1. Bone D, Bishop S, Black MP, Goodwin MS, Lord C, Narayanan SS. {{Use of machine learning to improve autism screening and diagnostic instruments: effectiveness, efficiency, and multi-instrument fusion}}. {J Child Psychol Psychiatry}. 2016.
BACKGROUND: Machine learning (ML) provides novel opportunities for human behavior research and clinical translation, yet its application can have noted pitfalls (Bone et al., 2015). In this work, we fastidiously utilize ML to derive autism spectrum disorder (ASD) instrument algorithms in an attempt to improve upon widely used ASD screening and diagnostic tools. METHODS: The data consisted of Autism Diagnostic Interview-Revised (ADI-R) and Social Responsiveness Scale (SRS) scores for 1,264 verbal individuals with ASD and 462 verbal individuals with non-ASD developmental or psychiatric disorders, split at age 10. Algorithms were created via a robust ML classifier, support vector machine, while targeting best-estimate clinical diagnosis of ASD versus non-ASD. Parameter settings were tuned in multiple levels of cross-validation. RESULTS: The created algorithms were more effective (higher performing) than the current algorithms, were tunable (sensitivity and specificity can be differentially weighted), and were more efficient (achieving near-peak performance with five or fewer codes). Results from ML-based fusion of ADI-R and SRS are reported. We present a screener algorithm for below (above) age 10 that reached 89.2% (86.7%) sensitivity and 59.0% (53.4%) specificity with only five behavioral codes. CONCLUSIONS: ML is useful for creating robust, customizable instrument algorithms. In a unique dataset comprised of controls with other difficulties, our findings highlight the limitations of current caregiver-report instruments and indicate possible avenues for improving ASD screening and diagnostic tools.
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2. Cantio C, Jepsen JR, Madsen GF, Bilenberg N, White SJ. {{Exploring ‘The autisms’ at a cognitive level}}. {Autism Res}. 2016.
The autism spectrum is characterized by genetic and behavioral heterogeneity. However, it is still unknown whether there is a universal pattern of cognitive impairment in autism spectrum disorder (ASD) and whether multiple cognitive impairments are needed to explain the full range of behavioral symptoms. This study aimed to determine whether three widely acknowledged cognitive abnormalities (Theory of Mind (ToM) impairment, Executive Function (EF) impairment, and the presence of a Local Processing Bias (LB)) are universal and fractionable in autism, and whether the relationship between cognition and behavior is dependent on the method of behavioral assessment. Thirty-one high-functioning children with ASD and thirty-seven children with neurotypical development (NTD), comparable in age, gender and Intelligence Quotient (IQ), completed several tasks tapping into ToM, EF, and LB, and autistic symptomatology was assessed through parental and teacher questionnaires, parental interview and direct observation. We found that ToM and EF deficits differentiated the groups and some ToM and EF tasks were related to each other. ToM and EF were together able to correctly classify more than three-quarters of the children into cases and controls, despite relating to none of the specific behavioral measures. Only a small subgroup of individuals displayed a LB, which was unrelated to ToM and EF, and did not aid diagnostic classification, most likely contributing to non-diagnostic symptoms in a subgroup. Despite the characteristic heterogeneity of the autism spectrum, it remains a possibility therefore that a single cognitive cause may underlie the range of diagnostic symptoms in all individuals with autism. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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3. Cascio CJ, Woynaroski T, Baranek GT, Wallace MT. {{Toward an interdisciplinary approach to understanding sensory function in autism spectrum disorder}}. {Autism Res}. 2016.
Heightened interest in sensory function in persons with autism spectrum disorder (ASD) presents an unprecedented opportunity for impactful, interdisciplinary work between neuroscientists and clinical practitioners for whom sensory processing is a focus. In spite of this promise, and a number of overlapping perspectives on sensory function in persons with ASD, neuroscientists and clinical practitioners are faced with significant practical barriers to transcending disciplinary silos. These barriers include divergent goals, values, and approaches that shape each discipline, as well as different lexical conventions. This commentary is itself an interdisciplinary effort to describe the shared perspectives, and to conceptualize a framework that may guide future investigation in this area. We summarize progress to date and issue a call for clinical practitioners and neuroscientists to expand cross-disciplinary dialogue and to capitalize on the complementary strengths of each field to unveil the links between neural and behavioral manifestations of sensory differences in persons with ASD. Joining forces to face these challenges in a truly interdisciplinary way will lead to more clinically informed neuroscientific investigation of sensory function, and better translation of those findings to clinical practice. Likewise, a more coordinated effort may shed light not only on how current approaches to treating sensory processing differences affect brain and behavioral responses to sensory stimuli in individuals with ASD, but also on whether such approaches translate to gains in broader characteristics associated with ASD. It is our hope that such interdisciplinary undertakings will ultimately converge to improve assessment and interventions for persons with ASD. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Ethridge LE, White SP, Mosconi MW, Wang J, Byerly MJ, Sweeney JA. {{Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome}}. {Transl Psychiatry}. 2016; 6: e787.
