1. Daniels J, Haber N, Voss C, Schwartz J, Tamura S, Fazel A, Kline A, Washington P, Phillips J, Winograd T, Feinstein C, Wall DP. {{Feasibility Testing of a Wearable Behavioral Aid for Social Learning in Children with Autism}}. {Applied clinical informatics}. 2018; 9(1): 129-40.
BACKGROUND: Recent advances in computer vision and wearable technology have created an opportunity to introduce mobile therapy systems for autism spectrum disorders (ASD) that can respond to the increasing demand for therapeutic interventions; however, feasibility questions must be answered first. OBJECTIVE: We studied the feasibility of a prototype therapeutic tool for children with ASD using Google Glass, examining whether children with ASD would wear such a device, if providing the emotion classification will improve emotion recognition, and how emotion recognition differs between ASD participants and neurotypical controls (NC). METHODS: We ran a controlled laboratory experiment with 43 children: 23 with ASD and 20 NC. Children identified static facial images on a computer screen with one of 7 emotions in 3 successive batches: the first with no information about emotion provided to the child, the second with the correct classification from the Glass labeling the emotion, and the third again without emotion information. We then trained a logistic regression classifier on the emotion confusion matrices generated by the two information-free batches to predict ASD versus NC. RESULTS: All 43 children were comfortable wearing the Glass. ASD and NC participants who completed the computer task with Glass providing audible emotion labeling (n = 33) showed increased accuracies in emotion labeling, and the logistic regression classifier achieved an accuracy of 72.7%. Further analysis suggests that the ability to recognize surprise, fear, and neutrality may distinguish ASD cases from NC. CONCLUSION: This feasibility study supports the utility of a wearable device for social affective learning in ASD children and demonstrates subtle differences in how ASD and NC children perform on an emotion recognition task.
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2. Kara T, Akaltun I, Cakmakoglu B, Kaya I, Zoroglu S. {{An Investigation of SDF1/CXCR4 Gene Polymorphisms in Autism Spectrum Disorder: A Family-Based Study}}. {Psychiatry investigation}. 2018.
Objective: Autism spectrum disorders (ASD) have a complex pathophysiology including genetic, inflammatory and neurodevelopmental components. We aim to investigate the relationship between ASD and gene polymorphisms of stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor-4 (CXCR4), which may affect inflammatory and neurodevelopmental processes. Methods: 101 children diagnosed with ASD aged 2-18 and their biological parents were included in the study. All participants were assessed using an information form and the Children were assessed using Childhood Autism Rating Scale (CARS). SDF-1 G801–>A and CXCR4 C13–>T polymorphisms were detected by genetic techniques. The results were evaluated using the transmission disequilibrium test (TDT) and haplotype relative risk (HRR). Results: Following TDT evaluation for CXCR4, the assumption of equality was not rejected (chi2=1.385, p=0.239). HRR for the C allele was 1.037 [HRR (95%CI)=0.937 (0.450-2.387), chi2=0.007, p=0.933] and HRR for the T allele was 0.965 [HRR (95%CI)=0.965 (0.419- 2.221), chi2=1.219, p=0.270], but the findings were statistically insignificant. Based on TDT evaluation for SDF1, the assumption of equality cannot be rejected (chi2=0, p=0.999). HRR for the A allele was 0.701 [HRR (95%CI)=0.701 (0.372-1.319), chi2=1.219, p=0.270] and HRR for the G allele was 1.427 [HRR (95%CI)=1.427 (0.758-2.686), chi2=1.219, p=0.270], but the findings were statistically insignificant. Conclusion: The genetic screening of blood samples from mother, father and child trios could not show a significant association between SDF1/CXCR4 genes and ASD on the basis of TDT and HRR tests. More extensive genetic studies are now needed to investigate the relationship between SDF1/CXCR4 gene polymorphisms and ASD.
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3. Leung RC, Pang EW, Anagnostou E, Taylor MJ. {{Young Adults with Autism Spectrum Disorder Show Early Atypical Neural Activity during Emotional Face Processing}}. {Front Hum Neurosci}. 2018; 12: 57.
