1. Davidson MM, Ellis Weismer S. {{Reading comprehension of ambiguous sentences by school-age children with autism spectrum disorder}}. {Autism Res};2017 (Aug 22)
Weak central coherence (processing details over gist), poor oral language abilities, poor suppression, semantic interference, and poor comprehension monitoring have all been implicated to affect reading comprehension in individuals with autism spectrum disorder (ASD). This study viewed the contributions of different supporting skills as a collective set of skills necessary for context integration-a multi-component view-to examine individual differences in reading comprehension in school-age children (8-14 years) with ASD (n = 23) and typically developing control peers (n = 23). Participants completed a written ambiguous sentence comprehension task in which participants had to integrate context to determine the correct homonym meaning via picture selection. Both comprehension products (i.e., offline representations after reading) and processes (i.e., online processing during reading) were evaluated. Results indicated that children with ASD, similar to their TD peers, integrated the context to access the correct homonym meanings while reading. However, after reading the sentences, when participants were asked to select the meanings, both groups experienced semantic interference between the two meanings. This semantic interference hindered the children with ASD’s sentence representation to a greater degree than their peers. Individual differences in age/development, word recognition, vocabulary breadth (i.e., number of words in the lexicon), and vocabulary depth (i.e., knowledge of the homonym meanings) contributed to sentence comprehension in both children with ASD and their peers. Together, this evidence supports a multi-component view, and that helping children with ASD develop vocabulary depth may have cascading effects on their reading comprehension. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Like their peers, children with ASD were able to integrate context, or link words while reading sentences with ambiguous words (words with two meanings). After reading the sentences, both groups found it hard to pick the correct meaning of the ambiguous sentence and this decision was more difficult for the participants with ASD. Older children, children with better word reading abilities, and children with higher vocabularies were better at understanding ambiguous sentences. Helping children with ASD to develop richer vocabularies could be important for improving their reading comprehension.
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2. Dempsey J, Dempsey AG, Voigt RG, Monteiro S. {{Associations Between Family Member BMI and Obesity Status of Children with Autism Spectrum Disorder}}. {J Dev Behav Pediatr};2017 (Aug 22)
OBJECTIVE: To determine whether there is an association between parent and sibling obesity status and obesity status in children with autism spectrum disorder (ASD). METHODS: We examined predictors of obesity in children with ASD with body mass index data for the proband, 1 sibling, and 2 parents using data from the multisite Simons Simplex Collection. RESULTS: In a stepwise logistic regression model, proband obesity status was associated with obesity status of the sibling (odds ratio [OR] 2.66; 95% confidence interval [CI], 1.92-3.70), mother (OR 2.10; 95% CI, 1.59-2.77), and father (OR 1.51; 95% CI, 1.15-1.98). Proband obesity was also related to somatic complaints (OR 1.60; 95% CI, 1.006-2.53), mood stabilizers (OR 1.80; 95% CI, 1.19-2.72), internalizing problems (OR 1.60; 95% CI, 1.14-2.30), age (OR 1.01; 95% CI, 1.00-1.01), and some adaptive functioning domains (OR 0.987; 95% CI, 0.977-0.997). Race, ethnicity, income, sex, and maternal education were not significant predictors. CONCLUSION: Familial factors were generally the strongest predictors of obesity rather than medication use, demographics, or psychological characteristics. Results support a family-centered approach to treatment of obesity in children with ASD.
