Language Ability Predicts Cortical Structure and Covariance in Boys with Autism Spectrum Disorder.

There is significant clinical heterogeneity in language and communication abilities of individuals with Autism Spectrum Disorders (ASD). However, no consistent pathology regarding the relationship of these abilities to brain structure has emerged. Recent developments in anatomical correlation-based approaches to map structural covariance networks (SCNs), combined with detailed behavioral characterization, offer an alternative for studying these relationships. In this study, such an approach was used to study the integrity of SCNs of cortical thickness and surface area associated with language and communication, in 46 high-functioning, school-age children with ASD compared with 50 matched, typically developing controls (all males) with IQ > 75. Findings showed that there was alteration of cortical structure and disruption of fronto-temporal cortical covariance in ASD compared with controls. Furthermore, in an analysis of a subset of ASD participants, alterations in both cortical structure and covariance were modulated by structural language ability of the participants, but not communicative function. These findings indicate that structural language abilities are related to altered fronto-temporal cortical covariance in ASD, much more than symptom severity or cognitive ability. They also support the importance of better characterizing ASD samples while studying brain structure and for better understanding individual differences in language and communication abilities in ASD.

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Auditory Pitch Perception in Autism Spectrum Disorder Is Associated With Nonverbal Abilities.

Atypical sensory perception and heterogeneous cognitive profiles are common features of autism spectrum disorder (ASD). However, previous findings on auditory sensory processing in ASD are mixed. Accordingly, auditory perception and its relation to cognitive abilities in ASD remain poorly understood. Here, children with ASD, and age- and intelligence quotient (IQ)-matched typically developing children, were tested on a low- and a higher level pitch processing task. Verbal and nonverbal cognitive abilities were measured using the Wechsler's Abbreviated Scale of Intelligence. There were no group differences in performance on either auditory task or IQ measure. However, there was significant variability in performance on the auditory tasks in both groups that was predicted by nonverbal, not verbal skills. These results suggest that auditory perception is related to nonverbal reasoning rather than verbal abilities in ASD and typically developing children. In addition, these findings provide evidence for preserved pitch processing in school-age children with ASD with average IQ, supporting the idea that there may be a subgroup of individuals with ASD that do not present perceptual or cognitive difficulties. Future directions involve examining whether similar perceptual-cognitive relationships might be observed in a broader sample of individuals with ASD, such as those with language impairment or lower IQ.

Atypical functional brain connectivity during rest in autism spectrum disorders.

OBJECTIVE: Connectivity atypicalities in autism spectrum disorders (ASD) have been extensively proposed. The default mode network (DMN) is critical in this study, given the insight it provides for long-distance connectivity, and the importance of regions in this network for introspection and social emotion processing, areas affected in ASD. However, study of this network has largely been limited to adults; research earlier in development is lacking. The objective of this study was to examine DMN connectivity in children/adolescents with ASD. METHODS: A total of 115 children/adolescents, aged 6 to 17 years (71 males with ASD and 44 group age-matched TD males) were included in these analyses. We examined group differences in (1) functional connectivity between the posterior cingulate cortex and regions across the brain, (2) connectivity within the DMN as a function of age and intelligence quotient (IQ), and (3) the association between DMN connectivity and empathic accuracy. RESULTS: Individuals with ASD, relative to controls, showed either stronger or weaker connectivity between the posterior cingulate cortex (PCC) and DMN regions, depending on the region, but also showed stronger connectivity with non-DMN regions. A significant group-by-age interaction was observed in functional connectivity between the PCC and medial prefrontal cortex; connectivity increased with age in controls, but decreased in individuals with ASD. No effects of IQ were found. There was a significant group difference in the relation between DMN connectivity and empathic accuracy. INTERPRETATION: Differences in functional connectivity may suggest the presence of neural atypicalities that impact the development of typical connectivity in ASD. In addition to affecting DMN dynamics, these atypicalities may also impact social-cognitive abilities.

Complex autism spectrum disorder in a patient with a 17q12 microduplication.

