Autism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5-7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy number variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy number variants using the PennCNV algorithm. We identified and validated a de novo 1.5 Mb microdeletion of 14q23.2-23.3 in our autistic patient. This region contains 15 genes, including spectrin beta (SPTB), encoding a cytoskeletal protein previously associated with spherocytosis, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a folate metabolizing enzyme previously associated with bipoloar disorder and schizophrenia, pleckstrin homology domain-containing family G member 3 (PLEKHG3), a guanide nucleotide exchange enriched in the brain, and churchill domain containing protein 1 (CHURC1), homologs of which regulate neuronal development in model organisms. While a similar deletion has previously been reported in a family with spherocytosis, severe learning disabilities, and mild mental retardation, this is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3, and CHURC1 as potential candidate genes contributing to autism risk.
In a developmentally delayed girl with an autism spectrum disorder, Single nucleotide polymorphism (SNP) array analysis showed a de novo 280 kb deletion on chromosome 16q23.2 involving two genes, GAN and CMIP. Inactivating mutations in GAN cause the autosomal recessive disorder giant axonal neuropathy, not present in our patient. CMIP was recently implicated in the etiology of specific language impairment by genome-wide association analysis. It modulates phonological short-term memory and hence plays an important role in language acquisition. Overlaps of specific language impairment and autism have been debated in the literature regarding the phenotypical language profile as well as etiology. Our patient illustrates that haploinsufficiency of CMIP may contribute to autism spectrum disorders. Our finding further supports the existence of a genetic overlap in the etiology of specific language impairment and autism.
Since the 1970s, the prevalence of multiple births (MBs) in the United States has increased significantly. This has been attributed, in large part, to iatrogenic MBs resulting from infertility treatments that include ovulation stimulation. A past study has indicated that children from MBs have an increased prevalence of cerebral palsy (CP). Other studies also have suggested an association between MBs and intellectual disabilities (ID) and autism spectrum disorders (ASDs); however, results have been inconsistent. From the Autism and Developmental Disabilities Monitoring (ADDM) Network, a surveillance project among several US populations, we obtained MB estimates among children born in 1994 and classified by 8 years of age as having: an ASD (n=1,626 total children from 11 sites; 50 born as part of an MB); CP (n=302 total children from 3 sites; 25 born as part of an MB); or ID (n=1,195 total children from 3 sites; 45 born as part of an MB). All three MB estimates were notably higher than age-adjusted expected estimates of naturally conceived MBs derived from 1971 US natality data. However, when MB estimates from the ADDM Network were compared with expected MB estimates derived from 1994 natality data for the states corresponding to the relevant ADDM Network sites, we observed no association with ASDs (observed/expected=1.08 [0.78-1.38]), a moderate, but not statistically significant association with ID (observed/expected=1.34 [0.95-1.73]), and a strong association with CP (observed/expected=2.96 [1.80-4.12]). Further investigation of specific types of MBs (natural vs. iatrogenic) is warranted.
Autism spectrum disorders (ASDs) are a phenotypically and etiologically heterogeneous set of disorders that include obsessive-compulsive behaviors (OCB) that partially overlap with symptoms associated with obsessive-compulsive disorder (OCD). The OCB seen in ASD vary depending on the individual's mental and chronological age as well as the etiology of their ASD. Although progress has been made in the measurement of the OCB associated with ASD, more work is needed including the potential identification of heritable endophenotypes. Likewise, important progress toward the understanding of genetic influences in ASD has been made by greater refinement of relevant phenotypes using a broad range of study designs, including twin and family-genetic studies, parametric and nonparametric linkage analyses, as well as candidate gene studies and the study of rare genetic variants. These genetic analyses could lead to the refinement of the OCB phenotypes as larger samples are studied and specific associations are replicated. Like ASD, OCB are likely to prove to be multidimensional and polygenic. Some of the vulnerability genes may prove to be generalist genes influencing the phenotypic expression of both ASD and OCD while others will be specific to subcomponents of the ASD phenotype. In order to discover molecular and genetic mechanisms, collaborative approaches need to generate shared samples, resources, novel genomic technologies, as well as more refined phenotypes and innovative statistical approaches. There is a growing need to identify the range of molecular pathways involved in OCB related to ASD in order to develop novel treatment interventions.
