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Previous investigations have reported decreased size of the corpus callosum (CC) in autism. However, little is known of the regional distribution of these callosal abnormalities. Additional uncertainty exists regarding the role of head size with respect to variations in callosal size in individuals with autism. This study investigated the size of the CC in 5 groups of high functioning individuals: (1) normocephalic autistic individuals; (2) autism with macrocephaly; (3) non-autistic normocephalic controls; (4) non-autistic participants with benign macrocephaly; and (5) a reading disordered (RD) group, comprised of non-autistic individuals with a deficit in reading. The CC was traced from midsaggital MRIs and the outlines partitioned into 99 equidistant width measures. Factor analysis of the 99 widths revealed 10 contiguous callosal regions. Individuals with macrocephaly (autistic and non-autistic) had larger total CC size. Regional analysis revealed a significantly larger CC midbody in macrocephaly, regardless of presence or absence of autism. Within normocephalic individuals, those with autism had a smaller CC genu and midbody than either non-autistic controls or RD individuals. These results underscore the importance of considering head size in studies of CC morphology in autism. These findings add to the literature implicating problems of interhemispheric connectivity being present in individuals with autism. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Oxytocin plays an important role in social-affiliative behaviors. It has been proposed that exposure to high levels of exogenous oxytocin at birth, via pitocin induction of delivery, might increase susceptibility to autism by causing a downregulation of oxytocin receptors in the developing brain. This study examined the rates of labor induction using pitocin in children with autism and matched controls with either typical development or mental retardation. Birth histories of 41 boys meeting the criteria for autistic disorder were compared to 25 age- and IQ-matched boys without autism (15 typically developing and 10 with mental retardation). There were no differences in pitocin induction rates as a function of either diagnostic group (autism vs. control) or IQ level (average vs. subaverage range), failing to support an association between exogenous exposure to oxytocin and neurodevelopmental abnormalities. [ABSTRACT FROM AUTHOR]

Purpose of Review: Impairments in social interaction/communication become apparent after 12 months of age in children who develop Autism spectrum disorder (ASD). Studies of baby siblings of children with ASD provide the means to detect changes in the brain that are present before behavioral symptoms appear. In this review, advances from brain imaging studies of infant siblings over the past 18 months are highlighted., Recent Findings: During the first 2 months of life, functional differences in social brain regions and microstructural differences in dorsal language tracks are found in some high-risk baby siblings. At 4-6 months of age, differences in subcortical and cerebellum volumes and atypical cortical responses to social stimuli are evident. At 6 months, extra-axial cerebrospinal fluid is increased, and at 8 months there is evidence of cortical hyper-reactivity. Patterns of functional connectivity are distinct in infant siblings and suggest dysfunctional activation and integration of information across the cortex and neural networks underlying social behaviors., Summary: Further replication in very large independent samples is needed to verify the majority of the findings discussed and understand how they are related within individual infants. Much more research is needed before translation to clinical practice.

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.

A gap exists in the literature regarding aggression in autism spectrum disorders and how this behavior compares to other groups. In this multisite study, the Children's Scale for Hostility and Aggression: Reactive/Proactive and the Aggression subscale of the Child Behavior Checklist were rated for 414 children with autism spectrum disorder (autistic disorder, 69%; pervasive developmental disorder not otherwise specified, 24%; Asperger's disorder, 7%) and 243 clinic-referred children without autism spectrum disorder, aged 1-21 years (mean age about 7 years). Participants were not selected for aggressive behavior. Relative to the comparison group, children with autism spectrum disorder were reported to have less aggression and were more likely to be rated as reactive rather than proactive. Among all subjects, sex was not associated with aggression; higher IQ/adaptive behavior and older age were associated with more sophisticated types of aggression, while lower scores on IQ, adaptive behavior, and communication measures were associated with more physical aggression. The interaction between demographic variables and diagnosis was significant only for age: younger but not older children with autism spectrum disorder showed less aggression than clinic-referred controls., (© The Author(s) 2014.)

Heightened auditory sensitivity and atypical auditory processing are common in autism. Functional studies suggest abnormal neural response and hemispheric activation to auditory stimuli, yet the neurodevelopment underlying atypical auditory function in autism is unknown. In this study, we model longitudinal volumetric growth of Heschl's gyrus gray matter and white matter during childhood and adolescence in 40 individuals with autism and 17 typically developing participants. Up to three time points of magnetic resonance imaging data, collected on average every 2.5 years, were examined from individuals 3-12 years of age at the time of their first scan. Consistent with previous cross-sectional studies, no group differences were found in Heschl's gyrus gray matter volume or asymmetry. However, reduced longitudinal gray matter volumetric growth was found in the right Heschl's gyrus in autism. Reduced longitudinal white matter growth in the left hemisphere was found in the right-handed autism participants. Atypical Heschl's gyrus white matter volumetric growth was found bilaterally in the autism individuals with a history of delayed onset of spoken language. Heightened auditory sensitivity, obtained from the Sensory Profile, was associated with reduced volumetric gray matter growth in the right hemisphere. Our longitudinal analyses revealed dynamic gray and white matter changes in Heschl's gyrus throughout childhood and adolescence in both typical development and autism., (© 2013 International Society for Autism Research, Wiley Periodicals, Inc.)