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3. DuBois D, Lymer E, Gibson BE, Desarkar P, Nalder E. {{Assessing Sensory Processing Dysfunction in Adults and Adolescents with Autism Spectrum Disorder: A Scoping Review}}. {Brain Sci};2017 (Aug 19);7(8)
Sensory reactivity is a diagnostic criterion for Autism Spectrum Disorder (ASD), and has been associated with poorer functional outcomes, behavioral difficulties, and autism severity across the lifespan. Yet, there is little consensus on best practice approaches to assessing sensory processing dysfunction in adolescents and adults with ASD. Despite growing evidence that sensory symptoms persist into adolescence and adulthood, there is a lack of norms for older age groups, and pediatric assessments may not target appropriate functional outcomes or environments. This review identified approaches used to measure sensory processing in the scientific literature, and to describe and compare these approaches to current best practice guidelines that can be incorporated into evidence-based practice. Method and Analysis: A search of scientific databases and grey literature (professional association and ASD society websites), from January 1987-May 2017, uncovered 4769 articles and 12 clinical guidelines. Study and sample characteristics were extracted, charted, and categorized according to assessment approach. RESULTS: There were 66 articles included after article screening. Five categories of assessment approaches were identified: Self- and Proxy-Report Questionnaires, Psychophysical Assessment, Direct Behavioral Observation, Qualitative Interview Techniques, and Neuroimaging/EEG. Sensory research to date has focused on individuals with high-functioning ASD, most commonly through the use of self-report questionnaires. The Adolescent and Adult Sensory Profile (AASP) is the most widely used assessment measure (n = 22), however, a number of other assessment approaches may demonstrate strengths specific to the ASD population. Multi-method approaches to assessment (e.g., combining psychophysical or observation with questionnaires) may have clinical applicability to interdisciplinary clinical teams serving adolescents and adults with ASD. Contribution: A comprehensive knowledge of approaches is critical in the clinical assessment of a population characterized by symptomatic heterogeneity and wide-ranging cognitive profiles. This review should inform future development of international interdisciplinary clinical guidelines on sensory processing assessment in ASD across the lifespan.
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4. Esse Wilson J, Quinn DK, Wilson JK, Garcia CM, Tesche CD. {{Transcranial Direct Current Stimulation to the Right Temporoparietal Junction for Social Functioning in Autism Spectrum Disorder: Case Report}}. {J ect};2017 (Aug 18)
OBJECTIVES: While there is evidence of improved social functioning after applying transcranial direct current stimulation (tDCS) at the right temporoparietal junction (rTPJ) in individuals who are healthy, no current studies have investigated the use of tDCS at the rTPJ to improve social functioning in individuals with autism spectrum disorder (ASD). This case investigates the use of tDCS applied to the rTPJ to target social functioning in a high-functioning adult with ASD. METHODS: The authors present a case of an 18-year old patient with ASD treated successfully with tDCS; 1.5 mA of tDCS was applied once a day for 30 minutes for 8 consecutive days with the anode electrode over rTPJ (CP6 in the 10/10 electroencephalogram system) and the cathode electrode placed on the ipsilateral deltoid. Behavioral outcome was assessed using the Autism Treatment Evaluation Checklist prior to tDCS, after the final tDCS session, and at 2 months after tDCS. An additional, informal follow-up was also made 1 year after tDCS. RESULTS: Autism Treatment Evaluation Checklist showed substantial improvement in social functioning from baseline to post-tDCS, which was maintained at 2 months. The patient also reported lessened feelings of anger and frustration over social disappointments. Informal follow-up 1 year after stimulation indicates that the patient continues to maintain many improvements. CONCLUSIONS: Anodal tDCS to the rTPJ may represent an effective treatment for improving social functioning in ASD, with a larger clinical trial needed to validate this effect.
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5. Fluegge K. {{Gene and environment interactions in autism risk: Reflections on the carnitine deficiency hypothesis by Beaudet (Comment on DOI 10.1002/bies.201700012)}}. {Bioessays};2017 (Aug 22)
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6. Fujino J, Tei S, Hashimoto RI, Itahashi T, Ohta H, Kanai C, Okada R, Kubota M, Nakamura M, Kato N, Takahashi H. {{Attitudes toward risk and ambiguity in patients with autism spectrum disorder}}. {Mol Autism};2017;8:45.
