Pubmed du 08/03/19

vendredi 8 mars 2019

1. Ajram LA, Pereira AC, Durieux AMS, Velthius HE, Petrinovic MM, McAlonan GM. The contribution of [1H] magnetic resonance spectroscopy to the study of excitation-inhibition in autism. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:236-244.

Autism spectrum disorder (ASD) affects over 1:100 of the population and costs the UK more than pound32bn and the USA more than $175bn ( pound104bn) annually. Its core symptoms are social and communication difficulties, repetitive behaviours and sensory hyper- or hypo-sensitivities. A highly diverse phenotypic presentation likely reflects its etiological heterogeneity and makes finding treatment targets for ASD challenging. In addition, there are no means to identify biologically responsive individuals who may benefit from specific interventions. There is hope however, and in this review we consolidate how findings from magnetic resonance spectroscopy (MRS) add to the evidence that differences in the brain’s excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) balance may be both a key biomarker and a tractable treatment target in ASD.

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2. Al-Zalabani AH, Al-Jabree AH, Zeidan ZA. Is cesarean section delivery associated with autism spectrum disorder ?. Neurosciences (Riyadh) ;2019 (Jan) ;24(1):11-15.

OBJECTIVE : To investigate a correlation between birth by caesarean section and autism spectrum disorder (ASD). METHODS : A case-control study with a case to control ratio of 1:2 was performed in Al-Madina Al-Munawarah city, Kingdom of Saudi Arabia during the year 2016. The cases were selected according to the eligibility criteria and children attending a well-baby clinic in the same hospital, were chosen as the control group subjects. Data was collected from the medical records and an interview-based questionnaire was administered to the mothers. The chi-square test was used for bivariate analysis and logistic regression to estimate the crude and adjusted odds ratios (ORs). RESULTS : Eighty-seven cases of ASD and 174 control group subjects were included in the current study. Approximately 39% (n=34) of the 87 children with ASD were delivered by cesarean section compared to 21% (n=36) of the 174 children in the control group. After adjusting for potentially confounding factors, the adjusted OR was 2.9 (95% confidence interval [CI] : 1.57-5.35). CONCLUSION : An association between delivery by cesarean section and ASD was found in this study, in support of the findings of other studies. It is recommended that preventive measures are adopted to avoid unnecessary cesarean sections.

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3. Ayhan F, Konopka G. Regulatory genes and pathways disrupted in autism spectrum disorders. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:57-64.

Autism spectrum disorder (ASD) is a highly prevalent and complex genetic disorder. The complex genetic make-up of ASD has been extensively studied and both common and rare genetic variants in up to 1000 genes have been linked to increased ASD risk. While these studies highlight the genetic complexity and begin to provide a window for delineating pathways at risk in ASD, the pathogenicity and specific contribution of many mutations to the disorder are poorly understood. Defining the convergent pathways disrupted by this large number of ASD-associated genetic variants will help to understand disease pathogenesis and direct future therapeutic efforts for the groups of patients with distinct etiologies. Here, we review some of the common regulatory pathways including chromatin remodeling, transcription, and alternative splicing that have emerged as common features from genetic and transcriptomic profiling of ASD. For each category, we focus on one gene (CHD8, FOXP1, and RBFOX1) that is significantly linked to ASD and functionally characterized in recent years. Finally, we discuss genetic and transcriptomic overlap between ASD and other neurodevelopmental disorders.

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4. Balestro JI, Fernandes FDM. Caregivers’ perception of children with Autism Spectrum Disorder regarding to the communicative profile of their children after a communicative orientation program. Codas ;2019 (Mar 7) ;31(1):e20170222.

PURPOSE : To analyze the perception of caregivers of children with Autism Spectrum Disorder regarding the functional profile of their children’s communication in three moments, before and after the guidelines. METHODS : Caregivers of 62 children diagnosed with ASD (AUTISM SPECTRUM DISORDER) participated in this study, divided into three groups of interventions. All interventions included a program with five pre-set monthly orientation sessions to provide information on the development of communication and encourage practical communication activities in daily life. In G1 (group 1), the caregivers received the group orientation program, and the children received individual speech therapy. In G2 (group 2), caregivers received the same program orientations but individually, and their children received different treatment. G3 (group 3), composed of caregivers of children waiting for speech-language pathology on the waiting list, received group guidance. All caregivers answered the Functional Communication Checklist (PFC-C) in three moments : baseline, five and eight months. RESULTS : In the PFC-C the parents reported an increase in the occurrence of gestural, vocal and verbal means in all groups, to express interpersonal communicative functions, except in G2. In non-interpersonal communicative functions, there was a decrease in the occurrence of the gestural communicative environment, an increase in the verbal climate, with no statistical difference between the groups. As for the vocal climate, there was no difference over time. CONCLUSION : Communication guidelines for caregivers of children with ASD (AUTISM SPECTRUM DISORDER) (Autism Spectrum Disorder) contributed to the understanding of the communicative process in different situations, by detecting differences in their perception of the communication functionality of their children.

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5. Crespi B, Dinsdale N, Read S, Hurd P. Spirituality, dimensional autism, and schizotypal traits : The search for meaning. PLoS One ;2019 ;14(3):e0213456.

