1. Chuang HC, Huang TN, Hsueh YP. {{T-Brain-1 – A Potential Master Regulator in Autism Spectrum Disorders}}. {Autism Res}. 2015.
T-Brain-1 (TBR1), a causative gene in autism spectrum disorders (ASDs), encodes a brain-specific T-box transcription factor. It is therefore possible that TBR1 controls the expression of other autism risk factors. The downstream genes of TBR1 have been identified using microarray and promoter analyses. In this study, we annotated individual genes downstream of TBR1 and investigated any associations with ASDs through extensive literature searches. Of 124 TBR1 target genes, 23 were reported to be associated with ASDs. In addition, one gene, Kiaa0319, is a known causative gene for dyslexia, a disorder frequently associated with autism. A change in expression level in 10 of these 24 genes has been previously confirmed. We further validated the alteration of RNA expression levels of Kiaa0319, Baiap2, and Gad1 in Tbr1 deficient mice. Among these 24 genes, four transcription factors Auts2, Nfia, Nr4a2, and Sox5 were found, suggesting that TBR1 controls a transcriptional cascade relevant to autism pathogenesis. A further five of the 24 genes (Cd44, Cdh8, Cntn6, Gpc6, and Ntng1) encode membrane proteins that regulate cell adhesion and axonal outgrowth. These genes likely contribute to the role of TBR1 in regulation of neuronal migration and axonal extension. Besides, decreases in Grin2b expression and increases in Gad1 expression imply that neuronal activity may be aberrant in Tbr1 deficient mice. These analyses provide direction for future experiments to reveal the pathogenic mechanism of autism. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Conti R. {{Compassionate Parenting as a Key to Satisfaction, Efficacy and Meaning Among Mothers of Children with Autism}}. {J Autism Dev Disord}. 2015.
Two studies examine the role of compassionate and self-image parenting goals in the experience of mothers of children with autism. In Study 1, a comparison sample was included. Study 1 included measures of parenting goals, life satisfaction, family life satisfaction, parenting satisfaction, and meaning in life. Study 2 incorporated a measure of parenting efficacy. Study 1 showed that mothers of children with autism were higher than comparison mothers in compassionate parenting goals. In both studies, compassionate parenting predicted positive outcomes including higher parenting satisfaction (both studies), family life satisfaction, meaning in life (Study 1) and higher parenting efficacy (Study 2). These studies support the notion that compassionate parenting is a key to satisfaction for mothers of children with autism.
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3. Davis JM, Finke EH. {{The Experience of Military Families with Children with Autism Spectrum Disorders During Relocation and Separation}}. {J Autism Dev Disord}. 2015.
Military families with a child with autism spectrum disorder (ASD) are underrepresented in the literature. In order to provide appropriate services, research must be done to determine the needs of these families. A qualitative methodology was used to interview military spouses with children with ASD about their experiences with therapeutic services. Overall, results indicate military families with a child with ASD experience challenges associated with both the military lifestyle and having a child with special needs. Due to their membership in two groups prone to support limitations and therapeutic service accessibility issues, military families with a child with ASD may be at additional risk for high levels of stress and difficulty obtaining and maintaining ASD related services.
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4. Eigsti IM, Rosset D, Col Cozzari G, da Fonseca D, Deruelle C. {{Effects of motor action on affective preferences in autism spectrum disorders: different influences of embodiment}}. {Dev Sci}. 2015.
In the embodied cognition framework, sensory, motor and emotional experiences are encoded along with sensorimotor cues from the context in which information was acquired. As such, representations retain an initial imprint of the manner in which information was acquired. The current study reports results indicating a lack of embodiment effects in ASD and, further, an association between embodiment differences and ASD symptomatology. The current results are consistent with an embodied account of ASD that goes beyond social experiences and could be driven by subtle deficits in sensorimotor coordination.
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5. Ekas NV, Timmons L, Pruitt M, Ghilain C, Alessandri M. {{The Power of Positivity: Predictors of Relationship Satisfaction for Parents of Children with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2015.
The current study uses the actor-partner interdependence model to examine the predictors of relationship satisfaction for mothers and fathers of children with autism spectrum disorder. Sixty-seven couples completed measures of optimism, benefit finding, coping strategies, social support, and relationship satisfaction. Results indicated that parent’s positive strengths predicted better personal relationship satisfaction. Moreover, parents’ benefit finding, use of emotional support, and perceived social support from their partner also predicted their partner’s relationship satisfaction. The results of this study highlight the importance of focusing on positive factors that can enhance relationship quality. Implications for the development of parent-focused interventions are discussed.
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6. El Achkar CM, Spence SJ. {{Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy}}. {Epilepsy Behav}. 2015.
