Pubmed du 30/07/14

Pubmed du jour

2014-07-30 12:03:50

1. {{Correction: are maternal social networks and perceptions of trust associated with suspected autism spectrum disorder in offspring? A population-based study in Japan}}. {PLoS One};2014;9(7):e104332.

[This corrects the article DOI: 10.1371/journal.pone.0101359.].

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2. Aoki Y, Watanabe T, Abe O, Kuwabara H, Yahata N, Takano Y, Iwashiro N, Natsubori T, Takao H, Kawakubo Y, Kasai K, Yamasue H. {{Oxytocin’s neurochemical effects in the medial prefrontal cortex underlie recovery of task-specific brain activity in autism: a randomized controlled trial}}. {Mol Psychiatry};2014 (Jul 29)
The neuropeptide oxytocin may be an effective therapeutic strategy for the currently untreatable social and communication deficits associated with autism. Our recent paper reported that oxytocin mitigated autistic behavioral deficits through the restoration of activity in the ventromedial prefrontal cortex (vmPFC), as demonstrated with functional magnetic resonance imaging (fMRI) during a socio-communication task. However, it is unknown whether oxytocin exhibited effects at the neuronal level, which was outside of the specific task examined. In the same randomized, double-blind, placebo-controlled, within-subject cross-over clinical trial in which a single dose of intranasal oxytocin (24 IU) was administered to 40 men with high-functioning autism spectrum disorder (UMIN000002241/000004393), we measured N-acetylaspartate (NAA) levels, a marker for neuronal energy demand, in the vmPFC using 1H-magnetic resonance spectroscopy (1H-MRS). The differences in the NAA levels between the oxytocin and placebo sessions were associated with oxytocin-induced fMRI signal changes in the vmPFC. The oxytocin-induced increases in the fMRI signal could be predicted by the NAA differences between the oxytocin and placebo sessions (P=0.002), an effect that remained after controlling for variability in the time between the fMRI and 1H-MRS scans (P=0.006) and the order of administration of oxytocin and placebo (P=0.001). Furthermore, path analysis showed that the NAA differences in the vmPFC triggered increases in the task-dependent fMRI signals in the vmPFC, which consequently led to improvements in the socio-communication difficulties associated with autism. The present study suggests that the beneficial effects of oxytocin are not limited to the autistic behavior elicited by our psychological task, but may generalize to other autistic behavioral problems associated with the vmPFC.Molecular Psychiatry advance online publication, 29 July 2014; doi:10.1038/mp.2014.74.

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3. Camacho J, Ejaz E, Ariza J, Noctor SC, Martinez-Cerdeno V. {{RELN-expressing Neuron Density in Layer I of the Superior Temporal Lobe is Similar in Human Brains with Autism and in Age-Matched Controls}}. {Neurosci Lett};2014 (Jul 24)
Reelin protein (RELN) level is reduced in the cerebral cortex and cerebellum of subjects with autism. RELN is synthesized and secreted by a subpopulation of neurons in the developing cerebral cortex termed Cajal-Retzius (CR) cells. These cells are abundant in the marginal zone during cortical development, many die after development is complete, but a small population persists into adulthood. In adult brains, RELN is secreted by the surviving CR cells, by a subset of GABAergic interneurons in layer I, and by pyramidal cells and GABAergic interneurons in deeper cortical layers. It is widely believed that decreased RELN in layer I of the cerebral cortex of subjects with autism may result from a decrease in the density of RELN expressing neurons in layer I; however, this hypothesis has not been tested. We examined RELN expression in layer I of the adult human cortex and found that 70% of cells express RELN in both control and autistic subjects. We quantified the density of neurons in layer I of the superior temporal cortex of subjects with autism and age-matched control subjects. Our data show that there is no change in the density of neurons in layer I of the cortex of subjects with autism, and therefore suggest that reduced RELN expression in the cerebral cortex of subjects with autism is not a consequence of decreased numbers of RELN-expressing neurons in layer I. Instead reduced RELN may result from abnormal RELN processing, or a decrease in the number of other RELN-expressing neuronal cell types.

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4. Cellot G, Cherubini E. {{GABAergic signaling as therapeutic target for autism spectrum disorders}}. {Front Pediatr};2014;2:70.

gamma-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation-chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders.

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5. Chang YS, Owen JP, Desai SS, Hill SS, Arnett AB, Harris J, Marco EJ, Mukherjee P. {{Autism and Sensory Processing Disorders: Shared White Matter Disruption in Sensory Pathways but Divergent Connectivity in Social-Emotional Pathways}}. {PLoS One};2014;9(7):e103038.