Autism spectrum disorders (ASDs) are phenotypically complex developmental neuropsychiatric disorders affecting approximately 0.6% of the population. About 30-70% of affected children are also considered to have intellectual disability (ID). The underlying genetic causes of ASDs are diverse with a defined etiology in 16-20%. Array comparative genomic hybridization (aCGH) has proven useful in identifying sub-microscopic chromosome aberrations in a subset of patients, some of which have been shown to be recurrent. One such aberration is the 1.4 Mb microdeletion at chromosome 17q12, which has been reported to be associated with renal disease, growth restriction, diabetes, cognitive impairment, seizures, and in some cases an ASD. Patients with the reciprocal chromosome 17q12 microduplication typically have also been identified with ID and in some cases seizures and behavioral abnormalities. Here we report a patient with a de novo, 1.4 Mb microduplication diagnosed with significant ID involving complex deficits and autism. To our knowledge, this is the first report of a patient with the 17q12 microduplication and a complex ASD phenotype.

Pitch direction ability predicts melodic perception in autism.

Individuals with autism spectrum disorders (ASDs) often present atypical auditory perception. Previous work has reported both enhanced low-level pitch discrimination and superior abilities to detect local pitch structure on higher-level melodic tasks in ASD. However, it is unclear how low and high levels of auditory perception are related in ASD or typical development (TD), or how this relationship might change across development and stimulus presentation rates. To these aims, in the present study, children with ASD and TD were tested on a low-level pitch direction discrimination task and a high-level melodic global-local task. Groups performed similarly on both of these auditory tasks. Moreover, individual differences in low-level pitch direction ability predicted performance on the higher-level global-local task, with a stronger relationship in ASD. Age did not affect the relationship between low-level and high-level pitch performance in either ASD or TD. However, there was a more positive effect of age on the high-level global-local task performance in TD than ASD. Finally, there was no effect of stimulus rate on the relationship between low-level and high-level pitch performance in either group. These findings provide a better understanding of how perception is associated across levels of processing in ASD versus TD. This work helps to better understand individual differences in auditory perception and to refine ASD phenotypes.

Speech perception in autism spectrum disorder: An activation likelihood estimation meta-analysis.

Autism spectrum disorder (ASD) is often characterized by atypical language profiles and auditory and speech processing. These can contribute to aberrant language and social communication skills in ASD. The study of the neural basis of speech perception in ASD can serve as a potential neurobiological marker of ASD early on, but mixed results across studies renders it difficult to find a reliable neural characterization of speech processing in ASD. To this aim, the present study examined the functional neural basis of speech perception in ASD versus typical development (TD) using an activation likelihood estimation (ALE) meta-analysis of 18 qualifying studies. The present study included separate analyses for TD and ASD, which allowed us to examine patterns of within-group brain activation as well as both common and distinct patterns of brain activation across the ASD and TD groups. Overall, ASD and TD showed mostly common brain activation of speech processing in bilateral superior temporal gyrus (STG) and left inferior frontal gyrus (IFG). However, the results revealed trends for some distinct activation in the TD group showing additional activation in higher-order brain areas including left superior frontal gyrus (SFG), left medial frontal gyrus (MFG), and right IFG. These results provide a more reliable neural characterization of speech processing in ASD relative to previous single neuroimaging studies and motivate future work to investigate how these brain signatures relate to behavioral measures of speech processing in ASD.

Effects of Age and Attention on Auditory Global-Local Processing in Children with Autism Spectrum Disorder.

In vision, typically-developing (TD) individuals perceive "global" (whole) before "local" (detailed) features, whereas individuals with autism spectrum disorder (ASD) exhibit a local bias. However, auditory global-local distinctions are less clear in ASD, particularly in terms of age and attention effects. To these aims, here ASD and TD children judged local and global pitch structure in nine-tone melodies. Both groups showed a similar global precedence effect, but ASD children were less sensitive to global interference than TD children at younger ages. There was no effect of attention task. These findings provide novel evidence of developmental differences in auditory perception and may help to refine sensory phenotypes in ASD.

Structural Gray Matter Differences During Childhood Development in Autism Spectrum Disorder: A Multimetric Approach.