The relationships of spirituality with human social cognition, as exemplified in autism spectrum and schizophrenia spectrum cognitive variation, remain largely unstudied. We quantified non-clinical levels of autism spectrum and schizotypal spectrum traits (using the Autism Quotient and the Schizotypal Personality Questionnaire-Brief Revised) and dimensions of spirituality (using the Hardt Spirituality Questionnaire) in a large sample of undergraduate students. We tested in particular the hypothesis, based on the diametrical model of autism and psychosis, that autism should be negatively associated, and positive schizotypal traits should be positively associated, with spirituality. Our primary findings were threefold. First, in support of the diametric model, total Spirituality score was significantly negatively correlated with total Autism Quotient score, and significantly positively correlated with Positive Schizotypal traits (the Schizotypal Personality Cognitive-Perceptual subscale), as predicted. Second, these associations were driven mainly by opposite patterns regarding the Search for Meaning Spirituality subscale, which was the only subscale that was significantly negatively associated with autism, and significantly positively associated with Positive Schizotypal traits. Third, Belief in God was positively correlated with Positive Schizotypal traits, but was uncorrelated with autism traits. The opposite findings for Search for Meaning can be interpreted in the contexts of well-supported cognitive models for understanding autism in terms of weak central coherence, and understanding Positive Schizotypal traits in terms of enhanced salience.

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6. Favre MR, Markram H, Markram K. Individual Differences in Sensory Sensitivity : Further Lessons from an Autism Model. Cogn Neurosci ;2019 (Mar 8)

In this commentary, we join Ward (2018) in the usefulness of conceptualizing neural output in terms of signal and noise relationships, to create the missing links between neural, behavioral and subjective sensory sensitivity. We draw from our work in the Intense World Theory of Autism and the VPA rodent model, to complement the discussion the consideration of developmental time and function of the system, for a neural output to serve as a predictor of atypical outcome in sensory sensitivity, and guide personalized therapies.

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7. Fernandes D, Santos SD, Coutinho E, Whitt JL, Beltrao N, Rondao T, Leite MI, Buckley C, Lee HK, Carvalho AL. Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2. Cereb Cortex ;2019 (Mar 4)

Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan’s syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

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8. Fessia G, Manni D, Contini L, Astorino F. [Strategies of planned physical activity in autism : systematic review]. Rev Salud Publica (Bogota) ;2018 (May-Jun) ;20(3):390-395.

OBJECTIVE : To identify the strategies used in the development of planned and scientifically documented physical activity, as well as the results achieved with those interventions in children with Autism Spectrum Disorder (ASD). METHODS : Systematic analysis of scientific articles regarding the use of physical activity as a therapeutic tool for children with ASD. Articles published between 2006 and 2016 were included in the review. Participants in the selected articles had to be children diagnosed with ASD ; the interventions carried out had to involve some kind of physical activity, and their effects had to be clearly exposed. RESULTS : Six intervention strategies with autistic children were found. DISCUSSION : Physical activity has a positive impact on the health and wellness of human beings, as well as a major role in the prevention of several chronic pathologies. Planned and correctly directed physical activity allows developing motor skills and generating positive psychological contexts and behavioral changes in children with ASD.

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9. Ganglmayer K, Schuwerk T, Sodian B, Paulus M. Do Children and Adults with Autism Spectrum Condition Anticipate Others’ Actions as Goal-Directed ? A Predictive Coding Perspective. J Autism Dev Disord ;2019 (Mar 8)

An action’s end state can be anticipated by considering the agent’s goal, or simply by projecting the movement trajectory. Theories suggest that individuals with autism spectrum condition (ASC) have difficulties anticipating other’s goal-directed actions, caused by an impairment using prior information. We examined whether children, adolescents and adults with and without ASC visually anticipate another’s action based on its goal or movement trajectory by presenting participants an agent repeatedly taking different paths to reach the same of two targets. The ASC group anticipated the goal and not just the movement pattern, but needed more time to perform goal-directed anticipations. Results are in line with predictive coding accounts, claiming that the use of prior information is impaired in ASC.

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10. Garcia Durand J, Batista Geraldini SAR, Perez Paschoal L, Cangueiro L, Tamarozzi Mamede D, Scandiuzzi de Brito T, Vaz Marques M, David V, Lerner R. Case-contrast study about parent-infant interaction in a Brazilian sample of siblings of children with autism spectrum disorders. Infant Ment Health J ;2019 (Mar 8)

Siblings of children with autism spectrum disorders (ASD) present greater susceptibility to developmental problems, in comparison with siblings of typically developing children. The greater prevalence of mental health disorders among parents of children with ASD increases younger siblings’ vulnerability to emotional problems. The aim of this study is to compare the interaction between carers and babies aged 2 to 26 months (M = 11.7, SD = 6.9) who are siblings of children with ASD (ASD dyads) with the interaction of dyads of siblings of typically developing children (TD dyads). The protocol of Clinical Indicators of Risk for Child Development and the Coding Interactive Behaviour measures were used to evaluate interaction. ASD dyads presented higher scores of constriction in their interaction, P = .024, with babies presenting higher scores of withdrawal behavior, P = .003, and carers presenting higher scores of depressive mood, P = .008, when compared to TD dyads. The ASD dyads have interactive impairments more frequently than do the TD dyads.

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11. Hickey EJ, Hartley SL, Papp L. Psychological Well-Being and Parent-Child Relationship Quality in Relation to Child Autism : An Actor-Partner Modeling Approach. Fam Process ;2019 (Mar 7)

Parents of children with autism spectrum disorder (ASD) often report poor psychological well-being, including a high level of parenting stress and depressive symptoms. Little is known about the extent to which poor parent psychological well-being alters the emotional quality of the parent-child relationship in a context of child ASD. This study examined the association between actor (one’s own) and partner (one’s partner’s) level of parenting stress and depressive symptoms and the emotional quality of the parent-child relationship using a Five Minute Speech Sample (FMSS) in 150 families of children with ASD, aged 5-12 years (85.7% male). Mothers and fathers were aged 38.69 (SD = 5.62) and 40.76 (SD = 6.19), respectively ; 76% of mothers and 68% of fathers had a college degree. Structural equation modeling, using Analysis of Moment Structures software, was used to test Actor-Partner Interdependence Models. Results indicated that mother’s level of parenting stress and depressive symptoms were associated with her own FMSS Warmth and Criticism toward the child with ASD 12 months later in negative and positive directions. Mother’s level of parenting stress was also negatively associated with father’s FMSS Warmth toward the child with ASD 12 months later. Finally, father’s level of parenting stress was positively associated with his FMSS Criticism toward the child with ASD. Overall, findings indicate that the mother-child and father-child relationship are both impacted by parent psychological well-being in families of children with ASD ; however, actor effects are stronger for mothers and partner effects were only found for fathers. Implications for interventions are discussed.