Prenatal testosterone (PT) effects have been proposed to increase systemizing (the drive to understand lawful input-output relationships), to decrease empathizing (the drive to understand others), and to cause autism via hypermasculinization of the brain. Digit ratio 2D:4D is a putative marker of PT effects in humans. An online study (n = 1896) into the relationship between the Reading the Mind in the Eyes Test (a widely used measure of empathizing) and self-measured 2D:4D in a nonclinical sample is reported. No evidence for a link between empathizing and 2D:4D in either females or males emerged. Further, three meta-analyses are presented that look into the relationships of 2D:4D with autism spectrum disorder (ASD), systemizing, and empathizing. 2D:4D was substantially lower (more masculine) in ASD-affected individuals than in normal controls (d = -0.58, P < 0.001). However, 2D:4D was found to be virtually unrelated to systemizing and empathizing in normal adults. The results support the idea that high PT is a risk factor for autism, but they challenge the view that PT substantially contributes to sex differences in systemizing and empathizing. Possibly, this pattern reflects an interaction effect, whereby PT drives ASD characteristic changes only in brains with a specific damage.
New evidence suggests that autism may be associated with (a) varied behavioral responses to folate therapy and (b) metabolic anomalies, including those in folate metabolism, that contribute to hypomethylation of DNA. We hypothesized that children with autism who are homozygous for the MTHFR 677 T allele (TT) and, to a lesser extent those with the CT variant, would exhibit more behavioral problems and/or more severe problematic behaviors than homozygous wild-type (CC) individuals because of difficulties in effectively converting 5,10-MTHF to 5-MTHF. Data from the Autism Genetic Resource Exchange (AGRE) collection were analyzed for all children who met strict criteria for autism per the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS) and who had been genotyped for the 677 C to T MTHFR polymorphism (n=147). Chi-square tests, logistic regression, and one-way ANOVAs were used to determine whether differences existed among MTHFR genotypes for specific behaviors on the ADI-R and indices for level of functioning. Exploratory results indicated four behaviors from the ADI-R that were more common and problematic (95% CI) among those with at least one copy of the T allele as compared to homozygous wild-type individuals: direct gaze, current complex body movements, a history of self-injurious behavior, and current overactivity (ORs=2.72, 2.33, 2.12, 2.47, respectively). No differences existed among genotypes for level of functioning as measured with the Peabody Picture Vocabulary Test-Third Edition, Ravens Colored Progressive Matrices, or the Vineland Adaptive Behavior Scales. Findings call for further investigation of the relationship between folate metabolism and problem behaviors among children with autism.
Homeobox A1 (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 nonsynonymous 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 of 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.
Neuroligin-3 is a member of the class of cell adhesion proteins that mediate synapse development and have been implicated in autism. Mice with the human R451C mutation (NL3), identical to the point mutation found in two brothers with autism spectrum disorders, were generated and phenotyped in multiple behavioral assays with face validity to the diagnostic symptoms of autism. No differences between NL3 and their wildtype (WT) littermate controls were detected on measures of juvenile reciprocal social interaction, adult social approach, cognitive abilities, and resistance to change in a spatial habit, findings which were replicated in several cohorts of males and females. Physical and procedural abilities were similar across genotypes on measures of general health, sensory abilities, sensorimotor gating, motor functions, and anxiety-related traits. Minor developmental differences were detected between NL3 and WT, including slightly different rates of somatic growth, slower righting reflexes at postnatal days 2-6, faster homing reflexes in females, and less vocalizations on postnatal day 8 in males. Significant differences in NL3 adults included somewhat longer latencies to fall from the rotarod, less vertical activity in the open field, and less acoustic startle to high decibel tones. The humanized R451C mutation in mice did not result in apparent autism-like phenotypes, but produced detectable functional consequences that may be interpreted in terms of physical development and/or reduced sensitivity to stimuli.
