1. Barendse EM, Hendriks MP, Jansen JF, Backes WH, Hofman PA, Thoonen G, Kessels RP, Aldenkamp AP. {{Working memory deficits in high-functioning adolescents with autism spectrum disorders: neuropsychological and neuroimaging correlates}}. {J Neurodev Disord};2013;5(1):14.
Working memory is a temporary storage system under attentional control. It is believed to play a central role in online processing of complex cognitive information and may also play a role in social cognition and interpersonal interactions. Adolescents with a disorder on the autism spectrum display problems in precisely these domains. Social impairments, communication difficulties, and repetitive interests and activities are core domains of autism spectrum disorders (ASD), and executive function problems are often seen throughout the spectrum. As the main cognitive theories of ASD, including the theory of mind deficit hypotheses, weak central coherence account, and the executive dysfunction theory, still fail to explain the broad spectrum of symptoms, a new perspective on the etiology of ASD is needed. Deficits in working memory are central to many theories of psychopathology, and are generally linked to frontal-lobe dysfunction. This article will review neuropsychological and (functional) brain imaging studies on working memory in adolescents with ASD. Although still disputed, it is concluded that within the working memory system specific problems of spatial working memory are often seen in adolescents with ASD. These problems increase when information is more complex and greater demands on working memory are made. Neuroimaging studies indicate a more global working memory processing or connectivity deficiency, rather than a focused deficit in the prefrontal cortex. More research is needed to relate these working memory difficulties and neuroimaging results in ASD to the behavioral difficulties as seen in individuals with a disorder on the autism spectrum.
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2. Cannell JJ. {{Autism, will vitamin D treat core symptoms?}}. {Med Hypotheses};2013 (May 29)
No medication exists to treat the core symptoms of autism. However, some children spontaneously improve and have optimal outcomes. Parents of autistic children who have access to swimming pool have reported summertime improvement in symptoms to me. A Japanese case report found the same summer times improvements. If the cause of that summertime improvement could be identified, it may lead to effective treatment. Vitamin D is highly seasonal with a summertime surfeit and a wintertime deficit. The hypotheses that the increased prevalence in the diagnosis of autism is due to better detection imply that parents, teachers and physicians of the 1950s, 60s, and 70s missed this non subtle diagnosis, an unlikely scenario. Recent research indicates that autism often first present itself during the second and third year of life. This is a time when most toddlers have no known sources of vitamin D. Vitamin D has remarkable antioxidant, anti-inflammatory, and anti-autoimmune properties. In vitro, in vivo, and animal experiments provide compelling data for vitamin D’s role brain proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. It also upregulates glutathione, upregulates a suit of genes involved in DNA repair and raises the seizure threshold. Adequate, perhaps pharmacological, doses of vitamin D may have a treatment effect in the core symptoms of autism.
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3. Castren M, Castren E. {{BDNF in Fragile X Syndrome}}. {Neuropharmacology};2013 (May 29)
Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity. However, numerous alterations are found during the early development in FXS, including abnormal differentiation of neural progenitors and impaired migration of newly born neurons. Several aspects of FMRP function are modulated by brain-derived neurotrophic factor (BDNF) signaling. Here, we review the evidence of the role for BDNF in the developing and adult FXS brain.
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4. Colic S, Wither RG, Zhang L, Eubanks JH, Bardakjian BL. {{Characterization of seizure-like events recorded in vivo in a mouse model of Rett syndrome}}. {Neural Netw};2013 (May 13);46C:109-115.
Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Spontaneous recurrent discharge episodes are displayed in Rett-related seizures as in other types of epilepsies. The aim of this paper is to investigate the seizure-like event (SLE) and inter-SLE states in a female MeCP2-deficient mouse model of Rett syndrome and compare them to those found in other spontaneous recurrent epilepsy models. The study was performed on a small population of female MeCP2-deficient mice using telemetric local field potential (LFP) recordings over a 24 h period. Durations of SLEs and inter-SLEs were extracted using a rule-based automated SLE detection system for both daytime and nighttime, as well as high and low power levels of the delta frequency range (0.5-4 Hz) of the recorded LFPs. The results suggest SLE occurrences are not influenced by circadian rhythms, but had a significantly greater association with delta power. Investigating inter-SLE and SLE states by fitting duration histograms to the gamma distribution showed that SLE initiation and termination were associated with random and deterministic mechanisms, respectively. These findings when compared to reported studies on epilepsy suggest that Rett-related seizures share many similarities with absence epilepsy.
