1. Bhattacharya A, Mamcarz M, Mullins C, Choudhury A, Boyle RG, Smith DG, Walker DW, Klann E. {{Targeting Translation Control with p70 S6 Kinase 1 Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice}}. {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology}. 2015 Dec 28.
Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1.However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases which are based on aberrant translation and protein expression. One such condition is Fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorders (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macro-orchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling.Neuropsychopharmacology accepted article preview online, 28 December 2015. doi:10.1038/npp.2015.369.
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2. Bora E, Pantelis C. {{Meta-analysis of social cognition in attention-deficit/hyperactivity disorder (ADHD): comparison with healthy controls and autistic spectrum disorder}}. {Psychological medicine}. 2015 Dec 28:1-18.
BACKGROUND: Impairment in social cognition is an established finding in autism spectrum disorders (ASD). Emerging evidence suggests that attention-deficit/hyperactivity disorder (ADHD) might be also associated with deficits in theory of mind (ToM) and emotion recognition. However, there are inconsistent findings, and it has been debatable whether such deficits persist beyond childhood and how similar social cognitive deficits are in ADHD v. ASD. METHOD: We conducted a meta-analysis of social cognition, including emotion recognition and ToM, studies in ADHD compared with healthy controls and ASD. The current meta-analysis involved 44 studies comparing ADHD (n = 1999) with healthy controls (n = 1725) and 17 studies comparing ADHD (n = 772) with ASD (n = 710). RESULTS: Facial and vocal emotion recognition (d = 0.40-0.44) and ToM (d = 0.43) abilities were significantly impaired in ADHD. The most robust facial emotion recognition deficits were evident in anger and fear. Social cognitive deficits were either very subtle (emotion recognition) or non-significant (ToM) in adults with ADHD. Deficits in social cognition, especially ToM, were significantly more pronounced in ASD compared with ADHD. General cognitive impairment has contributed to social cognitive deficits in ADHD. CONCLUSIONS: Performance of individuals with ADHD on social cognition lies intermediate between ASD and healthy controls. However, developmental trajectories of social cognition probably differ between ADHD and ASD as social cognitive deficits in ADHD might be improving with age in most individuals. There is a need for studies investigating a potential subtype of ADHD with persistent social cognitive deficits and exploring longitudinal changes in social cognition during development.
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3. Castren ML. {{Cortical neurogenesis in fragile X syndrome}}. {Frontiers in bioscience (Scholar edition)}. 2016;8:160-8.
The absence of fragile X mental retardation 1 protein (FMRP) results in fragile X syndrome (FXS) that is a common cause of intellectual disability and a variant of autism spectrum disorder. There is evidence that FMRP is involved in neurogenesis. FMRP is widely expressed throughout the embryonic brain development and its expression levels increases during neuronal differentiation. Cortical neural progenitors propagated from human fetal FXS brain show expression changes of genes which encode components of intracellular signal transduction cascades, including receptors, second messengers, and transduction factors. The absence of functional FMRP enhances transition of radial glia to intermediate progenitor cells. Radial glial cells provide scaffolding for migrating neurons and express functional receptors for metabotropic glutamate receptors. The absence of FMRP results in alterations of neuronal differentiation and migration, which contribute to developmental changes in brain structure and function in FXS. Here, cortical neurogenesis in FXS is reviewed and the putative contribution of brain-derived neurotrophic factor to defects of FXS neurogenesis is discussed.
4. Elton A, Di Martino A, Hazlett HC, Gao W. {{Neural Connectivity Evidence for a Categorical-Dimensional Hybrid Model of Autism Spectrum Disorder}}. {Biological psychiatry}. 2015 Nov 2.
BACKGROUND: Autism spectrum disorder (ASD) encompasses a complex manifestation of symptoms that include deficits in social interaction and repetitive or stereotyped interests and behaviors. In keeping with the increasing recognition of the dimensional characteristics of ASD symptoms and the categorical nature of a diagnosis, we sought to delineate the neural mechanisms of ASD symptoms based on the functional connectivity of four known neural networks (i.e., default mode network, dorsal attention network, salience network, and executive control network). METHODS: We leveraged an open data resource (Autism Brain Imaging Data Exchange) providing resting-state functional magnetic resonance imaging data sets from 90 boys with ASD and 95 typically developing boys. This data set also included the Social Responsiveness Scale as a dimensional measure of ASD traits. Seed-based functional connectivity was paired with linear regression to identify functional connectivity abnormalities associated with categorical effects of ASD diagnosis, dimensional effects of ASD-like behaviors, and their interaction. RESULTS: Our results revealed the existence of dimensional mechanisms of ASD uniquely affecting each network based on the presence of connectivity-behavioral relationships; these were independent of diagnostic category. However, we also found evidence of categorical differences (i.e., diagnostic group differences) in connectivity strength for each network as well as categorical differences in connectivity-behavioral relationships (i.e., diagnosis-by-behavior interactions), supporting the coexistence of categorical mechanisms of ASD. CONCLUSIONS: Our findings support a hybrid model for ASD characterization that includes a combination of categorical and dimensional brain mechanisms and provide a novel understanding of the neural underpinnings of ASD.