Social cognition is impaired in autism spectrum disorder (ASD). The ability to perceive and interpret affect is integral to successful social functioning and has an extended developmental course. However, the neural mechanisms underlying emotional face processing in ASD are unclear. Using magnetoencephalography (MEG), the present study explored neural activation during implicit emotional face processing in young adults with and without ASD. Twenty-six young adults with ASD and 26 healthy controls were recruited. Participants indicated the location of a scrambled pattern (target) that was presented alongside a happy or angry face. Emotion-related activation sources for each emotion were estimated using the Empirical Bayes Beamformer (pcorr Lien vers le texte intégral (Open Access ou abonnement)
4. Liu XS, Wu H, Krzisch M, Wu X, Graef J, Muffat J, Hnisz D, Li CH, Yuan B, Xu C, Li Y, Vershkov D, Cacace A, Young RA, Jaenisch R. {{Rescue of Fragile X Syndrome Neurons by DNA Methylation Editing of the FMR1 Gene}}. {Cell}. 2018; 172(5): 979-92.e6.
Fragile X syndrome (FXS), the most common genetic form of intellectual disability in males, is caused by silencing of the FMR1 gene associated with hypermethylation of the CGG expansion mutation in the 5′ UTR of FMR1 in FXS patients. Here, we applied recently developed DNA methylation editing tools to reverse this hypermethylation event. Targeted demethylation of the CGG expansion by dCas9-Tet1/single guide RNA (sgRNA) switched the heterochromatin status of the upstream FMR1 promoter to an active chromatin state, restoring a persistent expression of FMR1 in FXS iPSCs. Neurons derived from methylation-edited FXS iPSCs rescued the electrophysiological abnormalities and restored a wild-type phenotype upon the mutant neurons. FMR1 expression in edited neurons was maintained in vivo after engrafting into the mouse brain. Finally, demethylation of the CGG repeats in post-mitotic FXS neurons also reactivated FMR1. Our data establish that demethylation of the CGG expansion is sufficient for FMR1 reactivation, suggesting potential therapeutic strategies for FXS.
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5. Lo FS, Erzurumlu RS. {{Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism}}. {Mol Autism}. 2018; 9: 13.
Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1(cre)/Met(flox) mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1(cre)/Met(flox) mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment.
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6. Luebbert C, Sadowski G. {{In-situ determination of crystallization kinetics in ASDs via water sorption experiments}}. {European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik eV}. 2018.
Amorphous solid dispersions (ASD) are intended to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients. However, the development of long-term stable ASDs is often limited by the unwanted crystallization of the incorporated active pharmaceutical ingredient. Robust detection and quantification of crystal formation- especially at temperatures and humidites relevant for long-term storage tests – are essential for understanding crystallization phenomena. In this work, the crystallization kinetics in spray-dried nifedipine/poly (vinyl acetate) ASDs was investigated by measuring the time-dependent water sorption behavior at constant storage conditions. By coupling these experiments with thermodynamic predictions of the water sorption in amorphous and crystallized ASDs using the Perturbed-Chain Statistical Associating Fluid Theory, the amount of crystallized nifedipine as function of time could be determined in-situ just by weighing the ASD samples and without any calibration. The experimental findings were validated by X-ray diffraction measurements. Metastable ASDs with nifedipine contents between 70wt% and 90wt% were investigated at relative humidities between 60% RH and 90% RH and in a temperature range between 30 degrees C and 40 degrees C. Storage at high temperature and at high RH, and high nifedipine contents dramatically increased the crystallization rates.
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7. Mahapatra S, Vyshedsky D, Martinez S, Kannel B, Braverman J, Edelson SM, Vyshedskiy A. {{Autism Treatment Evaluation Checklist (ATEC) Norms: A « Growth Chart » for ATEC Score Changes as a Function of Age}}. {Children (Basel, Switzerland)}. 2018; 5(2).
