1. Balsters JH, Mantini D, Wenderoth N. {{Connectivity-based parcellation reveals distinct cortico-striatal connectivity fingerprints in Autism Spectrum Disorder}}. {Neuroimage};2017 (Feb 07)
Autism Spectrum Disorder (ASD) has been associated with abnormal synaptic development causing a breakdown in functional connectivity. However, when measured at the macro scale using resting state fMRI, these alterations are subtle and often difficult to detect due to the large heterogeneity of the pathology. Recently, we outlined a novel approach for generating robust biomarkers of resting state functional magnetic resonance imaging (RS-fMRI) using connectivity based parcellation of gross morphological structures to improve single-subject reproducibility and generate more robust connectivity fingerprints. Here we apply this novel approach to investigating the organization and connectivity strength of the cortico-striatal system in a large sample of ASD individuals and typically developed (TD) controls (N=130 per group). Our results showed differences in the parcellation of the striatum in ASD. Specifically, the putamen was found to be one single structure in ASD, whereas this was split into anterior and posterior segments in an age, IQ, and head movement matched TD group. An analysis of the connectivity fingerprints revealed that the group differences in clustering were driven by differential connectivity between striatum and the supplementary motor area, posterior cingulate cortex, and posterior insula. Our approach for analysing RS-fMRI in clinical populations has provided clear evidence that cortico-striatal circuits are organized differently in ASD. Based on previous task-based segmentations of the striatum, we believe that the anterior putamen cluster present in TD, but not in ASD, likely contributes to social and language processes.
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2. Borghi E, Borgo F, Severgnini M, Savini MN, Casiraghi MC, Vignoli A. {{Rett Syndrome: A Focus on Gut Microbiota}}. {Int J Mol Sci};2017 (Feb 07);18(2)
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder affecting 1 in 10,000 live female births. Changes in microbiota composition, as observed in other neurological disorders such as autism spectrum disorders, may account for several symptoms typically associated with RTT. We studied the relationship between disease phenotypes and microbiome by analyzing diet, gut microbiota, and short-chain fatty acid (SCFA) production. We enrolled eight RTT patients and 10 age- and sex-matched healthy women, all without dietary restrictions. The microbiota was characterized by 16S rRNA gene sequencing, and SCFAs concentration was determined by gas chromatographic analysis. The RTT microbiota showed a lower alpha diversity, an enrichment in Bacteroidaceae, Clostridium spp., and Sutterella spp., and a slight depletion in Ruminococcaceae. Fecal SCFA concentrations were similar, but RTT samples showed slightly higher concentrations of butyrate and propionate, and significant higher levels in branched-chain fatty acids. Daily caloric intake was similar in the two groups, but macronutrient analysis showed a higher protein content in RTT diets. Microbial function prediction suggested in RTT subjects an increased number of microbial genes encoding for propionate and butyrate, and amino acid metabolism. A full understanding of these critical features could offer new, specific strategies for managing RTT-associated symptoms, such as dietary intervention or pre/probiotic supplementation.
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3. Dang T, Duan WY, Yu B, Tong DL, Cheng C, Zhang YF, Wu W, Ye K, Zhang WX, Wu M, Wu BB, An Y, Qiu ZL, Wu BL. {{Autism-associated Dyrk1a truncation mutants impair neuronal dendritic and spine growth and interfere with postnatal cortical development}}. {Mol Psychiatry};2017 (Feb 07)
Autism is a prevailing neurodevelopmental disorder with a large genetic/genomic component. Recently, the dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) gene was implicated as a risk factor for autism spectrum disorder (ASD). We identified five DYRK1A variants in ASD patients and found that the dose of DYRK1A protein has a crucial role in various aspects of postnatal neural development. Dyrk1a loss of function and gain of function led to defects in dendritic growth, dendritic spine development and radial migration during cortical development. Importantly, two autism-associated truncations, R205X and E239X, were shown to be Dyrk1a loss-of-function mutants. Studies of the truncated Dyrk1a mutants may provide new insights into the role of Dyrk1a in brain development, as well as the role of Dyrk1a loss of function in the pathophysiology of autism.Molecular Psychiatry advance online publication, 7 February 2017; doi:10.1038/mp.2016.253.