This study further investigates findings of impairment in Gestalt, but not global processing in Autism Spectrum Disorder (ASD) [Brosnan, Scott, Fox, & Pye, 2004]. Nineteen males with ASD and nineteen typically developing (TD) males matched by nonverbal ability, took part in five Gestalt perceptual grouping tasks. Results showed that performance differed according to grouping type. The ASD group showed typical performance for grouping by proximity and by alignment, impairment on low difficulty trials for orientation and luminance similarity, and general impairment for grouping by shape similarity. Group differences were also observed developmentally; for the ASD group, with the exception of grouping by shape similarity, perceptual grouping performance was poorer at lower than higher levels of nonverbal ability. In contrast, no developmental progression was observed in the TD controls.
Although it has been well established that individuals with autism exhibit difficulties in their face recognition abilities, it has been debated whether this deficit reflects a category-specific impairment of faces or a general perceptual bias toward the local-level information in a stimulus. In this study, the Let's Face It! Skills Battery [Tanaka & Schultz, 2008] of developmental face- and object-processing measures was administered to a large sample of children diagnosed with autism spectrum disorder (ASD) and typically developing children. The main finding was that when matched for age and IQ, individuals with ASD were selectively impaired in their ability to recognize faces across changes in orientation, expression and featural information. In a face discrimination task, ASD participants showed a preserved ability to discriminate featural and configural information in the mouth region of a face, but were compromised in their ability to discriminate featural and configural information in the eyes. On object-processing tasks, ASD participants demonstrated a normal ability to recognize automobiles across changes in orientation and a superior ability to discriminate featural and configural information in houses. These findings indicate that the face-processing deficits in ASD are not due to a local-processing bias, but reflect a category-specific impairment of faces characterized by a failure to form view-invariant face representations and discriminate information in the eye region of the face.
Previous studies found substantial variability in adult outcome for people with autism whose cognitive functioning was within the near-average and average ranges. This study examined adult outcome for 41 such individuals (38 men and 3 women) originally identified through an epidemiological survey of autism in Utah. Mean age at the time of their previous cognitive assessment was 7.2 years (SD=4.1, range=3.1-25.9 years) and at follow-up was 32.5 years (SD=5.7 years, range=22.3-46.4 years). Outcome measures included standardized assessments of diagnostic status, cognitive ability, and adaptive behavior. Additional information collected concerned demographic variables, indicators of independence, social relationships, medical and psychiatric conditions, and social service use. Outcomes for this sample were better than outcomes described in previous work on individuals with similar cognitive functioning. For example, half of the participants were rated as "Very Good" or "Good" on a global outcome measure. As in previous studies, there was considerable variability in measured cognitive ability over time. Over half of the sample had large gains or losses of cognitive ability of greater than 1 standard deviation. Cognitive gain was associated with better outcome, as was better adaptive functioning. While all participants had baseline IQs in the nonimpaired range, there was limited evidence to support the use of other early childhood variables to predict adult outcome.
Autism spectrum disorder (ASD) and specific language impairment (SLI) are developmental disorders exhibiting language deficits, but it is unclear whether they arise from similar etiologies. Language impairments have been described in family members of children with ASD and SLI, but few studies have quantified them. In this study, we examined IQ, language, and reading abilities of ASD and SLI children and their first-degree relatives to address whether the language difficulties observed in some children with ASD are familial and to better understand the degree of overlap between these disorders and their broader phenotypes. Participants were 52 autistic children, 36 children with SLI, their siblings, and their parents. The ASD group was divided into those with (ALI, n=32) and without (ALN, n=20) language impairment. Relationships between ASD severity and language performance were also examined in the ASD probands. ALI and SLI probands performed similarly on most measures while ALN probands scored higher. ALN and ALI probands' language scores were not related to Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule algorithm scores. SLI relatives scored lowest on all measures, and while scores were not in the impaired range, relatives of ALI children scored lower than relatives of ALN children on some measures, though not those showing highest heritability in SLI. Given that ALI relatives performed better than SLI relatives across the language measures, the hypothesis that ALI and SLI families share similar genetic loading for language is not strongly supported.