Over 90% of children with Autism Spectrum Disorders (ASD) demonstrate atypical sensory behaviors. In fact, hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment is now included in the DSM-5 diagnostic criteria. However, there are children with sensory processing differences who do not meet an ASD diagnosis but do show atypical sensory behaviors to the same or greater degree as ASD children. We previously demonstrated that children with Sensory Processing Disorders (SPD) have impaired white matter microstructure, and that this white matter microstructural pathology correlates with atypical sensory behavior. In this study, we use diffusion tensor imaging (DTI) fiber tractography to evaluate the structural connectivity of specific white matter tracts in boys with ASD (n = 15) and boys with SPD (n = 16), relative to typically developing children (n = 23). We define white matter tracts using probabilistic streamline tractography and assess the strength of tract connectivity using mean fractional anisotropy. Both the SPD and ASD cohorts demonstrate decreased connectivity relative to controls in parieto-occipital tracts involved in sensory perception and multisensory integration. However, the ASD group alone shows impaired connectivity, relative to controls, in temporal tracts thought to subserve social-emotional processing. In addition to these group difference analyses, we take a dimensional approach to assessing the relationship between white matter connectivity and participant function. These correlational analyses reveal significant associations of white matter connectivity with auditory processing, working memory, social skills, and inattention across our three study groups. These findings help elucidate the roles of specific neural circuits in neurodevelopmental disorders, and begin to explore the dimensional relationship between critical cognitive functions and structural connectivity across affected and unaffected children.

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6. Cooper M, Thapar A, Jones DK. {{Erratum to: White Matter Microstructure Predicts Autistic Traits in Attention-Deficit/Hyperactivity Disorder}}. {J Autism Dev Disord};2014 (Jul 30)

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7. Daly E, Ecker C, Hallahan B, Deeley Q, Craig M, Murphy C, Johnston P, Spain D, Gillan N, Gudbrandsen M, Brammer M, Giampietro V, Lamar M, Page L, Toal F, Schmitz N, Cleare A, Robertson D, Rubia K, Murphy DG. {{Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion}}. {Brain};2014 (Jul 28)
It has been suggested that the restricted, stereotyped and repetitive behaviours typically found in autism are underpinned by deficits of inhibitory control. The biological basis of this is unknown but may include differences in the modulatory role of neurotransmitters, such as serotonin, which are implicated in the condition. However, this has never been tested directly. We therefore assessed the modifying role of serotonin on inhibitory brain function during a Go/No-Go task in 14 adults with autism and normal intelligence and 14 control subjects that did not differ in gender, age and intelligence. We undertook a double-blind, placebo-controlled, crossover trial of acute tryptophan depletion using functional magnetic resonance imaging. Following sham, adults with autism relative to controls had reduced activation in key inhibitory regions of inferior frontal cortex and thalamus, but increased activation of caudate and cerebellum. However, brain activation was modulated in opposite ways by depletion in each group. Within autistic individuals depletion upregulated fronto-thalamic activations and downregulated striato-cerebellar activations toward control sham levels, completely ‘normalizing’ the fronto-cerebellar dysfunctions. The opposite pattern occurred in controls. Moreover, the severity of autism was related to the degree of differential modulation by depletion within frontal, striatal and thalamic regions. Our findings demonstrate that individuals with autism have abnormal inhibitory networks, and that serotonin has a differential, opposite, effect on them in adults with and without autism. Together these factors may partially explain the severity of autistic behaviours and/or provide a novel (tractable) treatment target.

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8. Elsabbagh M, Bruno R, Wan MW, Charman T, Johnson MH, Green J. {{Infant Neural Sensitivity to Dynamic Eye Gaze Relates to Quality of Parent-Infant Interaction at 7-Months in Infants at Risk for Autism}}. {J Autism Dev Disord};2014 (Jul 30)
Links between brain function measures and quality of parent-child interactions within the early developmental period have been investigated in typical and atypical development. We examined such links in a group of 104 infants with and without a family history for autism in the first year of life. Our findings suggest robust associations between event related potential responses to eye gaze and observed parent-infant interaction measures. In both groups, infants with more positive affect exhibit stronger differentiation to gaze stimuli. This association was observed with the earlier P100 waveform component in the control group but with the later P400 component in infants at-risk. These exploratory findings are critical in paving the way for a better understanding of how infant laboratory measures may relate to overt behavior and how both can be combined in the context of predicting risk or clinical diagnosis in toddlerhood.

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9. Ervin DA, Williams A, Merrick J. {{Primary care: mental and behavioral health and persons with intellectual and developmental disabilities}}. {Front Public Health};2014;2:76.

INTRODUCTION: There are multiple ways to address the mental and behavioral health needs of people with intellectual and developmental disabilities (IDD). METHOD: In this paper, we do not argue for a particular approach or set of approaches, but instead review the benefits of integrating mental and behavioral health supports with primary healthcare based primarily on our experience in and understanding of healthcare systems in the United States. It is estimated that between 35 and 40% of people with IDD also live with psychiatric disorders. NADD, an association for persons with developmental disabilities and mental health needs in the US holds that coexisting IDD and a psychiatric disorder interferes with a person’s education and job readiness, and disrupts family and peer relationships. Historically, the presence of such disorders among people with IDD was not well understood or was discounted altogether. CONCLUSION: Over the past 15 years, however, greater attention is being paid to these comorbidities and their treatment, including the need to integrate mental and behavioral health treatments into primary care. Healthcare must account for multiple domains of quality of life, going beyond yearly physicals, and acute care visits, for example, to assess individuals’ healthcare goals and support them in achieving those goals. While integrated healthcare delivery systems can be difficult to find and access for people with IDD, such approaches are more responsive to the comprehensive needs and desires of people with IDD.