Although the ability to make optimal decisions under uncertainty is an integral part of everyday life, individuals with autism spectrum disorder (ASD) frequently report that they experience difficulties with this skill. In behavioral economics, researchers distinguish two types of uncertainty to understand decision-making in this setting: risk (known probabilities) and ambiguity (unknown probabilities). However, it remains unclear how individuals with ASD behave under risk and ambiguity, despite growing evidence of their altered decision-making under uncertainty. We therefore extended previous research by studying the attitudes of those with ASD toward risk and ambiguity in both positive and negative contexts (i.e., gain and loss). In gain contexts, no significant difference was observed between the groups in risk attitudes, but ambiguity aversion was attenuated in ASD. In loss contexts, ambiguity attitudes did not significantly differ between the groups, but the ASD participants were less risk-seeking compared with the controls. In addition, insensitivity to the context change under risk and ambiguity in ASD was both significantly associated with poor social skills. These results improve our understanding of altered decision-making under uncertainty by disentangling the attitudes toward risk and ambiguity in ASD individuals. Applying behavioral economic tools may provide insights into the mechanisms underlying behavioral disturbances in ASD.
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7. Gernsbacher MA, Raimond AR, Stevenson JL, Boston JS, Harp B. {{Do puzzle pieces and autism puzzle piece logos evoke negative associations?}}. {Autism};2017 (Aug 01):1362361317727125.
Puzzle pieces have become ubiquitous symbols for autism. However, puzzle-piece imagery stirs debate between those who support and those who object to its use because they believe puzzle-piece imagery evokes negative associations. Our study empirically investigated whether puzzle pieces evoke negative associations in the general public. Participants’ ( N = 400) implicit negative associations were measured with an Implicit Association Task, which is a speeded categorization task, and participants’ explicit associations were measured with an Explicit Association Task, which is a standard task for assessing consumers’ explicit associations with brands (and images of those brands). Puzzle pieces, both those used as autism logos and those used more generically, evoked negative implicit associations ( t(399) = -5.357, p < 0.001) and negative explicit associations ( z = 4.693, p < 0.001, d = 0.491). Participants explicitly associated puzzle pieces, even generic puzzle pieces, with incompleteness, imperfection, and oddity. Our results bear public policy implications. If an organization's intention for using puzzle-piece imagery is to evoke negative associations, our results suggest the organization's use of puzzle-piece imagery is apt. However, if the organization's intention is to evoke positive associations, our results suggest that puzzle-piece imagery should probably be avoided. Lien vers le texte intégral (Open Access ou abonnement)
8. Howard PL, Liversedge SP, Benson V. {{Processing of co-reference in autism spectrum disorder}}. {Autism Res};2017 (Aug 22)
Accuracy for reading comprehension and inferencing tasks has previously been reported as reduced for individuals with autism spectrum disorder (ASD), relative to typically developing (TD) controls. In this study, we used an eye movements and reading paradigm to examine whether this difference in performance accuracy is underpinned by differences in the inferential work required to compute a co-referential link. Participants read two sentences that contained a category noun (e.g., bird) that was preceded by and co-referred to an exemplar that was either typical (e.g., pigeon) or atypical (e.g., penguin). Both TD and ASD participants showed an effect of typicality for gaze durations upon the category noun, with longer times being observed when the exemplar was atypical, in comparison to typical. No group differences or interactions were detected for target processing, and verbal language proficiency was found to predict general reading and inferential skill. The only difference between groups was that individuals with ASD engaged in more re-reading than TD participants. These data suggest that readers with ASD do not differ in the efficiency with which they compute anaphoric links on-line during reading. Autism Res 2017. (c) 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Individuals with autism spectrum disorder (ASD) have previously been reported to have difficulties with reading comprehension. This study examined whether a difference in the speed with which individuals with ASD form connections between words (co-reference processing) may contribute to comprehension difficulties. No evidence was found to suggest that ASD readers differ to typically developing readers in the speed of co-reference processing. Therefore, this data would suggest that differences in co-reference processing are unlikely to account for reading comprehension difficulties in ASD.