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12. Iwama K, Mizuguchi T, Takeshita E, Nakagawa E, Okazaki T, Nomura Y, Iijima Y, Kajiura I, Sugai K, Saito T, Sasaki M, Yuge K, Saikusa T, Okamoto N, Takahashi S, Amamoto M, Tomita I, Kumada S, Anzai Y, Hoshino K, Fattal-Valevski A, Shiroma N, Ohfu M, Moroto M, Tanda K, Nakagawa T, Sakakibara T, Nabatame S, Matsuo M, Yamamoto A, Yukishita S, Inoue K, Waga C, Nakamura Y, Watanabe S, Ohba C, Sengoku T, Fujita A, Mitsuhashi S, Miyatake S, Takata A, Miyake N, Ogata K, Ito S, Saitsu H, Matsuishi T, Goto YI, Matsumoto N. Genetic landscape of Rett syndrome-like phenotypes revealed by whole exome sequencing. J Med Genet ;2019 (Mar 6)

BACKGROUND : Rett syndrome (RTT) is a characteristic neurological disease presenting with regressive loss of neurodevelopmental milestones. Typical RTT is generally caused by abnormality of methyl-CpG binding protein 2 (MECP2). Our objective to investigate the genetic landscape of MECP2-negative typical/atypical RTT and RTT-like phenotypes using whole exome sequencing (WES). METHODS : We performed WES on 77 MECP2-negative patients either with typical RTT (n=11), atypical RTT (n=22) or RTT-like phenotypes (n=44) incompatible with the RTT criteria. RESULTS : Pathogenic or likely pathogenic single-nucleotide variants in 28 known genes were found in 39 of 77 (50.6%) patients. WES-based CNV analysis revealed pathogenic deletions involving six known genes (including MECP2) in 8 of 77 (10.4%) patients. Overall, diagnostic yield was 47 of 77 (61.0 %). Furthermore, strong candidate variants were found in four novel genes : a de novo variant in each of ATPase H(+) transporting V0 subunit A1 (ATP6V0A1), ubiquitin-specific peptidase 8 (USP8) and microtubule-associated serine/threonine kinase 3 (MAST3), as well as biallelic variants in nuclear receptor corepressor 2 (NCOR2). CONCLUSIONS : Our study provides a new landscape including additional genetic variants contributing to RTT-like phenotypes, highlighting the importance of comprehensive genetic analysis.

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13. Jyonouchi H, Geng L, Rose S, Bennuri SC, Frye RE. Variations in Mitochondrial Respiration Differ in IL-1ss/IL-10 Ratio Based Subgroups in Autism Spectrum Disorders. Front Psychiatry ;2019 ;10:71.

Autism spectrum disorder (ASD)(7) is associated with multiple physiological abnormalities, including immune dysregulation, and mitochondrial dysfunction. However, an association between these two commonly reported abnormalities in ASD has not been studied in depth. This study assessed the association between previously identified alterations in cytokine profiles by ASD peripheral blood monocytes (PBMo) and mitochondrial dysfunction. In 112 ASD and 38 non-ASD subjects, cytokine production was assessed by culturing purified PBMo overnight with stimuli of innate immunity. Parameters of mitochondrial respiration including proton-leak respiration (PLR), ATP-linked respiration (ALR), maximal respiratory capacity (MRC), and reserve capacity (RC) were measured in peripheral blood mononuclear cells (PBMCs). The ASD samples were analyzed by subgrouping them into high, normal, and low IL-1ss/IL-10 ratio groups, which was previously shown to be associated with changes in behaviors and PBMo miRNA expression. MRC, RC, and RC/PLR, a marker of electron transport chain (ETC) efficiency, were higher in ASD PBMCs than controls. The expected positive associations between PLR and ALR were found in control non-ASD PBMCs, but not in ASD PBMCs. Higher MRC, RC, RC/PLR in ASD PBMCs were secondary to higher levels of these parameters in the high and normal IL-1ss/IL-10 ratio ASD subgroups than controls. Associations between mitochondrial parameters and monocyte cytokine profiles differed markedly across the IL-1ss/IL-10 ratio based ASD subgroups, rendering such associations less evident when ASD samples as a whole were compared to non-ASD controls. Our results indicate for the first time, an association between PBMC mitochondrial function and PBMo cytokine profiles in ASD subjects. This relationship differs across the IL-1ss/IL-10 ratio based ASD subgroups. Changes in mitochondrial function are likely due to adaptive changes or mitochondrial dysfunction, resulting from chronic oxidative stress. These results may indicate alteration in molecular pathways affecting both the immune system and mitochondrial function in some ASD subjects.

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14. Kamal Nor N, Ghozali AH, Ismail J. Prevalence of Overweight and Obesity Among Children and Adolescents With Autism Spectrum Disorder and Associated Risk Factors. Front Pediatr ;2019 ;7:38.