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4. Divan G, Hamdani SU, Vajartkar V, Minhas A, Taylor C, Aldred C, Leadbitter K, Rahman A, Green J, Patel V. {{Adapting an evidence-based intervention for autism spectrum disorder for scaling up in resource-constrained settings: the development of the PASS intervention in South Asia}}. {Glob Health Action};2015 (Jan);8(1):27278.
Background Evidence-based interventions for autism spectrum disorders evaluated in high-income countries typically require highly specialised manpower, which is a scarce resource in most low- and middle-income settings. This resource limitation results in most children not having access to evidence-based interventions. Objective This paper reports on the systematic adaptation of an evidence-based intervention, the Preschool Autism Communication Therapy (PACT) evaluated in a large trial in the United Kingdom for delivery in a low-resource setting through the process of task-shifting. Design The adaptation process used the Medical Research Council framework for the development and adaptation of complex interventions, focusing on qualitative methods and case series and was conducted simultaneously in India and Pakistan. Results The original intervention delivered by speech and language therapists in a high-resource setting required adaptation in some aspects of its content and delivery to enhance contextual acceptability and to enable the intervention to be delivered by non-specialists. Conclusions The resulting intervention, the Parent-mediated intervention for Autism Spectrum Disorder in South Asia (PASS), shares the core theoretical foundations of the original PACT but is adapted in several respects to enhance its acceptability, feasibility, and scalability in low-resource settings.
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5. Downs J, Leonard H, Wong K, Newton N, Hill K. {{Quantification of walking-based physical activity and sedentary time in individuals with Rett syndrome}}. {Dev Med Child Neurol};2017 (Feb 06)
AIM: To quantify, in individuals with Rett syndrome with the capacity to walk, walking-based activity and sedentary time, and to analyse the influences of age, walking ability, scoliosis, and the severity of epilepsy. METHOD: Sixty-four participants with a mean age of 17 years and 7 months (standard deviation [SD] 9y) were recruited from the Australian Rett Syndrome Database for this cross-sectional study. Each participant wore a StepWatch Activity Monitor for at least 4 days. Linear regression models were used to assess relationships between daily step count and the proportion of waking hours spent in sedentary time with the covariates of age group, walking ability, presence of scoliosis, and frequency of seizures. RESULTS: On average, 62% (SD 19%) of waking hours were sedentary and 20% (SD 8%) was at cadences lower than or equal to 20 steps in a minute. The median daily steps count was 5093 (interquartile range 2026-8602). Compared with females younger than 13 years of age and accounting for the effects of covariates, adults took fewer steps, and both adolescents and adults had more sedentary time. INTERPRETATION: Adolescents and adults led the least active lives and would appear to be in particular need of interventions aiming to optimize slow walking-based physical activity and reduce sedentary time.
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6. Jin Y, Kong J. {{Transcutaneous Vagus Nerve Stimulation: A Promising Method for Treatment of Autism Spectrum Disorders}}. {Front Neurosci};2016;10:609.
Transcutaneous Vagus Nerve Stimulation (tVNS) on the auricular branch of the vagus nerve has been receiving attention due to its therapeutic potential for neuropsychiatric disorders. Although the mechanism of tVNS is not yet completely understood, studies have demonstrated the potential role of vagal afferent nerve stimulation in the regulation of mood and visceral state associated with social communication. In addition, a growing body of evidence shows that tVNS can activate the brain regions associated with Autism Spectrum Disorder (ASD), trigger neuroimmune modulation and produce treatment effects for comorbid disorders of ASD such as epilepsy and depression. We thus hypothesize that tVNS may be a promising treatment for ASD, not only for comorbid epilepsy and depression, but also for the core symptoms of ASD. The goal of this manuscript is to summarize the findings and rationales for applying tVNS to treat ASD and propose potential parameters for tVNS treatment of ASD.
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7. Kaufmann WE, Stallworth JL, Everman DB, Skinner SA. {{Neurobiologically-based treatments in Rett syndrome: opportunities and challenges}}. {Expert Opin Orphan Drugs};2016 (Oct 02);4(10):1043-1055.