The association between autism spectrum disorder (ASD) and epilepsy has been described for decades, and yet we still lack the full understanding of this relationship both clinically and at the pathophysiologic level. This review evaluates the available data in the literature pertaining to the clinical characteristics of patients with autism spectrum disorder who develop epilepsy and, conversely, patients with epilepsy who develop autism spectrum disorder. Many studies demonstrate an increased risk of epilepsy in individuals with ASD, but rates vary widely. This variability is likely secondary to the different study methods employed, including the study population and definitions of the disorders. Established risk factors for an increased risk of epilepsy in patients with ASD include intellectual disability and female gender. There is some evidence of an increased risk of epilepsy associated with other factors such as ASD etiology (syndromic), severity of autistic features, developmental regression, and family history. No one epilepsy syndrome or seizure type has been associated, although focal or localization-related seizures are often reported. The age at seizure onset can vary from infancy to adulthood with some evidence of a bimodal age distribution. The severity and intractability of epilepsy in populations with ASD have not been well studied, and there is very little investigation of the role that epilepsy plays in the autism behavioral phenotype. There is evidence of abnormal EEGs (especially epileptiform abnormalities) in children with ASD even in the absence of clinical seizures, but very little is known about this phenomenon and what it means. The development of autism spectrum disorder in patients with epilepsy is less well studied, but there is evidence that the ASD risk is greater in those with epilepsy than in the general population. One of the risk factors is intellectual disability, and there is some evidence that the presence of a particular seizure type, infantile spasms, may increase risk, but some of the data are conflicting. We believe that one of the reasons that so little is known about this phenomenon is the lack of cross talk between researchers and clinicians alike in the two fields. We conclude that large systematic studies that employ strict ascertainment of samples using standardized definitions of both disorders, validated data collection tools, and appropriate longitudinal follow-up are needed to better shed light on certain clinical aspects of the comorbidity of ASD and epilepsy. Ideally, we could provide the optimal diagnostic and treatment services to these patients in a multidisciplinary setting with both epilepsy and neurobehavioral specialists. This article is part of a Special Issue entitled « Autism and Epilepsy ».
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7. Hagerman RJ, Polussa J. {{Treatment of the psychiatric problems associated with fragile X syndrome}}. {Curr Opin Psychiatry}. 2015.
PURPOSE OF REVIEW: This work reviews recent research regarding treatment of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder. The phenotype includes anxiety linked to sensory hyperarousal, hyperactivity, and attentional problems consistent with attention deficit hyperactivity disorder and social deficits leading to autism spectrum disorder in 60% of boys and 25% of girls with FXS. RECENT FINDINGS: Multiple targeted treatments for FXS have rescued the phenotype of the fmr1 knockout mouse, but few have been beneficial to patients with FXS. The failure of the metabotropic glutamate receptor 5 antagonists falls on the heels of the failure of Arbaclofen’s efficacy in children and adults with autism or FXS. In contrast, efficacy has been demonstrated in a controlled trial of minocycline in children with FXS. Minocycline lowers the abnormally elevated levels of matrix metalloproteinase 9 in FXS. Acamprosate and lovastatin have been beneficial in open-label trials in FXS. The first 5 years of life may be the most efficacious time for intervention when combined with behavioral and/or educational interventions. SUMMARY: Minocycline, acamprosate, lovastatin, and sertraline are treatments that can be currently prescribed and have shown benefit in children with FXS. Use of combined medical and behavioral interventions will likely be most efficacious for the treatment of FXS.
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8. Inoue E, Watanabe Y, Egawa J, Sugimoto A, Nunokawa A, Shibuya M, Igeta H, Someya T. {{Rare heterozygous truncating variations and risk of autism spectrum disorder: whole-exome sequencing of a multiplex family and follow-up study in a Japanese population}}. {Psychiatry Clin Neurosci}. 2015.
AIM: Rare heterozygous truncating variations in multiplex families with autism spectrum disorder (ASD) are suggested to play a major role in genetic etiology of ASD. To further investigate the role of rare heterozygous truncating variations, we performed whole-exome sequencing (WES) in a multiplex ASD family with four affected individuals (two siblings and two maternal cousins), and a follow-up case-control study in a Japanese population. METHODS: WES was performed in four individuals (a proband, his affected and unaffected siblings, and their putative carrier mother) from the multiplex ASD family. Rare heterozygous truncating variations prioritized in WES were genotyped in 243 patients and 667 controls. RESULTS: By WES of the multiplex family, we prioritized two rare heterozygous truncating variations, RPS24 Q191X and CD300LF P261fsX266. However, we did not identify these variations in patients or controls in the follow-up study. CONCLUSION: Our findings suggest that two rare heterozygous truncating variations (RPS24 Q191X and CD300LF P261fsX266) are risk candidates for ASD.