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5. Faller P, Hunt J, van Hooydonk E, Mailloux Z, Schaaf R. {{Application of Data-Driven Decision Making Using Ayres Sensory Integration With a Child With Autism}}. {The American journal of occupational therapy : official publication of the American Occupational Therapy Association}. 2016 Jan-Feb;70(1):7001220020p1-p9.
Health care and educational legislation and policy require that clinicians demonstrate, using measurement and report of outcomes, accountability for services rendered. Clinical algorithms have been developed and are used by various health care professionals to assist with hypothesis generation and systematic clinical reasoning; however, they do not explicitly guide measurement of outcomes as part of the reasoning process. Schaaf and colleagues developed the Data-Driven Decision Making (DDDM) process to address the greater need for outcome measurement, systematically support decision making, target intervention more precisely, and measure and document outcomes. This article describes the application of the DDDM process with a child with ASD who received occupational therapy using Ayres Sensory Integration(R).
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6. Hirjak D, Wolf RC, Paternoga I, Kubera KM, Thomann AK, Stieltjes B, Maier-Hein KH, Thomann PA. {{Neuroanatomical Markers of Neurological Soft Signs in Recent-Onset Schizophrenia and Asperger-Syndrome}}. {Brain topography}. 2015 Dec 26.
Neurological soft signs (NSS) are frequently found in psychiatric disorders of significant neurodevelopmental origin. Previous MRI studies in schizophrenia have shown that NSS are associated with abnormal cortical, thalamic and cerebellar structure and function. So far, however, no neuroimaging studies investigated brain correlates of NSS in individuals with Asperger-Syndrome (AS) and the question whether the two disorders exhibit common or disease-specific cortical correlates of NSS remains unresolved. High-resolution MRI data at 3 T were obtained from 48 demographically matched individuals (16 schizophrenia patients, 16 subjects with AS and 16 healthy individuals). The surface-based analysis via Freesurfer enabled calculation of cortical thickness, area and folding (local gyrification index, LGI). NSS were examined on the Heidelberg Scale and related to cortical measures. In schizophrenia, higher NSS were associated with reduced cortical thickness and LGI in fronto-temporo-parietal brain areas. In AS, higher NSS were associated with increased frontotemporal cortical thickness. This study lends further support to the hypothesis that disorder-specific mechanisms contribute to NSS expression in schizophrenia and AS. Pointing towards dissociable neural patterns may help deconstruct the complex processes underlying NSS in these neurodevelopmental disorders.
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7. Hong J, Bishop-Fitzpatrick L, Smith LE, Greenberg JS, Mailick MR. {{Factors Associated with Subjective Quality of Life of Adults with Autism Spectrum Disorder: Self-Report Versus Maternal Reports}}. {Journal of autism and developmental disorders}. 2015 Dec 26.
We examined factors related to subjective quality of life (QoL) of adults with autism spectrum disorder (ASD) aged 25-55 (n = 60), using the World Health Organization Quality of Life measure (WHOQOL-BREF). We used three different assessment methods: adult self-report, maternal proxy-report, and maternal report. Reliability analysis showed that adults with ASD rated their own QoL reliably. QoL scores derived from adult self-reports were more closely related to those from maternal proxy-report than from maternal report. Subjective factors such as perceived stress and having been bullied frequently were associated with QoL based on adult self-reports. In contrast, level of independence in daily activities and physical health were significant predictors of maternal reports of their son or daughter’s QoL.
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8. Keehn B, Nair A, Lincoln AJ, Townsend J, Muller RA. {{Under-reactive but easily distracted: An fMRI investigation of attentional capture in autism spectrum disorder}}. {Developmental cognitive neuroscience}. 2015 Dec 7;17:46-56.
For individuals with autism spectrum disorder (ASD), salient behaviorally-relevant information often fails to capture attention, while subtle behaviorally-irrelevant details commonly induce a state of distraction. The present study used functional magnetic resonance imaging (fMRI) to investigate the neurocognitive networks underlying attentional capture in sixteen high-functioning children and adolescents with ASD and twenty-one typically developing (TD) individuals. Participants completed a rapid serial visual presentation paradigm designed to investigate activation of attentional networks to behaviorally-relevant targets and contingent attention capture by task-irrelevant distractors. In individuals with ASD, target stimuli failed to trigger bottom-up activation of the ventral attentional network and the cerebellum. Additionally, the ASD group showed no differences in behavior or occipital activation associated with contingent attentional capture. Rather, results suggest that to-be-ignored distractors that shared either task-relevant or irrelevant features captured attention in ASD. Results indicate that individuals with ASD may be under-reactive to behaviorally-relevant stimuli, unable to filter irrelevant information, and that both top-down and bottom-up attention networks function atypically in ASD. Lastly, deficits in target-related processing were associated with autism symptomatology, providing further support for the hypothesis that non-social attentional processes and their neurofunctional underpinnings may play a significant role in the development of sociocommunicative impairments in ASD.