Individuals with an autism spectrum disorder (ASD) show difficulties identifying familiar faces, recognizing emotional expressions and judging eye-gaze direction. Recent research suggests that relatives of individuals with AS also show impairments in some aspects of face processing but no study has comprehensively assessed the nature and extent of face-processing difficulties in a group of relatives. This study compared the performance of 22 parents/adult siblings of individuals with ASD ("relatives" group), 26 adults with ASD, and 26 typically developing adults on tasks of face discrimination, facial expression recognition and judging eye-gaze direction. Relatives of individuals with ASD were less able to discriminate subtle differences between faces than typically developing adults, but were more sensitive to such differences than adults with ASD. Furthermore, relatives were significantly worse at identifying expressions of fear and disgust than typically developing adults and failed to show the typical sensitivity to direct compared with averted eye-gaze direction--a strikingly similar pattern to that observed in adults with ASD. These findings show that atypical patterns of face processing are found in some relatives of individuals with ASD and suggest that these difficulties may represent a cognitive endophenotype.
Magnetic resonance imaging (MRI) has been used quite extensively for examining morphological changes in human and animal brains. One of the many advantages to examining mouse models of human autism is that we are able to examine single gene targets, like that of Neuroligin3 R451C knockin (NL3 KI), which has been directly implicated in human autism. The NL3 KI mouse model has marked volume differences in many different structures in the brain: gray matter structures, such as the hippocampus, the striatum, and the thalamus, were all found to be smaller in the NL3 KI. Further, many white matter structures were found to be significantly smaller, such as the cerebral peduncle, corpus callosum, fornix/fimbria, and internal capsule. Fractional anisotropy measurements in these structures were also measured, and no differences were found. The volume changes in the white matter regions, therefore, are not due to a general breakdown in the microstructure of the tissue and seem to be caused by fewer axons or less mature axons. A larger radial diffusivity was also found in localized regions of the corpus callosum and cerebellum. The corpus callosal changes are particularly interesting as the thinning (or reduced volume) of the corpus callosum is a consistent finding in autism. This suggests that the NL3 KI model may be useful for examining white matter changes associated with autism.
A pervasive integration deficit could provide a powerful and elegant account of cognitive processing in autism spectrum disorders (ASD). However, in the case of visual Gestalt grouping, typically assessed by tasks that require participants explicitly to introspect on their own grouping perception, clear evidence for such a deficit remains elusive. To resolve this issue, we adopt an index of Gestalt grouping from the object-based attention literature that does not require participants to assess their own grouping perception. Children with ASD and mental- and chronological-age matched typically developing children (TD) performed speeded orientation discriminations of two diagonal lines. The lines were superimposed on circles that were either grouped together or segmented on the basis of color, proximity or these two dimensions in competition. The magnitude of performance benefits evident for grouped circles, relative to ungrouped circles, provided an index of grouping under various conditions. Children with ASD showed comparable grouping by proximity to the TD group, but reduced grouping by similarity. ASD seems characterized by a selective bias away from grouping by similarity combined with typical levels of grouping by proximity, rather than by a pervasive integration deficit.
Elevated whole blood serotonin 5-HT, or hyperserotonemia, is a common biomarker in autism spectrum disorder (ASD). The integrin β3 receptor subunit gene (ITGB3) is a quantitative trait locus for whole blood 5-HT levels. Recent work shows that integrin β3 interacts with the serotonin transporter (SERT) in both platelets and in the midbrain. Furthermore, multiple studies have now reported gene-gene interaction between the integrin β3 and SERT genes in association with ASD. Given the lack of previous data on the impact of integrin β3 on brain or behavioral phenotypes, we sought to compare mice with decreased or absent expression of the integrin β3 receptor subunit (Itgb3 +/- and -/-) with wildtype littermate controls in behavioral tasks relevant to ASD. These mice did not show deficits in activity level in the open field or anxiety-like behavior on the elevated plus maze, two potential confounds in the evaluation of mouse social behavior. In the three-chamber social test, mice lacking integrin β3 were shown to have normal sociability but did not show a preference for social novelty. Importantly, the absence of integrin β3 did not impair olfaction or the ability to recall familiar social odors. Additionally, mice lacking integrin β3 showed increased grooming behavior in novel environments. These preliminary studies reveal altered social and repetitive behavior in these mice, which suggests that the integrin β3 subunit may be involved in brain systems relevant to ASD. Further work is needed to fully characterize these behavioral changes and the underlying brain mechanisms.