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9. Kern JK, Geier D, King P, Sykes L, Mehta J, Geier M. {{Shared Brain Connectivity Issues, Symptoms, and Comorbidities in Autism Spectrum Disorder, Attention Deficit/Hyperactivity Disorder, and Tourette Syndrome}}. {Brain Connect}. 2015.
The prevalence of neurodevelopmental disorders, including autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and Tourette syndrome (TS), has increased over the past two decades. Currently, about 1 in 6 children in the United States is diagnosed with a neurodevelopmental disorder. Evidence suggests that ASD, ADHD, and TS have similar neuropathology, which includes long-range under-connectivity and short-range over-connectivity. They also share similar symptomatology, with considerable overlap in their core and associated symptoms and a frequent overlap in their comorbid conditions. Consequently, it is apparent that ASD, ADHD, and TS diagnoses belong to a broader spectrum of neurodevelopmental illness. Biologically, long-range under-connectivity and short-range over-connectivity are plausibly related to neuronal insult (e.g., neurotoxicity, neuroinflammation, excitotoxicity, sustained microglial activation, proinflammatory cytokines, toxic exposure, oxidative stress, etc.). Therefore, these disorders may a share a similar etiology. The main purpose of this review is to critically examine the evidence that ASD, ADHD, and TS belong to a broader spectrum of neurodevelopmental illness, an abnormal connectivity spectrum disorder (ACSD), which results from neural long-range under-connectivity and short-range over-connectivity. The review also discusses the possible reasons for these neuropathological connectivity findings. In addition, this review examines the role and issue of axonal injury and regeneration in order to better understand the neuropathophysiological interplay between short- and long-range axons in connectivity issues.
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10. Lainhart JE. {{Brain imaging research in autism spectrum disorders: in search of neuropathology and health across the lifespan}}. {Curr Opin Psychiatry}. 2015.
PURPOSE OF REVIEW: Advances in brain imaging research in autism spectrum disorders (ASD) are rapidly occurring, and the amount of neuroimaging research has dramatically increased over the past 5 years. In this review, advances during the past 12 months and longitudinal studies are highlighted. RECENT FINDINGS: Cross-sectional neuroimaging research provides evidence that the neural underpinnings of the behavioral signs of ASD involve not only dysfunctional integration of information across distributed brain networks but also basic dysfunction in primary cortices.Longitudinal studies of ASD show abnormally enlarged brain volumes and increased rates of brain growth during early childhood in only a small minority of ASD children. There is evidence of disordered development of white matter microstructure and amygdala growth, and at 2 years of age, network inefficiencies in posterior cerebral regions.From older childhood into adulthood, atypical age-variant and age-invariant changes in the trajectories of total and regional brain volumes and cortical thickness are apparent at the group level. SUMMARY: There is evidence of abnormalities in posterior lobes and posterior brain networks during the first 2 years of life in ASD and, even in older children and adults, dysfunction in primary cortical areas.
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11. Madsen GF, Bilenberg N, Jepsen JR, Glenthoj B, Cantio C, Oranje B. {{Normal P50 Gating in Children with Autism, Yet Attenuated P50 Amplitude in the Asperger Subcategory}}. {Autism Res}. 2015.
Autism spectrum disorders (ASD) and schizophrenia are separate disorders, but there is evidence of conversion or comorbid overlap. The objective of this paper was to explore whether deficits in sensory gating, as seen in some schizophrenia patients, can also be found in a group of ASD children compared to neurotypically developed children. An additional aim was to investigate the possibility of subdividing our ASD sample based on these gating deficits. In a case-control design, we assessed gating of the P50 and N100 amplitude in 31 ASD children and 39 healthy matched controls (8-12 years) and screened for differences between groups and within the ASD group. We did not find disturbances in auditory P50 and N100 filtering in the group of ASD children as a whole, nor did we find abnormal P50 and N100 amplitudes. However, the P50 amplitude to the conditioning stimulus was significantly reduced in the Asperger subgroup compared to healthy controls. In contrast to what is usually reported for patients with schizophrenia, we found no evidence for sensory gating deficits in our group of ASD children taken as a whole. However, reduced P50 amplitude to conditioning stimuli was found in the Asperger group, which is similar to what has been described in some studies in schizophrenia patients. There was a positive correlation between the P50 amplitude of the conditioning stimuli and anxiety score in the pervasive developmental disorder not otherwise specified group, which indicates a relation between anxiety and sensory registration in this group. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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12. Manning C, Charman T, Pellicano E. {{Brief Report: Coherent Motion Processing in Autism: Is Dot Lifetime an Important Parameter?}}. {J Autism Dev Disord}. 2015.