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9. Kotsopoulos S. {{[Early diagnosis of autism: Phenotype-endophenotype]}}. {Psychiatrike = Psychiatriki}. 2015 Oct-Dec;25(4):273-81.
Autism Spectrum Disorders have for some time been the focus of intense interest for clinicians and researchers because of the high prevalence of the disorders among children in the community (approximately 1%), their severity and pervasiveness. Particular attention has been paid to the early diagnosis of the disorder and to the intensive therapeutic intervention. Currently the best prognosis for autism lays in the early diagnosis and intervention. Postponing the diagnosis and the intervention beyond infancy is considered loss of precious time. The diagnosis of autism, which begins early in life, was until recently considered that could be reliability made at the age of 3 years. Recent follow up studies however on children at risk for autism (children who had an older sibling with autism) have shown that the clinical signs of autism emerge at the end of the first year and become distinct by the end of the second year when the diagnosis can reliably be made. From a clinical perspective it is noted that the early clinical signs of risk for autism are related to social communication (e.g. limited or absent response when calling his/her name and to joint attention), stereotype behaviours and body movements or unusual handling of objects (e.g. intensive observation of objects and stereotype movements of hands and tapping or spinning), incongruent regulation of emotions (reduced positive and increased negative emotion). There is also delay in developmental characteristics such as the language (both receptive and expressive) and motor (particularly in postural control – characteristic is the drop of the head backwards when the infant is held in horizontal position). Studies on various aspects of the endophenotype of certain clinical signs among infants at risk for Autism Spectrum Disorders, such as avoidance of eye contact, delay in verbal communication and increase of the head circumference, may provide useful information and may assist the clinician on follow up in the early diagnosis. Compared to the progress made for an early diagnosis of autism there is relatively no equal progress in the early intervention. However, some methods such as the ‘Early Start Denver Model’ which focuses in the family, which is the natural environment of the child, may provide a useful framework for effective work with the child and the family.
10. Shtayermman O. {{Angela Scarpa, Susan Williams White, Tony Attwood: CBT for Children and Adolescents with High Functioning Autism Spectrum Disorders : The Guilford Press, London and New York, 2013, 329 pp, ISBN: 978-1-4625-1048-1, $39.95 (hardcover)}}. {Journal of autism and developmental disorders}. 2015 Dec 26.
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11. Tick B, Bolton P, Happe F, Rutter M, Rijsdijk F. {{Heritability of autism spectrum disorders: a meta-analysis of twin studies}}. {Journal of child psychology and psychiatry, and allied disciplines}. 2015 Dec 27.
BACKGROUND: The etiology of Autism Spectrum Disorder (ASD) has been recently debated due to emerging findings on the importance of shared environmental influences. However, two recent twin studies do not support this and instead re-affirm strong genetic effects on the liability to ASD, a finding consistent with previous reports. This study conducts a systematic review and meta-analysis of all twin studies of ASD published to date and explores the etiology along the continuum of a quantitative measure of ASD. METHODS: A PubMed Central, Science Direct, Google Scholar, Web of Knowledge structured search conducted online, to identify all twin studies on ASD published to date. Thirteen primary twin studies were identified, seven were included in the meta-analysis by meeting Systematic Recruitment criterion; correction for selection and ascertainment strategies, and applied prevalences were assessed for these studies. In addition, a quantile DF extremes analysis was carried out on Childhood Autism Spectrum Test scores measured in a population sample of 6,413 twin pairs including affected twins. RESULTS: The meta-analysis correlations for monozygotic twins (MZ) were almost perfect at .98 (95% Confidence Interval, .96-.99). The dizygotic (DZ) correlation, however, was .53 (95% CI .44-.60) when ASD prevalence rate was set at 5% (in line with the Broad Phenotype of ASD) and increased to .67 (95% CI .61-.72) when applying a prevalence rate of 1%. The meta-analytic heritability estimates were substantial: 64-91%. Shared environmental effects became significant as the prevalence rate decreased from 5-1%: 07-35%. The DF analyses show that for the most part, there is no departure from linearity in heritability. CONCLUSIONS: We demonstrate that: (a) ASD is due to strong genetic effects; (b) shared environmental effects become significant as a function of lower prevalence rate; (c) previously reported significant shared environmental influences are likely a statistical artefact of overinclusion of concordant DZ twins.