Introduction : Prevalence of obesity in Autism Spectrum Disorder (ASD) has been reported to be higher than in the general population. Determining prevalence may help increase awareness of obesity in ASD and potentially lead to initiatives to reduce obesity. In order to understand obesity in ASD children, common risk factors were assessed including physical activity, feeding problems and sleep disturbances. Methods : This is a cross-sectional study performed at the Child Development Center at Universiti Kebangsaan Malaysia Medical Center on 151 ASD children aged 2-18 years. Anthropometric and demographic information were obtained and parents completed three questionnaires ; Children Sleep Habits Questionnaire (CSHQ), Physical Activity for Older Children Questionnaire (PAQ-C) and Brief Autism Mealtime Behavior Questionnaire (BAMBI). Results : For ASD children in our sample, the prevalence of overweight (BMI >/=85th to <95th percentiles) was 11.3% and the prevalence of obesity (BMI >/=95th percentile) was 21.9%. The overweight/obese ASD children’s median age was higher at 8.5 years (IQR 5.81-10.13) compared to the normal/underweight group of 6.33 years (IQR 4.75-7.7) with a p-value of 0.001. The two groups also differed significantly for maternal BMI and paternal age. The median maternal BMI in the overweight/obese group was 26.05 (IQR 23.35-32.25), statistically significantly higher (p = 0.003) than in the non-overweight/obese group, 24.7 (IQR 21-27.9). The median paternal age of 40 years (IQR 37-44) was statistically significantly higher (p = 0.039) in the overweight/obese group, compared to the median paternal age in the non-overweight/obese group of 38 (IQR 35-42). The male overweight/obese children had median PAQ-C score of 2.44 (IQR 2.00-3.00) vs. 2.89 (IQR 2.35-3.53) in the counterpart group with a p-value of 0.01. Using the multiple linear regression stepwise method, three predictors associated with BMI percentiles reached a statistical level of significance ; PAQ-C score in males (p < 0.001), the BAMBI domains of Food Refusal (p = 0.001) and Limited Variety of Food (p = 0.001). Conclusions : The prevalence of obesity and overweight is high among Malaysian ASD children and adolescents. Older child age, high maternal BMI, older paternal age, low physical activity, low likelihood of food refusal and high likelihood of food selectivity were found to be risk factors for high BMI in these children.

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15. Kuhn JL, Vanegas SB, Salgado R, Borjas SK, Magana S, Smith DaWalt L. The Cultural Adaptation of a Transition Program for Latino Families of Youth with Autism Spectrum Disorder. Fam Process ;2019 (Mar 7)

During the transition to adulthood, effective and culturally relevant supports are critical for families of youth with autism spectrum disorder (ASD). There is a dearth of documented program development and research on supports for Spanish-speaking Latino families during this life stage. The present work describes the cultural adaptation process of an evidence-based transition program for Latino families of youth with ASD. A model of the actions necessary to meaningfully conduct a cultural adaptation in this context is described. After implementing the culturally adapted program titled Juntos en la Transicion with five Spanish-speaking families, parents reported high social validity of the program through surveys and interviews. The cultural adaptation process followed in this work is important for the further development of programs that address the transition needs of Latino youth with ASD and their families. Our impressions may also be useful to those who aim to develop culturally sensitive and ecologically valid multifamily group intervention programs for families from cultural and linguistic minority groups.

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16. Liu Q, Chen MX, Sun L, Wallis CU, Zhou JS, Ao LJ, Li Q, Sham PC. Rational use of mesenchymal stem cells in the treatment of autism spectrum disorders. World J Stem Cells ;2019 (Feb 26) ;11(2):55-72.

Autism and autism spectrum disorders (ASD) refer to a range of conditions characterized by impaired social and communication skills and repetitive behaviors caused by different combinations of genetic and environmental influences. Although the pathophysiology underlying ASD is still unclear, recent evidence suggests that immune dysregulation and neuroinflammation play a role in the etiology of ASD. In particular, there is direct evidence supporting a role for maternal immune activation during prenatal life in neurodevelopmental conditions. Currently, the available options of behavioral therapies and pharmacological and supportive nutritional treatments in ASD are only symptomatic. Given the disturbing rise in the incidence of ASD, and the fact that there is no effective pharmacological therapy for ASD, there is an urgent need for new therapeutic options. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that make them relevant to several diseases associated with inflammation and tissue damage. The paracrine regenerative mechanisms of MSCs are also suggested to be therapeutically beneficial for ASD. Thus the underlying pathology in ASD, including immune system dysregulation and inflammation, represent potential targets for MSC therapy. This review will focus on immune dysfunction in the pathogenesis of ASD and will further discuss the therapeutic potential for MSCs in mediating ASD-related immunological disorders.

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17. Mepham JR, Boon FH, Foley KA, Cain DP, MacFabe DF, Ossenkopp KP. Impaired Spatial Cognition in Adult Rats Treated with Multiple Intracerebroventricular (ICV) Infusions of the Enteric Bacterial Metabolite, Propionic Acid, and Return to Baseline After 1 Week of No Treatment : Contribution to a Rodent Model of ASD. Neurotox Res ;2019 (Mar 8)

Propionic acid (PPA) is a dietary short chain fatty acid and an enteric bacterial metabolite. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioral changes similar to those seen in autism spectrum disorders (ASD), including perseveration. The effects of ICV infusions of PPA on spatial cognition were examined by giving rats infusions of either PPA (0.26 M, pH 7.4, 4 mul/infusion) or phosphate-buffered saline (PBS, 0.1 M) twice a day for 7 days. The rats were then tested in the Morris water maze (MWM) for acquisition of spatial learning. After a recovery period of 1 week of no treatment, the rats were then tested for reversal of spatial learning in the MWM. PPA-treated rats showed impaired spatial learning in the maze, relative to controls, as demonstrated by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. After a recovery period of 1 week of no treatment, these animals exhibited normal spatial reversal learning indicating that the behavioral cognitive deficits caused by PPA seem to be reversible.