Introduction: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that primarily affects females, typically resulting in a period of developmental regression in early childhood followed by stabilization and severe chronic cognitive, behavioral, and physical disability. No known treatment exists beyond symptomatic management, and while insights into the genetic cause, pathophysiology, neurobiology, and natural history of RTT have been gained, many challenges remain. Areas covered: Based on a comprehensive survey of the primary literature on RTT, this article describes and comments upon the general and unique features of the disorder, genetic and neurobiological bases of drug development, and the history of clinical trials in RTT, with an emphasis on drug trial design, outcome measures, and implementation. Expert opinion: Neurobiologically based drug trials are the ultimate goal in RTT, and due to the complexity and global nature of the disorder, drugs targeting both general mechanisms (e.g., growth factors) and specific systems (e.g., glutamate modulators) could be effective. Trial design should optimize data on safety and efficacy, but selection of outcome measures with adequate measurement properties, as well as innovative strategies, such as those enhancing synaptic plasticity and use of biomarkers, are essential for progress in RTT and other neurodevelopmental disorders.
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8. Mansilla A, Chaves-Sanjuan A, Campillo NE, Semelidou O, Martinez-Gonzalez L, Infantes L, Gonzalez-Rubio JM, Gil C, Conde S, Skoulakis EM, Ferrus A, Martinez A, Sanchez-Barrena MJ. {{Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome}}. {Proc Natl Acad Sci U S A};2017 (Feb 07);114(6):E999-e1008.
The protein complex formed by the Ca2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.
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9. Masri AT, Suluh NA, Nasir R. {{Diagnostic delay of autism in Jordan: review of 84 cases}}. {Libyan J Med};2013 (Jan);8(1):21725.
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10. McLaren J, Lichtenstein JD, Lynch D, Becker D, Drake R. {{Individual Placement and Support for People with Autism Spectrum Disorders: A Pilot Program}}. {Adm Policy Ment Health};2017 (Feb 07)
Young adults with autism spectrum disorder (ASD) experience significant rates of unemployment and underemployment, and the field needs an inexpensive, evidence-based vocational intervention. We examined an approach developed for people with serious mental illness, IPS supported employment, for young adults with ASD. We described a pilot IPS program for young adults with ASD and evaluated the first five participants over 1 year. The first five IPS participants succeeded in competitive employment, expanded independence, and achieved broad psychosocial gains. IPS could help young adults with ASD succeed in competitive employment at a relatively low cost.
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11. Meshalkina DA, Kizlyuk M, Kisel E, Collier AD, Echevarria DJ, Abreu MS, Barcellos LJ, Song C, Warnick JE, Kyzar EJ, Kalueff AV. {{Zebrafish models of autism spectrum disorder}}. {Exp Neurol};2017 (Feb 02)
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by motor, social and cognitive deficits that develop during childhood. The pathogenesis of ASD is not well characterized and involves a multifaceted interaction between genetic, neurobiological and environmental factors. Animal (experimental) models possess evolutionarily conserved behaviors and molecular pathways that are highly relevant for studying ASD. The zebrafish (Danio rerio) is a relatively new animal model with promise for understanding the pathogenesis of complex brain disorders and discovering novel treatments. As a highly social and genetically tractable organism, zebrafish have recently been applied to model a variety of deficits relevant to ASD. Here, we discuss the developing utility of zebrafish models of ASD, as well as current behavioral, toxicological and genetic models of ASD, and future directions of research in this field.
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12. Miller M, Iosif AM, Hill M, Young GS, Schwichtenberg AJ, Ozonoff S. {{Response to Name in Infants Developing Autism Spectrum Disorder: A Prospective Study}}. {J Pediatr};2017 (Feb 02)
OBJECTIVE: To examine longitudinal patterns of response to name from 6-24 months of age in infants at high and low risk for autism spectrum disorder (ASD). STUDY DESIGN: A response to name task was tested at 6, 9, 12, 15, 18, and 24 months of age in 156 infant siblings of children with ASD (high-risk) or typical development (low-risk). At 36 months of age, participants were classified into 1 of 3 outcome groups: group with ASD (n = 20), high-risk group without ASD (n = 76), or low-risk group without ASD (n = 60). Differences in longitudinal performance were assessed using generalized estimating equations, and sensitivity and specificity for identifying ASD were calculated. Differences in age 36-month functioning were examined between infants who developed ASD and repeatedly vs infrequently failed to respond to name. RESULTS: At 9 months of age, infants developing ASD were more likely to fail to orient to their names, persisting through 24 months. Sensitivity/specificity for identifying ASD based on at least 1 failure between 12 and 24 months were estimated at .70 in this sample. One-half of the infants who developed ASD had repeated failures in this timeframe, and demonstrated lower age 36-month receptive language, and earlier diagnosis of ASD than infants with ASD who had infrequent failures. CONCLUSIONS: In addition to recommended routine broad-based and ASD-specific screening, response to name should be regularly monitored in infants at risk for ASD. Infants who consistently fail to respond to their names in the second year of life may be at risk not only for ASD but also for greater impairment by age 3 years.
