1. Altay MA, Gorker I, Aslanova R, Bozatli L, Turan N, Kaplan PB. {{Association between Beta-Sympathomimetic Tocolysis and Risk of Autistic Spectrum Disorders, Behavioural and Developmental Outcome in Toddlers}}. {Open Access Maced J Med Sci}. 2017; 5(6): 730-5.
AIM: To investigate whether maternal intravenous beta-mimetic tocolytic therapy increases the risk of autistic spectrum disorders (ASD) and poorer behavioural and developmental outcomes. METHOD: Our study is a prospective case-control study among 90 children between 1.5 and three years old. Cases (n = 46) were toddlers with betamimetic tocolytic exposure; control group toddlers (n = 44) were tocolytic untreated. Treated and untreated groups were also divided into subgroups: term and preterm delivered. The gestational age of tocolytic treatment start, the dose and duration of exposure in hours were obtained from obstetric medical records. The Brief Infant-Toddler Social and Emotional Assessment (BITSEA), the Modified Checklist for Autism in Toddlers (M-CHAT) and the Denver Developmental Screening Test (DDST) tests were applied for evaluation of social, emotional problems, autism and developmental disorders. RESULTS: Term and preterm born toddlers treated tocolytically in utero didn’t demonstrate a higher risk of autistic disorders or poorer behavioural and developmental results than controls. In the preterm group, the earliest start of tocolytic treatment was correlated with toddlers lower score of the Competencies Scale (p = 0.009) and a higher score of the Problems Scale (p = 0.048). Also, we concluded that preterm membrane rupture was associated with higher ASD risk in the untreated group (p = 0.043). CONCLUSION: Exposure to betamimetics during pregnancy was not associated with an increased risk of autism, behavioural and developmental disorders.
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2. Brumback AC, Ellwood IT, Kjaerby C, Iafrati J, Robinson S, Lee AT, Patel T, Nagaraj S, Davatolhagh F, Sohal VS. {{Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior}}. {Mol Psychiatry}. 2017.
Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects.Molecular Psychiatry advance online publication, 7 November 2017; doi:10.1038/mp.2017.213.
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3. Ceolin L, Bouquier N, Vitre-Boubaker J, Rialle S, Severac D, Valjent E, Perroy J, Puighermanal E. {{Cell Type-Specific mRNA Dysregulation in Hippocampal CA1 Pyramidal Neurons of the Fragile X Syndrome Mouse Model}}. {Front Mol Neurosci}. 2017; 10: 340.
Fragile X syndrome (FXS) is a genetic disorder due to the silencing of the Fmr1 gene, causing intellectual disability, seizures, hyperactivity, and social anxiety. All these symptoms result from the loss of expression of the RNA binding protein fragile X mental retardation protein (FMRP), which alters the neurodevelopmental program to abnormal wiring of specific circuits. Aberrant mRNAs translation associated with the loss of Fmr1 product is widely suspected to be in part the cause of FXS. However, precise gene expression changes involved in this disorder have yet to be defined. The objective of this study was to identify the set of mistranslated mRNAs that could contribute to neurological deficits in FXS. We used the RiboTag approach and RNA sequencing to provide an exhaustive listing of genes whose mRNAs are differentially translated in hippocampal CA1 pyramidal neurons as the integrative result of FMRP loss and subsequent neurodevelopmental adaptations. Among genes differentially regulated between adult WT and Fmr1(-/y) mice, we found enrichment in FMRP-binders but also a majority of non-FMRP-binders. Interestingly, both up- and down-regulation of specific gene expression is relevant to fully understand the molecular deficiencies triggering FXS. More importantly, functional genomic analysis highlighted the importance of genes involved in neuronal connectivity. Among them, we show that Klk8 altered expression participates in the abnormal hippocampal dendritic spine maturation observed in a mouse model of FXS.
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4. Chistol LT, Bandini LG, Must A, Phillips S, Cermak SA, Curtin C. {{Sensory Sensitivity and Food Selectivity in Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2017.
