Laurent Mottron

Enhanced Pitch Sensitivity in Individuals with Autism: A Signal Detection Analysis

Past research has shown a superiority of participants with high-functioning autism over comparison groups in memorizing picture-pitch associations and in detecting pitch changes in melodies. A subset of individuals with autism, known as musical savants, is also known to possess absolute pitch. This superiority might be due to an abnormally high sensitivity to fine-grained pitch differences in sounds. To test this hypothesis, psychoacoustic tasks were devised so as to use a signal detection methodology. Participants were all musically untrained and were divided into a group of 12 high-functioning individuals with autism and a group of 12 normally developing individuals. Their task was to judge the pitch of pure tones in a same-different discrimination task and in a high-low categorization task. In both tasks, the obtained psychometric functions revealed higher pitch sensitivity for subjects with autism, with a more pronounced advantage over control participants in the categorization task. These findings confirm that pitch processing is enhanced in high-functioning autism. Superior performance in pitch discrimination and categorization extends previous findings of enhanced visual performance to the auditory domain. Thus, and as predicted by the enhanced perceptual functioning model for peaks of ability in autism (Mottron & Burack, 2001), autistic individuals outperform typically developing population in a variety of low-level perceptual tasks.

The Level and Nature of Autistic Intelligence

Autistics are presumed to be characterized by cognitive impairment, and their cognitive strengths (e.g., in Block Design performance) are frequently interpreted as low-level by-products of high-level deficits, not as direct manifestations of intelligence. Recent attempts to identify the neuroanatomical and neurofunctional signature of autism have been positioned on this universal, but untested, assumption. We therefore assessed a broad sample of 38 autistic children on the preeminent test of fluid intelligence, Ravens Progressive Matrices. Their scores were, on average, 30 percentile points, and in some cases more than 70 percentile points, higher than their scores on the Wechsler scales of intelligence. Typically developing control children showed no such discrepancy, and a similar contrast was observed when a sample of autistic adults was compared with a sample of nonautistic adults. We conclude that intelligence has been underestimated in autistics.

Epilepsy in Autism is Associated with Intellectual Disability and Gender: Evidence from a Meta-Analysis

BACKGROUND The association between epilepsy and autism is consistently reported, with a wide range of prevalence rates. This may be attributed to the heterogeneity of the samples with respect to age, comorbidity, sex, and intellectual disability (ID). We aimed to compare the prevalence of epilepsy 1) among autistic patients with ID versus autistic patients without ID and 2) among male versus female autistic patients. METHODS We reviewed all data available from published reports (1963-2006) on autism and epilepsy and conducted a meta-analysis of 10 and 14 studies, respectively, to assess the relative risk (RR) of epilepsy in autism according to ID and gender. The pooled groups included 2112 (627 with IQ > or = 70, 1485 with IQ < 70) and 1530 (1191 male, 339 female) patients, respectively. RESULTS There was a strong discrepancy in relative risk (RR) according to IQ, with more autistic patients with ID having epilepsy (RR = .555; 95% confidence interval [CI]: .42-.73; p < .001). The pooled prevalence of epilepsy was 21.5% in autistic subjects with ID versus 8% in autistic subjects without ID. There was a strong discrepancy in RR according to sex, favoring comorbidity of epilepsy in autistic girls (RR = .549; 95% CI: .45-.66; p < .001). The male:female ratio of autism comorbid with epilepsy was close to 2:1 whereas the male:female ratio of autism without epilepsy was 3.5:1. CONCLUSIONS The results of this meta-analysis indicate that risk for epilepsy in autism is a function of ID severity and distinguishes autism associated with epilepsy as a subgroup of autism by its male-female ratio.

Motion Perception in Autism: A Complex Issue

We present the first assessment of motion sensitivity for persons with autism and normal intelligence using motion patterns that require neural processing mechanisms of varying complexity. Compared to matched controls, our results demonstrate that the motion sensitivity of observers with autism is similar to that of nonautistic observers for different types of first-order (luminance-defined) motion stimuli, but significantly decreased for the same types of second-order (texture-defined) stimuli. The latter class of motion stimuli has been demonstrated to require additional neural computation to be processed adequately. This finding may reflect less efficient integrative functioning of the neural mechanisms that mediate visuoperceptual processing in autism. The contribution of this finding with regards to abnormal perceptual integration in autism, its effect on cognitive operations, and possible behavioral implications are discussed.

