Autism Spectrum Disorder Endophenotypes Research Articles

Pten haploinsufficient mice show broad brain overgrowth but selective impairments in autism-relevant behavioral tests

Accelerated head and brain growth (macrocephaly) during development is a replicated biological finding in a subset of individuals with autism spectrum disorder (ASD). However, the relationship between brain overgrowth and the behavioral and cognitive symptoms of ASD is poorly understood. The PI3K-Akt-mTOR pathway regulates cellular growth; several genes encoding negative regulators of this pathway are ASD risk factors, including PTEN. Mutations in PTEN have been reported in individuals with ASD and macrocephaly. We report that brain overgrowth is widespread in Pten germline haploinsufficient (Pten(+/-)) mice, reflecting Pten mRNA expression in the developing brain. We then ask if broad brain overgrowth translates into general or specific effects on the development of behavior and cognition by testing Pten(+/-) mice using assays relevant to ASD and comorbidities. Deficits in social behavior were observed in both sexes. Males also showed abnormalities related to repetitive behavior and mood/anxiety. Females exhibited circadian activity and emotional learning phenotypes. Widespread brain overgrowth together with selective behavioral impairments in Pten(+/-) mice raises the possibility that most brain areas and constituent cell types adapt to an altered trajectory of growth with minimal impact on the behaviors tested in our battery; however, select areas/cell types relevant to social behavior are more vulnerable or less adaptable, thus resulting in social deficits. Probing dopaminergic neurons as a candidate vulnerable cell type, we found social behavioral impairments in mice with Pten conditionally inactivated in dopaminergic neurons that are consistent with the possibility that desynchronized growth in key cell types may contribute to ASD endophenotypes.

Nonverbal and Verbal Cognitive Discrepancy Profiles in Autism Spectrum Disorders: Influence of Age and Gender

Research suggests that discrepant cognitive abilities are more common in children with autism spectrum disorder (ASD) and may indicate an important ASD endophenotype. The current study examined the frequency of IQ discrepancy profiles (nonverbal IQ > verbal IQ [NVIQ > VIQ], verbal IQ > nonverbal IQ [VIQ > NVIQ], and no split) and the relationship of gender, age, and ASD symptomatology to IQ discrepancy profile in a large sample of children with ASD. The NVIQ > VIQ profile occurred at a higher frequency than expected, had more young males, and showed more autism symptoms than the other groups. Results suggest that the NVIQ > VIQ profile may be less likely to represent a subtype of ASD, but rather a common developmental pathway for children with ASD and other disorders.

Alpha Asymmetry in Infants at Risk for Autism Spectrum Disorders

An emerging focus of research on autism spectrum disorder (ASD) targets the identification of early-developing ASD endophenotypes using infant siblings of affected children. One potential neural endophenotype is resting frontal electroencephalogram (EEG) alpha asymmetry, a metric of hemispheric organization. Here, we examined the development of frontal EEG alpha asymmetry in ASD high-risk and low-risk infant populations. Our findings demonstrate that low and high-risk infants show different patterns of alpha asymmetry at 6 months of age and opposite growth trajectories in asymmetry over the following 12 months. These results support the candidacy of alpha asymmetry as an early neural ASD endophenotype.

Behavioral and cognitive core domains shared between autism spectrum disorder and schizophrenia

Growing genetic evidence including results of genome-wide association studies and whole-genome sequencing is still perplexing scientists in the fields of human complex traits and compels them to reconsider the relationship between autism spectrum disorder (ASD) and schizophrenia. The developmental trajectory of schizophrenia may be characterized by difficulties in “theory of mind” tasks, poor insight or imagination, low empathy level, weak executive function, failure in social judgments, delayed language development, movement mannerisms, motoric rituals, strong preoccupation with unusual objects, bizarre habits, and high intelligence. Most of these characteristics are associated with the standard criteria for ASD and all of them are core domains or endophenotypes of ASD. The diagnosed ASD cases, which were found in individuals with schizophrenia, have a significant tendency to be highfunctioning and to have atypical age of ASD manifestation. Episodic features including reality distortion, which can be seen in individual with ASD, may be associated with hyperarousal conditions with cognitive hypersensitivity, misattribution of negative experiences, and the perceptual thinking style. Together with the emerging new genetic concepts concerning human behavioral complex traits, the results and constructions of these recent studies may further warrant that reconsideration of the relationship between ASD and psychotic conditions is necessary. In addition, the possibility that psychotic conditions are the secondary derivative states in individuals with ASD or in individuals with subclinical ASD components should be constructively examined.