Few studies have compared atypical sensory characteristics and food selectivity between children with and without autism spectrum disorder (ASD). We compared oral sensory processing between children with (n = 53) and without ASD (n = 58), ages 3-11 years. We also examined the relationships between atypical oral sensory processing, food selectivity, and fruit/vegetable consumption in children with ASD. We found that more children with ASD presented with atypical sensory processing than children without ASD. Among children with ASD, those with atypical oral sensory sensitivity refused more foods and ate fewer vegetables than those with typical oral sensory sensitivity. The findings suggest that efforts to address food selectivity in children with ASD may be enhanced by including strategies that address oral sensory processing.
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5. Church JS, Tijerina PB, Emerson FJ, Coburn MA, Blum JL, Zelikoff JT, Schwartzer JJ. {{Perinatal exposure to concentrated ambient particulates results in autism-like behavioral deficits in adult mice}}. {Neurotoxicology}. 2017.
Exposure to fine ambient particulates (PM2.5) during gestation or neonatally has potent neurotoxic effects. While biological and behavioral data indicate a vulnerability to environmental pollutants across distinct neurodevelopmental windows, the behavioral consequences following exposure across the entire developmental period remain unknown. Moreover, several epidemiological studies support a link between developmental exposure to air pollution and an increased risk of later receiving a diagnosis of autism spectrum disorders (ASD), a neurodevelopmental disorder that persists throughout life. In the current study we sought to determine whether perinatal exposure to PM2.5 would reduce sociability and increase repetitive deficits in mice, two hallmark characteristics of ASD. Pregnant female B6C3F1 mice were exposed daily to concentrated ambient PM2.5 (CAPs) (135.8mug/m(3)) or filtered air (3.1mug/m(3)) throughout gestation followed by additional exposures to both dams and their litters from days 2-10 postpartum. Adult offspring were subsequently assessed for social and repetitive behaviors at 20 weeks of age. Daily perinatal exposure to CAPs significantly decreased sociability in male and female mice as measured by the social approach task; however, reductions in reciprocal social interaction and increased grooming behavior were only present in male offspring exposed to CAPs. These findings demonstrate that exposure to particulate air pollutants throughout early neurodevelopment induces long lasting behavioral deficits in a sex-dependent manner and may be an underlying cause of neurodevelopmental disorders such as ASD.
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6. Dinora P, Bogenschutz M, Lynch K. {{Factors That May Influence Parent Treatment Decision Making for Young Children with Autism Spectrum Disorder}}. {J Soc Work Disabil Rehabil}. 2017.
The number of interventions available for children with Autism Spectrum Disorder (ASD) has expanded greatly in recent years, though relatively little is known about the factors that influence family caregivers as they make treatment decisions for their children. This study involved a statewide survey of parents of young children with ASD to examine the relative weights of the factors that influenced their treatment decisions. Results suggested that caregivers rely on their own intuition for much decision making, though selected professionals are also influential. Implications for professionals working with children with ASD and their families are discussed.
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7. Downs JM, Lechler S, Dean H, Sears N, Patel R, Shetty H, Simonoff E, Hotopf M, Ford TJ, Diaz-Caneja CM, Arango C, MacCabe JH, Hayes RD, Pina-Camacho L. {{The Association Between Comorbid Autism Spectrum Disorders and Antipsychotic Treatment Failure in Early-Onset Psychosis: A Historical Cohort Study Using Electronic Health Records}}. {J Clin Psychiatry}. 2017.
OBJECTIVE: In a sample of children and adolescents with first-episode psychosis, we investigated whether multiple treatment failure (MTF, defined as the initiation of a third trial of novel antipsychotic due to nonadherence, adverse effects, or insufficient response) was associated with comorbid autism spectrum disorders. METHODS: Data were from the electronic health records of 638 children (51% male) aged from 10 to 17 years with first-episode psychosis (per ICD-10 criteria) from January 1, 2008, to November 1, 2014, referred to mental health services in South London, United Kingdom; data were extracted using the Clinical Record Interactive Search (CRIS) system. The effect of autism spectrum disorder comorbidity on the development of MTF during a 5-year period was modeled using Cox regression. RESULTS: There were 124 cases of MTF prior to the age of 18 (19.4% of the sample). Comorbid autism spectrum disorders were significantly associated with MTF (adjusted hazard ratio = 1.99; 95% CI, 1.19-3.31; P = .008) after controlling for a range of potential confounders. Other factors significantly associated with MTF included higher age at first presentation (P = .001), black ethnicity (P = .03), and frequency of clinical contact (P < .001). No significant association between other comorbid neurodevelopmental disorders (hyperkinetic disorder or intellectual disability) and MTF was found. CONCLUSIONS: Children with first-episode psychosis and comorbid autism spectrum disorders at first presentation are less likely to have a beneficial response to antipsychotics. Lien vers le texte intégral (Open Access ou abonnement)
8. Dvornek NC, Ventola P, Pelphrey KA, Duncan JS. {{Identifying Autism from Resting-State fMRI Using Long Short-Term Memory Networks}}. {Mach Learn Med Imaging}. 2017; 10541: 362-70.