Contrasting reports of reduced and intact sensitivity to coherent motion in autistic individuals may be attributable to stimulus parameters. Here, we investigated whether dot lifetime contributes to elevated thresholds in children with autism. We presented a standard motion coherence task to 31 children with autism and 31 typical children, with both limited and unlimited lifetime conditions. Overall, children had higher thresholds in the limited lifetime condition than in the unlimited lifetime condition. However, children with autism were affected by this manipulation to the same extent as typical children and were equally sensitive to coherent motion. Our results suggest that dot lifetime is not a critical stimulus parameter and speak against pervasive difficulties in coherent motion perception in children with autism.
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13. Mazurek MO, Petroski GF. {{Sleep problems in children with autism spectrum disorder: examining the contributions of sensory over-responsivity and anxiety}}. {Sleep Med}. 2014.
OBJECTIVES: Children with autism spectrum disorder (ASD) are at high risk for sleep problems. Previous research suggests that sensory problems and anxiety may be related to the development and maintenance of sleep problems in children with ASD. However, the relationships among these co-occurring conditions have not been previously studied. The current study examined the interrelations of these symptoms in a large well-characterized sample of children and adolescents with ASD. METHODS: The current study examined the relationships among sleep problems, sensory over-responsivity, and anxiety in 1347 children enrolled in the Autism Speaks Autism Treatment Network. The primary measures included the Children’s Sleep Habits Questionnaire, the Child Behavior Checklist, and the Short Sensory Profile. RESULTS: In bivariate correlations and multivariate path analyses, anxiety was associated with all types of sleep problems (ie, bedtime resistance, sleep-onset delay, sleep duration, sleep anxiety, and night wakings; p <0.01 to p <0.001; small to medium effect sizes). Sensory over-responsivity (SOR) was correlated with all sleep problems in bivariate analyses (p <0.01 to p <0.001; small effect sizes). In multivariate path models, SOR remained significantly associated with all sleep problems except night awakenings for older children, while SOR was no longer significantly associated with bedtime resistance or sleep anxiety for younger children. CONCLUSIONS: Children with ASD who have anxiety and SOR may be particularly predisposed to sleep problems. These findings suggest that some children with ASD and sleep disturbance may have difficulties with hyperarousal. Future research using physiological measures of arousal and objective measures of sleep are needed.
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14. Meziane H, Schaller F, Bauer S, Villard C, Matarazzo V, Riet F, Guillon G, Lafitte D, Desarmenien MG, Tauber M, Muscatelli F. {{An Early Postnatal Oxytocin Treatment Prevents Social and Learning Deficits in Adult Mice Deficient for Magel2, a Gene Involved in Prader-Willi Syndrome and Autism}}. {Biol Psychiatry}. 2014.
BACKGROUND: Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth. METHODS: We assessed the social and cognitive behavior of Magel2-deficient mice, analyzed the OT system of mutant mice treated or not by a postnatal administration of OT, and determined the effect of this treatment on the brain. RESULTS: Magel2 inactivation induces a deficit in social recognition and social interaction and a reduced learning ability in adult male mice. In these mice, we reveal anatomical and functional modifications of the OT system and show that these defects change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behavior and learning abilities in adult mutant male mice. We show that this OT treatment partly restores a normal OT system. Thus, we report that an alteration of the OT system around birth has long-term consequences on behavior and on cognition. Importantly, an acute OT treatment of Magel2-deficient pups has a curative effect. CONCLUSIONS: Our study reveals that OT plays a crucial role in setting social behaviors during a period just after birth. An early OT treatment in this critical period could be a novel therapeutic approach for the treatment of neurodevelopmental disorders such as Prader-Willi syndrome and autism.
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15. Mohler H. {{The legacy of the benzodiazepine receptor: from flumazenil to enhancing cognition in down syndrome and social interaction in autism}}. {Adv Pharmacol}. 2015; 72: 1-36.
The study of the psychopharmacology of benzodiazepines continues to provide new insights into diverse brain functions related to vigilance, anxiety, mood, epileptiform activity, schizophrenia, cognitive performance, and autism-related social behavior. In this endeavor, the discovery of the benzodiazepine receptor was a key event, as it supplied the primary benzodiazepine drug-target site, provided the molecular link to the allosteric modulation of GABAA receptors and, following the recognition of GABAA receptor subtypes, furnished the platform for future, more selective drug actions. This review has two parts. In a retrospective first part, it acknowledges the contributions to the field made by my collaborators over the years, initially at Hoffmann-La Roche in Basle and later, in academia, at the University and the ETH of Zurich. In the second part, the new frontier of GABA pharmacology, targeting GABAA receptor subtypes, is reviewed with special focus on nonsedative anxiolytics, antidepressants, analgesics, as well as enhancers of cognition in Down syndrome and attenuators of symptoms of autism spectrum disorders. It is encouraging that a clinical trial has been initiated with a partial inverse agonist acting on alpha5 GABAA receptors in an attempt to alleviate the cognitive deficits in Down syndrome.
