1. Bennett R, Somandapalli K, Di Martino A, Roy A. {{The neural correlates of emotional lability in children with ASD}}. {Brain Connect};2017 (May 15)
OBJECTIVE: Autism spectrum disorder (ASD) is exceptionally heterogeneous in both clinical and physiopathological presentations. Clinical variability applies to ASD-specific symptoms as well as frequent comorbid psychopathology such as emotional lability (EL). To date, the physiopathological underpinnings of the co-occurrence of EL and ASD are unknown. As a first step, we examined within-ASD inter-individual variability of EL and its neuronal correlates using resting-state fMRI (R-fMRI). METHODS: We analyzed R-fMRI data from 58 children diagnosed with ASD (5-12 years) in relation to the Conners’ Parent Rating Scale EL index. We performed both an a priori amygdala region-of-interest (ROI) analysis, and a multivariate unbiased whole-brain data-driven approach. RESULTS: While no significant brain-behavior relationships were identified regarding amygdala intrinsic functional connectivity (iFC), multivariate whole-brain analyses revealed an extended functional circuitry centered on two regions: middle frontal gyrus (MFG) and posterior insula (PI). Follow-up parametric and non-parametric ROI-analyses of these regions revealed relationships between EL and MFG- and PI-iFC with default, salience, and visual networks suggesting that higher-order cognitive and somatosensory processes are critical for emotion regulation in ASD. CONCLUSIONS: We did not detect evidence of amygdala iFC underpinning EL in ASD. However, exploratory whole-brain analyses identified large-scale networks that have been previously reported abnormal in ASD. Future studies should consider EL as a potential source of neuronal heterogeneity in ASD and focus on multinetwork interactions.
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2. Cai Y, Wang L, Xiao R, Li X, He X, Gao J, Xu H, Fan X. {{Autism-like behavior in the BTBR mouse model of autism is improved by propofol}}. {Neuropharmacology};2017 (May 15);118:175-187.
Autism spectrum disorder (ASD) is a developmental disorder that is characterized by symptoms of impaired social interactions, restricted interests and repetitive behaviors. Recent studies in humans and animal-models suggest that reduced GABAergic neurotransmission in the brain may underlie autism-related behavioral symptoms. It has been shown that propofol, a commonly used anesthetic, facilitates gamma-aminobutyric acid-mediated inhibitory synaptic transmission. The present study investigated whether propofol improved autistic phenotypes in BTBR T + Itpr3tf/J (BTBR) mice, a model of idiopathic autism. We found that i.p. injection of propofol in BTBR mice significantly improved aspects of social approach and repetitive behaviors without affecting reciprocal social interactions and without any detrimental effects in C57BL/6J mice. The ability of propofol to improve autistic phenotypes in BTBR mice through GABAergic neurotransmission suggests a potential pharmacological target for interventions to treat symptoms of autism.
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3. Croydon A, Karaminis T, Neil L, Burr D, Pellicano E. {{The light-from-above prior is intact in autistic children}}. {J Exp Child Psychol};2017 (May 15);161:113-125.
Sensory information is inherently ambiguous. The brain disambiguates this information by anticipating or predicting the sensory environment based on prior knowledge. Pellicano and Burr (2012) proposed that this process may be atypical in autism and that internal assumptions, or « priors, » may be underweighted or less used than in typical individuals. A robust internal assumption used by adults is the « light-from-above » prior, a bias to interpret ambiguous shading patterns as if formed by a light source located above (and slightly to the left) of the scene. We investigated whether autistic children (n=18) use this prior to the same degree as typical children of similar age and intellectual ability (n=18). Children were asked to judge the shape (concave or convex) of a shaded hexagon stimulus presented in 24 rotations. We estimated the relation between the proportion of convex judgments and stimulus orientation for each child and calculated the light source location most consistent with those judgments. Children behaved similarly to adults in this task, preferring to assume that the light source was from above left, when other interpretations were compatible with the shading evidence. Autistic and typical children used prior assumptions to the same extent to make sense of shading patterns. Future research should examine whether this prior is as adaptable (i.e., modifiable with training) in autistic children as it is in typical adults.