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10. Friedrich EV, Suttie N, Sivanathan A, Lim T, Louchart S, Pineda JA. {{Brain-computer interface game applications for combined neurofeedback and biofeedback treatment for children on the autism spectrum}}. {Front Neuroeng};2014;7:21.

Individuals with autism spectrum disorder (ASD) show deficits in social and communicative skills, including imitation, empathy, and shared attention, as well as restricted interests and repetitive patterns of behaviors. Evidence for and against the idea that dysfunctions in the mirror neuron system are involved in imitation and could be one underlying cause for ASD is discussed in this review. Neurofeedback interventions have reduced symptoms in children with ASD by self-regulation of brain rhythms. However, cortical deficiencies are not the only cause of these symptoms. Peripheral physiological activity, such as the heart rate and its variability, is closely linked to neurophysiological signals and associated with social engagement. Therefore, a combined approach targeting the interplay between brain, body, and behavior could be more effective. Brain-computer interface applications for combined neurofeedback and biofeedback treatment for children with ASD are currently nonexistent. To facilitate their use, we have designed an innovative game that includes social interactions and provides neural- and body-based feedback that corresponds directly to the underlying significance of the trained signals as well as to the behavior that is reinforced.

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11. Holt RJ, Chura LR, Lai MC, Suckling J, von dem Hagen E, Calder AJ, Bullmore ET, Baron-Cohen S, Spencer MD. {{‘Reading the Mind in the Eyes’: an fMRI study of adolescents with autism and their siblings}}. {Psychol Med};2014 (Feb 26):1-13.

BACKGROUND: Mentalizing deficits are a hallmark of the autism spectrum condition (ASC) and a potential endophenotype for atypical social cognition in ASC. Differences in performance and neural activation on the ‘Reading the Mind in the Eyes’ task (the Eyes task) have been identified in individuals with ASC in previous studies. METHOD: Performance on the Eyes task along with the associated neural activation was examined in adolescents with ASC (n = 50), their unaffected siblings (n = 40) and typically developing controls (n = 40). Based on prior literature that males and females with ASC display different cognitive and associated neural characteristics, analyses were stratified by sex. Three strategies were applied to test for endophenotypes at the level of neural activation: (1) identifying and locating conjunctions of ASC-control and sibling-control differences; (2) examining whether the sibling group is comparable to the ASC or intermediate between the ASC and control groups; and (3) examining spatial overlaps between ASC-control and sibling-control differences across multiple thresholds. RESULTS: Impaired behavioural performance on the Eyes task was observed in males with ASC compared to controls, but only at trend level in females; and no difference in performance was identified between sibling and same-sex control groups in both sexes. Neural activation showed a substantial endophenotype effect in the female groups but this was only modest in the male groups. CONCLUSIONS: Behavioural impairment on complex emotion recognition associated with mental state attribution is a phenotypic, rather than an endophenotypic, marker of ASC. However, the neural response during the Eyes task is a potential endophenotypic marker for ASC, particularly in females.

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12. Hong YZ, Zhang XJ, Hong L, Huang QR, Wu Q. {{[Influence of acupuncture of « Changqiang » (GV 1) on learning-memory ability and gap junction-related protein expression in the prefrontal cortex in autism rats]}}. {Zhen Ci Yan Jiu};2014 (Jun);39(3):173-179.

OBJECTIVE: To observe the effect of acupuncture stimulation of « Changqiang » (GV 1) on learning-memory ability and gap junction-related protein expression in the prefrontal cortex in autism rats. METHODS: Forty Wistar rats were equally randomized into control, model, GV 1 and non-acupoint groups. For establishing autism model, Valproate acid (VPA) sodium (600 mg/kg) was given (i. p.) to pregnancy rats whose intimate filial generation was confirmed to be successful autism by eye-open tests, swimming test and Morris water maze swimming tasks. GV 1 or non-acupoint (the spot below the costal region, i.e., 2 cm superior to the posterior superior iliac spine and about 3 cm lateral to the spine) was punctured and stimulated for about 1 min by using a filiform needle, once daily for 30 days except the weekends. The rats’ learning-memory ability was detected by Morris water maze tasks. The expression of gap junction-related proteins connexin 43 (CX 43), CX 32 and CX 36 in the frontal cortex tissue was detected by immunohistochemistry. RESULTS: After modeling, the postnatal rats’ eye-open time on day 14, 15 and 16 was significantly later (P < 0.05); and the swimming ability on postnatal day 13 and 15 was obviously lower in comparison with that of the control group (P < 0.05). After acupuncture treatment, the increased escape latency and the decreased swimming velocity of the autism rats were obviously suppressed in the GV 1 group, rather than in the non-acupoint group (P < 0.05). It suggests an improvement of learning-memory ability after acupuncture stimulation of GV 1. In comparison with the control group, the expression levels of cerebral CX 43, CX 32 and CX 36 proteins (mean grey values) were considerably down-regulated in the model group (P < 0.05). While compared to the model group, their expression levels were apparently up-regulated in the GV 1 group (P < 0.05) but not in the non-acupoint group. CONCLUSION: Acupuncture intervention of GV 1 can improve the learning- memory ability in autism rats, which may be closely related to its effects in up-regulating expression levels of CX 43, CX 32 and CX 36 in the frontal cortex.