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16. Neuhaus E, Bernier RA, Beauchaine TP. {{Electrodermal Response to Reward and Non-Reward Among Children With Autism}}. {Autism Res}. 2015.
Pervasive social difficulties among individuals with autism spectrum disorder (ASD) are often construed as deriving from reduced sensitivity to social stimuli. Behavioral and neurobiological evidence suggests that typical individuals show preferential processing of social (e.g., voices, faces) over nonsocial (e.g., nonvocal sounds, images of objects) information, whereas individuals with ASD may not. This reduction in sensitivity may reflect disrupted reward processing [Dawson & Bernier, ], with significant developmental consequences for affected individuals. In this study, we explore effects of social and monetary reward on behavioral and electrodermal responses (EDRs) among 8- to 12-year-old boys with (n = 18) and without (n = 18) ASD, with attention to the potential moderating effects of stimulus familiarity. During a simple matching task, participants with and without ASD had marginally slower reactions during social vs. nonsocial reward, and boys with ASD had less accurate responses than controls. Compared to baseline, reward and non-reward conditions elicited more frequent and larger EDRs for participants as a whole, and both groups showed similar patterns of EDR change within reward blocks. However, boys with and without ASD differed in their EDRs to non-reward, and response amplitude was correlated with social and emotional functioning. These findings provide some support for altered reward responding in ASD at the autonomic level, and highlight the discontinuation of reward as an important component of reward-based learning that may play a role in shaping behavior and guiding specialized brain development to subserve social behavior and cognition across the lifespan. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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17. Penagarikano O, Lazaro MT, Lu XH, Gordon A, Dong H, Lam HA, Peles E, Maidment NT, Murphy NP, Yang XW, Golshani P, Geschwind DH. {{Exogenous and evoked oxytocin restores social behavior in the Cntnap2 mouse model of autism}}. {Sci Transl Med}. 2015; 7(271): 271ra8.
Mouse models of neuropsychiatric diseases provide a platform for mechanistic understanding and development of new therapies. We previously demonstrated that knockout of the mouse homolog of CNTNAP2 (contactin-associated protein-like 2), in which mutations cause cortical dysplasia and focal epilepsy (CDFE) syndrome, displays many features that parallel those of the human disorder. Because CDFE has high penetrance for autism spectrum disorder (ASD), we performed an in vivo screen for drugs that ameliorate abnormal social behavior in Cntnap2 mutant mice and found that acute administration of the neuropeptide oxytocin improved social deficits. We found a decrease in the number of oxytocin immunoreactive neurons in the paraventricular nucleus (PVN) of the hypothalamus in mutant mice and an overall decrease in brain oxytocin levels. Administration of a selective melanocortin receptor 4 agonist, which causes endogenous oxytocin release, also acutely rescued the social deficits, an effect blocked by an oxytocin antagonist. We confirmed that oxytocin neurons mediated the behavioral improvement by activating endogenous oxytocin neurons in the paraventricular hypothalamus with Designer Receptors Exclusively Activated by Designer Drugs (DREADD). Last, we showed that chronic early postnatal treatment with oxytocin led to more lasting behavioral recovery and restored oxytocin immunoreactivity in the PVN. These data demonstrate dysregulation of the oxytocin system in Cntnap2 knockout mice and suggest that there may be critical developmental windows for optimal treatment to rectify this deficit.
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18. Perrone-McGovern K, Simon-Dack S, Niccolai L. {{Prenatal and Perinatal Factors Related to Autism, IQ, and Adaptive Functioning}}. {J Genet Psychol}. 2015: 1-10.
ABSTRACT This study focused on prenatal and perinatal factors related to autism spectrum disorder (ASD). The authors hypothesized that mothers who exposed their infants to intrauterine toxicity or who had complications with labor or delivery would be more likely to give birth to individuals with lower IQ scores, higher scores on a measure of ASD, and lower scores on a measure of adaptive functioning. This clinical sample consisted of 33 children who presented for neuropsychological assessment with symptoms of ASD. Results indicated that individuals with a history of intrauterine toxicity had lower IQ scores than individuals who did not have a history of intrauterine toxicity. However, no significant effects were found for intrauterine toxicity and ASD or adaptive functioning. Results indicated that individuals with a history of complications during labor and delivery had lower IQ scores, higher scores on a measure of ASD, and lower scores on a measure of adaptive functioning. Findings may lend support to the oxidative stress theory of ASD.
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19. Picardi A, Fagnani C, Medda E, Toccaceli V, Brambilla P, Stazi MA. {{Genetic and environmental influences underlying the relationship between autistic traits and temperament and character dimensions in adulthood}}. {Compr Psychiatry}. 2014.
