The relationship between sensory sensitivity and autistic traits in the general population.

Individuals with Autism Spectrum Disorders (ASDs) tend to have sensory processing difficulties (Baranek et al. in J Child Psychol Psychiatry 47:591–601, 2006). These difficulties include over- and under-responsiveness to sensory stimuli, and problems modulating sensory input (Ben-Sasson et al. in J Autism Dev Disorders 39:1–11, 2009). As those with ASD exist at the extreme end of a continuum of autistic traits that is also evident in the general population, we investigated the link between ASD and sensory sensitivity in the general population by administering two questionnaires online to 212 adult participants. Results showed a highly significant positive correlation (r = .775, p < .001) between number of autistic traits and the frequency of sensory processing problems. These data suggest a strong link between sensory processing and autistic traits in the general population, which in turn potentially implicates sensory processing problems in social interaction difficulties

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Infant head growth in male siblings of children with and without autism spectrum disorders

Previous research has indicated that children with autism exhibit accelerated head growth (HG) in infancy, although the timing of acceleration varies between studies. We examined infant HG trajectory as a candidate autism endophenotype by studying sibling pairs. We retrospectively obtained serial head orbitofrontal circumference measurements of: a) 48 sibling pairs in which one (n = 28) or both (n = 20) sibs were affected by an autism spectrum disorder (ASD); and b) 85 control male sibling pairs. Rate of HG of ASD subjects was slightly accelerated compared to controls, but the magnitude of difference was below the limit of reliability of standard measurement methods. Sibling intra class correlation for rate of HG was highly statistically significant; the magnitude was significantly stronger among autism-affected families (ICC = .63) than among controls (ICC = .26), p < .01. Infant HG trajectory appears familial—possibly endophenotypic—but was not a reliable marker of autism risk among siblings of ASD probands in this sample

A Pilot Study of Abnormal Growth in Autism Spectrum Disorders and Other Childhood Psychiatric Disorders

The aims of the current study were to examine whether early growth abnormalities are (a) comparable in autism spectrum disorders (ASD) and other childhood psychiatric disorders, and (b) specific to the brain or generalized to the whole body. Head circumference, height, and weight were measured during the first 19 months of life in 129 children with ASD and 59 children with non-ASD psychiatric disorders. Both groups showed comparable abnormal patterns of growth compared to population norms, especially regarding height and head circumference in relation to height. Thus abnormal growth appears to be related to psychiatric disorders in general and is mainly expressed as an accelerated growth of height not matched by an increase in weight or head circumference

Examining ecological validity in social interaction: problems of visual fidelity, gaze, and social potential

Social interaction is an essential part of the human experience, and much work has been done to study it. However, several common approaches to examining social interactions in psychological research may inadvertently either unnaturally constrain the observed behaviour by causing it to deviate from naturalistic performance, or introduce unwanted sources of variance. In particular, these sources are the differences between naturalistic and experimental behaviour that occur from changes in visual fidelity (quality of the observed stimuli), gaze (whether it is controlled for in the stimuli), and social potential (potential for the stimuli to provide actual interaction). We expand on these possible sources of extraneous variance and why they may be important. We review the ways in which experimenters have developed novel designs to remove these sources of extraneous variance. New experimental designs using a ‘two-person’ approach are argued to be one of the most effective ways to develop more ecologically valid measures of social interaction, and we suggest that future work on social interaction should use these designs wherever possible

Age-related change in brain metabolite abnormalities in autism: a meta-analysis of proton magnetic resonance spectroscopy studies

Abnormal trajectory of brain development has been suggested by previous structural magnetic resonance imaging and head circumference findings in autism spectrum disorders (ASDs); however, the neurochemical backgrounds remain unclear. To elucidate neurochemical processes underlying aberrant brain growth in ASD, we conducted a comprehensive literature search and a meta-analysis of 1H-magnetic resonance spectroscopy (1H-MRS) studies in ASD. From the 22 articles identified as satisfying the criteria, means and s.d. of measure of N-acetylaspartate (NAA), creatine, choline-containing compounds, myo-Inositol and glutamate+glutamine in frontal, temporal, parietal, amygdala-hippocampus complex, thalamus and cerebellum were extracted. Random effect model analyses showed significantly lower NAA levels in all the examined brain regions but cerebellum in ASD children compared with typically developed children (n=1295 at the maximum in frontal, P<0.05 Bonferroni-corrected), although there was no significant difference in metabolite levels in adulthood. Meta-regression analysis further revealed that the effect size of lower frontal NAA levels linearly declined with older mean age in ASD (n=844, P<0.05 Bonferroni-corrected). The significance of all frontal NAA findings was preserved after considering between-study heterogeneities (P<0.05 Bonferroni-corrected). This first meta-analysis of 1H-MRS studies in ASD demonstrated robust developmental changes in the degree of abnormality in NAA levels, especially in frontal lobes of ASD. Previously reported larger-than-normal brain size in ASD children and the coincident lower-than-normal NAA levels suggest that early transient brain expansion in ASD is mainly caused by an increase in non-neuron tissues, such as glial cell proliferation