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18. Moreno-Rius J. Is there an "antisocial" cerebellum ? Evidence from disorders other than autism characterized by abnormal social behaviours. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:1-8.

The cerebellum is a hindbrain structure which involvement in functions not related to motor control and planning is being increasingly recognized in the last decades. Studies on Autism Spectrum Disorders (ASD) have reported cerebellar involvement on these conditions characterized by social deficits and repetitive motor behavior patterns. Although such an involvement hints at a possible cerebellar participation in the social domain, the fact that ASD patients present both social and motor deficits impedes drawing any firm conclusion regarding cerebellar involvement in pathological social behaviours, probably influenced by the classical view of the cerebellum as a purely "motor" brain structure. Here, we suggest the cerebellum can be a key node for the production and control of normal and particularly aberrant social behaviours, as indicated by its involvement in other neuropsychiatric disorders which main symptom is deregulated social behaviour. Therefore, in this work, we briefly review cerebellar involvement in social behavior in rodent models, followed by discussing the findings linking the cerebellum to those other psychiatric conditions characterized by defective social behaviours. Finally, possible commonalities between the studies and putative underlying impaired functions will be discussed and experimental approaches both in patients and experimental animals will also be proposed, aimed at stimulating research on the role of the cerebellum in social behaviours and disorders characterized by social impairments, which, if successful, will definitely help reinforcing the proposed cerebellar involvement in the social domain.

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19. Morrison KE, DeBrabander KM, Faso DJ, Sasson NJ. Variability in first impressions of autistic adults made by neurotypical raters is driven more by characteristics of the rater than by characteristics of autistic adults. Autism ;2019 (Mar 8):1362361318824104.

Previous work indicates that first impressions of autistic adults are more favorable when neurotypical raters know their clinical diagnosis and have high understanding about autism, suggesting that social experiences of autistic adults are affected by the knowledge and beliefs of the neurotypical individuals they encounter. Here, we examine these patterns in more detail by assessing variability in first impression ratings of autistic adults ( N = 20) by neurotypical raters ( N = 505). Variability in ratings was driven more by characteristics of raters than those of autistic adults, particularly for items related to "intentions to interact." Specifically, variability in rater stigma toward autism and autism knowledge contributed to first impression ratings. Only ratings of "awkwardness" were driven more by characteristics of the autistic adults than characteristics of the raters. Furthermore, although first impressions of autistic adults generally improved when raters were informed of their autism status, providing a diagnosis worsened impressions made by neurotypical raters with high stigma toward autism. Variations in how the diagnosis was labeled (e.g. "autistic" vs "has autism") did not affect results. These findings indicate a large role of neurotypical perceptions and biases in shaping the social experiences for autistic adults that may be improved by reducing stigma and increasing acceptance.

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20. Nadeem A, Ahmad SF, Al-Harbi NO, Attia SM, Alshammari MA, Alzahrani KS, Bakheet SA. Increased oxidative stress in the cerebellum and peripheral immune cells leads to exaggerated autism-like repetitive behavior due to deficiency of antioxidant response in BTBR T+tf/J mice. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:245-253.

Autism is a neurodevelopmental disorder that affects social cognitive abilities resulting in communication or sensory deficits, and stereotyped behaviors in millions of people worldwide. Oxidant-antioxidant imbalance contributes significantly to the neurobehavioral dysregulations and severity of symptoms in patients with autism, however it has not been explored earlier whether it affects autism-like behavior directly. Therefore, we investigated oxidant-antioxidant balance in peripheral immune cells (neutrophils and CD3+ T cells) and cerebellum of BTBR T+tf/J (BTBR) mice which show autism-like behavior and the social C57BL/6J (C57) mice. Further, we utilized buthionine sulfoximine (BSO), a glutathione depleting agent to assess the impact of oxidant-antioxidant dysregulation on autism-like behavior. Our study shows that BTBR mice have increased lipid/protein oxidation products in cerebellum and neutrophils/CD3+ T cells along with increased NADPH oxidase (NOX2) and inducible nitric oxide synthase (iNOS) expression. This was concurrent with lower levels of glutathione and enzymatic antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the cerebellum and peripheral immune cells. BSO administration led to further lowering of glutathione with a concurrent upregulation of iNOS, and NOX2 in cerebellum and peripheral immune cells. However, there was deficiency of an adaptive antioxidant response which was associated with exaggerated repetitive behaviors in BTBR mice. On the other hand, C57 mice also had increased oxidative stress after BSO treatment, however there was an enzymatic antioxidant response both in cerebellum and periphery. Overall, this study suggests that BTBR mice have increased oxidative stress with a deficient enzymatic antioxidant response that is associated with autism-like repetitive behaviors.

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21. Nomi JS, Molnar-Szakacs I, Uddin LQ. Insular function in autism : Update and future directions in neuroimaging and interventions. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:412-426.

The insular cortex, hidden within the lateral sulcus of the human brain, participates in a range of cognitive, affective, and sensory functions. Autism spectrum disorder (ASD), a neurodevelopmental condition affecting all of these functional domains, has increasingly been linked with atypical activation and connectivity of the insular cortices. Here we review the latest research linking atypical insular function to a range of behaviors characteristic of ASD, with an emphasis on neuroimaging findings in the domains of social cognition and executive function. We summarize some of the recent work linking the insula to interventions in autism, including oxytocin-based pharmacological treatments and music therapy. We suggest that future directions likely to yield significant insights into insular pathology in ASD include the analysis of the dynamics of this brain region. We also conclude that more basic research is necessary on the use of oxytocin pharmacotherapy, and larger studies addressing participant heterogeneity are needed on the use of music therapy in ASD. Long-term studies are needed to ascertain sustained effects of these interventions.