BACKGROUND: In recent years, several twin studies adopted a dimensional approach to Autism Spectrum Disorders (ASD) and estimated the contribution of genetic and environmental influences to variation in autistic traits. However, no study was performed on adults over 18years of age and all but two studies were based on parent or teacher ratings. Also, the genetic and environmental contributions to the interplay between autistic traits and adult personality dimensions have not been investigated. METHODS: A sample of 266 complete twin pairs (30% males, mean age 40+/-12years) drawn from the population-based Italian Twin Register was administered the Autism-Spectrum Quotient, Temperament and Character Inventory (TCI-125), and General Health Questionnaire (GHQ-12). Genetic structural equation modelling was performed with the Mx program. Estimates were adjusted for gender, age, and GHQ-12 score. RESULTS: Genetic factors accounted for 44% and 20%-49% of individual differences in autistic traits and TCI dimensions, respectively. Unshared environmental factors explained the remaining proportion of variance. Consistently with the notion of a personality profile in ASD characterised by obsessive temperament, autistic traits showed significant phenotypic correlations with several TCI dimensions (positive: HA; negative: NS, RD, SD, C). Genetic and unshared environmental correlations between AQ and these TCI dimensions were significant. The degree of genetic overlap was generally greater than the degree of environmental overlap. CONCLUSIONS: Despite some limitations, this study suggests that genetic factors contribute substantially to individual differences in autistic traits in adults, with unshared environmental influences also playing an important role. It also suggests that autistic traits and the majority of temperament and character dimensions share common genetic and environmental aetiological factors.
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20. Schneider I, Regenbogen C, Kohn N, Zepf FD, Bubenzer-Busch S, Schneider F, Gur RC, Habel U. {{Reduced Responsiveness to Social Provocation in Autism Spectrum Disorder}}. {Autism Res}. 2015.
Deficits in emotion processing and social interaction are prominent symptoms of autism spectrum disorder (ASD). ASD has also been associated with aggressive tendencies towards self and others. The prevalence of aggressive behavior in this disorder, its etiology and its impact on social life are still unclear. This study investigated behavioral and physiological effects of social provocation in patients with ASD and healthy controls. We used a modified Taylor Aggression Paradigm in 24 high-functioning patients with ASD and 24 healthy controls. Participants were instructed to play against a fictitious human opponent. Money withdrawals toward the participant represented provocation and money deduction by the participant denoted aggressive behavior. Throughout the measurement, electrodermal activity (EDA) was recorded. Healthy controls showed higher aggressive responses to high provocation compared to low provocation, which demonstrated the effectiveness of the used procedure in eliciting aggression. Patients’ responses were not influenced by the level of social provocation, although in both groups aggression was higher after lost compared to won trials. Physiologically, controls showed fewer but higher EDA amplitudes when responding aggressively, whereas patients displayed the opposite pattern of more but lower EDA amplitudes. The modified Taylor Aggression Paradigm successfully elicited aggression and revealed different behavioral and neurophysiological responses in patients and healthy controls. Patients’ aggressive behavior as well as their physiological responses were less modulated by level of provocation compared to controls. Therapeutic attempts for patients might concentrate on improving empathic abilities and the understanding of social situations, including provocation and aggressive behavior. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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21. Stagi S, Cavalli L, Congiu L, Scusa MF, Ferlini A, Bigoni S, Benincasa A, Rossi B, Pini G. {{Thyroid Function in Rett Syndrome}}. {Horm Res Paediatr}. 2015: 118-25.