Novel de novo SHANK3 mutation in autistic patients

A number of studies have confirmed that genetic factors play an important role in autism spectrum disorder (ASD). More recently de novo mutations in the SHANK3 gene, a synaptic scaffolding protein, have been associated with the ASD phenotype. As part of our gene discovery strategy, we sequenced the SHANK3 gene in a cohort of 427 ASD subjects and 190 controls. Here, we report the identification of two putative causative mutations: one being a de novo deletion at an intronic donor splice site and one missense transmitted from an epileptic father. We were able to confirm the deleterious effect of the splice site deletion by RT‐PCR using mRNA extracted from cultured lymphoblastoid cells. The missense mutation, a leucine to proline at amino acid position 68, is perfectly conserved across all species examined, and would be predicted to disrupt an alpha‐helical domain. These results further support the role of SHANK3 gene disruption in the etiology of ASD.

Neuroanatomical differences in brain areas implicated in perceptual and other core features of autism revealed by cortical thickness analysis and voxel-based morphometry

Autism spectrum disorder is a complex neurodevelopmental variant thought to affect 1 in 166 [Fombonne ( 2003 ): J Autism Dev Disord 33:365–382]. Individuals with autism demonstrate atypical social interaction, communication, and repetitive behaviors, but can also present enhanced abilities, particularly in auditory and visual perception and nonverbal reasoning. Structural brain differences have been reported in autism, in terms of increased total brain volume (particularly in young children with autism), and regional gray/white matter differences in both adults and children with autism, but the reports are inconsistent [Amaral et al. (2008): Trends Neurosci 31:137–145]. These inconsistencies may be due to differences in diagnostic/inclusion criteria, and age and Intelligence Quotient of participants. Here, for the first time, we used two complementary magnetic resonance imaging techniques, cortical thickness analyses, and voxel‐based morphometry (VBM), to investigate the neuroanatomical differences between a homogenous group of young adults with autism of average intelligence but delayed or atypical language development (often referred to as “high‐functioning autism”), relative to a closely matched group of typically developing controls. The cortical thickness and VBM techniques both revealed regional structural brain differences (mostly in terms of gray matter increases) in brain areas implicated in social cognition, communication, and repetitive behaviors, and thus in each of the core atypical features of autism. Gray matter increases were also found in auditory and visual primary and associative perceptual areas. We interpret these results as the first structural brain correlates of atypical auditory and visual perception in autism, in support of the enhanced perceptual functioning model [Mottron et al. (2006): J Autism Dev Disord 36:27–43]. Hum Brain Mapp, 2010.

Direct Measure of the De Novo Mutation Rate in Autism and Schizophrenia Cohorts

The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (μ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ∼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n=142; 122 males and 20 females) or SCZ (n=143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Mutations in SYNGAP1 in Autosomal Nonsyndromic Mental Retardation

Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPase-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation. We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients. In contrast, we observed no de novo or truncating mutations in SYNGAP1 in samples from 142 subjects with autism spectrum disorders, 143 subjects with schizophrenia, and 190 control subjects. These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.

Enhanced visual functioning in autism: An ALE meta-analysis

Autistics often exhibit enhanced perceptual abilities when engaged in visual search, visual discrimination, and embedded figure detection. In similar fashion, while performing a range of perceptual or cognitive tasks, autistics display stronger physiological engagement of the visual system than do non‐autistics. To account for these findings, the Enhanced Perceptual Functioning Model proposes that enhanced autistic performance in basic perceptual tasks results from stronger engagement of sensory processing mechanisms, a situation that may facilitate an atypically prominent role for perceptual mechanisms in supporting cognition. Using quantitative meta‐analysis of published functional imaging studies from which Activation Likelihood Estimation maps were computed, we asked whether autism is associated with enhanced task‐related activity for a broad range of visual tasks. To determine whether atypical engagement of visual processing is a general or domain‐specific phenomenon, we examined three different visual processing domains: faces, objects, and words. Overall, we observed more activity in autistics compared to non‐autistics in temporal, occipital, and parietal regions. In contrast, autistics exhibited less activity in frontal cortex. The spatial distribution of the observed differential between‐group patterns varied across processing domains. Autism may be characterized by enhanced functional resource allocation in regions associated with visual processing and expertise. Atypical adult organizational patterns may reflect underlying differences in developmental neural plasticity that can result in aspects of the autistic phenotype, including enhanced visual skills, atypical face processing, and hyperlexia. Hum Brain Mapp, 2011