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5. Goncalves JT, Anstey JE, Golshani P, Portera-Cailliau C. {{Circuit level defects in the developing neocortex of Fragile X mice}}. {Nat Neurosci};2013 (Jun 2)
Subtle alterations in how cortical network dynamics are modulated by different behavioral states could disrupt normal brain function and underlie symptoms of neuropsychiatric disorders, including Fragile X syndrome (FXS). Using two-photon calcium imaging and electrophysiology, we recorded spontaneous neuronal ensemble activity in mouse somatosensory cortex. Unanesthetized Fmr1-/- mice exhibited abnormally high synchrony of neocortical network activity, especially during the first two postnatal weeks. Neuronal firing rates were threefold higher in Fmr1-/- mice than in wild-type mice during whole-cell recordings manifesting Up/Down states (slow-wave sleep, quiet wakefulness), probably as a result of a higher firing probability during Up states. Combined electroencephalography and calcium imaging experiments confirmed that neurons in mutant mice had abnormally high firing and synchrony during sleep. We conclude that cortical networks in FXS are hyperexcitable in a brain state-dependent manner during a critical period for experience-dependent plasticity. These state-dependent network defects could explain the intellectual, sleep and sensory integration dysfunctions associated with FXS.
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6. Lo-Castro A, Curatolo P. {{Epilepsy associated with autism and attention deficit hyperactivity disorder: Is there a genetic link?}}. {Brain Dev};2013 (May 29)
Autism Spectrum Disorders (ASDs) and Attention Deficit and Hyperactivity Disorder (ADHD) are the most common comorbid conditions associated with childhood epilepsy. The co-occurrence of an epilepsy/autism phenotype or an epilepsy/ADHD phenotype has a complex and heterogeneous pathogenesis, resulting from several altered neurobiological mechanisms involved in early brain development, and influencing synaptic plasticity, neurotransmission and functional connectivity. Rare clinically relevant chromosomal aberrations, in addition to environmental factors, may confer an increased risk for ASDs/ADHD comorbid with epilepsy. The majority of the candidate genes are involved in synaptic formation/remodeling/maintenance (NRX1, CNTN4, DCLK2, CNTNAP2, TRIM32, ASTN2, CTNTN5, SYN1), neurotransmission (SYNGAP1, GABRG1, CHRNA7), or DNA methylation/chromatin remodeling (MBD5). Two genetic disorders, such as Tuberous sclerosis and Fragile X syndrome may serve as models for understanding the common pathogenic pathways leading to ASDs and ADHD comorbidities in children with epilepsy, offering the potential for new biologically focused treatment options.
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7. Miller VM, Gupta D, Neu N, Cotroneo A, Boulay CB, Seegal RF. {{Novel inter-hemispheric white matter connectivity in the BTBR mouse model of autism}}. {Brain Res};2013 (Jun 4);1513:26-33.
Alterations in the volume, density, connectivity and functional activation of white matter tracts are reported in some individuals with autism and may contribute to their abnormal behaviors. The BTBR (BTBR T+tf/J) inbred strain of mouse, is used to model facets of autism because they develop low social behaviors, stereotypical and immune changes similar to those found in people with autism. Previously, it was thought a total absence of corpus callosal interhemispheric connective tissues in the BTBR mice may underlie their abnormal behaviors. However, postnatal lesions of the corpus callosum do not precipitate social behavioral problems in other strains of mice suggesting a flaw in this theory. In this study we used digital pathological methods to compare subcortical white matter connective tracts in the BTBR strain of mice with those found in the C57Bl/6 mouse and those reported in a standardized mouse brain atlas. We report, for the first time, a novel connective subcortical interhemispheric bridge of tissue in the posterior, but not anterior, cerebrum of the BTBR mouse. These novel connective tissues are comprised of myelinated fibers, with reduced myelin basic protein levels (MBP) compared to levels in the C57Bl/6 mouse. We used electrophysiological analysis and found increased inter-hemispheric connectivity in the posterior hemispheres of the BTBR strain compared with the anterior hemispheres. The conduction velocity was slower than that reported in normal mice. This study shows there is novel abnormal interhemispheric connectivity in the BTBR strain of mice, which may contribute to their behavioral abnormalities.