Prototype formation is a critical skill for category learning. Research suggests that individuals with autism may have a deficit in prototype formation of some objects; however, results are mixed. This study used a natural category, faces, to further examine prototype formation in high-functioning individuals with autism. High-functioning children (age 8-13 years) and adults with autism (age 17-53 years) and matched controls were tested in a facial prototype formation task that has been used to test prototype formation abilities in typically developing infants and adults [Strauss, 1979]. Participants were familiarized to a series of faces depicting subtle variations in the spatial distance of facial features, and were then given a forced choice familiarity test between the mean prototype and the mode prototype. Overall, individuals in the autism group were significantly less likely to select the mean prototype face. Even though the children with autism showed this difference in prototype formation, this pattern was driven primarily by the adults, because the adults with autism were approximately four times less likely to select the mean prototype than were the control adults. These results provide further evidence that individuals with autism have difficulty abstracting subtle spatial information that is necessary not only for the formation of a mean prototype, but also for categorizing faces and objects.
Grammar is frequently considered to be a strength in the cognitive profile of individuals with autism spectrum disorders (ASDs); however, few studies have investigated how abstract (i.e. distinct from specific lexical items) is the grammatical knowledge of individuals with ASD. In this study, we examine the extent to which children with ASD have abstracted the transitive (SVO) frame in English. Participants in a longitudinal study of language acquisition in children with autism (17 children with ASD averaging 41 months of age, 18 TD children averaging 28 months of age) were taught two novel verbs in transitive sentences and asked (via intermodal preferential looking) whether these verbs mapped onto novel causative vs. noncausative actions. Both groups consistently mapped the verbs onto the causative actions (i.e. they engaged in syntactic bootstrapping). Moreover, the children with ASD's performance on this task was significantly and independently predicted by both vocabulary and sentence-processing measures obtained 8 months earlier. We conclude that many children with ASD are able to generalize grammatical patterns, and this ability may derive from earlier lexical and grammatical knowledge.
Autism spectrum disorder (ASD) is considered among the most heritable of all neurodevelopmental and psychiatric disorders, but identification of etiologically significant genetic markers and risk variants has been hampered by a lack of sufficiently large samples. Rapid phenotyping procedures, where self-report measures are used instead of extensive clinical assessment, have been proposed as methods for amassing large genetic databases due to their hypothesized time-efficiency and affordability. We assessed the diagnostic accuracy of potential rapid phenotyping procedures using the Social Communication Questionnaire and the Social Responsiveness Scale in a sample of 333 children who also received extensive phenotypic assessments. While the rapid phenotyping measures were able to accurately identify a large number of children with ASD, they also frequently failed to differentiate children with ASD from children with other complex neurobehavioral profiles. These data support the continued need of expert clinical validation in combination with rapid phenotyping procedures in order to accurately amass large-scale genetic collections of children with ASD.