Atypical lateralization of ERP response to native and non-native speech in infants at risk for autism spectrum disorder

Language impairment is common in autism spectrum disorders (ASD) and is often accompanied by atypical neural lateralization. However, it is unclear when in development language impairment or atypical lateralization first emerges. To address these questions, we recorded event-related-potentials (ERPs) to native and non-native speech contrasts longitudinally in infants at risk for ASD (HRA) over the first year of life to determine whether atypical lateralization is present as an endophenotype early in development and whether these infants show delay in a very basic precursor of language acquisition: phonemic perceptual narrowing. ERP response for the HRA group to a non-native speech contrast revealed a trajectory of perceptual narrowing similar to a group of low-risk controls (LRC), suggesting that phonemic perceptual narrowing does not appear to be delayed in these high-risk infants. In contrast there were significant group differences in the development of lateralized ERP response to speech: between 6 and 12 months the LRC group displayed a lateralized response to the speech sounds, while the HRA group failed to display this pattern. We suggest the possibility that atypical lateralization to speech may be an ASD endophenotype over the first year of life.

Developmental Trajectories of Resting EEG Power: An Endophenotype of Autism Spectrum Disorder

Current research suggests that autism spectrum disorder (ASD) is characterized by asynchronous neural oscillations. However, it is unclear whether changes in neural oscillations represent an index of the disorder or are shared more broadly among both affected and unaffected family members. Additionally, it remains unclear how early these differences emerge in development and whether they remain constant or change over time. In this study we examined developmental trajectories in spectral power in infants at high- or low-risk for ASD. Spectral power was extracted from resting EEG recorded over frontal regions of the scalp when infants were 6, 9, 12, 18 and 24 months of age. We used multilevel modeling to assess change over time between risk groups in the delta, theta, low alpha, high alpha, beta, and gamma frequency bands. The results indicated that across all bands, spectral power was lower in high-risk infants as compared to low-risk infants at 6-months of age. Furthermore high-risk infants showed different trajectories of change in spectral power in the subsequent developmental window indicating that not only are the patterns of change different, but that group differences are dynamic within the first two years of life. These findings remained the same after removing data from a subset of participants who displayed ASD related behaviors at 24 or 36 months. These differences in the nature of the trajectories of EEG power represent important endophenotypes of ASD.

MeCP2+/− mouse model of RTT reproduces auditory phenotypes associated with Rett syndrome and replicate select EEG endophenotypes of autism spectrum disorder

Impairments in cortical sensory processing have been demonstrated in Rett syndrome (RTT) and Autism Spectrum Disorders (ASD) and are thought to contribute to high-order phenotypic deficits. However, underlying pathophysiological mechanisms for these abnormalities are unknown. This study investigated auditory sensory processing in a mouse model of RTT with a heterozygous loss of MeCP2 function. Cortical abnormalities in a number of neuropsychiatric disorders, including ASD are reflected in auditory evoked potentials and fields measured by EEG and MEG. One of these abnormalities, increased latency of cortically sourced components, is associated with language and developmental delay in autism. Additionally, gamma-band abnormalities have recently been identified as an endophenotype of idiopathic autism. Both of these cortical abnormalities are potential clinical endpoints for assessing treatment. While ascribing similar mechanisms of idiopathic ASD to Rett syndrome (RTT) has been controversial, we sought to determine if mouse models of RTT replicate these intermediate phenotypes. Mice heterozygous for the null mutations of the gene MeCP2, were implanted for EEG. In response to auditory stimulation, these mice recapitulated specific latency differences as well as select gamma and beta band abnormalities associated with ASD. MeCP2 disruption is the predominant cause of RTT, and reductions in MeCP2 expression predominate in ASD. This work further suggests a common cortical pathophysiology for RTT and ASD, and indicates that the MeCP2+/− model may be useful for preclinical development targeting specific cortical processing abnormalities in RTT with potential relevance to ASD.