Audiovisual Non-Verbal Dynamic Faces Elicit Converging fMRI and ERP Responses

In an everyday social interaction we automatically integrate another’s facial movements and vocalizations, be they linguistic or otherwise. This requires audiovisual integration of a continual barrage of sensory input—a phenomenon previously well-studied with human audiovisual speech, but not with non-verbal vocalizations. Using both fMRI and ERPs, we assessed neural activity to viewing and listening to an animated female face producing non-verbal, human vocalizations (i.e. coughing, sneezing) under audio-only (AUD), visual-only (VIS) and audiovisual (AV) stimulus conditions, alternating with Rest (R). Underadditive effects occurred in regions dominant for sensory processing, which showed AV activation greater than the dominant modality alone. Right posterior temporal and parietal regions showed an AV maximum in which AV activation was greater than either modality alone, but not greater than the sum of the unisensory conditions. Other frontal and parietal regions showed Common-activation in which AV activation was the same as one or both unisensory conditions. ERP data showed an early superadditive effect (AV > AUD + VIS, no rest), mid-range underadditive effects for auditory N140 and face-sensitive N170, and late AV maximum and common-activation effects. Based on convergence between fMRI and ERP data, we propose a mechanism where a multisensory stimulus may be signaled or facilitated as early as 60 ms and facilitated in sensory-specific regions by increasing processing speed (at N170) and efficiency (decreasing amplitude in auditory and face-sensitive cortical activation and ERPs). Finally, higher-order processes are also altered, but in a more complex fashion

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly

<p>Abstract</p> <p>Background</p> <p>Sotos syndrome is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the <it>NSD1 </it>gene, located at 5q35. Sotos syndrome has been described in a number of patients with autism spectrum disorders, suggesting that <it>NSD1 </it>could be involved in other cases of autism and macrocephaly.</p> <p>Methods</p> <p>We screened the <it>NSD1 </it>gene for mutations and deletions in 88 patients with autism spectrum disorders and macrocephaly (head circumference 2 standard deviations or more above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions. Dosage analysis of <it>NSD1 </it>was carried out using multiplex ligation-dependent probe amplification.</p> <p>Results</p> <p>We identified three missense variants (R604L, S822C and E1499G) in one patient each, but none is within a functional domain. In addition, segregation analysis showed that all variants were inherited from healthy parents and in two cases were also present in unaffected siblings, indicating that they are probably nonpathogenic. No partial or whole gene deletions/duplications were observed.</p> <p>Conclusion</p> <p>Our findings suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for <it>NSD1 </it>mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.</p

Medical conditions in autism spectrum disorders

Autism spectrum disorder (ASD) is a behaviourally defined syndrome where the etiology and pathophysiology is only partially understood. In a small proportion of children with the condition, a specific medical disorder is identified, but the causal significance in many instances is unclear. Currently, the medical conditions that are best established as probable causes of ASD include Fragile X syndrome, Tuberous Sclerosis and abnormalities of chromosome 15 involving the 15q11-13 region. Various other single gene mutations, genetic syndromes, chromosomal abnormalities and rare de novo copy number variants have been reported as being possibly implicated in etiology, as have several ante and post natal exposures and complications. However, in most instances the evidence base for an association with ASD is very limited and largely derives from case reports or findings from small, highly selected and uncontrolled case series. Not only therefore, is there uncertainty over whether the condition is associated, but the potential basis for the association is very poorly understood. In some cases the medical condition may be a consequence of autism or simply represent an associated feature deriving from an underlying shared etiology. Nevertheless, it is clear that in a growing proportion of individuals potentially causal medical conditions are being identified and clarification of their role in etio-pathogenesis is necessary. Indeed, investigations into the causal mechanisms underlying the association between conditions such as tuberous sclerosis, Fragile X and chromosome 15 abnormalities are beginning to cast light on the molecular and neurobiological pathways involved in the pathophysiology of ASD. It is evident therefore, that much can be learnt from the study of probably causal medical disorders as they represent simpler and more tractable model systems in which to investigate causal mechanisms. Recent advances in genetics, molecular and systems biology and neuroscience now mean that there are unparalleled opportunities to test causal hypotheses and gain fundamental insights into the nature of autism and its development

Acoustic Oddball during NREM Sleep: A Combined EEG/fMRI Study

Background: A condition vital for the consolidation and maintenance of sleep is generally reduced responsiveness to external stimuli. Despite this, the sleeper maintains a level of stimulus processing that allows to respond to potentially dangerous environmental signals. The mechanisms that subserve these contradictory functions are only incompletely understood. Methodology/Principal Findings: Using combined EEG/fMRI we investigated the neural substrate of sleep protection by applying an acoustic oddball paradigm during light NREM sleep. Further, we studied the role of evoked K-complexes (KCs), an electroencephalographic hallmark of NREM sleep with a still unknown role for sleep protection. Our main results were: (1) Other than in wakefulness, rare tones did not induce a blood oxygenation level dependent (BOLD) signal increase in the auditory pathway but a strong negative BOLD response in motor areas and the amygdala. (2) Stratification of rare tones by the presence of evoked KCs detected activation of the auditory cortex, hippocampus, superior and middle frontal gyri and posterior cingulate only for rare tones followed by a KC. (3) The typical high frontocentral EEG deflections of KCs were not paralleled by a BOLD equivalent. Conclusions/Significance: We observed that rare tones lead to transient disengagement of motor and amygdala responses during light NREM sleep. We interpret this as a sleep protective mechanism to delimit motor responses and to reduce the sensitivity of the amygdala towards further incoming stimuli. Evoked KCs are suggested to originate from a brain state wit