It is unclear how standardized neuropsychological measures of motor function relate to brain volumes of motor regions in autism spectrum disorder (ASD). An all-male sample composed of 59 ASD and 30 controls (ages 5-33 years) completed three measures of motor function: strength of grip (SOG), finger tapping test (FTT), and grooved pegboard test (GPT). Likewise, all participants underwent magnetic resonance imaging with region of interest (ROI) volumes obtained to include the following regions: motor cortex (precentral gyrus), somatosensory cortex (postcentral gyrus), thalamus, basal ganglia, cerebellum, and caudal middle frontal gyrus. These traditional neuropsychological measures of motor function are assumed to differ in motor complexity, with GPT requiring the most followed by FTT and SOG. Performance by ASD participants on the GPT and FTT differed significantly from that of controls, with the largest effect size differences observed on the more complex GPT task. Differences on the SOG task between the two groups were nonsignificant. Since more complex motor tasks tap more complex networks, poorer GPT performance by those with ASD may reflect less efficient motor networks. There was no gross pathology observed in classic motor areas of the brain in ASD, as ROI volumes did not differ, but FTT was negatively related to motor cortex volume in ASD. The results suggest a hierarchical motor disruption in ASD, with difficulties evident only in more complex tasks as well as a potential anomalous size-function relation in motor cortex in ASD.

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.

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.

The frequency, course, and inter-relationships of atypical eating, sleeping, self-injurious behavior, aggression and temper tantrums in children with autism and children with a history of language impairment (HLI), was investigated using a parent interview that was created to examine these problem behaviors. The relationships between these behaviors and language, IQ, severity of autistic symptoms and depression were also assessed. Atypical eating behavior, abnormal sleep patterns, temper tantrums, and self-injurious behavior were significantly more common in the children with autism than those with HLI. Within the autism group, children who exhibited more atypical behaviors tended to have a lower nonverbal IQ, lower levels of expressive language, more severe social deficits and more repetitive behaviors. No relationship between the number of atypical behaviors and measures of cognitive or language ability was noted in the HLI group. However, having more atypical behaviors was related to increased restricted, repetitive behaviors in children with HLI. The atypical behaviors could be divided into two groups: abnormal eating and sleeping, which were independent and tended to begin early in life; and self-injury, tantrums and aggression, which began later and were inter-related. Sleep abnormalities were more common in children (groups combined) diagnosed with major depression.

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

We report a possible association between autism in our sample and a recently described brain-expressed tryptophan hydroxylase gene (TPH2). The well-replicated involvement of the serotonin neurotransmitter system in autism has stimulated interest in many genes in the serotonin pathway as possible candidates for mutations leading to autism susceptibility. Serotonin synthesis is controlled by the rate-limiting enzyme tryptophan hydroxylase. A mouse study of the original tryptophan hydroxylase gene (TPH1) and the new isoform (TPH2) showed that while TPH1 is primarily expressed peripherally, TPH2 is found exclusively in brain tissue. We searched for human sequence variants in 6,467 nucleotides covering all 11 exons of TPH2, and also 248 nucleotides upstream of the start codon, and 935 nucleotides downstream of the stop codon. Eighteen variants were characterized in 88 subjects with autism studied at our two centers, and 95 unrelated control subjects. Using a model-free association method and empirical P value estimation, two variants showed frequency differences between autism and control subjects (P = 0.01 for a T-G variant in intron 1, and P = 0.02 for a A-T variant in intron 4). A haplotype including these variants showed slightly increased significance (P = 0.005). Further investigation of clinical phenotypes showed a possible association between presence of the variants at these two SNPs and higher scores on the Autism Diagnostic Interview (ADI) domain describing repetitive and stereotyped behaviors (P = 0.007). We conclude that TPH2 may play a modest role in autism susceptibility, perhaps relating specifically to repetitive behaviors, pending replication of this result., (Copyright 2005 Wiley-Liss, Inc.)

Though autism shows strong evidence for genetic etiology, specific genes have not yet been found. We tested for linkage in a candidate region on chromosome 3q25-27 first identified in Finnish autism families [1]. The peak in this previous study was at D3S3037 (183.9 cM). We tested this region in seven affected family members and 24 of their relatives from a single large extended Utah pedigree of Northern European ancestry. A total of 70 single nucleotide polymorphisms (SNPs) were analyzed from 165 to 204 cM. The maximum NPL-all nonparametric score using SimWalk2snp was 3.53 (empirical p val ue = 0.0003) at 185.2 cM (SNP rs1402229), close to the Finnish peak. A secondary analysis using MCLINK supported this result, with a maximum of 3.92 at 184.6 cM (SNP rs1362645). We tested for alterations in a candidate gene in this region, the fragile X autosomal homolog, FXR1. No variants likely to contribute to autism were found in the coding sequence, exon-intron boundaries, or the promoter region of this gene., (Copyright (c) 2005 S. Karger AG, Basel)

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.

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.

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.