Motor impairment in sibling pairs concordant and discordant for autism spectrum disorders

Although motor impairment is frequently observed in children with autism spectrum disorders (ASD), the manner in which these impairments aggregate in families affected by autism is unknown. We used a standardized measure of motor proficiency to objectively examine quantitative variation in motor proficiency in sibling pairs concordant and discordant for ASD. Motor impairment of sibling pairs from 67 ASD-affected families comprising 29 concordant pairings and 48 discordant pairings were assessed using the Bruininks Oseretsky Test of Motor Proficiency, 2nd Edition, a standardized measure of motor proficiency. Motor skills were substantially impaired among ASD-affected children and highly correlated with autistic severity and IQ, whereas motor skills in unaffected siblings were essentially normal. Total motor composite scores of at least one standard deviation below the general population mean were seen in 83% of the affected group compared with 6% in the unaffected siblings. Findings indicate that motor impairment constitutes a core characteristic of ASD (not necessarily an ASD endophenotype), which has distinct implications for taxonomy, diagnosis, and approaches to intervention.

Neural Correlates of Familiar and Unfamiliar Face Processing in Infants at Risk for Autism Spectrum Disorders

Examining the neural correlates associated with processing social stimuli offers a viable option to the challenge of studying early social processing in infants at risk for autism spectrum disorders (ASDs). The present investigation included 32 12-month olds at high risk for ASD and 24 low-risk control infants, defined on the basis of family history. Infants were presented with familiar and unfamiliar faces, and three components of interest were explored for amplitude and latency differences. The anticipated developmental effects of emerging hemispheric asymmetry for face-sensitive components (the N290 and P400) were observed, as were familiarity effects for a component related to attention (the Nc). Although there were no striking group differences in the neural response to faces, there was some evidence for a developmental lag in an attentional component for the high-risk group. The infant ASD endophenotype, though elusive, may be better defined through expanding the age of study and addressing change over time in response to varied stimuli.

Contrast sensitivity for motion detection and direction discrimination in adolescents with autism spectrum disorders and their siblings

The magnocellular (M) pathway hypothesis proposes that impaired visual motion perception observed in individuals with Autism Spectrum Disorders (ASD) might be mediated by atypical functioning of the subcortical M pathway, as this pathway provides the bulk of visual input to cortical motion detectors. To test this hypothesis, we measured luminance and chromatic contrast sensitivity, thought to tap M and Parvocellular (P) pathway processing, respectively. We also tested the hypothesis that motion processing is impaired in ASD using a novel paradigm that measures motion processing while controlling for detectabilty. Specifically, this paradigm compares contrast sensitivity for detection of a moving grating with contrast sensitivity for direction-of-motion discrimination of that same moving grating. Contrast sensitivities from adolescents with ASD were compared to typically-developing adolescents, and also unaffected siblings of individuals with ASD (SIBS). The results revealed significant group differences on P, but not M, pathway processing, with SIBS showing higher chromatic contrast sensitivity than both participants with ASD and TD participants. This atypicality, unique to SIBS, suggests the possible existence of a protective factor in these individuals against developing ASD. The results also revealed impairments in motion perception in both participants with ASD and SIBS, which may be an endophenotype of ASD. This impairment may be driven by impairments in motion detectors and/or by reduced input from neural areas that project to motion detectors, the latter possibility being consistent with the notion of reduced connectivity between neural areas in ASD.

Toddlers with Elevated Autism Symptoms Show Slowed Habituation to Faces

We explored social information processing and its relation to social and communicative symptoms in toddlers with Autism Spectrum Disorder (ASD) and their siblings. Toddlers with more severe symptoms of autism showed slower habituation to faces than comparison groups; slower face learning correlated with poorer social skills and lower verbal ability. Unaffected toddlers who were siblings of children with ASD also showed slower habituation to faces compared with toddlers without siblings with ASD. We conclude that slower rates of face learning may be an endophenotype of ASD and is associated with more severe symptoms among affected individuals.