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9. Huang D, Yu L, Wang X, Fan Y, Wang S, Zhang Y. {{Distinct patterns of discrimination and orienting for temporal processing of speech and nonspeech in Chinese children with autism: An event-related potential study}}. {Eur J Neurosci};2017 (Aug 22)
Although many studies have reported domain-general impaired duration perception for speech and nonspeech sounds in children with autism, it remained unclear whether this phenomenon is universally applicable regardless of language background. In some languages such as Finnish and Japanese, vowel duration serves a phonemic role that can signify semantic distinction, and in others (e.g., Mandarin Chinese), vowel duration does not carry this phonemic function. The present event-related potential study investigated neural sensitivity to duration contrasts in speech and nonspeech contexts in Mandarin-speaking children with autism and a control group of age-matched typically developing (TD) children. A passive oddball paradigm was adopted to elicit the mismatch negativity (MMN) and involuntary orienting response (P3a) for change detection. A pure tone condition and a vowel condition were used. The MMN results showed that the autism group had diminished response amplitudes and delayed latency in the pure tone condition compared to the TD group, whereas no group difference was found in the vowel condition. The P3a results showed no significant between-group MMN difference in the pure tone condition. In the vowel condition, the autism group had smaller P3a than the TD group. Together, the distinct patterns of discrimination and orienting responses for duration contrasts in pure tones and vowels are consistent with the « allophonic perception » theory for autism, which may reflect a compromised perceptual weighting system for speech learning. This article is protected by copyright. All rights reserved.
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10. Jahedi A, Nasamran CA, Faires B, Fan J, Muller RA. {{Distributed intrinsic functional connectivity patterns predict diagnostic status in large autism cohort}}. {Brain Connect};2017 (Aug 21)
Diagnosis of autism spectrum disorder (ASD) currently relies on behavioral observations because brain markers are unknown. Machine learning approaches can identify patterns in imaging data that predict diagnostic status, but most studies using functional connectivity MRI (fcMRI) data achieved only modest accuracies of 60-80%. We employed conditional random forest (CRF), an ensemble learning technique protected against bias from feature correlation (which exists in fcMRI matrices). We selected 252 low-motion resting-state functional MRI scans from the Autism Brain Imaging Data Exchange, including 126 typically developing (TD) and 126 ASD participants, matched for age, non-verbal IQ, and head motion. A matrix of functional connectivities between 220 functionally defined regions of interest was used for diagnostic classification. In several runs, we achieved accuracies of 92-99% for classifiers with >300 features (most informative connections). Features including pericentral somatosensory and motor regions were disproportionately informative. Findings differed partially from a previous study in the same sample that used feature selection with random forest (which is biased by feature correlations). External validation in a smaller in-house dataset, however, achieved only 67-71% accuracy. The large number of features in optimal models can be attributed to etiological heterogeneity under the clinical ASD umbrella. Lower accuracy in external validation is expected due to differences in unknown composition of ASD variants across samples. High accuracy in the main dataset is unlikely due to noise overfitting, but rather indicates optimized characterization of a given cohort.
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11. Khemakhem AM, Frye RE, El-Ansary A, Al-Ayadhi L, Bacha AB. {{Novel biomarkers of metabolic dysfunction is autism spectrum disorder: potential for biological diagnostic markers}}. {Metab Brain Dis};2017 (Aug 22)
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is behaviorally defined by social and communication impairments and restricted interests and repetitive behaviors. There is currently no biomarkers that can help in the diagnosis. Several studies suggest that mitochondrial dysfunction is commonly involved in ASD pathophysiology, but standard mitochondrial biomarkers are thought to be very variable. In the present study we examine a wide variety of plasma biomarkers of mitochondrial metabolism and the related abnormalities of oxidative stress and apoptosis in 41 ASD patients assessed for ASD severity using the Childhood Autism Rating Scales and 41 non-related age and sex matched healthy controls. Our findings confirm previous studies indicating abnormal mitochondrial and related biomarkers in children with ASD including pyruvate, creatine kinase, Complex 1, Glutathione S-Transferase, glutathione and Caspase 7. As a novel finding, we report that lactate dehydrogenase is abnormal in children with ASD. We also identified that only the most severe children demonstrated abnormalities in Complex 1 activity and Glutathione S-Transferase. Additionally, we find that several biomarkers could be candidates for differentiating children with ASD and typically developing children, including Caspase 7, gluthatione and Glutathione S-Transferase by themselves and lactate dehydrogenase and Complex I when added to other biomarkers in combination. Caspase 7 was the most discriminating biomarker between ASD patients and healthy controls suggesting its potential use as diagnostic marker for the early recognition of ASD pathophysiology. This study confirms that several mitochondrial biomarkers are abnormal in children with ASD and suggest that certain mitochondrial biomarkers can differentiate between ASD and typically developing children, making them possibly useful as a tool to diagnosis ASD and identify ASD subgroups.