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13. Jiang-Xie LF, Liao HM, Chen CH, Chen YT, Ho SY, Lu DH, Lee LJ, Liou HH, Fu WM, Gau SS. {{Autism-associated gene Dlgap2 mutant mice demonstrate exacerbated aggressive behaviors and orbitofrontal cortex deficits}}. {Mol Autism};2014;5:32.

BACKGROUND: As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap2, which encodes one of the main components of scaffold proteins in postsynaptic density (PSD), has been addressed as a candidate gene in autism spectrum disorders. To elucidate the disturbance of synaptic balance arising from Dlgap2 loss-of-function in vivo, we thus generated Dlgap2 (-/-) mice to investigate their phenotypes of synaptic function and social behaviors. METHODS: The creation of Dlgap2 (-/-) mice was facilitated by the recombineering-based method, Cre-loxP system and serial backcross. Reversal learning in a water T-maze was used to determine repetitive behaviors. The three-chamber approach task, resident-intruder test and tube task were performed to characterize the social behaviors of mutant mice. Cortical synaptosomal fraction, Golgi-Cox staining, whole-cell patch electrophysiology and transmission electron microscopy were all applied to investigate the function and structure of synapses in the orbitofrontal cortex (OFC) of Dlgap2 (-/-) mice. RESULTS: Dlgap2 (-/-) mice displayed exacerbated aggressive behaviors in the resident-intruder task, and elevated social dominance in the tube test. In addition, Dlgap2 (-/-) mice exhibited a clear reduction of receptors and scaffold proteins in cortical synapses. Dlgap2 (-/-) mice also demonstrated lower spine density, decreased peak amplitude of miniature excitatory postsynaptic current and ultra-structural deficits of PSD in the OFC. CONCLUSIONS: Our findings clearly demonstrate that Dlgap2 plays a vital role in social behaviors and proper synaptic functions of the OFC. Moreover, these results may provide valuable insights into the neuropathology of autism.

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14. Kitzbichler MG, Khan S, Ganesan S, Vangel MG, Herbert MR, Hamalainen MS, Kenet T. {{Altered Development and Multifaceted Band-Specific Abnormalities of Resting State Networks in Autism}}. {Biol Psychiatry};2014 (Jun 18)
BACKGROUND: Extensive evidence indicates that cortical connectivity patterns are abnormal in autism spectrum disorders (ASD), showing both overconnectivity and underconnectivity. Since, however, studies to date have focused on either spatial or spectral dimensions, but not both simultaneously, much remains unknown about the nature of these abnormalities. In particular, it remains unknown whether abnormal connectivity patterns in ASD are driven by specific frequency bands, by spatial network properties, or by some combination of these factors. METHODS: Magnetoencephalography recordings (15 ASD, 15 control subjects) mapped back onto cortical space were used to study resting state networks in ASD with both spatial and spectral specificity. The data were quantified using graph theoretic metrics. RESULTS: The two major factors that drove the nature of connectivity abnormalities in ASD were the mediating frequency band and whether the network included frontal nodes. These factors determined whether clustering and integration were increased or decreased in cortical resting state networks in ASD. These measures also correlated with abnormalities in the developmental trajectory of resting state networks in ASD. Lastly, these measures correlated with ASD severity in some frequency bands and spatially specific subnetworks. CONCLUSIONS: Our findings suggest that network abnormalities in ASD are widespread, are more likely in subnetworks that include the frontal lobe, and can be opposite in nature depending on the frequency band. These findings thus elucidate seemingly contradictory prior findings of both overconnectivity and underconnectivity in ASD.

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15. Klaiman C, Quintin EM, Jo B, Lightbody AA, Hazlett HC, Piven J, Hall SS, Reiss AL. {{Longitudinal Profiles of Adaptive Behavior in Fragile X Syndrome}}. {Pediatrics};2014 (Jul 28)
OBJECTIVE: To examine longitudinally the adaptive behavior patterns in fragile X syndrome. METHOD: Caregivers of 275 children and adolescents with fragile X syndrome and 225 typically developing children and adolescents (2-18 years) were interviewed with the Vineland Adaptive Behavior Scales every 2 to 4 years as part of a prospective longitudinal study. RESULTS: Standard scores of adaptive behavior in people with fragile X syndrome are marked by a significant decline over time in all domains for males and in communication for females. Socialization skills are a relative strength as compared with the other domains for males with fragile X syndrome. Females with fragile X syndrome did not show a discernible pattern of developmental strengths and weaknesses. CONCLUSIONS: This is the first large-scale longitudinal study to show that the acquisition of adaptive behavior slows as individuals with fragile X syndrome age. It is imperative to ensure that assessments of adaptive behavior skills are part of intervention programs focusing on childhood and adolescence in this condition.