Sensory hypersensitivities are common, clinically distressing features of Fragile X Syndrome (FXS). Preclinical evidence suggests this abnormality may result from synaptic hyper-excitability in sensory systems. This model predicts reduced sensory habituation to repeated stimulus presentation. Fourteen adolescents and adults with FXS and 15 age-matched controls participated in a modified auditory gating task using trains of 4 identical tones during dense array electroencephalography (EEG). Event-related potential and single trial time-frequency analyses revealed decreased habituation of the N1 event-related potential response in FXS, and increased gamma power coupled with decreases in gamma phase-locking during the early-stimulus registration period. EEG abnormalities in FXS were associated with parent reports of heightened sensory sensitivities and social communication deficits. Reduced habituation and altered gamma power and phase-locking to auditory cues demonstrated here in FXS patients parallels preclinical findings with Fmr1 KO mice. Thus, the EEG abnormalities seen in FXS patients support the model of neocortical hyper-excitability in FXS, and may provide useful translational biomarkers for evaluating novel treatment strategies targeting its neural substrate.
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5. Hebron J, Oldfield J, Humphrey N. {{Cumulative risk effects in the bullying of children and young people with autism spectrum conditions}}. {Autism}. 2016.
Students with autism are more likely to be bullied than their typically developing peers. However, several studies have shown that their likelihood of being bullied increases in the context of exposure to certain risk factors (e.g. behaviour difficulties and poor peer relationships). This study explores vulnerability to bullying from a cumulative risk perspective, where the number of risks rather than their nature is considered. A total of 722 teachers and 119 parents of young people with autism spectrum conditions participated in the study. Established risk factors were summed to form a cumulative risk score in teacher and parent models. There was evidence of a cumulative risk effect in both models, suggesting that as the number of risks increased, so did exposure to bullying. A quadratic effect was found in the teacher model, indicating that there was a disproportionate increase in the likelihood of being bullied in relation to the number of risk factors to which a young person was exposed. In light of these findings, it is proposed that more attention needs to be given to the number of risks to which children and young people with autism spectrum conditions are exposed when planning interventions and providing a suitable educational environment.
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6. Hecht PM, Hudson M, Connors SL, Tilley MR, Liu X, Beversdorf DQ. {{Maternal serotonin transporter genotype affects risk for ASD with exposure to prenatal stress}}. {Autism Res}. 2016.
Stress exposure during gestation is implicated in several neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous research showed that prenatal stress increases risk for ASD with peak exposure during the end of the second and the beginning of the third trimester. However, exposures to prenatal stress do not always result in ASD, suggesting that other factors may interact with environmental stressors to increase ASD risk. The present study examined a maternal genetic variation in the promoter region of the serotonin transporter gene (5-HTTLPR) affecting stress tolerance and its interaction with the effect of environmental stressors on risk for ASD. Two independent cohorts of mothers of ASD children recruited by the University of Missouri and Queen’s University were surveyed regarding the prenatal environment and genotyping on 5-HTTLPR was performed to explore this relationship. In both samples, mothers of children with ASD carrying the stress susceptible short allele variant of 5-HTTLPR experienced a greater number of stressors and greater stress severity when compared to mothers carrying the long allele variant. The temporal peak of stressors during gestation in these mothers was consistent with previous findings. Additionally, increased exposure to prenatal stress was not reported in the pregnancies of typically developing siblings from the same mothers, regardless of maternal genotype, suggesting against the possibility that the short allele might increase the recall of stress during pregnancy. The present study provides further evidence of a specific maternal polymorphism that may affect the risk for ASD with exposure to prenatal stress. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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7. Hoffmann E, Bruck C, Kreifelts B, Ethofer T, Wildgruber D. {{Reduced functional connectivity to the frontal cortex during processing of social cues in autism spectrum disorder}}. {J Neural Transm (Vienna)}. 2016.
People diagnosed with autism spectrum disorder (ASD) characteristically present with severe difficulties in interpreting every-day social signals. Currently it is assumed that these difficulties might have neurobiological correlates in alterations in activation as well as in connectivity in and between regions of the social perception network suggested to govern the processing of social cues. In this study, we conducted functional magnetic resonance imaging (fMRI)-based activation and connectivity analyses focusing on face-, voice-, and audiovisual-processing brain regions as the most important subareas of the social perception network. Results revealed alterations in connectivity among regions involved in the processing of social stimuli in ASD subjects compared to typically developed (TD) controls-specifically, a reduced connectivity between the left temporal voice area (TVA) and the superior and medial frontal gyrus. Alterations in connectivity, moreover, were correlated with the severity of autistic traits: correlation analysis indicated that the connectivity between the left TVA and the limbic lobe, anterior cingulate and the medial frontal gyrus as well as between the right TVA and the frontal lobe, anterior cingulate, limbic lobe and the caudate decreased with increasing symptom severity. As these frontal regions are understood to play an important role in interpreting and mentalizing social signals, the observed underconnectivity might be construed as playing a role in social impairments in ASD.