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4. Foss-Feig JH, Adkinson BD, Ji JL, Yang G, Srihari VH, McPartland JC, Krystal JH, Murray JD, Anticevic A. {{Searching for Cross-Diagnostic Convergence: Neural Mechanisms Governing Excitation and Inhibition Balance in Schizophrenia and Autism Spectrum Disorders}}. {Biol Psychiatry};2017 (May 15);81(10):848-861.
Recent theoretical accounts have proposed excitation and inhibition (E/I) imbalance as a possible mechanistic, network-level hypothesis underlying neural and behavioral dysfunction across neurodevelopmental disorders, particularly autism spectrum disorder (ASD) and schizophrenia (SCZ). These two disorders share some overlap in their clinical presentation as well as convergence in their underlying genes and neurobiology. However, there are also clear points of dissociation in terms of phenotypes and putatively affected neural circuitry. We highlight emerging work from the clinical neuroscience literature examining neural correlates of E/I imbalance across children and adults with ASD and adults with both chronic and early-course SCZ. We discuss findings from diverse neuroimaging studies across distinct modalities, conducted with electroencephalography, magnetoencephalography, proton magnetic resonance spectroscopy, and functional magnetic resonance imaging, including effects observed both during task and at rest. Throughout this review, we discuss points of convergence and divergence in the ASD and SCZ literature, with a focus on disruptions in neural E/I balance. We also consider these findings in relation to predictions generated by theoretical neuroscience, particularly computational models predicting E/I imbalance across disorders. Finally, we discuss how human noninvasive neuroimaging can benefit from pharmacological challenge studies to reveal mechanisms in ASD and SCZ. Collectively, we attempt to shed light on shared and divergent neuroimaging effects across disorders with the goal of informing future research examining the mechanisms underlying the E/I imbalance hypothesis across neurodevelopmental disorders. We posit that such translational efforts are vital to facilitate development of neurobiologically informed treatment strategies across neuropsychiatric conditions.
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5. Gantois I, Khoutorsky A, Popic J, Aguilar-Valles A, Freemantle E, Cao R, Sharma V, Pooters T, Nagpal A, Skalecka A, Truong VT, Wiebe S, Groves IA, Jafarnejad SM, Chapat C, McCullagh EA, Gamache K, Nader K, Lacaille JC, Gkogkas CG, Sonenberg N. {{Metformin ameliorates core deficits in a mouse model of fragile X syndrome}}. {Nat Med};2017 (May 15)
Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1-/y mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.
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6. Lamont RF, Jorgensen JS. {{Oxytocin-receptor antagonists in the aetiology of autism spectrum disorder}}. {Early Hum Dev};2017 (May 15)
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7. Lee E, Lee J, Kim E. {{Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders}}. {Biol Psychiatry};2017 (May 15);81(10):838-847.
Imbalances between excitation and inhibition in synaptic transmission and neural circuits have been implicated in autism spectrum disorders. Excitation and inhibition imbalances are frequently observed in animal models of autism spectrum disorders, and their correction normalizes key autistic-like phenotypes in these animals. These results suggest that excitation and inhibition imbalances may contribute to the development and maintenance of autism spectrum disorders and represent an important therapeutic target.
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8. Lim YH, Partridge K, Girdler S, Morris SL. {{Standing Postural Control in Individuals with Autism Spectrum Disorder: Systematic Review and Meta-analysis}}. {J Autism Dev Disord};2017 (May 15)
Impairments in postural control affect the development of motor and social skills in individuals with autism spectrum disorder (ASD). This review compared the effect of different sensory conditions on static standing postural control between ASD and neurotypical individuals. Results from 19 studies indicated a large difference in postural control between groups across all sensory conditions. This review revealed sensorimotor and multiple sensory processing deficits in ASD. The tendency for individuals with ASD to be more susceptible to postural instability with use of visual information compared with somatosensory information suggests perinatal alterations in sensory development. There is further scope for studies on the use of sensory information and postural control to provide additional evidence about sensorimotor processing in ASD.