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22. Poleg S, Golubchik P, Offen D, Weizman A. Cannabidiol as a suggested candidate for treatment of autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:90-96.

Autism Spectrum Disorder (ASD) is characterized by persistent deficits in social communication, restricted and repetitive patterns of behavior, interests, or activities and often intellectual disabilities. ASD has a number of prevalent co-morbidities, such as sleep disorders, attention deficit/hyperactivity disorder and epilepsy. No effective treatment for the core symptoms of ASD is currently available. There is increasing interest in cannabinoids, especially cannabidiol (CBD), as monotherapy or add-on treatment for the core symptoms and co-morbidities of ASD. In this review we summarize the available pre-clinical and clinical data regarding the safety and effectiveness of medical cannabis, including CBD, in young ASD patients. Cannabidiol seems to be a candidate for the treatment of ASD. At present, however, there are no convincing pre-clinical or clinical data showing efficacy and safety of cannabinoid treatment in ASD patients.

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23. Rast JE, Roux AM, Shattuck PT. Use of Vocational Rehabilitation Supports for Postsecondary Education Among Transition-Age Youth on the Autism Spectrum. J Autism Dev Disord ;2019 (Mar 8)

Transition-age youth with autism (TAY-ASD) experience poor employment outcomes and gaps in services that could assist them in securing jobs. Vocational rehabilitation (VR) is a source of public assistance for people with disabilities seeking employment and TAY-ASD are a growing segment of VR service users. Postsecondary education (PSE) is essential for building vocational skills, contributing to employment satisfaction and better wages. VR provides services to support PSE success. Fewer TAY-ASD received PSE training from VR (18%) than TAY with other disabilities (32%), but more than TAY with an intellectual disability (15%). TAY-ASD who received PSE training were more likely to exit VR with a job. The importance of PSE to employment should be considered in TAY-ASD who seek employment supports.

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24. Rogers EJ, Jada R, Schragenheim-Rozales K, Sah M, Cortes M, Florence M, Levy NS, Moss R, Walikonis RS, Palty R, Shalgi R, Lichtman D, Kavushansky A, Gerges NZ, Kahn I, Umanah GKE, Levy AP. An IQSEC2 Mutation Associated With Intellectual Disability and Autism Results in Decreased Surface AMPA Receptors. Front Mol Neurosci ;2019 ;12:43.

We have recently described an A350V mutation in IQSEC2 associated with intellectual disability, autism and epilepsy. We sought to understand the molecular pathophysiology of this mutation with the goal of developing targets for drug intervention. We demonstrate here that the A350V mutation results in interference with the binding of apocalmodulin to the IQ domain of IQSEC2. We further demonstrate that this mutation results in constitutive activation of the guanine nucleotide exchange factor (GEF) activity of IQSEC2 resulting in increased production of the active form of Arf6. In a CRISPR generated mouse model of the A350V IQSEC2 mutation, we demonstrate that the surface expression of GluA2 AMPA receptors in mouse hippocampal tissue was significantly reduced in A350V IQSEC2 mutant mice compared to wild type IQSEC2 mice and that there is a significant reduction in basal synaptic transmission in the hippocampus of A350V IQSEC2 mice compared to wild type IQSEC2 mice. Finally, the A350V IQSEC2 mice demonstrated increased activity, abnormal social behavior and learning as compared to wild type IQSEC2 mice. These findings suggest a model of how the A350V mutation in IQSEC2 may mediate disease with implications for targets for drug therapy. These studies provide a paradigm for a personalized approach to precision therapy for a disease that heretofore has no therapy.

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25. Rosen TE, Spaulding CJ, Gates JA, Lerner MD. Autism severity, co-occurring psychopathology, and intellectual functioning predict supportive school services for youth with autism spectrum disorder. Autism ;2019 (Mar 8):1362361318809690.

Supportive school services are a primary service modality for youth with autism spectrum disorder. Autism spectrum disorder, as well as co-occurring psychiatric symptoms and low intellectual abilities, interfere with academic achievement and therefore influence decisions about school services. Therefore, we examined the association of parent, teacher, and clinician ratings of autism spectrum disorder and co-occurring psychiatric symptom severity and intellectual functioning with school services. In total, 283 youth with autism spectrum disorder were assessed with clinical evaluation via the Autism Diagnostic Observation Schedule and parent and teacher versions of the CASI-4R ( Child and Adolescent Symptom Inventory). Full Scale Intelligence Quotient scores were obtained from case records. Clinical and teacher evaluations of autism spectrum disorder severity predicted services and were more strongly associated with school services than parent ratings. Teacher ratings were only associated with common school services (e.g. speech/language therapy, occupational therapy, and/or social skills training) frequency at medium and high levels of clinician-rated autism spectrum disorder severity. Higher IQ and parent-rated externalizing symptoms predicted lower likelihood of receiving school services, whereas internalizing symptoms were not predictive of school services. Autism spectrum disorder symptoms may overshadow externalizing and internalizing symptoms when considering school service supports. Results highlight the importance of evaluating autism spectrum disorder severity via multiple sources, especially in cases of unclear symptom presentation, when examining correlates of school services for youth with autism spectrum disorder.

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26. Shields MC, Akobirshoev I, Dembo RS, Mitra M. Self-Injurious Behavior Among Adults With ASD : Hospitalizations, Length of Stay, and Costs of Resources to Deliver Care. Psychiatr Serv ;2019 (Mar 7):appips201800318.