Functional magnetic resonance imaging (fMRI) has helped characterize the pathophysiology of autism spectrum disorders (ASD) and carries promise for producing objective biomarkers for ASD. Recent work has focused on deriving ASD biomarkers from resting-state functional connectivity measures. However, current efforts that have identified ASD with high accuracy were limited to homogeneous, small datasets, while classification results for heterogeneous, multi-site data have shown much lower accuracy. In this paper, we propose the use of recurrent neural networks with long short-term memory (LSTMs) for classification of individuals with ASD and typical controls directly from the resting-state fMRI time-series. We used the entire large, multi-site Autism Brain Imaging Data Exchange (ABIDE) I dataset for training and testing the LSTM models. Under a cross-validation framework, we achieved classification accuracy of 68.5%, which is 9% higher than previously reported methods that used fMRI data from the whole ABIDE cohort. Finally, we presented interpretation of the trained LSTM weights, which highlight potential functional networks and regions that are known to be implicated in ASD.
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9. Friedman C, Rizzolo MC. {{Correlates of Voting Participation of People with Intellectual and Developmental Disabilities}}. {J Soc Work Disabil Rehabil}. 2017.
People with intellectual and developmental disabilities (IDD) vote less frequently than nondisabled people and people with other disabilities. This study explores what factors facilitate and hinder people with IDD’s voting participation. To do so, 1,341 people with IDD were surveyed using the Personal Outcome Measures(R). Binary logistic regressions revealed significant relationships between voting participation, and support needs, residence types, guardianship statuses, and organizational supports. Along with the right supports, attention to barriers that might exist can ensure people with IDD are able to make use of their civil rights and participate in this crucial form of civic engagement.
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10. Gonzalez-Barrero AM, Nadig AS. {{Can Bilingualism Mitigate Set-Shifting Difficulties in Children With Autism Spectrum Disorders?}}. {Child Dev}. 2017.
This study investigated the effects of bilingualism on set-shifting and working memory in children with autism spectrum disorders (ASD). Bilinguals with ASD were predicted to display a specific bilingual advantage in set-shifting, but not working memory, relative to monolinguals with ASD. Forty 6- to 9-year-old children participated (20 ASD, 20 typically-developing). Set-shifting was measured using a computerized dimensional change card sort (DCCS) task, and by parent report of executive functioning in daily life. Results showed an advantage for bilingual relative to monolingual children with ASD on the DCCS task, but not for set-shifting in daily life. Working memory was similar for bilinguals and monolinguals with ASD. These findings suggest that bilingualism may mitigate some set-shifting difficulties in children with ASD.
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11. Gurney ME, Cogram P, Deacon RM, Rex C, Tranfaglia M. {{Multiple Behavior Phenotypes of the Fragile-X Syndrome Mouse Model Respond to Chronic Inhibition of Phosphodiesterase-4D (PDE4D)}}. {Sci Rep}. 2017; 7(1): 14653.
Fragile-X syndrome (FXS) patients display intellectual disability and autism spectrum disorder due to silencing of the X-linked, fragile-X mental retardation-1 (FMR1) gene. Dysregulation of cAMP metabolism is a consistent finding in patients and in the mouse and fly FXS models. We therefore explored if BPN14770, a prototypic phosphodiesterase-4D negative allosteric modulator (PDE4D-NAM) in early human clinical trials, might provide therapeutic benefit in the mouse FXS model. Daily treatment of adult male fmr1 C57Bl6 knock-out mice with BPN14770 for 14 days reduced hyperarousal, improved social interaction, and improved natural behaviors such as nesting and marble burying as well as dendritic spine morphology. There was no decrement in behavioral scores in control C57Bl6 treated with BPN14770. The behavioral benefit of BPN14770 persisted two weeks after washout of the drug. Thus, BPN14770 may be useful for the treatment of fragile-X syndrome and other disorders with decreased cAMP signaling.