Introduction: Thyroid function in Rett syndrome (RTT) has rarely been studied with unanimous results. However, this aspect is of great concern regarding the effect thyroid hormones (TH) have on proper mammalian brain development. Objective: To evaluate the prevalence of abnormalities of thyroid function in a cohort of children with RTT. Patients and Methods: Forty-five consecutive Caucasian girls (mean age: 8.6 +/- 5.3 years, range: 2.0-26.1) meeting the clinical criteria for RTT were recruited. In all of the subjects, we evaluated the serum concentrations of free-T3 (FT3), free-T4 (FT4), thyroid-stimulating hormone (TSH), thyroperoxidase autoantibodies, thyroglobulin autoantibodies (TgA), and TSH receptor (TSHr) autoantibodies. The results were compared with a group of 146 age-matched healthy Caucasian children and adolescent girls (median age: 9.5 years, range: 1.8-14.6) from the same geographical area. Results: Mean FT3 and TSH levels were not significantly different between the RTT patients and controls. Nevertheless, FT4 levels were significantly higher in RTT patients than in controls (p < 0.005). In particular, 17.7% showed FT4 levels higher than the upper reference limit (vs. 0.7% of controls, p < 0.0001), whereas 12 patients (26.7%) showed higher FT3 levels than the upper reference limit, significantly differing in respect to controls (2.0%, p < 0.0001). Finally, 5 patients (11.1%) showed higher levels of TSH, statistically differing from the control subjects (2.0%, p < 0.0001). However, evaluating the patients on the basis of different RTT genotype subgroups, patients with CDKL5 deletions showed significantly higher FT4 values than patients with MeCP2 deletions (p < 0.05). On the other hand, patients with other types of MeCP2 mutations also showed FT4 levels significantly higher than patients with MeCP2 deletions (p < 0.05). In fact, out of 8 patients with FT4 levels higher than the upper references limit, 3 of them presented with CDKL5 deletions (3 patients, 37.5%), 4 (50%) had MeCP2 mutations, and 1 (12.5%) belonged to the subgroup of MeCP2 deletions. However, when analyzing FT3 levels of the 12 patients showing higher FT3 levels than the upper references limit, 6 (50%) belonged to the subgroup with MeCP2 mutations, 4 (33.3%) to the subgroup with MeCP2 deletions, and 2 (16.7%) to the subgroups with CDKL5 deletions. Furthermore, no patient with RTT was positive for antithyroglobulin autoantibodies, antithyroid peroxidase, or anti-TSHr, with no statistical differences in respect to the controls. L-thyroxine treatment was not necessary for any patient. Conclusions: Abnormalities of thyroid function are not rare in RTT. The possible relationship between these disorders and the RTT phenotype should be confirmed and studied. Children with RTT should be screened for potential thyroid dysfunction. (c) 2015 S. Karger AG, Basel.
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22. Taylor MJ, Charman T, Ronald A. {{Where are the strongest associations between autistic traits and traits of ADHD? evidence from a community-based twin study}}. {Eur Child Adolesc Psychiatry}. 2015.
Autism spectrum conditions (ASC) and attention-deficit/hyperactivity disorder (ADHD) regularly co-occur. Twin studies increasingly indicate that these conditions may have overlapping genetic causes. Less is known about the degree to which specific autistic traits relate to specific behaviours characteristic of ADHD. We hence tested, using the classical twin design, whether specific dimensional autistic traits, including social difficulties, communication atypicalities and repetitive behaviours, would display differential degrees of aetiological overlap with specific traits of ADHD, including hyperactivity/impulsivity and inattention. Parents of approximately 4,000 pairs of 12-year-old twins completed the Childhood Autism Spectrum Test and Conners’ Parent Rating Scale. These measures were divided into subscales corresponding to different types of autistic and ADHD behaviours. Twin model fitting suggested that the degree of genetic overlap was particularly strong between communication difficulties and traits of ADHD (genetic correlations = .47-.51), while repetitive behaviours and social difficulties showed moderate (genetic correlations = .12-.33) and modest (.05-.11) genetic overlap respectively. Environmental overlap was low across all subscales (correlations = .01-.23). These patterns were also apparent at the extremes of the general population, with communication difficulties showing the highest genetic overlap with traits of ADHD. These findings indicate that molecular genetic studies seeking to uncover the shared genetic basis of ASC and ADHD would benefit from taking a symptom-specific approach. Furthermore, they could also help to explain why studies of the communication abilities of individuals with ASC and ADHD have produced overlapping findings.
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23. Vasa RA, Mazurek MO. {{An update on anxiety in youth with autism spectrum disorders}}. {Curr Opin Psychiatry}. 2015.
PURPOSE OF REVIEW: Anxiety is one of the most common co-occurring psychiatric conditions in youth with autism spectrum disorders (ASDs). This article reviews recent evidence as well as earlier relevant studies regarding the characteristics, assessment, and treatment of anxiety in youth with ASD. RECENT FINDINGS: It is well established that the prevalence of anxiety in youth with an ASD is significantly greater than the prevalence of anxiety in the general population. Recent studies have highlighted the importance of informant, method, and instrument when measuring anxiety in this population. Despite the high prevalence, findings to date have been unable to identify any consistent risk factors for anxiety. New psychological treatments, including modified cognitive behavioral therapy for youth with high functioning ASD and co-occurring anxiety, are emerging. Pharmacological data, however, are scant. Existing studies show that youth with ASD are at increased risk for behavioral activation when taking SSRIs. SUMMARY: Clinicians working with youth with ASD are encouraged to routinely screen for anxiety. Until further data are available, clinical judgment is needed when prescribing treatments, particularly selective serotonin reuptake inhibitors, which require close monitoring of side-effects. Research on risk factors, pathophysiology, and treatment of this condition is needed.
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24. Yang Q, Yang L, Zhang K, Guo YY, Liu SB, Wu Y, Li XQ, Song Q, Zhuo M, Zhao MG. {{Increased coupling of caveolin-1 and ERalpha contributes to the Fragile X syndrome}}. {Ann Neurol}. 2015.