Most early-intervention Autism Spectrum Disorder (ASD) clinical trials are limited by the availability of psychometric technicians who assess each child’s abilities before and after therapeutic intervention. If parents could administer regular psychometric evaluations of their children, then the cost of clinical trials will be reduced, enabling longer clinical trials with the larger number of participants. The Autism Treatment Evaluation Checklist (ATEC) was designed nearly two decades ago to provide such a tool, but the norms on the longitudinal changes in ATEC in the « treatment as usual » population were lacking. Here we report the norms of the observational cohort who voluntarily completed ATEC evaluations over the period of four years from 2013 to 2017.
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8. Prehn-Kristensen A, Lorenzen A, Grabe F, Baving L. {{Negative emotional face perception is diminished on a very early level of processing in autism spectrum disorder}}. {Social neuroscience}. 2018: 1-4.
Deficits in facial affect recognition (FAR) are often reported in autism spectrum disorder (ASD) due to inappropriate visual search strategies. It is unclear, however, whether or not deficits in subliminal FAR are still present in autism when visual focus is controlled. Thirteen persons with ASD and 13 healthy participants took part in this experiment. Supraliminal FAR was assessed using a standardized, computer-aided test. Subliminal FAR was obtained by an emotional face priming paradigm. By using an eye-tracking technique, it was assured that the initial visual focus was on the eyes of the prime. Persons with ASD showed worse FAR in supraliminal face recognition. Although controlled for initial gaze direction, participants also showed reduced negative face priming. These data confirm that FAR is disturbed already on a pre-attentive level in autism.
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9. Shepherd D, Landon J, Taylor S, Goedeke S. {{Coping and care-related stress in parents of a child with autism spectrum disorder}}. {Anxiety, stress, and coping}. 2018: 1-14.
BACKGROUND AND OBJECTIVES: Parenting a child with Autism Spectrum Disorder (ASD) is challenging and can result in elevated levels of parenting stress. This study investigated the relationship between parent-ratings of their child’s ASD symptoms and two conceptually different measures of parenting stress: One specific to the ASD context and the other a general stress measure applicable to the broader caregiving context. Additionally, the influence of coping style on the relationship between child’s ASD symptoms and parenting stress was investigated. DESIGN AND METHODS: Using an internet survey, parents (N = 178) caring for a child with ASD reported on coping strategies, completed two measures of parenting stress, and assessed their child’s ASD symptoms. RESULTS: Parenting stress increased with severity of the child’s ASD symptoms, but the strength of this relationship depended on whether a general or disorder-specific measure of parenting stress was used. Regression analyses indicated that some coping strategies moderated the impact of ASD symptom severity on the parent’s care-related stress, but moderation depended on how stress was conceptualized. CONCLUSION: This study reinforces the importance of identifying the coping strategies of parents of children with developmental disorders, and highlights the consequences of using different conceptual approaches to measure parenting stress.
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10. Stivaros S, Garg S, Tziraki M, Cai Y, Thomas O, Mellor J, Morris AA, Jim C, Szumanska-Ryt K, Parkes LM, Haroon HA, Montaldi D, Webb N, Keane J, Castellanos FX, Silva AJ, Huson S, Williams S, Gareth Evans D, Emsley R, Green J. {{Randomised controlled trial of simvastatin treatment for autism in young children with neurofibromatosis type 1 (SANTA)}}. {Mol Autism}. 2018; 9: 12.
Background: Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods: A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results: Thirty subjects had a mean age of 8.1 years (SD 1.8). Simvastatin was well tolerated. The amount of imaging data varied by test. Simvastatin treatment was associated with (i) increased frontal white matter MRS GABA (t(12) = – 2.12, p = .055), GABA/Glx ratio (t(12) = – 2.78, p = .016), and reduced grey nuclei Glx (ANCOVA p < 0.05, Mann-Whitney p < 0.01); (ii) increased ASL perfusion in ventral diencephalon (Mann-Whitney p < 0.01); and (iii) decreased ADC in cingulate gyrus (Mann-Whitney p < 0.01). Machine-learning classification of imaging outcomes achieved 79% (p < .05) accuracy differentiating groups at endpoint against chance level (64%, p = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions: We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration: EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu). Lien vers le texte intégral (Open Access ou abonnement)