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12. Korb E, Herre M, Zucker-Scharff I, Gresack J, Allis CD, Darnell RB. {{Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition}}. {Cell};2017 (Aug 12)
Fragile X syndrome (FXS) is a leading genetic cause of intellectual disability and autism. FXS results from the loss of function of fragile X mental retardation protein (FMRP), which represses translation of target transcripts. Most of the well-characterized target transcripts of FMRP are synaptic proteins, yet targeting these proteins has not provided effective treatments. We examined a group of FMRP targets that encode transcriptional regulators, particularly chromatin-associated proteins. Loss of FMRP in mice results in widespread changes in chromatin regulation and aberrant gene expression. To determine if targeting epigenetic factors could reverse phenotypes associated with the disorder, we focused on Brd4, a BET protein and chromatin reader targeted by FMRP. Inhibition of Brd4 function alleviated many of the phenotypes associated with FXS. We conclude that loss of FMRP results in significant epigenetic misregulation and that targeting transcription via epigenetic regulators like Brd4 may provide new treatments for FXS.
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13. Lohr WD, Daniels K, Wiemken T, Williams PG, Kelley RR, Kuravackel G, Sears L. {{The Screen for Child Anxiety-Related Emotional Disorders Is Sensitive but Not Specific in Identifying Anxiety in Children with High-Functioning Autism Spectrum Disorder: A Pilot Comparison to the Achenbach System of Empirically Based Assessment Scales}}. {Front Psychiatry};2017;8:138.
Validated brief screening instruments are needed to improve the detection of anxiety disorders in autism spectrum disorder (ASD). The Screen for Child Anxiety-Related Emotional Disorders (SCARED), a 41-item parent- and self-reported scale measuring anxiety, was compared to the Achenbach System of Empirically Based Assessment (ASEBA) scales. One hundred participants with a clinical diagnosis of high-functioning ASD, aged 8-18 years, and their parents completed the above scales. We hypothesized that the SCARED would be useful in screening for anxiety and its results for total scores of anxiety would converge with ASEBA syndrome scales for anxiety and internalizing disorders. Significant correlations were shown between the SCARED and the Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) across a broad spectrum of scales. The CBCL syndrome scale for anxious/depressed showed the highest correlation and predicted anxiety scores on the SCARED. While many of the YSR scales significantly correlated with child ratings of anxiety, none of the scales predicted the SCARED child scores. Differences in self and parent reports suggest that parents interpret externalizing behaviors as signs of anxiety in ASD, whereas youth may describe internalized symptoms as anxiety. Females were more likely to self-report anxiety than males. Results support the use of the SCARED as a screening tool for anxiety in high-functioning ASD, but it should be supplemented with other tools to increase the specificity of its results.
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14. Mahmood U, Ahn S, Yang EJ, Choi M, Kim H, Regan P, Cho K, Kim HS. {{Dendritic Spine Anomalies and PTEN Alterations in a Mouse Model of VPA-induced Autism Spectrum Disorder}}. {Pharmacol Res};2017 (Aug 17)
Mounting evidence suggests that the etiology of autism spectrum disorders (ASDs) is profoundly influenced by exposure to environmental factors, although the precise molecular and cellular links remain ill-defined. In this study, we examined how exposure to valproic acid (VPA) during pregnancy is associated with an increased incidence of ASD. A mouse model was established by injecting VPA at embryonic day 13, and its behavioral phenotypes including impaired social interaction, increased repetitive behaviors and decreased nociception were observed at postnatal days 21-42. VPA-treated mice showed dysregulation of synaptic structure in cortical neurons, including a reduced proportion of filopodium-type and stubby spines and increased proportions of thin and mushroom-type spines, along with a decreased spine head size. We also found that VPA-treatment led to decreased expression of phosphate and tensin homolog (PTEN) and increased levels of p-AKT protein in the hippocampus and cortex. Our data suggest that there is a correlation between VPA exposure and dysregulation of PTEN with ASD-like behavioral and neuroanatomical changes, and this may be a potential mechanism of VPA-induced ASD.