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13. Park BY, Lee BK, Burstyn I, Tabb LP, Keelan JA, Whitehouse AJ, Croen LA, Fallin MD, Hertz-Picciotto I, Montgomery O, Newschaffer CJ. {{Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study}}. {Mol Autism};2017;8:3.
BACKGROUND: Autism spectrum disorder (ASD) affects more than 1% of children in the USA. The male-to-female prevalence ratio of roughly 4:1 in ASD is a well-recognized but poorly understood phenomenon. An explicit focus on potential etiologic pathways consistent with this sex difference, such as those involving prenatal androgen exposure, may help elucidate causes of ASD. Furthermore, the multi-threshold liability model suggests that the genetic mechanisms in females with ASD may be distinct and may modulate ASD risk in families with female ASD in the pedigree. METHODS: We examined umbilical cord blood from 137 children in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is an ASD-enriched risk cohort with all children having an older sibling already diagnosed with ASD. Fetal testosterone (T), androstenedione (A4), and dehyroepiandrosterone (DHEA) levels were measured in cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Robust linear regression models were used to determine associations between cord blood androgen levels and 12-month Autism Observation Scales for Infants (AOSI) scores and 36-month Social Responsiveness Scale (SRS) scores adjusting for potential confounders. RESULTS: Increasing androgens were not associated with increasing 12-month AOSI score or 36-month total SRS score in either boys or girls. However, the association between T and autistic traits among subjects with a female older affected sibling was greater at 12 months (test of interaction, P = 0.008) and deficits in reciprocal social behavior at 36 months were also greater (test of interaction, P = 0.006) than in subjects whose older affected sibling was male. CONCLUSIONS: While increased prenatal testosterone levels were not associated with autistic traits at 12 or 36 months, our findings of a positive association in infants whose older ASD-affected siblings were female suggests an androgen-related mechanism that may be dependent on, or related to, genetic liability factors present more often in families containing female ASD cases. However, this initial finding, based on a small subgroup of our sample, should be interpreted with considerable caution.
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14. Ruskin DN, Murphy MI, Slade SL, Masino SA. {{Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder}}. {PLoS One};2017;12(2):e0171643.
Prenatal factors influence autism spectrum disorder (ASD) incidence in children and can increase ASD symptoms in offspring of animal models. These may include maternal immune activation (MIA) due to viral or bacterial infection during the first trimesters. Unfortunately, regardless of ASD etiology, existing drugs are poorly effective against core symptoms. For nearly a century a ketogenic diet (KD) has been used to treat seizures, and recent insights into mechanisms of ASD and a growing recognition that immune/inflammatory conditions exacerbate ASD risk has increased interest in KD as a treatment for ASD. Here we studied the effects of KD on core ASD symptoms in offspring exposed to MIA. To produce MIA, pregnant C57Bl/6 mice were injected with the viral mimic polyinosinic-polycytidylic acid; after weaning offspring were fed KD or control diet for three weeks. Consistent with an ASD phenotype of a higher incidence in males, control diet-fed MIA male offspring were not social and exhibited high levels of repetitive self-directed behaviors; female offspring were unaffected. However, KD feeding partially or completely reversed all MIA-induced behavioral abnormalities in males; it had no effect on behavior in females. KD-induced metabolic changes of reduced blood glucose and elevated blood ketones were quantified in offspring of both sexes. Prior work from our laboratory and others demonstrate KDs improve relevant behaviors in several ASD models, and here we demonstrate clear benefits of KD in the MIA model of ASD. Together these studies suggest a broad utility for metabolic therapy in improving core ASD symptoms, and support further research to develop and apply ketogenic and/or metabolic strategies in patients with ASD.