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9. Luo M, Fan J, Wenger TL, Harr MH, Racobaldo M, Mulchandani S, Dubbs H, Zackai EH, Spinner NB, Conlin LK. {{CMIP haploinsufficiency in two patients with autism spectrum disorder and co-occurring gastrointestinal issues}}. {Am J Med Genet A};2017 (May 15)
Autism spectrum disorder (ASD) is a genetically heterogeneous group of disorders characterized by impairments in social communication and restricted interests. Though some patients with ASD have an identifiable genetic cause, the cause of most ASD remains elusive. Many ASD susceptibility loci have been identified through clinical studies. We report two patients with syndromic ASD and persistent gastrointestinal issues who carry de novo deletions involving the CMIP gene detected by genome-wide SNP microarray and fluorescence in situ hybridization (FISH) analysis. Patient 1 has a 517 kb deletion within 16q23.2q23.3 including the entire CMIP gene. Patient 2 has a 1.59 Mb deletion within 16q23.2q23.3 that includes partial deletion of CMIP in addition to 12 other genes, none of which have a known connection to ASD or other clinical phenotypes. The deletion of CMIP is rare in general population and was not found among a reference cohort of approximately 12,000 patients studied in our laboratory who underwent SNP array analysis for various indications. A 280 kb de novo deletion containing the first 3 exons of CMIP was reported in one patient who also demonstrated ASD and developmental delay. CMIP has previously been identified as a susceptibility locus for specific language impairment (SLI). It is notable that both patients in this study had significant gastrointestinal issues requiring enteral feedings, which is unusual for patients with ASD, in addition to unusually elevated birth length, further supporting a shared causative gene. These findings suggest that CMIP haploinsufficiency is the likely cause of syndromic ASD in our patients.
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10. Solders SK, Carper RA, Muller RA. {{White matter compromise in autism? Differentiating motion confounds from true differences in diffusion tensor imaging}}. {Autism Res};2017 (May 15)
Common findings from diffusion tensor imaging (DTI) in autism spectrum disorder (ASD) include reduced fractional anisotropy (FA), and increased mean and radial diffusivity (MD, RD) of white matter tracts. However, findings may be confounded by head motion. We examined how group-level motion matching affects DTI comparisons between ASD and typically developing (TD) groups. We included 57 ASD and 50 TD participants, comparing three subsets at increasing levels of motion-matching stringency: full sample (FS); quality-controlled (QC); and quantitatively-matched (QM). Groups were compared on diffusivity measures using Tract-Based Spatial Statistics (TBSS) and probabilistic tractography. Two methods for estimating diffusivity were compared: dti-fit and restore. TBSS: In set FS, FA was reduced in the ASD compared to the TD group throughout the right hemisphere. This effect was less extensive in set QC and absent in set QM. However, effect sizes remained stable or increased with better quality-control in some regions. Tractography: In set QM, MD was significantly higher in ASD overall and RD was higher in bilateral ILF. Effects were more robust in QM than in FS or QC sets. Effect sizes in several tracts increased with stringent quality matching. Restore improved tensor estimates, with some increases in effect sizes, but did not fully compensate for reduced quality. Findings suggest that some previously reported DTI findings for ASD may have been confounded by motion. However, effects in the tightly matched subset indicate that tract-specific anomalies probably do exist in ASD. Our results highlight the need for careful quality-control and motion-matching. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Stern YS, Maltman N, Roberts MY. {{The Influence of Maternal Pragmatics on the Language Skills of Children with Autism}}. {J Dev Behav Pediatr};2017 (May 15)
OBJECTIVE: This study examined the relationship between mothers’ pragmatics and child language in autism spectrum disorder (ASD) and non-ASD language delay (LD) mother-child dyads. METHODS: Participants consisted of 20 dyads of mothers and their toddlers aged 24 to 48 months, with ASD (n = 10) or non-ASD LD (n = 10). Groups were matched on child chronological age, language, and cognition. Maternal pragmatic language was qualified based on the degree of pragmatic violations during a semistructured interview, and was examined in relation to both child language, as measured by the Preschool Language Scale-4 and maternal use of language facilitation strategies during play. RESULTS: Lower rates of maternal pragmatic violations were associated with higher expressive language scores in children with ASD, and with higher receptive language scores for children with non-ASD LD. Within ASD dyads, maternal pragmatic violations were negatively related to mothers’ use of linguistic expansions. CONCLUSION: These findings indicate that parental pragmatics likely contribute to early language learning, and that the effects of maternal pragmatics on early language in ASD may be indirect (e.g., through parents’ use of facilitative strategies). Parent-mediated language interventions for ASD should therefore consider parent pragmatics, especially given that pragmatic differences have been identified in unaffected family members of individuals with ASD.