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12. Hollway JA, Mendoza-Burcham M, Andridge R, Aman MG, Handen B, Arnold LE, Lecavalier L, Williams C, Silverman L, Smith T. {{Atomoxetine, Parent Training, and Their Effects on Sleep in Youth with Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder}}. {J Child Adolesc Psychopharmacol}. 2017.
OBJECTIVE: Sleep disturbance is often a problem for children with either autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD). Psychostimulant medications used to treat ADHD symptoms can exacerbate this problem. For children with ASD and ADHD, atomoxetine (ATX) is a viable alternative to psychostimulants. We investigated the effects of ATX and a manualized parent training (PT) program targeting noncompliance, on the sleep quality of children with ASD and ADHD. METHODS: Participants in a randomized clinical trial were treated with ATX + PT, ATX alone, PT alone, or placebo (PBO) alone, for 10 weeks. Fifty-four of 128 (42%) caregivers completed the Children’s Sleep Habits Questionnaire (CSHQ) at baseline and endpoint. Analysis of covariance was used to investigate possible differences between treatment groups. RESULTS: There were no significant differences between treatment groups, including PBO on the CSHQ 33-Item total score, total hours of sleep per day, and total minutes awake after sleep onset at the study endpoint. CONCLUSION: ATX appears sleep neutral. Clinicians who treat ADHD symptoms in children and adolescents with ASD may prefer ATX over psychostimulants when sleep disturbance is an issue.
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13. Hu Y, Chen Z, Huang L, Xi Y, Li B, Wang H, Yan J, Lee TMC, Tao Q, So KF, Ren C. {{A translational study on looming-evoked defensive response and the underlying subcortical pathway in autism}}. {Sci Rep}. 2017; 7(1): 14755.
Rapidly approaching objects indicating threats can induce defensive response through activating a subcortical pathway comprising superior colliculus (SC), lateral posterior nucleus (LP), and basolateral amygdala (BLA). Abnormal defensive response has been reported in autism, and impaired synaptic connections could be the underlying mechanism. Whether the SC-LP-BLA pathway processes looming stimuli abnormally in autism is not clear. Here, we found that looming-evoked defensive response is impaired in a subgroup of the valproic acid (VPA) mouse model of autism. By combining the conventional neurotracer and transneuronal rabies virus tracing techniques, we demonstrated that synaptic connections in the SC-LP-BLA pathway were abnormal in VPA mice whose looming-evoked defensive responses were absent. Importantly, we further translated the finding to children with autism and observed that they did not present looming-evoked defensive response. Furthermore, the findings of the DTI with the probabilistic tractography showed that the structural connections of SC-pulvinar-amygdala in autism children were weak. The pulvinar is parallel to the LP in a mouse. Because looming-evoked defensive response is innate in humans and emerges much earlier than do social and language functions, the absence of defensive response could be an earlier sign of autism in children.
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14. Kanner AM, Scharfman H, Jette N, Anagnostou E, Bernard C, Camfield C, Camfield P, Legg K, Dinstein I, Giacobbe P, Friedman A, Pohlmann-Eden B. {{Epilepsy as a Network Disorder (1): What can we learn from other network disorders such as autistic spectrum disorder and mood disorders?}}. {Epilepsy Behav}. 2017; 77: 106-13.