About 80% of cases with autism express intellectual disability. Both in autism and in mental retardation without autism the majority of the cases are males, suggesting a X-chromosomal effect. In fact, some molecular evidence has been obtained for a common genetic background for autism spectrum disorders (ASD) and X-linked mental retardation (XLMR). In several genome-wide scans (GWS), evidence for linkage at X-chromosome has been reported including the GWS of Finnish ASD families with the highest multipoint lod score (MLS) of 2.75 obtained close to DXS7132 at Xq11.1. To further dissect the relationship between autism and genes implicated in XLMR, we have fine-mapped Xq11.1-q21.33 and analyzed five candidate genes in the region. We refined the region using 26 microsatellite markers and linkage analysis in 99 Finnish families with ASD. The most significant evidence for linkage was observed at DXS1225 on Xq21.1 with a nonparametric multipoint NPL(all) value of 3.43 (P = 0.0004). We sequenced the coding regions and splice sites of RPS6KA6 and ZNF711 residing at the peak region in 42 male patients from families contributing to the linkage. We also analyzed ACSL4 and DLG3, which have previously been known to cause XLMR and IL1RAPL2, a homologous gene for IL1RAPL1 that is mutated in autism and XLMR. A total of six novel and 11 known single nucleotide polymorphisms were identified. Further studies are warranted to analyze the candidate genes at Xq11.1-q21.33.
Although widespread alterations in cortical structure have been documented in individuals with autism, the functional implications of these alterations remain to be determined. Here, we adopted a novel inter-subject correlation (inter-SC) and intra-subject correlation (intra-SC) technique to quantify the reliability of the spatio-temporal responses of functional MR activity in adults with autism during free-viewing of a popular audio-visual movie. Whereas these complex stimuli evoke highly reliable shared response time courses in typical individuals, cortical activity was more variable across individuals with autism (low inter-SC). Interestingly, when we measured the responses within an autistic individual across repeated presentations of the movie, we observed a unique, idiosyncratic response time course that was reliably replicated within each individual (high intra-SC). Encouragingly, after filtering out the idiosyncratic responses from each individual time course, we were able to uncover a more typical response profile, which resembles the shared responses seen in the typical subjects. These findings indicate that, under conditions approximating real-life situations, the neural activity of individuals with autism is characterized by individualistic responses that, although reliable within an autistic individual, are both highly variable across autistic individuals and different from the responses observed within the typical subjects. These idiosyncratic responses may underlie the atypical behaviors observed in autism. At the same time, we are encouraged by the presence of the more typical activation pattern lurking beneath these idiosyncratic fluctuations. Taken together, these findings may pave the way to future research aimed at characterizing the idiosyncratic response profiles, which, in turn, might contribute to a better understanding of the heterogeneity of the autism spectrum and its diagnosis.
Structural alterations in brain morphology have been inconsistently reported in children compared to adults with autism spectrum disorder (ASD). We assessed these differences by performing meta-analysis on the data from 19 voxel-based morphometry studies. Common findings across the age groups were grey matter reduction in left putamen and medial prefrontal cortex (mPFC) and grey matter increases in the lateral PFC, while white matter decreases were seen mainly in the children in frontostriatal pathways. In the ASD sample, children/adolescents were more likely than adults to have increased grey matter in bilateral fusiform gyrus, right cingulate and insula. Results show that clear maturational differences exist in social cognition and limbic processing regions only in children/adolescents and not in adults with ASD, and may underlie the emotional regulation that improves with age in this population.
Autism is associated with widespread atypicalities in perception, cognition and social behavior. A crucial question concerns how these atypicalities are reflected in the underlying brain activation. One way to examine possible perturbations of cortical organization in autism is to analyze the activation of category-selective ventral visual cortex, already clearly delineated in typical populations. We mapped out the neural correlates of face, place and common object processing, using functional magnetic resonance imaging (fMRI), in a group of high-functioning adults with autism and a typical comparison group, under both controlled and more naturalistic, viewing conditions. There were no consistent group differences in place-related regions. Although there were no significant differences in the extent of the object-related regions, there was more variability for these regions in the autism group. The most marked group differences were in face-selective cortex, with individuals with autism evincing reduced activation, not only in fusiform face area but also in superior temporal sulcus and occipital face area. Ventral visual cortex appears to be organized differently in high-functioning adults with autism, at least for face-selective regions, although subtle differences may also exist for other categories. We propose that cascading developmental effects of low-level differences in neuronal connectivity result in a much more pronounced effect on later developing cortical systems, such as that for face-processing, than earlier maturing systems (those for objects and places).