Objective: Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Interaction between estrogen receptor (ER) and lipid raft caveolae is critical for the estrogen signaling. Here, we tested the hypothesis that impaired ER-caveolae coupling contributes to the mental retardation of Fragile X syndrome. Methods: Fmr1 knockout (KO) mouse was used as the model of Fragile X syndrome. Multiple techniques were performed including primary neuronal culture, shRNA interference, western blot, electrophysiological recording, RNA-binding protein immunoprecipitation, RT-PCR, and behavioral tests. Results: In this study, we reported that GluA1 surface expression and phosphorylation induced by 17beta-estradiol (E2) were impaired in the Fmr1 KO neurons. The E2-mediated facilitation of long-term potentiation and fear memory was impaired in the anterior cingulate cortex of Fmr1 KO mice. The increased coupling of caveolin-1 (CAV1) and the membrane estrogen receptor ERalpha under basal conditions contributed to the impairment of ER signaling in Fmr1 KO neurons. FMRP interacted with CAV1 mRNA, and knockdown of CAV1 with shRNA rescued the synaptic GluA1 delivery, plasticity, and memory in Fmr1 KO mice. Interpretation: This is the first demonstration that the coupling between ERalpha and lipid raft CAV1 is critical for the membrane estrogen receptor signaling in synaptic plasticity. Therefore, increased coupling of CAV1 and ERalpha may elucidate one of the critical abnormal mechanisms for fragile X syndrome. This article is protected by copyright. All rights reserved.
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25. Yerys BE, Antezana L, Weinblatt R, Jankowski KF, Strang J, Vaidya CJ, Schultz RT, Gaillard WD, Kenworthy L. {{Neural Correlates of Set-Shifting in Children With Autism}}. {Autism Res}. 2015.
Autism spectrum disorder (ASD) is often associated with high levels of inflexible thinking and rigid behavior. The neural correlates of these behaviors have been investigated in adults and older adolescents, but not children. Prior studies utilized set-shifting tasks that engaged multiple levels of shifting, and depended on learning abstract rules and establishing a strong prepotent bias. These additional demands complicate simple interpretations of the results. We used functional magnetic resonance imaging (fMRI) to investigate the neural correlates of set-shifting in 20 children (ages 7-14) with ASD and 19 typically developing, matched, control children. Participants completed a set-shifting task that minimized nonshifting task demands through the use of concrete instructions that provide spatial mapping of stimuli-responses. The shift/stay sets were given an equal number of trials to limit the prepotent bias. Both groups showed an equivalent « switch cost, » responding less accurately and slower to Switch stimuli than Stay stimuli, although the ASD group was less accurate overall. Both groups showed activation in prefrontal, striatal, parietal, and cerebellum regions known to govern effective set-shifts. Compared to controls, children with ASD demonstrated decreased activation of the right middle temporal gyrus across all trials, but increased activation in the mid-dorsal cingulate cortex/superior frontal gyrus, left middle frontal, and right inferior frontal gyri during the Switch vs. Stay contrast. The successful behavioral switching performance of children with ASD comes at the cost of requiring greater engagement of frontal regions, suggesting less efficiency at this lowest level of shifting. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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26. Young NJ, Findling RL. {{An update on pharmacotherapy for autism spectrum disorder in children and adolescents}}. {Curr Opin Psychiatry}. 2015.
PURPOSE OF REVIEW: Although there is no known efficacious pharmacotherapy for core symptoms of autism spectrum disorder (ASD), psychotropic medications are commonly prescribed for behavioral/emotional symptoms associated with ASD. We reviewed current evidence-based pharmacotherapy options and updates from recent noteworthy studies. RECENT FINDINGS: Atypical antipsychotics, particularly risperidone and aripiprazole, are effective in reducing irritability, stereotypy and hyperactivity. Metabolic adverse events, including weight gain and dyslipidemia, are common. Methylphenidate is effective in reducing attention-deficit hyperactivity disorder (ADHD) symptoms. Atomoxetine and alpha-2 agonists appear effective in reducing ADHD symptoms. Selective serotonin reuptake inhibitors are not effective in improving repetitive behaviors in children with ASD, and frequently cause activating adverse events. Efficacy of antiepileptic drugs is inconclusive. Overall, efficacy and tolerability of pharmacotherapy in children with ASD are less favorable than data seen in typically developing children with similar symptoms. Newer agents, including glutamatergic agents and oxytocin, appear promising albeit with mixed results. SUMMARY: Current evidence-based pharmacotherapy options in children with ASD are very limited, and many have substantial adverse events. Clinicians should use pharmacotherapy as a part of comprehensive treatment, and judiciously weigh risks and benefits. New pharmacotherapy options for core symptoms as well as co-occurring symptoms of ASD are in urgent need.