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15. Schaafsma SM, Gagnidze K, Reyes A, Norstedt N, Mansson K, Francis K, Pfaff DW. {{Sex-specific gene-environment interactions underlying ASD-like behaviors}}. {Proc Natl Acad Sci U S A};2017 (Feb 07);114(6):1383-1388.
The male bias in the incidence of autism spectrum disorders (ASDs) is one of the most notable characteristics of this group of neurodevelopmental disorders. The etiology of this sex bias is far from known, but pivotal for understanding the etiology of ASDs in general. Here we investigate whether a « three-hit » (genetic load x environmental factor x sex) theory of autism may help explain the male predominance. We found that LPS-induced maternal immune activation caused male-specific deficits in certain social responses in the contactin-associated protein-like 2 (Cntnap2) mouse model for ASD. The three « hits » had cumulative effects on ultrasonic vocalizations at postnatal day 3. Hits synergistically affected social recognition in adulthood: only mice exposed to all three hits showed deficits in this aspect of social behavior. In brains of the same mice we found a significant three-way interaction on corticotropin-releasing hormone receptor-1 (Crhr1) gene expression, in the left hippocampus specifically, which co-occurred with epigenetic alterations in histone H3 N-terminal lysine 4 trimethylation (H3K4me3) over the Crhr1 promoter. Although it is highly likely that multiple (synergistic) interactions may be at work, change in the expression of genes in the hypothalamic-pituitary-adrenal/stress system (e.g., Crhr1) is one of them. The data provide proof-of-principle that genetic and environmental factors interact to cause sex-specific effects that may help explain the male bias in ASD incidence.
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16. Schumann CM, Sharp FR, Ander BP, Stamova B. {{Possible sexually dimorphic role of miRNA and other sncRNA in ASD brain}}. {Mol Autism};2017;8:4.
BACKGROUND: Autism spectrum disorder (ASD) is sexually dimorphic in brain structure, genetics, and behaviors. In studies of brain tissue, the age of the population is clearly a factor in interpreting study outcome, yet sex is rarely considered. To begin to address this issue, we extend our previously published microarray analyses to examine expression of small noncoding RNAs (sncRNAs), including microRNAs (miRNAs), in ASD and in the control temporal cortex in males and females. Predicted miRNA targets were identified as well as the pathways they overpopulate. FINDINGS: After considering age, sexual dimorphism in ASD sncRNA expression persists in the temporal cortex and in the patterning that distinguishes regions. Among the sexually dimorphic miRNAs are miR-219 and miR-338, which promote oligodendrocyte differentiation, miR-125, implicated in neuronal differentiation, and miR-488, implicated in anxiety. Putative miRNA targets are significantly over-represented in immune and nervous system pathways in both sexes, consistent with previous mRNA studies. Even for common pathways, the specific target mRNAs are often sexually dimorphic. For example, both male and female target genes significantly populate the Axonal Guidance Signaling pathway, yet less than a third of the targets are common to both sexes. CONCLUSIONS: Our findings of sexual dimorphism in sncRNA levels underscore the importance of considering sex, in addition to age, when interpreting molecular findings on ASD brain.
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17. Telman LG, van Steensel FJ, Maric M, Bogels SM. {{Are Anxiety Disorders in Children and Adolescents Less Impairing Than ADHD and Autism Spectrum Disorders? Associations with Child Quality of Life and Parental Stress and Psychopathology}}. {Child Psychiatry Hum Dev};2017 (Feb 07)
We compared clinically referred children with anxiety disorders (AD; n = 63) to children with autism spectrum disorder (ASD; n = 39), ADHD Combined (ADHD-C; n = 62), ADHD Predominantly Inattentive (ADHD-I; n = 64), and typically developing children (n = 42) on child quality of life (QOL), paternal and maternal psychopathology and parental stress. Diagnoses were based on DSM-IV-TR criteria. Multilevel analyses showed that QOL in AD was higher on school and social functioning, compared to respectively ADHD and ASD, and lower compared to normal controls on all five domains. Fathers reported their AD children higher QOL than mothers. Also, AD appeared to be associated with less parental stress and parental psychopathology than other child psychopathology. Therefore, parental factors may need to be considered more in treatment of children with ADHD/ASD than AD.
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18. Xiang AH. {{Association of Maternal Diabetes With Autism in Offspring}}. {Jama};2017 (Feb 07);317(5):537-538.