Although autism presents a unique perceptual phenotype defined in part by atypical (often enhanced) analysis of spatial information, few biologically plausible hypotheses have been advanced to explain its neural underpinnings. One plausible explanation is functional but altered lateral connectivity mediating early or local mechanisms selectively responsive to different stimulus attributes, including spatial frequency and contrast. The goal of the present study was first to assess far visual acuity in autism using Landolt-C optotypes defined by different local stimulus attributes. Second, we investigated whether acuity is differentially affected in autism when target optotypes are simultaneously presented with flanking stimuli at different distances. This typical detrimental "crowding effect" of flanking stimuli on target optotype discrimination is attributed to lateral inhibitory interaction of neurons encoding for visual properties of distracters close to the target. Results failed to demonstrate a between-group difference in acuity to Landolt-C optotypes, whether defined by luminance- or texture-contrast. However, the expected crowding effect at one gap-size opening distance was evidenced for the control group only; a small effect was observed for the autism group at two gap-size opening. These results suggest that although far visual acuity is unremarkable in autism, altered local lateral connectivity within early perceptual areas underlying spatial information processing in autism is atypical. Altered local lateral connectivity in autism might originate from an imbalance in excitatory/inhibitory neural signaling, resulting in changes regarding elementary feature extraction and subsequent downstream visual integration and visuo-spatial analysis. This notion is discussed within the context of characteristic lower- and higher-level perceptual processing in autism.
This study compared the object descriptions of school-age children with high-functioning autism (HFA) with those of a matched group of typically developing children. Descriptions were elicited in a referential communication task where shared information was manipulated, and in a guessing game where clues had to be provided about the identity of an object that was hidden from the addressee. Across these tasks, increasingly complex levels of audience design were assessed: (1) the ability to give adequate descriptions from one's own perspective, (2) the ability to adjust descriptions to an addressee's perspective when this differs from one's own, and (3) the ability to provide indirect yet identifying descriptions in a situation where explicit labeling is inappropriate. Results showed that there were group differences in all three cases, with the HFA group giving less efficient descriptions with respect to the relevant context than the comparison group. More revealing was the identification of distinct adaptation profiles among the HFA participants: those who had difficulty with all three levels, those who displayed Level 1 audience design but poor Level 2 and Level 3 design, and those demonstrated all three levels of audience design, like the majority of the comparison group. Higher structural language ability, rather than symptom severity or social skills, differentiated those HFA participants with typical adaptation profiles from those who displayed deficient audience design, consistent with previous reports of language use in autism.
The brain builds an association between action and sensory feedback to predict the sensory consequence of self-generated motor commands. This internal model of action is central to our ability to adapt movements and may also play a role in our ability to learn from observing others. Recently, we reported that the spatial generalization patterns that accompany adaptation of reaching movements were distinct in children with autism spectrum disorder (ASD) as compared with typically developing (TD) children. To test whether the generalization patterns are specific to ASD, here, we compared the patterns of adaptation with those in children with attention deficit hyperactivity disorder (ADHD). Consistent with our previous observations, we found that in ASD, the motor memory showed greater than normal generalization in proprioceptive coordinates compared with both TD children and children with ADHD; children with ASD also showed slower rates of adaptation compared with both control groups. Children with ADHD did not show this excessive generalization to the proprioceptive target, but they did show excessive variability in the speed of movements with an increase in the exponential distribution of responses (τ) as compared with both TD children and children with ASD. The results suggest that slower rate of adaptation and anomalous bias towards proprioceptive feedback during motor learning are characteristics of autism, whereas increased variability in execution is a characteristic of ADHD.