Epilepsy is a neurologic condition which often occurs with other neurologic and psychiatric disorders. The relation between epilepsy and these conditions is complex. Some population-based studies have identified a bidirectional relation, whereby not only patients with epilepsy are at increased risk of suffering from some of these neurologic and psychiatric disorders (migraine, stroke, dementia, autism, depression, anxiety disorders, Attention deficit hyperactivity disorder (ADHD), and psychosis), but also patients with these conditions are at increased risk of suffering from epilepsy. The existence of common pathogenic mechanisms has been postulated as a potential explanation of this phenomenon. To reassess the relationships between neurological and psychiatric conditions in general, and specifically autism, depression, Alzheimer’s disease, schizophrenia, and epilepsy, a recent meeting brought together basic researchers and clinician scientists entitled « Epilepsy as a Network Disorder. » This was the fourth in a series of conferences, the « Fourth International Halifax Conference and Retreat ». This manuscript summarizes the proceedings on potential relations between Epilepsy on the one hand and autism and depression on the other. A companion manuscript provides a summary of the proceedings about the relation between epilepsy and Alzheimer’s disease and schizophrenia, closed by the role of translational research in clarifying these relationships. The review of the topics in these two manuscripts will provide a better understanding of the mechanisms operant in some of the common neurologic and psychiatric comorbidities of epilepsy.
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15. Li K, Li L, Cui B, Gai Z, Li Q, Wang S, Yan J, Lin B, Tian L, Liu H, Liu X, Xi Z. {{Early postnatal exposure to airborne fine particulate matter induces autism-like phenotypes in male rats}}. {Toxicol Sci}. 2017.
Epidemiological studies have revealed that ambient fine particulate matter (PM2.5) exposure is closely associated with autism spectrum disorder (ASD). However, there is a relative paucity of laboratory data to support this epidemic finding. In order to assess the relationship between PM2.5 exposure and ASD, neonatal male Sprague-Dawley (SD) rats were chosen and exposed to PM2.5 (2 or 20 mg/kg body weight, once a day) by intranasal instillation from postnatal day (PND) 8 to 22. It was found that when exposed to PM2.5 in the early neonatal period for two weeks, both groups of the exposure rats manifested typical behavioral features of autism, including communication deficits, poor social interaction and novelty avoidance. And, we further found, among five ASD candidate genes we chose, both the mRNA level and protein expression of SH3 and multiple ankyrin repeat domains 3 (Shank3) decreased significantly in the rat hippocampus after high dose of PM2.5 exposure. Moreover, results showed that PM2.5-exposure significantly increased the levels of pro-inflammatory cytokines, IL-1beta, IL-6, and TNF-alpha in the hippocampus and prefrontal cortex. The expression of Glial fibrillary acidic protein (GFAP) and ionized binding calcium adapter molecule (IBA1), markers of astrocytes and microglial cell activation, respectively, also increased in the exposed animals. Our work provides new data on the link between postnatal exposure to ambient PM2.5 and the onset of ASD-like symptoms in human beings, and the increased inflammatory response and abnormalities in Shank3 expression in the brain may contribute to the mechanisms of PM2.5 exposure induced ASD.
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16. Linke AC, Olson L, Gao Y, Fishman I, Muller RA. {{Psychotropic medication use in autism spectrum disorders may affect functional brain connectivity}}. {Biol Psychiatry Cogn Neurosci Neuroimaging}. 2017; 2(6): 518-27.
Background: Prescription of psychotropic medications is common in autism spectrum disorders (ASDs), either off-label or to treat comorbid conditions such as ADHD or depression. Psychotropic medications are intended to alter brain function. Yet, studies investigating the functional brain organization in ASDs rarely take medication usage into account. This could explain some of the inconsistent findings of atypical brain network connectivity reported in the autism literature. Methods: The current study tested whether functional connectivity patterns, as assessed with functional magnetic resonance imaging (fMRI), differed in a cohort of 49 children and adolescents with ASDs based on psychotropic medication status, and in comparison with 50 matched typically developing (TD) participants. Twenty-five participants in the ASD group (51%) reported current psychotropic medication usage, including stimulants, antidepressants, antipsychotics, and anxiolytics. Age, IQ, head motion, and ASD symptom severity did not differ between groups. Whole-brain functional connectivity between 132 regions of interest was assessed. Results: Different functional connectivity patterns were identified in the ASD group taking psychotropic medications (ASD-on), as compared to the TD group and the ASD subgroup not using psychotropic medications (ASD-none). The ASD-on group showed distinct underconnectivity between the cerebellum and basal ganglia but cortico-cortical overconnectivity compared to the TD group. Cortical underconnectivity relative to the TD pattern, on the other hand, was pronounced in the ASD-none group. Conclusions: These results suggest that psychotropic medications may affect functional connectivity, and that medication status should be taken into consideration when studying brain function in autism.