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16. Lotta LT, Conrad K, Cory-Slechta D, Schor NF. {{Cerebellar Purkinje cell p75 neurotrophin receptor and autistic behavior}}. {Transl Psychiatry};2014;4:e416.

The p75 neurotrophin receptor (p75NTR) is normally expressed in cerebellar Purkinje cells throughout the lifespan. Children with autism spectrum behavior exhibit apparent cerebellar Purkinje cell loss. Cerebellar transcriptome changes seen in the murine prenatal valproate exposure model of autism include all of the proteins known to constitute the p75NTR interactome. p75NTR is a modulator of cytoplasmic and mitochondrial redox potential, and others have suggested that aberrant response to oxidant stress has a major role in the pathogenesis of autism. We have created Purkinje cell-selective p75NTR knockout mice that are the progeny of hemizygous Cre-Purkinje cell protein 2 C57Bl mice and p75NTR floxed C57Bl mice. These Cre-loxP mice exhibit complete knockout of p75NTR in ~50% of the cerebellar Purkinje cells. Relative to Cre-only mice and wild-type C57Bl mice, this results in a behavioral phenotype characterized by less allogrooming of (P<0.05; one-way analysis of variance) and socialization or fighting with (each P<0.05) other mice; less (1.2-fold) non-ambulatory exploration of their environment than wild-type (P<0.01) or Cre only (P<0.01) mice; and almost twofold more stereotyped jumping behavior than wild-type (P<0.05) or Cre (P<0.02) mice of the same strain. Wild-type mice have more complex dendritic arborization than Cre-loxP mice, with more neurites per unit area (P<0.025, Student’s t-test), more perpendicular branches per unit area (P<0.025) and more short branches/long neurite (P<0.0005). Aberrant developmental regulation of expression of p75NTR in cerebellar Purkinje cells may contribute to the pathogenesis of autism.

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17. Matthews NL, Ly AR, Goldberg WA. {{College Students’ Perceptions of Peers with Autism Spectrum Disorder}}. {J Autism Dev Disord};2014 (Jul 29)
Little is known about peer attitudes toward college students with autism spectrum disorder (ASD). Affective, behavioral, and cognitive attitudes toward vignette characters displaying behaviors characteristic of ASD were examined among 224 four-year university students who were randomly assigned to one of three labeling conditions for the primary vignette characters: high functioning autism (HFA), typical college student, or no label. Students in the HFA label condition reported more positive behavioral and cognitive attitudes toward the vignette characters than students in the no label condition. Male students and students with lower scores on the Broad Autism Phenotype Questionnaire reported more positive attitudes across study conditions. These experimental results suggest that knowledge of a diagnosis might improve attitudes toward college students with ASD.

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18. McMahon CM, Henderson HA. {{Error-monitoring in response to social stimuli in individuals with higher-functioning Autism Spectrum Disorder}}. {Dev Sci};2014 (Jul 28)
Error-monitoring, or the ability to recognize one’s mistakes and implement behavioral changes to prevent further mistakes, may be impaired in individuals with Autism Spectrum Disorder (ASD). Children and adolescents (ages 9-19) with ASD (n = 42) and typical development (n = 42) completed two face processing tasks that required discrimination of either the gender or affect of standardized face stimuli. Post-error slowing and the difference in Error-Related Negativity amplitude between correct and incorrect responses (ERNdiff ) were used to index error-monitoring ability. Overall, ERNdiff increased with age. On the Gender Task, individuals with ASD had a smaller ERNdiff than individuals with typical development; however, on the Affect Task, there were no significant diagnostic group differences on ERNdiff . Individuals with ASD may have ERN amplitudes similar to those observed in individuals with typical development in more social contexts compared to less social contexts due to greater consequences for errors, more effortful processing, and/or reduced processing efficiency in these contexts. Across all participants, more post-error slowing on the Affect Task was associated with better social cognitive skills.

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19. McMillin SE, Bultas MW, Wilmott J, Grafeman S, Zand DH. {{Rapid-Response Parenting Intervention in Diagnostic Centers as a Patient-Centered Innovation for Autism Spectrum Disorders}}. {J Autism Dev Disord};2014 (Jul 27)
Parents of children newly diagnosed with autism spectrum disorders are a high-need population for whom skills-based parenting interventions likely help. Diagnostic centers are compelling locations to deliver parenting interventions because families are served in an accessible location and at a time they receive overwhelming treatment recommendations. Additionally, behavioral interventions in these settings may be especially effective in helping parents feel an early sense of mastery of disruptive child behaviors and enable families grappling with this diagnosis to be proactive and build resilience. Providing parenting interventions in diagnostic centers is a promising service delivery innovation and deserves expanded piloting and testing.