Behavioral therapies are currently the most effective interventions for treating the diagnostic symptoms of autism. We employed a mouse model of autism to evaluate components of behavioral interventions that improve sociability in mice. BTBR T+tf/J (BTBR) is an inbred mouse strain that exhibits prominent behavioral phenotypes with face validity to all three diagnostic symptom categories of autism, including robust and well-replicated deficits in social approach and reciprocal social interactions. To investigate the role of peer interactions in the development of sociability, BTBR juvenile mice were reared in the same home cage with juvenile mice of a highly social inbred strain, C57BL/6J (B6). Subject mice were tested as young adults for sociability and repetitive behaviors. B6 controls reared with B6 showed their strain-typical high sociability. BTBR controls reared with BTBR showed their strain-typical lack of sociability. In contrast, BTBR reared with B6 as juveniles showed significant sociability as young adults. A 20-day intervention was as effective as a 40-day intervention for improving social approach behavior. High levels of repetitive self-grooming in BTBR were not rescued by peer-rearing with B6, indicating specificity of the intervention to the social domain. These results from a robust mouse model of autism support the interpretation that social enrichment with juvenile peers is a beneficial intervention for improving adult outcome in the social domain. This novel paradigm may prove useful for discovering factors that are essential for effective behavioral treatments, and biological mechanisms underlying effective behavioral interventions.
It has been suggested that atypicalities in low-level visual processing contribute to the expression and development of the unusual cognitive and behavioral profile seen in autism spectrum disorders (ASD). However, previous investigations have yielded mixed results. In the largest study of its kind (ASD n = 89; non-ASD = 52; mean age 15 years 6 months) and testing across the spectrum of IQ (range 52-133), we investigated performance on three measures of basic visual processing: motion coherence, form-from-motion and biological motion (BM). At the group level, we found no evidence of differences between the two groups on any of the tasks, suggesting that there is no fundamental visual motion processing deficit in individuals with an ASD, at least by adolescence. However, we identified a tail of individuals with ASD (18% of the sample) who had exceptionally poor BM processing abilities compared to the non-ASD group, and who were characterized by low IQ. For the entire sample of those both with and without ASD, performance on the BM task uniquely correlated with performance on the Frith-Happé animations, a higher-level task that demands the interpretation of moving, interacting agents in order to understand mental states. We hypothesize that this association reflects the shared social-cognitive characteristics of the two tasks, which have a common neural underpinning in the superior temporal sulcus.
Individuals with autism spectrum disorders (ASD) are impaired in understanding the emotional undertones of speech, many of which are communicated through prosody. Musical performance also employs a form of prosody to communicate emotion, and the goal of this study was to examine the ability of adolescents with ASD to understand musical emotion. We designed an experiment in which each musical stimulus served as its own control while we varied the emotional expressivity by manipulating timing and amplitude variation. We asked children and adolescents with ASD and matched controls as well as individuals with Williams syndrome (WS) to rate how emotional these excerpts sounded. Results show that children and adolescents with ASD are impaired relative to matched controls and individuals with WS at judging the difference in emotionality among the expressivity levels. Implications for theories of emotion in autism are discussed in light of these findings.
Individuals with autism have an atypical pattern of visual processing. Various studies have provided evidence that individuals with autism perceive the details of stimuli before the gestalt, the reverse of the typical pattern of visual processing. This study used the Rey Osterreith Complex Figure (ROCF) task and an objective scoring system to examine local/global processing approaches to its reproduction in 37 individuals diagnosed with high-functioning autism (HFA) compared to 49 age-, IQ-, and gender-matched typically developing controls (TD). The sample was divided into children (aged 8-14 years) and adolescents/adults (aged 15-47 years) to assess age effects. Results showed no difference in overall performance on the ROCF between HFA and TD children. TD participants displayed improved organizational and planning skills with age and a shift to global processing approaches, but there were no differences in performance between children and adolescents/adults with HFA. There was no evidence of enhanced local processing in either HFA group. These findings suggest that HFA individuals with average IQ scores do not have the clinically demonstrable evidence of the enhanced local processing thought to reflect increased local brain connectivity in more severely autistic individuals. The deficient global processing of the HFA adults reflects dependence of performance on impaired strategic problem-solving abilities, which has been demonstrated to result from under development of neural connectivity between visuo-spatial and frontal brain regions in HFA adults.