2016 Research Findings

The following studies were published in 2016. The grants awarded by ASF to fund these studies may have been distributed in years prior to 2016.

Mechanisms of Diminished Attention to Eyes in Autism
Moriuchi JM, Klin A, Jones W
OBJECTIVE: Two hypotheses, gaze aversion and gaze indifference, are commonly cited to explain a diagnostic hallmark of autism: reduced attention to others’ eyes. The two posit different areas of atypical brain function, different pathogenic models of disability, and different possible treatments. Evidence for and against each hypothesis is mixed but has thus far focused on older children and adults. The authors evaluated both mechanistic hypotheses in two sets of experiments at the time of initial diagnosis.
METHOD: Eye-tracking data were collected in 86 2-year-olds: 26 with autism, tested at initial diagnosis; 38 matched typically developing children; and 22 matched developmentally delayed children. In two experiments, the authors measured response to direct and implicit cueing to look at the eyes.
RESULTS: When directly cued to look at the eyes, 2-year-olds with autism did not look away faster than did typically developing children; their latency varied neither categorically nor dimensionally by degree of eye cueing. Moreover, direct cueing had a stronger sustained effect on their amount of eye-looking than on that of typically developing children. When presented with implicit social cues for eye-looking, 2-year-olds with autism neither shifted their gaze away nor more subtly averted their gaze to peripheral locations.
CONCLUSIONS: The results falsify the gaze aversion hypothesis; instead, at the time of initial diagnosis, diminished eye-looking in autism is consistent with passive insensitivity to the social signals in others’ eyes.
PMID: 27855484

Maturation of auditory neural processes in autism spectrum disorder — A longitudinal MEG study
Port RG, Edgar JC, Ku M, Bloy L, Murray R, Blaskey L, Levy SE, Roberts TP.
BACKGROUND: Individuals with autism spectrum disorder (ASD) show atypical brain activity, perhaps due to delayed maturation. Previous studies examining the maturation of auditory electrophysiological activity have been limited due to their use of cross-sectional designs. The present study took a first step in examining magnetoencephalography (MEG) evidence of abnormal auditory response maturation in ASD via the use of a longitudinal design.
METHODS: Initially recruited for a previous study, 27 children with ASD and nine typically developing (TD) children, aged 6- to 11-years-old, were re-recruited two to five years later. At both timepoints, MEG data were obtained while participants passively listened to sinusoidal pure-tones. Bilateral primary/secondary auditory cortex time domain (100 ms evoked response latency (M100)) and spectrotemporal measures (gamma-band power and inter-trial coherence (ITC)) were examined. MEG measures were also qualitatively examined for five children who exhibited “optimal outcome”, participants who were initially on spectrum, but no longer met diagnostic criteria at follow-up.
RESULTS: M100 latencies were delayed in ASD versus TD at the initial exam (~ 19 ms) and at follow-up (~ 18 ms). At both exams, M100 latencies were associated with clinical ASD severity. In addition, gamma-band evoked power and ITC were reduced in ASD versus TD. M100 latency and gamma-band maturation rates did not differ between ASD and TD. Of note, the cohort of five children that demonstrated “optimal outcome” additionally exhibited M100 latency and gamma-band activity mean values in-between TD and ASD at both timepoints. Though justifying only qualitative interpretation, these “optimal outcome” related data are presented here to motivate future studies.
CONCLUSIONS: Children with ASD showed perturbed auditory cortex neural activity, as evidenced by M100 latency delays as well as reduced transient gamma-band activity. Despite evidence for maturation of these responses in ASD, the neural abnormalities in ASD persisted across time. Of note, data from the five children whom demonstrated “optimal outcome” qualitatively suggest that such clinical improvements may be associated with auditory brain responses intermediate between TD and ASD. These “optimal outcome” related results are not statistically significant though, likely due to the low sample size of this cohort, and to be expected as a result of the relatively low proportion of “optimal outcome” in the ASD population. Thus, further investigations with larger cohorts are needed to determine if the above auditory response phenotypes have prognostic utility, predictive of clinical outcome.
PMID: 27158589

Brain responses to biological motion predict treatment outcome in young children with autism
Yang YJD, Allen T, Abdullahi SM, Pelphrey KA, Volkmar FR, Chapman SB
Autism Spectrum Disorder (ASD) is characterized by remarkable heterogeneity in social, communication, and behavioral deficits, creating a major barrier in identifying effective treatments for a given individual with ASD. To facilitate precision medicine in ASD, we utilized a well-validated biological motion neuroimaging task to identify pretreatment biomarkers that can accurately forecast the response to an evidence-based behavioral treatment, Virtual Reality-Social Cognition Training (VR-SCT). In a preliminary sample of 17 young adults with high-functioning ASD, we identified neural predictors of change in emotion recognition after VR-SCT. The predictors were characterized by the pretreatment brain activations to biological vs. scrambled motion in the neural circuits that support (a) language comprehension and interpretation of incongruent auditory emotions and prosody, and (b) processing socio-emotional experience and interpersonal affective information, as well as emotional regulation. The predictive value of the findings for individual adults with ASD was supported by regression-based multivariate pattern analyses with cross validation. To our knowledge, this is the first pilot study that shows neuroimaging-based predictive biomarkers for treatment effectiveness in adults with ASD. The findings have potentially far-reaching implications for developing more precise and effective treatments for ASD.
PMID: 28384509