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8. Ishizuka Y, Yamamoto JI. {{Contingent imitation increases verbal interaction in children with autism spectrum disorders}}. {Autism}. 2016.
Several studies have suggested that contingent adult imitation increase nonverbal communication, such as attention and proximity to adults, in children with autism spectrum disorders. However, few studies have shown the effect of contingent imitation on verbal communication. This study examined whether children with autism were able to promote verbal interaction such as vocal imitation, vocalization, and vocal turn-taking via contingent imitation. We used an alternating treatment design composed of the conditions of contingent imitation and control for six children with autism (aged 33-63 months). For contingent imitation condition, adults imitated children’s vocalization immediately. For control condition, adults did not imitate but gave a vocal response immediately. Results showed that in contingent imitation condition, all children increased the number of vocal imitations and vocal turn-takings compared with control condition. The number of vocalizations increased in both condition for all children. Overall, it is suggested that all children promote verbal interaction via contingent imitation.
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9. Kuiper MW, Verhoeven EW, Geurts HM. {{The role of interstimulus interval and « Stimulus-type » in prepotent response inhibition abilities in people with ASD: A quantitative and qualitative review}}. {Autism Res}. 2016.
Autism spectrum disorders (ASD) are associated with prepotent response inhibition difficulties. However, the large variation between studies suggests that understudied factors, such as interstimulus interval (ISI) and « stimulus-type » (both hypothesized proxies of stressors influencing arousal), might influence the inhibitory abilities of people with ASD. Using meta-analysis, we tested whether differences in prepotent response inhibition between people with and without ASD was influenced by ISI. There was not enough variation in « stimulus-type » between the studies to include it as a moderator. Thirty-seven studies met inclusion criteria, with a combined sample size of 950 people with ASD and 966 typically developing controls. Additionally, a qualitative review including studies comparing a neutral and an arousing condition in one experiment was performed to examine whether fast ISI or specific arousing stimuli directly influence prepotent response inhibition. The meta-analysis indicated that ISI was not a relevant moderator. The qualitative review showed that ISI and « stimulus-type » had the same effect for both groups. Although all studies regarding ISI indicated that fast ISI worsened performance, different types of stimuli had either a positive or a negative influence. This could suggest that distinctive stimuli might affect arousal differently. While we replicated the inhibition difficulties in people with ASD (g = .51), our results do not show strong ASD-specific effects of ISI or « stimulus-type » on inhibition. Nonetheless, ISI and « stimulus-type » do seem to influence performance. Future research focusing on potential underlying factors (e.g., baseline physiological arousal) is needed to examine why this is the case. Autism Res 2016,. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Monyak RE, Emerson D, Schoenfeld BP, Zheng X, Chambers DB, Rosenfelt C, Langer S, Hinchey P, Choi CH, McDonald TV, Bolduc FV, Sehgal A, McBride SM, Jongens TA. {{Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model}}. {Mol Psychiatry}. 2016.
Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.Molecular Psychiatry advance online publication, 19 April 2016; doi:10.1038/mp.2016.51.
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11. Patel S, Day TN, Jones N, Mazefsky CA. {{Association between anger rumination and autism symptom severity, depression symptoms, aggression, and general dysregulation in adolescents with autism spectrum disorder}}. {Autism}. 2016.
Rumination has a large direct effect on psychopathology but has received relatively little attention in autism spectrum disorder despite the propensity to perseverate in this population. This study provided initial evidence that adolescents with autism spectrum disorder self-report more anger-focused rumination than typically developing controls, though there was substantial within-group variability. Anger rumination was positively correlated with autism symptom severity with both groups combined. Future studies that include measures of perseveration on special interests are needed to understand whether anger rumination is a manifestation of a perseverative type of repetitive behavior or a distinct trait. Even when controlling for autism symptom severity, however, anger-focused rumination was associated with poorer functioning, including more depression symptoms and overall emotional and behavioral dysregulation. Therefore, further inquiry regarding anger rumination in autism spectrum disorder is clinically important, and the potential impact of rumination-focused interventions should be explored.
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12. Pell PJ, Mareschal I, Calder AJ, von dem Hagen EA, Clifford CW, Baron-Cohen S, Ewbank MP. {{Intact priors for gaze direction in adults with high-functioning autism spectrum conditions}}. {Mol Autism}. 2016; 7: 25.