BACKGROUND: Autism spectrum disorder is a complex neurodevelopmental disorder characterized by impaired social interaction and communication, repetitive behaviors, and restricted interests. Gray matter differences linked to autism spectrum disorder have been studied using a variety of structural imaging methods, but yielded little consensus; the extent to which disparate results reflect differences in methodology or heterogeneity within autism spectrum disorder is not yet clear. Moreover, very few studies have examined gray matter changes as a function of age in autism spectrum disorder. METHOD: A detailed investigation of gray matter structural development was performed via voxel-based morphometry, cortical thickness, and cortical surface area analyses in 38 autism spectrum disorder versus 46 typically developing children. RESULTS: Relative to typically developing children, the autism spectrum disorder group showed gray matter increases most prominently in the frontal and temporal lobes (including regions such as medial frontal gyrus, Broca's area and posterior temporal cortex), as well as certain parietal and occipital subcortical regions. Gray matter decreases were found only near the temporoparietal junction. Subcortical gray matter increases were found in the putamen and caudate nucleus, while decreases were found in cerebellum. There were age-dependent GM differences in distributed regions including prefrontal cortex, primary sensorimotor cortex, and temporoparietal junction. CONCLUSION: The results underline the distributed nature of gray matter structural differences in autism spectrum disorder and provide a more comprehensive characterization of autism spectrum disorder-related cortical and subcortical gray matter structural differences during childhood and adolescent development.

Auditory-musical processing in autism spectrum disorders: a review of behavioral and brain imaging studies.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by atypical social and communication skills, repetitive behaviors, and atypical visual and auditory perception. Studies in vision have reported enhanced detailed ("local") processing but diminished holistic ("global") processing of visual features in ASD. Individuals with ASD also show enhanced processing of simple visual stimuli but diminished processing of complex visual stimuli. Relative to the visual domain, auditory global-local distinctions, and the effects of stimulus complexity on auditory processing in ASD, are less clear. However, one remarkable finding is that many individuals with ASD have enhanced musical abilities, such as superior pitch processing. This review provides a critical evaluation of behavioral and brain imaging studies of auditory processing with respect to current theories in ASD. We have focused on auditory-musical processing in terms of global versus local processing and simple versus complex sound processing. This review contributes to a better understanding of auditory processing differences in ASD. A deeper comprehension of sensory perception in ASD is key to better defining ASD phenotypes and, in turn, may lead to better interventions.

Analysis of a purported SHANK3 mutation in a boy with autism: clinical impact of rare variant research in neurodevelopmental disabilities.

There is strong evidence for rare, highly penetrant genetic variants playing an etiological role in multiple neurodevelopmental disabilities, including autism spectrum disorders. The rate of discovery of such rare variants is increasing with the advent of larger sample collections, chromosome microarray analyses, and high-throughput sequencing. As the variants that are being discovered can be highly penetrant, they lead immediately to model systems with construct validity, critical for understanding the underlying neurobiology of these conditions, which in turn can provide leads for novel therapeutic targets. Moreover, these discoveries can benefit families with information about recurrence risk, resolve concerns about etiology, provide information about associated medical issues, and engender directed advocacy for specific genetic conditions. For these reasons, diagnostic laboratories are taking advantage of research data as they are produced. In the current report, we present our molecular analysis of a child with a purported disruptive mutation in SHANK3 identified by a commercial genetic testing laboratory and we provide evidence that this was not an etiological variant. The variant was a 1-bp insertion in exon 11 of the RefSeq gene, which we then determined was inherited from a healthy mother and found in ~1% of controls. Since the variant would be predicted to disrupt the reference gene, and the penetrance of SHANK3 mutations is very high, we did follow up molecular and bioinformatic analyses and concluded that the presumptive exon containing the variant is not likely to be present in most or all SHANK3 transcripts. The results highlight difficulties that can arise with rapid translation of research findings to clinical practice. Researchers are in a unique position to generate resources with collated and curated information that can inform research, genetic testing, clinicians, and families about the best practices as pertains to rare genetic variants in neurodevelopmental disabilities. Of immediate importance would be a well-curated database of gene variation identified in large numbers of typically developing individuals and in individuals affected with neurodevelopmental disabilities. Such a database would reduce false-positive results in clinical settings, would be helpful in structure-function analyses, and would direct translational research to pathways most likely to benefit families.