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17. Mandy W, Clarke K, McKenner M, Strydom A, Crabtree J, Lai MC, Allison C, Baron-Cohen S, Skuse D. {{Assessing Autism in Adults: An Evaluation of the Developmental, Dimensional and Diagnostic Interview-Adult Version (3Di-Adult)}}. {J Autism Dev Disord}. 2017.
We developed a brief, informant-report interview for assessing autism spectrum conditions (ASC) in adults, called the Developmental, Dimensional and Diagnostic Interview-Adult Version (3Di-Adult); and completed a preliminary evaluation. Informant reports were collected for participants with ASC (n = 39), a non-clinical comparison group (n = 29) and a clinical comparison group (n = 20) who had non-autistic mental health conditions. Mean administration time was 38 min (50 min for ASC). Internal consistency (alphas >/= 0.93) and inter-rater agreement (ICCs >/= 0.99) were high. When discriminating ASC from non-ASC, the 3Di-Adult showed excellent sensitivity (95%) and specificity (92%). The 3Di-Adult shows promise as a psychometrically sound and time-efficient interview for collecting standardised informant reports for DSM-5 assessments of ASC in adults, in research and clinical practice.
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18. Montino S, Agostinelli A, Trevisi P, Martini A, Ghiselli S. {{Check-list for the assessment of functional impairment in children with congenital aural atresia}}. {Int J Pediatr Otorhinolaryngol}. 2017; 102: 174-9.
OBJECTIVES: Congenital Aural Atresia (CAA) is a deformity of the external ear and it is commonly associated with malformations of middle and inner ear and, in some cases, with other facial deformities. Very few assessment measures exist for evaluating the functional impairment in children with CAA. Purpose of this study is to introduce and describe an assessment Checklist, (nominated FOS Checklist) that covers feeding abilities (F), oralmotor skills (O), communication/language development (S) in children with CAA. FOS wants to offer a range of assessment providing a profile of the child in comparison to hearing peers and it aims to make clinicians able to identify additional problems and areas of difficulties as well as specific abilities and skills. Secondary, we want to investigate the presence of correlations between disorders and side of CAA. METHODS: a new Checklist (FOS Checklist) was administered to 68 children with CAA. RESULTS: Feeding abilities are age-adequate in 94,3% of all patients. 54,4% of all patients are in need for further assessment of their oral-motor skills; delays in language development were found in 44,1% of cases. Orofacial development delays have been observed in 57.2% of subjects among the bilateral CAA group, in 53.9% among the right CAA group and in 53.4% among the left CAA group. Patients referred for further language evaluation were 42,9% in the bilateral CAA group, 33.3% in the right CAA group and 33.3% in the left CAA group. According to the chi(2) analysis, referral for further assessment is independent from side of aural atresia. CONCLUSIONS: Subjects with bilateral CAA are more likely to be referred for further assessment, both for oral motor aspects and for speech perception and language development. However, there is not a significant statistical difference between the performances of children with bilateral or unilateral CAA. FOS Checklist is simple, reliable and time effective and can be used in everyday clinical practice. FOS enable clinicians to identify additional problems and areas of difficulties as well as specific abilities and skills; moreover, FOS allows to determine appropriate referrals and intervention strategies.
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19. Pyronneau A, He Q, Hwang JY, Porch M, Contractor A, Zukin RS. {{Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome}}. {Sci Signal}. 2017; 10(504).
Fragile X syndrome (FXS) is the most common inherited cause of intellectual disabilities and a leading cause of autism. FXS is caused by a trinucleotide expansion in the gene FMR1 on the X chromosome. The neuroanatomical hallmark of FXS is an overabundance of immature dendritic spines, a factor thought to underlie synaptic dysfunction and impaired cognition. We showed that aberrantly increased activity of the Rho GTPase Rac1 inhibited the actin-depolymerizing factor cofilin, a major determinant of dendritic spine structure, and caused disease-associated spine abnormalities in the somatosensory cortex of FXS model mice. Increased cofilin phosphorylation and actin polymerization coincided with abnormal dendritic spines and impaired synaptic maturation. Viral delivery of a constitutively active cofilin mutant (cofilinS3A) into the somatosensory cortex of Fmr1-deficient mice rescued the immature dendritic spine phenotype and increased spine density. Inhibition of the Rac1 effector PAK1 with a small-molecule inhibitor rescued cofilin signaling in FXS mice, indicating a causal relationship between PAK1 and cofilin signaling. PAK1 inhibition rescued synaptic signaling (specifically the synaptic ratio of NMDA/AMPA in layer V pyramidal neurons) and improved sensory processing in FXS mice. These findings suggest a causal relationship between increased Rac1-cofilin signaling, synaptic defects, and impaired sensory processing in FXS and uncover a previously unappreciated role for impaired Rac1-cofilin signaling in the aberrant spine morphology and spine density associated with FXS.