BACKGROUND: Autism Spectrum Conditions (ASC) are associated with a range of perceptual atypicalities, including abnormalities in gaze processing. Pellicano and Burr (Trends Cogn Sci 16(10):504-10, 2012) have argued that these atypicalities might be explained within a Bayesian framework, in which perception represents the combination of sensory information with prior knowledge. They propose that the Bayesian priors of individuals with ASC might be attenuated, such that their perception is less reliant on prior knowledge than neurotypical individuals. An important tenet of Bayesian decision theory is that increased uncertainty about incoming sensory information will lead to a greater influence of the prior on perception. Consistent with this, Mareschal et al. (Curr Biol 23(8):717-21, 2013) showed that when noise is added to the eyes of a face (increasing uncertainty about gaze direction), gaze is more likely to be perceived as direct. METHODS: We adopted the same paradigm as Mareschal et al. to determine whether the influence of a prior on gaze perception is reduced in neurotypical participants with high numbers of autistic traits (experiment 1) and in individuals with a clinical diagnosis of ASC (experiment 2). Participants were presented with synthetic faces and asked to make a judgement about the relative gaze directions of the faces. Uncertainty about gaze direction was manipulated by adding noise to the eyes of a face. RESULTS: Consistent with previous work, in both experiment 1 and experiment 2, participants showed a bias towards perceiving gaze as direct under conditions of uncertainty. However, there was no evidence that the magnitude of this bias was reduced either in the ASC group or in neurotypical controls with a high number of autistic traits. CONCLUSIONS: Our findings challenge the attenuated priors theory of perception in ASC (Trends Cogn Sci 16(10):504-10, 2012) and related proposals (Trends Cogn Sci 17(1):1, 2013, Front Hum Neurosci 8:302, 2014), and suggest priors for gaze direction are intact in high-functioning ASC.
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13. Schuh JM, Eigsti IM, Mirman D. {{Discourse comprehension in autism spectrum disorder: Effects of working memory load and common ground}}. {Autism Res}. 2016.
Pragmatic language impairments are nearly universal in autism spectrum disorders (ASD). Discourse requires that we monitor information that is shared or mutually known, called « common ground. » While many studies have examined the role of Theory of Mind (ToM) in such impairments, few have examined working memory (WM). Common ground impairments in ASD could reflect limitations in both WM and ToM. This study explored common ground use in youth ages 8-17 years with high-functioning ASD (n = 13) and typical development (n = 22); groups did not differ on age, gender, IQ, or standardized language. We tracked participants’ eye movements while they performed a discourse task in which some information was known only to the participant (e.g., was privileged; a manipulation of ToM). In addition, the amount of privileged information varied (a manipulation of WM). All participants were slower to fixate the target when considering privileged information, and this effect was greatest during high WM load trials. Further, the ASD group was more likely to fixate competing (non-target) shapes. Predictors of fixation patterns included ASD symptomatology, language ability, ToM, and WM. Groups did not differ in ToM. Individuals with better WM fixated the target more rapidly, suggesting an association between WM capacity and efficient discourse. In addition to ToM knowledge, WM capacity constrains common ground representation and impacts pragmatic skills in ASD. Social impairments in ASD are thus associated with WM capacity, such that deficits in domain-general, nonsocial processes such as WM exert an influence during complex social interactions. Autism Res 2016. (c) 2016 International Society for Autism Research, Wiley Periodicals, Inc.
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14. Zerbo O, Traglia M, Yoshida C, Heuer LS, Ashwood P, Delorenze GN, Hansen RL, Kharrazi M, Van de Water J, Yolken RH, Weiss LA, Croen LA. {{Maternal mid-pregnancy C-reactive protein and risk of autism spectrum disorders: the early markers for autism study}}. {Transl Psychiatry}. 2016; 6: e783.
Maternal pregnancy levels of the inflammatory marker C-reactive protein (CRP) has been previously associated with autism spectrum disorder (ASD) in the offspring. We conducted a population-based nested case-control study with 500 children with ASD, 235 with developmental delay (DD) and 580 general population (GP) controls to further investigate whether elevated CRP during pregnancy increases the risk of ASD. Maternal CRP concentration was measured in archived serum collected during 15-19 weeks of pregnancy and genome-wide single-nucleotide polymorphism (SNP) data were generated. The levels of CRP were compared between ASD vs GP and DD vs GP. The genetic associations with CRP were assessed via linear regression. Maternal CRP levels in mid-pregnancy were lower in mothers of ASD compared with controls. The maternal CRP levels in the upper third and fourth quartiles were associated with a 45 and 44% decreased risk of ASD, respectively. Two SNPs at the CRP locus showed strong association with CRP levels but they were not associated with ASD. No difference was found between maternal CRP levels of DD and controls. The reasons for the lower levels of CRP in mothers of ASD are not known with certainty but may be related to alterations in the immune response to infectious agents. The biological mechanisms underlying this association remain to be clarified.