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15. McKenzie K, Martin L, Ouellette-Kuntz H. {{Needles in the haystack: Using open-text fields to identify persons with intellectual and developmental disabilities in administrative home care data}}. {Res Dev Disabil};2017 (Aug 22);69:85-95.
BACKGROUND: Use of administrative health data to study populations of interest is becoming more common. Identifying individuals with intellectual and developmental disabilities (IDD) in existing databases can be challenging due to inconsistent definitions and terminologies of IDD over time and across sectors, and the inability to rely on etiologies of IDD as they are frequently unknown. AIMS: To identify diagnoses related to IDD in an administrative database and create a cohort of persons with IDD. METHODS: Open-text diagnostic entries related to IDD were identified in an Ontario home care database (2003-2015) and coded as being either acceptable (e.g. Down syndrome) or ambiguous (e.g. intellectually challenged). The cognitive and functional skills of the resulting groups were compared using logistic regressions and standardized differences, and their age distributions were compared to that of the general home care population. RESULTS: Just under 1% of the home care population had a diagnostic entry related to IDD. Ambiguous terms were most commonly used (61%), and this group tended to be older and less impaired than the group with more acceptable terms used to describe their IDD. CONCLUSIONS: Open-text diagnostic variables in administrative health records can be used to identify and study individuals with IDD. IMPLICATIONS: Future work is needed to educate assessors on the importance of using standard, accepted terminology when recording diagnoses related to IDD.
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16. Sato W, Kochiyama T, Uono S, Yoshimura S, Kubota Y, Sawada R, Sakihama M, Toichi M. {{Reduced Gray Matter Volume in the Social Brain Network in Adults with Autism Spectrum Disorder}}. {Front Hum Neurosci};2017;11:395.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by behavioral impairment in social interactions. Although theoretical and empirical evidence suggests that impairment in the social brain network could be the neural underpinnings of ASD, previous structural magnetic resonance imaging (MRI) studies in adults with ASD have not provided clear support for this, possibly due to confounding factors, such as language impairments. To further explore this issue, we acquired structural MRI data and analyzed gray matter volume in adults with ASD (n = 36) who had no language impairments (diagnosed with Asperger’s disorder or pervasive developmental disorder not otherwise specified, with symptoms milder than those of Asperger’s disorder), had no comorbidity, and were not taking medications, and in age- and sex-matched typically developing (TD) controls (n = 36). Univariate voxel-based morphometry analyses revealed that regional gray matter volume was lower in the ASD than in the control group in several brain regions, including the right inferior occipital gyrus, left fusiform gyrus, right middle temporal gyrus, bilateral amygdala, right inferior frontal gyrus, right orbitofrontal cortex, and left dorsomedial prefrontal cortex. A multivariate approach using a partial least squares (PLS) method showed that these regions constituted a network that could be used to discriminate between the ASD and TD groups. A PLS discriminant analysis using information from these regions showed high accuracy, sensitivity, specificity, and precision (>80%) in discriminating between the groups. These results suggest that reduced gray matter volume in the social brain network represents the neural underpinnings of behavioral social malfunctioning in adults with ASD.
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17. Upthegrove R, Abu-Akel A, Chisholm K, Lin A, Zahid S, Pelton M, Apperly I, Hansen PC, Wood SJ. {{Autism and psychosis: Clinical implications for depression and suicide}}. {Schizophr Res};2017 (Aug 18)
There is increasing recognition of the co-occurrence of autism and schizophrenia spectrum disorders. However, the clinical significance of this on outcomes such as depression and suicidal thinking has not been explored. This study examines the association of autism spectrum traits, depressive symptoms and suicidal behaviour in individuals with psychotic experiences. In two cross sectional studies, individuals from a non-help seeking university student sample and patients with first episode psychosis (FEP) service completed standardized measures of autism spectrum traits, psychotic experiences, depressive symptoms and suicidal thinking. In healthy non-help seeking students, increased autism traits and increased subclinical psychotic experiences were significantly associated with depressive symptoms; a significant interaction effect suggests their combined presence has a greater impact on depression. In FEP, high autism traits and positive symptoms were associated with increased depression, hopelessness and suicidality, however there was no significant interaction effect. In FEP a multiple mediation model revealed that the relationship between autism traits and risk for suicidality was mediated through hopelessness. Young people with subclinical psychotic experiences and all patients with FEP should be screened for autism spectrum traits, which may have significant impact on clinical outcomes. Tailored interventions for patients with high levels of autistic spectrum co-morbidities in FEP should be a priority for future research.