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12. Vivanti G, Nuske HJ. {{Autism, attachment, and social learning: Three challenges and a way forward}}. {Behav Brain Res};2017 (May 15);325(Pt B):251-259.
We explore three challenges that Autism Spectrum Disorder (ASD) poses to our understanding of the processes underlying early attachment. First, while caregiver-infant attachment and later social-affiliative behavior share common biobehavioral mechanisms, individuals with ASD are able to form secure attachment relationships, despite reduced social-emotional reciprocity and motivation for social interaction. Therefore, disruptions in social affiliation mechanisms can co-exist with secure caregiver-infant bonding. Second, while early attachment quality is associated with later social outcomes in typical development, interventions targeting caregiver-child interaction in ASD often show positive effects on parental responsivity and attachment quality, but not on child social behavior. Therefore, improvements in parent-child bonding do not necessarily result in improvements in social functioning in ASD. Third, individuals with ASD show normative brain activity and selective social affiliative behaviors in response to people that they know but not to unfamiliar people. We propose a conceptual framework to reformulate and address these three theoretical impasses posed by ASD, arguing that the dissociable pathways of child-parent bonding and social development in ASD are shaped by (1) a dissociation between externally-driven and internally-driven attachment responses and (2) atypical learning dynamics occurring during child-caregiver bonding episodes, which are governed by and influence social-affiliation motives and other operant contingencies.
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13. Vogel Ciernia A, Pride MC, Durbin-Johnson B, Noronha A, Chang A, Yasui DH, Crawley JN, LaSalle JM. {{Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering}}. {Hum Mol Genet};2017 (May 15);26(10):1839-1854.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) that occur sporadically in 1:10,000 female births. RTT is characterized by a period of largely normal development followed by regression in language and motor skills at 6-18 months of age. Mecp2 mutant mice recapitulate many of the clinical features of RTT, but the majority of behavioral assessments have been conducted in male Mecp2 hemizygous null mice as offspring of heterozygous dams. Given that RTT patients are predominantly female, we conducted a systematic analysis of developmental milestones, sensory abilities, and motor deficits, following the longitudinal decline of function from early postnatal to adult ages in female Mecp2 heterozygotes of the conventional Bird line (Mecp2tm1.1bird-/+), as compared to their female wildtype littermate controls. Further, we assessed the impact of postnatal maternal environment on developmental milestones and behavioral phenotypes. Cross-fostering to CD1 dams accelerated several developmental milestones independent of genotype, and induced earlier onset of weight gain in adult female Mecp2tm1.1bird-/+ mice. Cross-fostering improved the sensitivity of a number of motor behaviors that resulted in observable deficits in Mecp2tm1.1bird-/+ mice at much earlier (6-7 weeks) ages than were previously reported (6-9 months). Our findings indicate that female Mecp2tm1.1bird-/+ mice recapitulate many of the motor aspects of RTT syndrome earlier than previously appreciated. In addition, rearing conditions may impact the phenotypic severity and improve the ability to detect genotype differences in female Mecp2 mutant mice.
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14. Weiner DJ, Wigdor EM, Ripke S, Walters RK, Kosmicki JA, Grove J, Samocha KE, Goldstein JI, Okbay A, Bybjerg-Grauholm J, Werge T, Hougaard DM, Taylor J, Skuse D, Devlin B, Anney R, Sanders SJ, Bishop S, Mortensen PB, Borglum AD, Smith GD, Daly MJ, Robinson EB. {{Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders}}. {Nat Genet};2017 (May 15)
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways.