Revealing the world of autism through the lens of a camera
Wang S, Fan S, Chen B, Hakimi S, Paul LK, Zhao Q, Adolphs R
People with autism spectrum disorder (ASD) show atypical attention to social stimuli [1] and gaze at faces [2] and complex images [3] in unusual ways. But all studies to date are limited by the experimenter’s selected stimuli, which are generally photographs taken by people without autism. What might participants with ASD show us if they were the ones taking the photos? We gave participants a digital camera and analysed the photos they took: images taken by participants with ASD had unusual features and showed strikingly different ways of photographing other people.
PMID: 27780054

Race, disability, and grade: Social relationships in children with autism spectrum disorders
Azad GF, Locke J, Kasari C, Mandell DS
Race is associated with social relationships among typically developing children; however, studies rarely examine the impact of race on social outcomes for children with autism spectrum disorder. This study examined how race (African American, Latino, Asian, or White) in conjunction with disability status (autism spectrum disorders or typically developing) and grade (grades K-2 or 3-5) affects friendships and social networks. The sample comprises 85 children with autism spectrum disorders and 85 typically developing controls matched on race, gender, age/grade, and classroom (wherever possible). Race, disability, and grade each had an independent effect on friendship nominations, and there was an interaction among the three variables. Specifically, children with autism spectrum disorders who were African American or Latino in the upper elementary grades received fewer friendship nominations than typically developing White children in the lower elementary grades. Only the presence of autism spectrum disorders was associated with social network centrality. Our results also suggested that Latino children with autism spectrum disorders in the upper elementary grades were at the highest risk of social isolation. Implications for re-conceptualizing social skills interventions are discussed.
PMID: 26966285

Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain. 

Goeden N, Velasquez J, Arnold KA, Chan Y, Lund BT, Anderson GM, Bonnin A.
Maternal inflammation during pregnancy affects placental function and is associated with increased risk of neurodevelopmental disorders in the offspring. The molecular mechanisms linking placental dysfunction to abnormal fetal neurodevelopment remain unclear. During typical development, serotonin (5-HT) synthesized in the placenta from maternal l-tryptophan (TRP) reaches the fetal brain. There, 5-HT modulates critical neurodevelopmental processes. We investigated the effects of maternal inflammation triggered in midpregnancy in mice by the immunostimulant polyriboinosinic-polyribocytidylic acid [poly(I:C)] on TRP metabolism in the placenta and its impact on fetal neurodevelopment. We show that a moderate maternal immune challenge upregulates placental TRP conversion rapidly to 5-HT through successively transient increases in substrate availability and TRP hydroxylase (TPH) enzymatic activity, leading to accumulation of exogenous 5-HT and blunting of endogenous 5-HT axonal outgrowth specifically within the fetal forebrain. The pharmacological inhibition of TPH activity blocked these effects. These results establish altered placental TRP conversion to 5-HT as a new mechanism by which maternal inflammation disrupts 5-HT-dependent neurogenic processes during fetal neurodevelopment.
The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.

Mice with Shank3 Mutations Associated with ASD and Schizophrenia Display Both Shared and Distinct Defects
Zhou Y, Kaiser T, Monteiro P, Zhang X, Van der Goes MS, Wang D, Barak B, Zeng M, Li C, Wells M, Amaya A, Nguyen S, Lewis M, Sanjana N, Zhou Y, Zhang M, Zhang F, Fu Z, Feng G.
Genetic studies have revealed significant overlaps of risk genes among psychiatric disorders. However, it is not clear how different mutations of the same gene contribute to different disorders. We characterized two lines of mutant mice with Shank3 mutations linked to ASD and schizophrenia. We found both shared and distinct synaptic and behavioral phenotypes. Mice with the ASD-linked InsG3680 mutation manifest striatal synaptic transmission defects before weaning age and impaired juvenile social interaction, coinciding with the early onset of ASD symptoms. On the other hand, adult mice carrying the schizophrenia-linked R1117X mutation show profound synaptic defects in prefrontal cortex and social dominance behavior. Furthermore, we found differential Shank3 mRNA stability and SHANK1/2 upregulation in these two lines. These data demonstrate that different alleles of the same gene may have distinct phenotypes at molecular, synaptic, and circuit levels in mice, which may inform exploration of these relationships in human patients.

Neurobiology of social behavior abnormalities in autism and Williams syndrome.
Barak B, Feng G.
Social behavior is a basic behavior mediated by multiple brain regions and neural circuits, and is crucial for the survival and development of animals and humans. Two neuropsychiatric disorders that have prominent social behavior abnormalities are autismspectrum disorders (ASD), which is characterized mainly by hyposociability, and Williams syndrome (WS), whose subjects exhibit hypersociability. Here we review the unique properties of social behavior in ASD and WS, and discuss the major theories in social behavior in the context of these disorders. We conclude with a discussion of the research questions needing further exploration to enhance our understanding of social behavior abnormalities.