informant interviews only. The implications of these findings for future family studies of autism are discussed.

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