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20. Napoli E, Duenas N, Giulivi C. {{Potential therapeutic use of the ketogenic diet in autism spectrum disorders}}. {Front Pediatr};2014;2:69.

The ketogenic diet (KGD) has been recognized as an effective treatment for individuals with glucose transporter 1 (GLUT1) and pyruvate dehydrogenase (PDH) deficiencies as well as with epilepsy. More recently, its use has been advocated in a number of neurological disorders prompting a newfound interest in its possible therapeutic use in autism spectrum disorders (ASD). One study and one case report indicated that children with ASD treated with a KGD showed decreased seizure frequencies and exhibited behavioral improvements (i.e., improved learning abilities and social skills). The KGD could benefit individuals with ASD affected with epileptic episodes as well as those with either PDH or mild respiratory chain (RC) complex deficiencies. Given that the mechanism of action of the KGD is not fully understood, caution should be exercised in ASD cases lacking a careful biochemical and metabolic characterization to avoid deleterious side effects or refractory outcomes.

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21. Neul JL, Lane JB, Lee HS, Geerts S, Barrish JO, Annese F, Baggett LM, Barnes K, Skinner SA, Motil KJ, Glaze DG, Kaufmann WE, Percy AK. {{Developmental delay in Rett syndrome: data from the natural history study}}. {J Neurodev Disord};2014;6(1):20.

BACKGROUND: Early development appears normal in Rett syndrome (OMIM #312750) and may be more apparent than real. A major purpose of the Rett Syndrome (RTT) Natural History Study (NHS) was to examine achievement of developmental skills or abilities in classic and atypical RTT and assess phenotype-genotype relations in classic RTT. METHODS: Developmental skills in four realms, gross and fine motor, and receptive and expressive communication from initial enrollment and longitudinal assessments for up to 7 years, were assessed from 542 females meeting criteria for classic RTT and 96 females with atypical RTT divided into two groups: 50 with better and 46 with poorer functional scores. Data were analyzed for age at acquisition and loss of developmental features and for phenotype-genotype effects. Acquired, lost, and retained skills were compared between classic RTT and atypical RTT with better or poorer functional scores using Fisher’s Exact test. To examine if the mean total score from the Motor Behavioral Assessment during follow-up differed for acquiring a skill, we used a generalized estimating equation assuming compound symmetry correlation structure within a subject. A general linear model was used to examine whether the mean age of acquisition or loss of a developmental skill differed by mutation type. P values <0.05 were considered significant and were two-sided without adjustment for multiple testing. Statistical analyses utilized SAS 9.3 (SAS Institute, Cary, NC, USA). RESULTS: Early developmental skills or abilities were often acquired albeit later than normal. More complex motor and communication acquisitions were delayed or absent. Clinical severity was less in those achieving the respective skill. Individuals with R133C, R294X, and R306C point mutations and 3′ truncations tended to have better developmental outcomes. CONCLUSIONS: Early developmental skills were acquired by many, but clear differences from normal emerged, particularly in skills expected after age 6 months. When comparing clinical severity, greater acquisition of specific skills was associated with specific mutations, confirming the impression that these mutations confer milder developmental abnormalities. These data may serve for planning and interpretation of early intervention studies in RTT. TRIAL REGISTRATION: This NHS study, clinicaltrials.gov (NCT00296764), represents the largest group of RTT participants assessed repeatedly by direct examination.

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22. Okamoto Y, Kitada R, Tanabe HC, Hayashi MJ, Kochiyama T, Munesue T, Ishitobi M, Saito DN, Yanaka HT, Omori M, Wada Y, Okazawa H, Sasaki AT, Morita T, Itakura S, Kosaka H, Sadato N. {{Attenuation of the contingency detection effect in the extrastriate body area in Autism Spectrum Disorder}}. {Neurosci Res};2014 (Jul 24)
Detection of the contingency between one’s own behavior and consequent social events is important for normal social development, and impaired contingency detection may be a cause of Autism Spectrum Disorder (ASD). To depict the neural underpinnings of this contingency effect, 19 adults with ASD and 22 control participants underwent functional MRI while imitating another’s actions and their actions being imitated by the other. As the extrastriate body area (EBA) receives efference copies of one’s own movements, we predicted that the EBA would show an atypical response during contingency detection in ASD. We manipulated two factors: the congruency of the executed and observed actions, and the order of action execution and observation. Both groups showed the congruency effect in the bilateral EBA during imitation. When action preceded observation, the left EBA of the control group showed the congruency effect, representing the response to being imitated, indicating contingency detection. The ASD group showed a reduced contingency effect in the left EBA. These results indicate that the function of the EBA in the contingency detection is altered in ASD.