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8. Mostafa GA, Al-Ayadhi LY. {{The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children}}. {J Neuroimmunol};2013 (May 29)
Etiology of autism has become an area of a significant controversy. Allergy induced autism is an area of research wherein immune responses to some allergens may play a pathogenic role in autism. Allergy may induce the production of brain specific auto-antibodies in a subgroup of autistic children. We are the first to investigate the possible link between allergic manifestations and serum levels of both anti-myelin basic protein (anti-MBP) and anti-myelin associated glycoprotein (anti-MAG) brain-specific auto-antibodies, which were measured by ELISA method, in 42 autistic children in comparison to 42 healthy-matched children. Allergic manifestations (bronchial asthma, atopic dermatitis and/or allergic rhinitis) were found in 47.6% of autistic patients. Increased serum levels of anti-MBP and anti-MAG auto-antibodies were found in 57.1% and 66.7%, respectively of autistic children. In addition, 78.5% of autistic children had increased serum levels of both anti-MBP and/or anti-MAG auto-antibodies. Autistic patients with allergic manifestations had significantly higher serum levels of anti-MBP and anti-MAG auto-antibodies than those without these manifestations (P<0.001 and P=0.001, respectively). In conclusion, allergy may be a contributing factor to the increased serum levels of anti-MBP and anti-MAG auto-antibodies in some autistic children. Indeed, we need to know more about the links between allergy, immune system and brain in autism for finding new therapeutic modalities in autism.
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9. Ouss L, Saint-Georges C, Robel L, Bodeau N, Laznik MC, Crespin GC, Chetouani M, Bursztejn C, Golse B, Nabbout R, Desguerre I, Cohen D. {{Infant’s engagement and emotion as predictors of autism or intellectual disability in West syndrome}}. {Eur Child Adolesc Psychiatry};2013 (Jun 1)
West syndrome (WS) is a rare epileptic encephalopathy with early onset and a high risk of autistic outcome. The PreAut grid assesses this risk following WS onset by taking into account synchrony and emotion in interactions and by evaluating the baby’s active desire to engage in pleasant interactions (especially the infant’s early active behaviors that encourage being gazed at or kissed by the mother or to share joy with her). We followed a sample of 25 WS patients prospectively from disease onset and assessed whether the PreAut grid before 9 months, and the checklist for autism in toddlers (CHAT) at 18 and 24 months predicted autism or intellectual disability (ID) outcomes at 4 years. We found that the PreAut grid at 9 months (sensitivity = 0.83; specificity = 1) had similar prediction parameters as the CHAT at 18 months (sensitivity = 0.90; specificity = 0.83) and 24 months (sensitivity = 0.92; specificity = 1). WS patients with a positive PreAut screening at 9 months had a risk of having autism or ID at 4 years, which is 38 times that of children with a negative PreAut grid [OR = 38.6 (95 % CI 2.2-2961); p = 0.006]. We conclude that the PreAut grid could be a useful tool for the early detection of autism or ID risk in the context of WS. Further research is needed to assess the PreAut grid in other contexts (e.g. infants at high-risk for non-syndromic autism).
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10. Pacey LK, Xuan IC, Guan S, Sussman D, Henkelman RM, Chen Y, Thomsen C, Hampson DR. {{Delayed Myelination in a Mouse Model of Fragile X Syndrome}}. {Hum Mol Genet};2013 (Jun 4)
Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain FMRP is expressed primarily in neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age).At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared to wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons, and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2, and the number of PDGFRalpha+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.
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11. Wang P, Carrion P, Qiao Y, Tyson C, Hrynchak M, Calli K, Lopez-Rangel E, Andrieux J, Delobel B, Duban-Bedu B, Thuresson AC, Anneren G, Liu X, Rajcan-Separovic E, Suzanne Lewis ME. {{Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism}}. {Eur J Med Genet};2013 (May 29)
Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage-sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome.
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12. Zakrajsek AG, Hammel J, Scazzero JA. {{Supporting People with Intellectual and Developmental Disabilities to Participate in their Communities through Support Staff Pilot Intervention}}. {J Appl Res Intellect Disabil};2013 (Jun 4)
BACKGROUND: Increasingly, people with intellectual and developmental disabilities (I/DD) are supported to participate in least-restricted settings in the community. However, little is known about desired community participation choice and control of people with I/DD, nor effective strategies to support full participation. Furthermore, service providers of this population in community and residential settings have unique roles in influencing choice and control in community participation. RESEARCH AIM: The purpose of this project is to empower adults with I/DD in community participation by collaborating with agency staff and administrators to strategize change in service provision and programming. METHODS: This article describes the development, imple-mentation and mixed-methods evaluation of a pilot staff intervention. RESULTS: Findings indicate staff who participated in pilot intervention report increased confidence in supporting adults with I/DD to participate in their communities. CONCLUSIONS: Intervention development has implications for staff, administrators and agencies in planning and executing opportunities to support choice and control for community participation for adults with I/DD.