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20. Santini E, Huynh TN, Longo F, Koo SY, Mojica E, D’Andrea L, Bagni C, Klann E. {{Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice}}. {Sci Signal}. 2017; 10(504).
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which subsequently sequesters and inhibits eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP-eIF4E complex and the Rac1-Wave regulatory complex, thereby connecting translational regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP. Treating FXS mice with 4EGI-1, which blocks interactions between eIF4E and eIF4G, a critical interaction partner for translational initiation, reversed defects in hippocampus-dependent memory and spine morphology. We also found that 4EGI-1 normalized the phenotypes of enhanced metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), enhanced Rac1-p21-activated kinase (PAK)-cofilin signaling, altered actin dynamics, and dysregulated CYFIP1/eIF4E and CYFIP1/Rac1 interactions in FXS mice. Our findings are consistent with the idea that an imbalance in protein synthesis and actin dynamics contributes to pathophysiology in FXS mice, and suggest that targeting eIF4E may be a strategy for treating FXS.
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21. Stefanik L, Erdman L, Ameis SH, Foussias G, Mulsant BH, Behdinan T, Goldenberg A, O’Donnell LJ, Voineskos AN. {{Brain-Behavior Participant Similarity Networks Among Youth and Emerging Adults with Schizophrenia Spectrum, Autism Spectrum, or Bipolar Disorder and Matched Controls}}. {Neuropsychopharmacology}. 2017.
There is considerable heterogeneity in social cognitive and neurocognitive performance among people with schizophrenia spectrum disorders (SSD), autism spectrum disorders (ASD), bipolar disorder (BD), and healthy individuals. This study used Similarity Network Fusion (SNF), a novel data-driven approach, to identify participant similarity networks based on relationships among demographic, brain imaging, and behavioral data. T1-weighted and diffusion-weighted magnetic resonance images were obtained for 174 adolescents and young adults (aged 16-35 years) with an SSD (n=51), an ASD without intellectual disability (n=38), euthymic BD (n=34), and healthy controls (n=51). A battery of social cognitive and neurocognitive tasks were administered. Data integration, cluster determination, and biological group formation were then obtained using SNF. We identified four new groups of individuals, each with distinct neural circuit-cognitive profiles. The most influential variables driving the formation of the new groups were robustly reliable across embedded resampling techniques. The data-driven groups showed considerably greater differentiation on key social and neurocognitive circuit nodes than groups generated by diagnostic analyses or dimensional social cognitive analyses. The data-driven groups were validated through functional outcome and brain network property measures not included in the SNF model. Cutting across diagnostic boundaries, our approach can effectively identify new groups of people based on a profile of neuroimaging and behavioural data. Our findings bringing us closer to disease subtyping that can be leveraged toward targeting of specific neural circuitry among participant subgroups to ameliorate social cognitive and neurocognitive deficits.Neuropsychopharmacology accepted article preview online, 06 November 2017. doi:10.1038/npp.2017.274.
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22. Tchanturia K, Adamson J, Leppanen J, Westwood H. {{Characteristics of autism spectrum disorder in anorexia nervosa: A naturalistic study in an inpatient treatment programme}}. {Autism}. 2017: 1362361317722431.