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23. Ousley O, Cermak T. {{Autism Spectrum Disorder: Defining Dimensions and Subgroups}}. {Curr Dev Disord Rep};2014 (Mar 1);1(1):20-28.

Autism spectrum disorder (ASD) is a behaviorally defined neurodevelopmental disorder associated with the presence of social-communication deficits and restricted and repetitive behaviors. In the latest conceptualization of ASD, these two behavioral dimensions represent the core defining features of ASD, whereas associated dimensions, such as intellectual and language ability, provide a means for describing the ASD heterogeneity. In addition, the characterization of ASD subgroups, defined by the presence of known medical, genetic, or other psychiatric disorders, furthers our understanding of ASD heterogeneity. This paper reviews the history of autism, describes its core defining features, and provides an overview of the clinically and etiologically relevant subgroups that add to the complexity of this condition.

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24. Ritvo ER. {{Autism treatments proposed by clinical studies and human genetics are complementary}}. {Transl Psychiatry};2014;4:e415.

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25. Rivard M, Terroux A, Mercier C, Parent-Boursier C. {{Indicators of Intellectual Disabilities in Young Children with Autism Spectrum Disorders}}. {J Autism Dev Disord};2014 (Jul 29)
No agreement has been reached yet on the co-occurrence of Intellectual Disability (ID) and Autism Spectrum Disorders (ASD) in young children. This study describes the clinical profiles of 253 children with ASD between 30 and 65 months old, on IQ and adaptive behaviors, prior to their entry in an early behavioral intervention program. Results showed that 36.8 % of the children met the criteria for ID, with 60.2 % of these in the mild range (IQ 50-69) and 39.8 % in the moderate range (IQ 35-49). ID profiles were similar for boys and girls. Intellectual and adaptive behavior profiles are described as well as their links to various socioeconomic factors.

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26. Sondenaa E, Helverschou SB, Steindal K, Rasmussen K, Nilson B, Nottestad JA. {{VIOLENCE AND SEXUAL OFFENDING BEHAVIOR IN PEOPLE WITH AUTISM SPECTRUM DISORDER WHO HAVE UNDERGONE A PSYCHIATRIC FORENSIC EXAMINATION}}. {Psychol Rep};2014 (Jul 29)
Summary.-The increased awareness of Autism Spectrum Disorders (ASD) over the last few decades as well as the potential association between ASD and offending behaviors has spurred a need for increased research in this area. In order to explore any possible relationship between ASD and violent or sexual crime the present study examines all forensic examination reports over a 10-yr. period in Norway where the charged persons were diagnosed with ASD and charged with either a violent (N = 21) or a sexual (N = 12) offense. Differences between these two groups regarding previous contact with child welfare and confessions to the offense were found. There was also a tendency toward more severe mental health problems and less intellectual problems among the violent offenders than the sexual offenders.

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27. Tabuchi K, Hang W, Asgar NF, Pramanik G. {{[Synapse maturation and autism: learning from neuroligin model mice]}}. {Nihon Shinkei Seishin Yakurigaku Zasshi};2014 (Feb);34(1):1-4.

Autism is a neurodevelopmental disorder characterized by impairments in social interaction, communication, and restricted and repetitive behavior. Synaptic defects have been implicated in autism; nevertheless, the cause is still largely unknown. A mutation that substitutes cysteine for arginine at residue 451 of Neuroligin-3 (R451C) is the first monogenic mutation identified in idiopathic autism patients. To study the relationship between this mutation and autism, we generated knock-in mice that recapitulated this mutation. The knock-in mice were born and grew up normally without showing any major physical phenotypes, but showed a deficit in social interaction. We studied synaptic function in the layer II/III pyramidal neurons in the somatosensory cortex and found inhibitory synaptic transmission was enhanced in the knock-in mice. The administration of GABA blocker rescued social interaction, suggesting that this caused autistic behavior in these mice. We also found, by Morris water maze test, that spatial learning and memory were significantly enhanced in the knock-in mice. Electrophysiology in the CA1 region of the hippocampus revealed that LTP, the NMDA/AMPA ratio, and NR2B function were enhanced, indicating that synaptic maturation was impaired in the knock-in mice. This may cause the deficit in social behavior and extraordinary memory ability occasionally seen in autistic patients.

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28. Titeca D, Roeyers H, Josephy H, Ceulemans A, Desoete A. {{Preschool predictors of mathematics in first grade children with autism spectrum disorder}}. {Res Dev Disabil};2014 (Jul 25);35(11):2714-2727.

