1. Andersen PN, Skogli EW, Hovik KT, Egeland J, Oie M. {{Associations Among Symptoms of Autism, Symptoms of Depression and Executive Functions in Children with High-Functioning Autism: A 2 Year Follow-Up Study}}. {J Autism Dev Disord};2015 (Mar 13)
This study investigated the course of and association among changes in autism symptoms, depression symptoms and executive functions (EF) in children with high-functioning autism (HFA). Thirty-four children with HFA and 45 typically developing children (age 9-16) were assessed at baseline and after 2 years. Children with HFA had impaired scores on all measures at both time points. According to parent reports, depressive symptoms decreased over time, while EF improved and autism symptoms were stable. Children’s reports did not reveal less depressive symptoms over time. A positive association was found only between changes in autism symptoms and changes in symptoms of depression. A possible implication is that interventions aimed at either autism symptoms or symptoms of depression may improve the other.
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2. Aoki Y, Yamasue H. {{Reply: Does imitation act as an oxytocin nebulizer in autism spectrum disorder?}}. {Brain};2015 (Mar 11)
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3. Fujita-Jimbo E, Tanabe Y, Yu Z, Kojima K, Mori M, Li H, Iwamoto S, Yamagata T, Momoi MY, Momoi T. {{The association of GPR85 with PSD-95-neuroligin complex and autism spectrum disorder: a molecular analysis}}. {Mol Autism};2015;6:17.
BACKGROUND: Autism spectrum disorder (ASD) has a complex genetic etiology. Some symptoms and mutated genes, including neuroligin (NLGN), neurexin (NRXN), and SH3 and multiple ankyrin repeat domains protein (SHANK), are shared by schizophrenia and ASD. Little is known about the molecular pathogenesis of ASD. One of the possible molecular pathogenesis is an imbalance of excitatory and inhibitory receptors linked with the NLGN-PSD-95-SHANK complex via postsynaptic density protein/Drosophila disc large tumor suppressor/zonula occludens-1 protein (PDZ) binding. In the present study, we focused on GPR85 as a candidate gene for ASD because the C-terminal amino acid sequence of GPR85 [Thr-Cys-Val-Ile (YCVI)] is classified as a type II PDZ-binding motif, and GPR85 is a risk factor for schizophrenia. GPR85 is an orphan receptor that regulates neural and synaptic plasticity and modulates diverse behaviors, including learning and memory. While searching for molecules that associate with GPR85, we found that GPR85 was associated with postsynaptic density protein (PSD)-95 linked with NLGN in the brain. METHODS: We examined the proteins that associate with the C-terminal sequence of GPR85 by pull-down assay and immunoblot analysis and searched for a mutation of the GPR85 gene in patients with ASD. We used immunostaining to examine the intracellular localization of mutated GPR85 and its influence on the morphology of cells and neurons. RESULTS: The C-terminal sequence of GPR85 interacted with PSD-95 at PDZ1, while NLGN interacted with PSD-95 at PDZ3. Two male patients with ASD from independent Japanese families possessed inherited missense mutations at conserved sites in GPR85: one had T1033C (M152T) and the other had G1239T (V221L). These mutations were located in a domain related to G protein interaction and signal transduction. In contrast to wild-type GPR85, mutated GPR85 was more preferentially accumulated, causing endoplasmic reticulum stress, and disturbed the dendrite formation of hippocampal neurons. CONCLUSIONS: GPR85 associated with the PSD-95 linked with NLGN, which is related to ASD. GPR85 carrying the mutations detected in ASD patients disturbed dendrite formation that could be the candidate for molecular pathogenesis of ASD through the associated NLGN-PSD-95 receptor complex.
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4. Gabel HW, Kinde B, Stroud H, Gilbert CS, Harmin DA, Kastan NR, Hemberg M, Ebert DH, Greenberg ME. {{Disruption of DNA-methylation-dependent long gene repression in Rett syndrome}}. {Nature};2015 (Mar 11)
Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.
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5. Kazim SF, Cardenas-Aguayo Mdel C, Arif M, Blanchard J, Fayyaz F, Grundke-Iqbal I, Iqbal K. {{Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats}}. {PLoS One};2015;10(3):e0118627.
Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.