Previous research has demonstrated links between anorexia nervosa and autism spectrum disorder however, few studies have examined the possible impact of symptoms of autism spectrum disorder on clinical outcomes in anorexia nervosa. The aim of this study was to examine the association between symptoms of autism spectrum disorder and eating disorders, and other psychopathology during the course of inpatient treatment in individuals with anorexia nervosa. Participants with anorexia nervosa (n = 171) completed questionnaires exploring eating disorder psychopathology, symptoms of depression and anxiety, and everyday functioning at both admission and discharge. Characteristics associated with autism spectrum disorder were assessed using the Autism Spectrum Quotient, short version. Autism spectrum disorder symptoms were significantly positively correlated with eating disorder psychopathology, work and social functioning, and symptoms of depression and anxiety, but not with body mass index. Autism Spectrum Quotient, short version scores remained relatively stable from admission to discharge but there was a small, significant reduction in scores. There was no interaction between time and Autism Spectrum Quotient, short version scores on clinical symptom change. In anorexia nervosa, autism spectrum disorder symptoms appear to be associated with a more severe clinical presentation on admission to inpatient care. Autism spectrum disorder symptoms as assessed by self-report measures may be exacerbated by other mental health psychopathology, which warrants further investigation.
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23. Unichenko P, Yang JW, Kirischuk S, Kolbaev S, Kilb W, Hammer M, Krueger-Burg D, Brose N, Luhmann HJ. {{Autism Related Neuroligin-4 Knockout Impairs Intracortical Processing but not Sensory Inputs in Mouse Barrel Cortex}}. {Cereb Cortex}. 2017: 1-14.
Neuroligin-4 (Nlgn4) is a cell adhesion protein that regulates synapse organization and function. Mutations in human NLGN4 are among the causes of autism spectrum disorders. In mouse, Nlgn4 knockout (KO) perturbs GABAergic synaptic transmission and oscillatory activity in hippocampus, and causes social interaction deficits. The complex profile of cellular and circuit changes that are caused by Nlgn4-KO is still only partly understood. Using Nlgn4-KO mice, we found that Nlgn4-KO increases the power in the alpha frequency band of spontaneous network activity in the barrel cortex under urethane anesthesia in vivo. Nlgn4-KO did not affect single-whisker-induced local field potentials, but suppressed the late evoked multiunit activity in vivo. Although Nlgn4-KO did not affect evoked EPSCs in layer 4 (L4) spiny stellate cells in acute thalamocortical slices elicited by electrical stimulation of thalamocortical inputs, it caused a lower frequency of both miniature (m) IPSCs and mEPSCs, and a decrease in the number of readily releasable vesicles at GABAergic and glutamatergic connections, weakening both excitatory and inhibitory transmission. However, Nlgn4 deficit strongly suppresses glutamatergic activity, shifting the excitation-inhibition balance to inhibition. We conclude that Nlgn4-KO does not influence the incoming whisker-mediated sensory information to the barrel cortex, but modifies intracortical information processing.
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24. Zeidler S, de Boer H, Hukema RK, Willemsen R. {{Combination Therapy in Fragile X Syndrome; Possibilities and Pitfalls Illustrated by Targeting the mGluR5 and GABA Pathway Simultaneously}}. {Front Mol Neurosci}. 2017; 10: 368.
Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism. The disorder is characterized by altered synaptic plasticity in the brain. Synaptic plasticity is tightly regulated by a complex balance of different synaptic pathways. In FXS, various synaptic pathways are disrupted, including the excitatory metabotropic glutamate receptor 5 (mGluR5) and the inhibitory gamma-aminobutyric acid (GABA) pathways. Targeting each of these pathways individually, has demonstrated beneficial effects in animal models, but not in patients with FXS. This lack of translation might be due to oversimplification of the disease mechanisms when targeting only one affected pathway, in spite of the complexity of the many pathways implicated in FXS. In this report we outline the hypothesis that targeting more than one pathway simultaneously, a combination therapy, might improve treatment effects in FXS. In addition, we present a glance of the first results of chronic combination therapy on social behavior in Fmr1 KO mice. In contrast to what we expected, targeting both the mGluR5 and the GABAergic pathways simultaneously did not result in a synergistic effect, but in a slight worsening of the social behavior phenotype. This does implicate that both pathways are interconnected and important for social behavior. Our results underline the tremendous fine-tuning that is needed to reach the excitatory-inhibitory balance in the synapse in relation to social behavior. We believe that alternative strategies focused on combination therapy should be further explored, including targeting pathways in different cellular compartments or cell-types.