Up till now, research evidence on the mathematical abilities of children with autism spectrum disorder (ASD) has been scarce and provided mixed results. The current study examined the predictive value of five early numerical competencies for four domains of mathematics in first grade. Thirty-three high-functioning children with ASD were followed up from preschool to first grade and compared with 54 typically developing children, as well as with normed samples in first grade. Five early numerical competencies were tested in preschool (5-6 years): verbal subitizing, counting, magnitude comparison, estimation, and arithmetic operations. Four domains of mathematics were used as outcome variables in first grade (6-7 years): procedural calculation, number fact retrieval, word/language problems, and time-related competences. Children with ASD showed similar early numerical competencies at preschool age as typically developing children. Moreover, they scored average on number fact retrieval and time-related competences and higher on procedural calculation and word/language problems compared to the normed population in first grade. When predicting first grade mathematics performance in children with ASD, both verbal subitizing and counting seemed to be important to evaluate at preschool age. Verbal subitizing had a higher predictive value in children with ASD than in typically developing children. Whereas verbal subitizing was predictive for procedural calculation, number fact retrieval, and word/language problems, counting was predictive for procedural calculation and, to a lesser extent, number fact retrieval. Implications and directions for future research are discussed.

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29. Vasa RA, Carroll LM, Nozzolillo AA, Mahajan R, Mazurek MO, Bennett AE, Wink LK, Bernal MP. {{A Systematic Review of Treatments for Anxiety in Youth with Autism Spectrum Disorders}}. {J Autism Dev Disord};2014 (Jul 29)
This study systematically examined the efficacy and safety of psychopharmacological and non-psychopharmacological treatments for anxiety in youth with autism spectrum disorders (ASD). Four psychopharmacological, nine cognitive behavioral therapy (CBT), and two alternative treatment studies met inclusion criteria. Psychopharmacological studies were descriptive or open label, sometimes did not specify the anxiety phenotype, and reported behavioral activation. Citalopram and buspirone yielded some improvement, whereas fluvoxamine did not. Non-psychopharmacological studies were mainly randomized controlled trials (RCTs) with CBT demonstrating moderate efficacy for anxiety disorders in youth with high functioning ASD. Deep pressure and neurofeedback provided some benefit. All studies were short-term and included small sample sizes. Large scale and long term RCTs examining psychopharmacological and non-psychopharmacological treatments are sorely needed.

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30. Wang X, Xu Q, Bey AL, Lee Y, Jiang YH. {{Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice}}. {Mol Autism};2014;5:30.

BACKGROUND: Considerable clinical heterogeneity has been well documented amongst individuals with autism spectrum disorders (ASD). However, little is known about the biological mechanisms underlying phenotypic diversity. Genetic studies have established a strong causal relationship between ASD and molecular defects in the SHANK3 gene. Individuals with various defects of SHANK3 display considerable clinical heterogeneity. Different lines of Shank3 mutant mice with deletions of different portions of coding exons have been reported recently. Variable synaptic and behavioral phenotypes have been reported in these mice, which makes the interpretations for these data complicated without the full knowledge of the complexity of the Shank3 transcript structure. METHODS: We systematically examined alternative splicing and isoform-specific expression of Shank3 across different brain regions and developmental stages by regular RT-PCR, quantitative real time RT-PCR (q-PCR), and western blot. With these techniques, we also investigated the effects of neuronal activity and epigenetic modulation on alternative splicing and isoform-specific expression of Shank3. We explored the localization and influence on dendritic spine development of different Shank3 isoforms in cultured hippocampal neurons by cellular imaging. RESULTS: The Shank3 gene displayed an extensive array of mRNA and protein isoforms resulting from the combination of multiple intragenic promoters and extensive alternative splicing of coding exons in the mouse brain. The isoform-specific expression and alternative splicing of Shank3 were brain-region/cell-type specific, developmentally regulated, activity-dependent, and involved epigenetic regulation. Different subcellular distribution and differential effects on dendritic spine morphology were observed for different Shank3 isoforms. CONCLUSIONS: Our results indicate a complex transcriptional regulation of Shank3 in mouse brains. Our analysis of select Shank3 isoforms in cultured neurons suggests that different Shank3 isoforms have distinct functions. Therefore, the different types of SHANK3 mutations found in patients with ASD and different exonic deletions of Shank3 in mutant mice are predicted to disrupt selective isoforms and result in distinct dysfunctions at the synapse with possible differential effects on behavior. Our comprehensive data on Shank3 transcriptional regulation thus provides an essential molecular framework to understand the phenotypic diversity in SHANK3 causing ASD and Shank3 mutant mice.

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31. Woodman AC, Smith LE, Greenberg JS, Mailick MR. {{Change in Autism Symptoms and Maladaptive Behaviors in Adolescence and Adulthood: The Role of Positive Family Processes}}. {J Autism Dev Disord};2014 (Jul 29)
Little is known about outcomes for individuals with autism spectrum disorders (ASD) into adulthood. Several characteristics of individuals with ASD predict long-term outcomes, and the family environment may also play a role. The present study uses a prospective, longitudinal design to describe and predict trajectories of autism symptoms and maladaptive behaviors over 8.5 years in a large, community-based sample of adolescents and adults with ASD. Overall, autism symptoms and maladaptive behaviors were observed to improve over the study period. Above and beyond the adult’s gender, age, and level of intellectual disability, greater improvements were associated with higher levels of maternal praise (based on maternal speech samples) and higher quality mother-child relationships. Implications for future research and intervention are discussed.

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