OBJECTIVE :: Research on hospitalizations related to self-injurious behavior and ideation among adults with autism spectrum disorder (ASD) is limited. This study compared admissions, average length of stay, and costs of resources to deliver care for such hospitalizations between adults with and without ASD. METHODS :: The 2014 Healthcare Cost and Utilization Project National Inpatient Sample was used to compare 5,341 discharge records for adults with ASD and 16,023 records for adults without ASD, matched on age and gender in a 1:3 ratio. Hierarchical logistic and linear regressions accounted for clustering by hospital. Covariates included gender, race-ethnicity, age, region, comorbidities, number of procedures, and insurance. RESULTS :: Among hospitalized adults, those with ASD were twice as likely as those without ASD to have a hospitalization related to self-injurious behavior and ideation. Among hospital stays for self-injurious behavior and ideation, adults with ASD had average lengths of stay that were 2.14 days longer (95% confidence interval [CI]=1.20-3.08) compared with adults without ASD. Among adults with a hospitalization related to self-injurious behavior and ideation, unadjusted average costs for those with ASD were 36.8% higher than for adults without ASD. After the analysis accounted for covariates and length of stay, adults with ASD still had 7.48% (95% CI=1.05%-14.32%) higher costs. CONCLUSIONS :: Adults with ASD were twice as likely as adults without ASD to have a hospitalization related to self-injurious behavior and ideation. Among adults with such a hospitalization, those with ASD had longer stays and, even after the analysis accounted for length of stay, higher costs.

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27. Stephenson KG, Luke SG, South M. Separate contributions of autistic traits and anxious apprehension, but not alexithymia, to emotion processing in faces. Autism ;2019 (Mar 8):1362361319830090.

Reduced eye fixation has been commonly reported in autistic samples but may be at least partially explained by alexithymia (i.e., difficulty understanding and describing one’s emotional state). Because anxiety is often elevated in autism, and emotion-processing differences have also been observed in anxious samples, anxiety traits may also influence emotion processing within autism. This study tested the contribution of dimensional traits of autism, anxious apprehension, and alexithymia in mediating eye fixation during face processing. Participants included 105 adults from three samples : autistic adults (AS ; n = 30), adults with clinically elevated anxiety and no autism (HI-ANX ; n = 29), and neurotypical adults without elevated anxiety (NT ; n = 46). Experiment 1 used an emotion identification task with dynamic stimuli, while Experiment 2 used a static luminance change detection task with emotional- and neutral-expression static photos. The emotions of interest were joy, anger, and fear. Dimensional mixed-effects models showed that autism traits, but not alexithymia, predicted reduced eye fixation across both tasks. Anxious apprehension was negatively related to response time in Experiment 1 and positively related to eye fixation in Experiment 2. Attentional avoidance of negative stimuli occurred at lower levels of autism traits and higher levels of worry traits. The results highlight the contribution of autism traits to emotional processing and suggest additional effects of worry-related traits.

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28. Urbano MR, Teal Raffaele C, Kreiser NL, Flaherty JM, Hartmann K. Clinical considerations for the inclusion of individuals with autism spectrum disorder in clinical trials. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:295-302.

Diagnoses of autism spectrum disorder (ASD) have increased considerably over the past 20years. Because of this rise and the inherent complexity of ASD, there is a need for an increased number of scientifically valid basic and clinical research studies addressing this disorder. This manuscript serves as an introduction to the clinical presentation of ASD as well as the unique challenges and modifications required to conduct clinical research with this population. This includes detailing the current diagnostic criteria, process of receiving an ASD diagnosis, information on assessment measures, and special considerations when developing research. It is the hope that this information will provide researchers interested in conducting clinical trials with those with ASD with baseline information and considerations when developing their research topics and methodology.

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29. Wang K, Xu M, Ji Y, Zhang L, Du X, Li J, Luo Q, Li F. Altered social cognition and connectivity of default mode networks in the co-occurrence of autistic spectrum disorder and attention deficit hyperactivity disorder. Aust N Z J Psychiatry ;2019 (Mar 7):4867419836031.

OBJECTIVE :: As two common neurodevelopmental disorders, autistic spectrum disorder and attention deficit hyperactivity disorder frequently occur together. Until now, only a few studies have investigated the co-occurrence of attention deficit hyperactivity disorder and autistic spectrum disorder, this is due to restrictions associated with previous Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Most previous research has focused on the developmental trajectories for autistic spectrum disorder and attention deficit hyperactivity disorder separately, while the neural mechanisms underpinning the co-occurrence of autistic spectrum disorder and attention deficit hyperactivity disorder remain largely unknown. METHODS :: We studied 162 autistic spectrum disorder individuals (including 79 co-attention deficit hyperactivity disorder and 83 non-attention deficit hyperactivity disorder patients) and 177 typical developing individuals using resting-state functional magnetic resonance imaging data from the Autism Brain Imaging Data Exchange II, an aggregated magnetic resonance imaging dataset from 19 centers. Independent component analysis was used to extract sub-networks from the classic resting-state networks. Functional connectivity values within (intra-iFC) and between (inter-iFC) these networks were then determined. Subsequently, we compared the ASD_coADHD group with the ASD_nonADHD group in relation to the abnormal intra-iFC and inter-iFC of autistic spectrum disorder group relative to the typical developing group. RESULTS :: The ASD_coADHD group showed more severe social impairment and decreased intra-iFC in the bilateral posterior cingulate cortex of the default mode network (independent component 17) and increased inter-iFC between the default mode network (independent component 8) and the somatomotor networks (independent component 2) compared to the ASD_nonADHD group. In addition, the strength of the intra-iFC in the default mode network was associated with the severity of autistic traits across the entire autistic spectrum disorder group and particularly the ASD_coADHD group. CONCLUSION :: Our results showed that dysfunction of the default mode network is a central feature in the co-occurrence of autistic spectrum disorder and attention deficit hyperactivity disorder, including connectivity within the default mode network as well as between the default mode network and the somatomotor networks, thus supporting the existence of a clinically combined phenotype (autistic spectrum disorder + attention deficit hyperactivity disorder).