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18. Wu YJ, Hsu MT, Ng MC, Amstislavskaya TG, Tikhonova MA, Yang YL, Lu KT. {{Fragile X Mental Retardation-1 Knockout Zebrafish Shows Precocious Development in Social Behavior}}. {Zebrafish};2017 (Aug 22)
Fragile X syndrome (FXS) is a generally hereditary form of human mental retardation that is caused by triplet repeat expansion (CGG) mutation in fragile X mental retardation 1 (fmr1) gene promoter and that results in the absence of the fragile X mental retardation protein (FMRP) expression. The common symptoms of FXS patients include learning disabilities, anxiety, autistic behaviors, as well as other behavioral abnormalities. Our previous results demonstrated the behavioral abnormalities in fmr1 knockout (KO) zebrafish such as fear memory impairment and autism-like behavior. Here, we studied the functional role of fmr1 gene on the development of social behavior by behavioral experiments, including shoaling behavior, shoaling preference, light/dark test, and novel tank task. Our results demonstrated that precocious development of shoaling behavior is found in fmr1 KO zebrafish without affecting the shoaling preference on conspecific zebrafish. The shoaling behavior appeared after 14 days postfertilization (dpf), and the level of shoaling elevated in fmr1 KO zebrafish. Furthermore, the fmr1 KO zebrafish at 28 dpf expressed higher anxiety level in novel tank task. These results suggest that the change of shoaling behavior in fmr1 KO zebrafish may result from hyperactivity and an increase of anxiety.
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19. Zhang N, Peng Z, Tong X, Lindemeyer AK, Cetina Y, Huang CS, Olsen RW, Otis TS, Houser CR. {{Decreased surface expression of the delta subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome}}. {Exp Neurol};2017 (Aug 16);297:168-178.
While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABAA receptors (GABAARs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the delta subunit of the GABAAR, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two delta subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that delta subunit-containing GABAARs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in delta subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the delta subunit led to studies of surface expression of the delta subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total delta subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the delta subunit in these mice. No significant changes were observed in total or surface expression of the alpha4 subunit protein, a major partner of the delta subunit in the forebrain. Postembedding immunogold labeling for the delta subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with immunolabeling at perisynaptic locations in Fmr1 KO mice. While alpha4 immunogold particles were also reduced at perisynaptic locations in the Fmr1 KO mice, the labeling was increased at synaptic sites. Together these findings suggest that, in the dentate gyrus, altered surface expression of the delta subunit, rather than a decrease in delta subunit expression alone, could be limiting delta subunit-mediated tonic inhibition in this model of FXS. Finding ways to increase surface expression of the delta subunit of the GABAAR could be a novel approach to treatment of hyperexcitability-related alterations in FXS.
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20. Zou Y, Lu Q, Zheng D, Chu Z, Liu Z, Chen H, Ruan Q, Ge X, Zhang Z, Wang X, Lou W, Huang Y, Wang Y, Huang X, Liu Z, Xie W, Zhou Y, Yao P. {{Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala}}. {Mol Autism};2017;8:46.
BACKGROUND: Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear. METHODS: The dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERbeta overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks. RESULTS: We show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERbeta (estrogen receptor beta) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERbeta suppression is due to LNG-mediated altered methylation on the ERbeta promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERbeta in the amygdala completely restores LNG-induced ERbeta suppression and autism-like behaviors in offspring, while ERbeta knockdown mimics this effect, indicating that ERbeta expression in the amygdala plays an important role in autism-like behavior development. CONCLUSIONS: We conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered.