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6. Li Q, Loh DH, Kudo T, Truong D, Derakhshesh M, Kaswan ZM, Ghiani CA, Tsoa R, Cheng Y, Sun YE, Colwell CS. {{Circadian rhythm disruption in a mouse model of Rett syndrome circadian disruption in RTT}}. {Neurobiol Dis};2015 (Mar 14)
Disturbances in the sleep/wake cycle are prevalent in patients with Rett syndrome (RTT). We sought to determine whether the circadian system is disrupted in a RTT model, Mecp2-/y mice. We found that MeCP2 mutants showed decreased strength and precision of daily rhythms of activity coupled with extremely fragmented sleep. The central circadian clock (suprachiasmatic nucleus) exhibited significant reduction in the number of neurons expressing vasoactive intestinal peptide (VIP) as well as compromised spontaneous neural activity. The molecular clockwork was disrupted both centrally in the SCN and in peripheral organs, indicating a general disorganization of the circadian system. Disruption of the molecular clockwork was observed in fibroblasts of RTT patients. Finally, MeCP2 mutant mice were vulnerable to circadian disruption as chronic jet lag accelerated mortality. Our findings suggest that an integral role for MeCP2 in the circadian timing system provides a possible mechanistic explanation for the sleep/wake disturbances observed in RTT patients. The work raises the possibility that RTT patients may benefit from a temporally structured environment.
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7. Moore DJ, Reidy J, Heavey L. {{Attentional allocation of autism spectrum disorder individuals: Searching for a Face-in-the-Crowd}}. {Autism};2015 (Mar 13)
A study is reported which tests the proposition that faces capture the attention of those with autism spectrum disorders less than a typical population. A visual search task based on the Face-in-the-Crowd paradigm was used to examine the attentional allocation of autism spectrum disorder adults for faces. Participants were required to search for discrepant target images from within 9-image arrays. Both participants with autism spectrum disorder and control participants demonstrated speeded identification of faces compared to non-face objects. This indicates that when attention is under conscious control, both autism spectrum disorder and typically developing comparison adults show an attentional bias for faces, which contrasts with previous research which found an absence of an attentional bias for faces in autism spectrum disorder. Theoretical implications of this differentiation are discussed.
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8. Oddi D, Subashi E, Middei S, Bellocchio L, Lemaire-Mayo V, Guzman M, Crusio WE, D’Amato FR, Pietropaolo S. {{Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile x syndrome}}. {Neuropsychopharmacology};2015;40:1113-1122.
Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases.
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9. O’Keefe JA, Robertson-Dick E, Dunn EJ, Li Y, Deng Y, Fiutko AN, Berry-Kravis E, Hall DA. {{Characterization and Early Detection of Balance Deficits in Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)}}. {Cerebellum};2015 (Mar 13)
Fragile X-associated tremor/ataxia syndrome (FXTAS) results from a « premutation » size 55-200 CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Core motor features include cerebellar gait ataxia and kinetic tremor, resulting in progressive mobility disability. There are no published studies characterizing balance deficits in FMR1 premutation carriers with and without FXTAS using a battery of quantitative measures to test the sensory integration underlying postural control, automatic postural reflexes, and dynamic postural stability limits. Computerized dynamic posturography (CDP) and two performance-based balance measures were administered in 44 premutation carriers, 21 with FXTAS and 23 without FXTAS, and 42 healthy controls to compare balance and functional mobility between these groups. Relationships between FMR1 molecular variables, age, and sex and CDP scores were explored. FXTAS subjects demonstrated significantly lower scores on the sensory organization test (with greatest reductions in the vestibular control of balance), longer response latencies to balance perturbations, and reduced stability limits compared to controls. Premutation carriers without FXTAS also demonstrated significantly delayed response latencies and disrupted sensory weighting for balance control. Advancing age, male sex, increased CGG repeat size, and reduced X activation of the normal allele in premutation carrier women predicted balance dysfunction. These postural control deficits in carriers with and without FXTAS implicate dysfunctional cerebellar neural networks and may provide valuable outcome markers for tailored rehabilitative interventions. Our findings suggest that CDP may provide sensitive measures for early detection of postural control impairments in at-risk carriers and better characterize balance dysfunction and progression in FXTAS.