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30. Weiss EM, Rominger C, Hofer E, Fink A, Papousek I. Less differentiated facial responses to naturalistic films of another person’s emotional expressions in adolescents and adults with High-Functioning Autism Spectrum Disorder. Prog Neuropsychopharmacol Biol Psychiatry ;2019 (Mar 8) ;89:341-346.

BACKGROUND : Reduced facial expressivity (flat affect) and deficits in nonverbal communicative behaviors are characteristic symptoms of autism spectrum disorder (ASD). Based on the important interpersonal functions of facial emotional responsiveness the present study aimed at a comprehensive and differentiated analysis of perceptible facial behavior in response to another person’s naturalistic, dynamic facial expressions of emotion. METHODS : In a group of 21 adolescent and adult individuals with High-Funtioning autism spectrum disorder (HF-ASD) and in 21 matched healthy controls we examined perceptible facial responses using the whole range of action units of the Facial Action Coding System (FACS) while participants were watching films displaying continuous, dynamic real-life facial expressions of four universal emotions (cheerfulness, anger, sadness, anxiety). The duration of the 80s films was in the typical range of casual face-to-face interactions. RESULTS : Overall, the number of congruent facial muscle movements while watching the emotion-laden stimulus films did not differ in the two groups. However, the comprehensive FACS analysis indicated that participants with HF-ASD displayed less differentiated facial responses to the watched emotional expressions. CONCLUSIONS : The unusual or awkward patterns of facial emotional responses in ASD may hamper the recognition of affect in other people as well as the interaction partner’s sense of interpersonal resonance, and thereby lead to social disadvantage in individuals with ASD.

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31. Wiggins LD, Rice CE, Barger B, Soke GN, Lee LC, Moody E, Edmondson-Pretzel R, Levy SE. DSM-5 criteria for autism spectrum disorder maximizes diagnostic sensitivity and specificity in preschool children. Soc Psychiatry Psychiatr Epidemiol ;2019 (Mar 8)

PURPOSE : The criteria for autism spectrum disorder (ASD) were revised in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). The objective of this study was to compare the sensitivity and specificity of DSM-IV-Text Revision (DSM-IV-TR) and DSM-5 definitions of ASD in a community-based sample of preschool children. METHODS : Children between 2 and 5 years of age were enrolled in the Study to Explore Early Development-Phase 2 (SEED2) and received a comprehensive developmental evaluation. The clinician(s) who evaluated the child completed two diagnostic checklists that indicated the presence and severity of DSM-IV-TR and DSM-5 criteria. Definitions for DSM-5 ASD, DSM-IV-TR autistic disorder, and DSM-IV-TR Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) were created from the diagnostic checklists. RESULTS : 773 children met SEED2 criteria for ASD and 288 met criteria for another developmental disorder (DD). Agreement between DSM-5 and DSM-IV-TR definitions of ASD were good for autistic disorder (0.78) and moderate for PDD-NOS (0.57 and 0.59). Children who met DSM-IV-TR autistic disorder but not DSM-5 ASD (n = 71) were more likely to have mild ASD symptoms, or symptoms accounted for by another disorder. Children who met PDD-NOS but not DSM-5 ASD (n = 66), or vice versa (n = 120) were less likely to have intellectual disability and more likely to be female. Sensitivity and specificity were best balanced with DSM-5 ASD criteria (0.95 and 0.78, respectively). CONCLUSIONS : The DSM-5 definition of ASD maximizes diagnostic sensitivity and specificity in the SEED2 sample. These findings support the DSM-5 conceptualization of ASD in preschool children.

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32. Wiklund M, Laakso M. Ungrammatical utterances and disfluent speech as causes of comprehension problems in interactions of preadolescents with high functioning autism. Clin Linguist Phon ;2019 (Mar 8):1-23.

This study describes the role of ungrammatical utterances and disfluent speech in the creation of comprehension problems between the participants in group therapy sessions of preadolescents with autism. The speech of the autistic preadolescents included frequent disfluencies and morpho-syntactic problems, such as wrong case endings, ambiguous pronominal references, grammatically incoherent syntactic structures and inaccurate tenses, which caused problems of comprehension. Three different interactional trajectories occurred when solving the potential problems of comprehension following the morpho-syntactically disfluent turns. First, the disfluent turn sometimes led to a clarification request by a co-participant, either a therapist or another participant with ASD. The preadolescents with ASD showed interactional skilfulness in requesting clarification when faced with comprehension problems. Second, in contrast, other occurrences included one or several self-repairs by the speaker with ASD. In these cases, the other group participants either did not react or they encouraged the speaker to continue using discourse particles. If the self-repairing disfluencies led to a persisting problem of comprehension, the therapists sometimes intervened and resolved the problem. However, direct interventions by the therapists were infrequent because the participants with ASD were mostly able to resolve the comprehension problems by themselves. Third, some disfluent and/or grammatically incorrect turns were not treated as problematic by the co-participants nor by the speaker himself. Abbreviations : ADE : Adessive ; ALL : Allative ; CLI : clitic ; GEN : Genitive ; INE : Inessive ; NOM : Nominative ; PER : person ; PL : plural ; PRT : particle ; SG : singular.

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