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10. Retico A, Tosetti M, Muratori F, Calderoni S. {{Neuroimaging-based methods for autism identification: a possible translational application?}}. {Funct Neurol};2014 (Oct-Dec);29(4):231-239.
Classification methods based on machine learning (ML) techniques are becoming widespread analysis tools in neuroimaging studies. They have the potential to enhance the diagnostic power of brain data, by assigning a predictive index, either of pathology or of treatment response, to the single subject’s acquisition. ML techniques are currently finding numerous applications in psychiatric illness, in addition to the widely studied neurodegenerative diseases. In this review we give a comprehensive account of the use of classification techniques applied to structural magnetic resonance images in autism spectrum disorders (ASDs). Understanding of these highly heterogeneous neurodevelopmental diseases could greatly benefit from additional descriptors of pathology and predictive indices extracted directly from brain data. A perspective is also provided on the future developments necessary to translate ML methods from the field of ASD research into the clinic.
11. Sarrett JC. {{Custodial Homes, Therapeutic Homes, and Parental Acceptance: Parental Experiences of Autism in Kerala, India and Atlanta, GA USA}}. {Cult Med Psychiatry};2015 (Mar 13)
The home is a critical place to learn about cultural values of childhood disability, including autism and intellectual disabilities. The current article describes how the introduction of autism into a home and the availability of intervention options change the structure and meaning of a home and reflect parental acceptance of a child’s autistic traits. Using ethnographic data from Kerala, India and Atlanta, GA USA, a description of two types of homes are developed: the custodial home, which is primarily focused on caring for basic needs, and the therapeutic home, which is focused on changing a child’s autistic traits. The type of home environment is respondent to cultural practices of child rearing in the home and influences daily activities, management, and care in the home. Further, these homes differ in parental acceptance of their autistic children’s disabilities, which is critical to understand when engaging in international work related to autism and intellectual disability. It is proposed that parental acceptance can be fostered through the use of neurodiverse notions that encourage autism acceptance.
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12. Schunke O, Schottle D, Vettorazzi E, Brandt V, Kahl U, Baumer T, Ganos C, David N, Peiker I, Engel AK, Brass M, Munchau A. {{Mirror me: Imitative responses in adults with autism}}. {Autism};2015 (Mar 13)
Dysfunctions of the human mirror neuron system have been postulated to underlie some deficits in autism spectrum disorders including poor imitative performance and impaired social skills. Using three reaction time experiments addressing mirror neuron system functions under simple and complex conditions, we examined 20 adult autism spectrum disorder participants and 20 healthy controls matched for age, gender and education. Participants performed simple finger-lifting movements in response to (1) biological finger and non-biological dot movement stimuli, (2) acoustic stimuli and (3) combined visual-acoustic stimuli with different contextual (compatible/incompatible) and temporal (simultaneous/asynchronous) relation. Mixed model analyses revealed slower reaction times in autism spectrum disorder. Both groups responded faster to biological compared to non-biological stimuli (Experiment 1) implying intact processing advantage for biological stimuli in autism spectrum disorder. In Experiment 3, both groups had similar ‘interference effects’ when stimuli were presented simultaneously. However, autism spectrum disorder participants had abnormally slow responses particularly when incompatible stimuli were presented consecutively. Our results suggest imitative control deficits rather than global imitative system impairments.
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13. Wang L, Wee CY, Tang X, Yap PT, Shen D. {{Multi-task feature selection via supervised canonical graph matching for diagnosis of autism spectrum disorder}}. {Brain Imaging Behav};2015 (Mar 12)
In this paper, we propose a novel framework for ASD diagnosis using structural magnetic resonance imaging (MRI). Our method deals explicitly with the distributional differences of gray matter (GM) and white matter (WM) features extracted from MR images. We project linearly the GM and WM features onto a canonical space where their correlations are mutually maximized. In this canonical space, features that are highly correlated with the class labels are selected for ASD diagnosis. In addition, graph matching is employed to preserve the geometrical relationships between samples when projected onto the canonical space. Our evaluations based on a public ASD dataset show that the proposed method outperforms all competing methods on all clinically important measures in differentiating ASD patients from healthy individuals.
