Pubmed du 10/01/19

jeudi 10 janvier 2019

1. Adams D, MacDonald L, Keen D. Teacher responses to anxiety-related behaviours in students on the autism spectrum. Res Dev Disabil. 2019 ; 86 : 11-9.

BACKGROUND : At least 50% of students on the autism spectrum experience clinical or subclinical levels of anxiety but there is scant research on how teachers respond to anxiety in children on the spectrum. AIMS : To compare teacher responses to anxiety-related behaviour in students who do and do not have a diagnosis on the spectrum using the Teacher Responses to Anxiety in Children (TRAC). METHODS AND PROCEDURES : Teachers (N = 64), predominantly from mainstream primary schools, completed an online survey comprised of a demographic questionnaire and two versions of the TRAC, one for students without autism and one for students with autism. OUTCOMES AND RESULTS : Teachers report differences in the way they would likely respond to anxiety-related behaviours observed in students with and without autism. Teachers reported being more likely to use anxiety-promoting responses for students with autism who are showing behaviours indicative of general and separation anxiety, but not when they are showing behaviours indicative of social anxiety. Whilst there was no significant difference in the overall likelihood of use of autonomy-promoting responses between groups, there were differences in the likelihood of using specific autonomy-promoting responses dependent upon diagnosis and type of anxiety. CONCLUSIONS AND IMPLICATIONS : Teachers report they are likely to respond differently to anxiety-related behaviours of students on the autism spectrum but the impact of this on the behaviour of these students is yet to be determined. Professional development is a priority to increase teacher knowledge about anxiety-related behaviours in students with autism and the ways in which teachers’ responses may promote or reduce anxiety and autonomy.

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2. Bicikova M, Macova L, Ostatnikova D, Hanzlikova L. Vitamin D in autistic children and healthy controls. Physiol Res. 2019.

Insufficient levels of vitamin D have been demonstrated by many authors as a risk factor for autistic patients, however, the causality has not been reliably elucidated. In the present study, levels of calcidiol were determined in group of autistic children and compared with age matched healthy children as controls. Suboptimal levels of calcidiol in more than 60 % of both autistic patients as well as of control group were found. No significant differences in vitamin D between autistic children and healthy controls were observed.

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3. Calorio C, Gavello D, Guarina L, Salio C, Sassoe-Pognetto M, Riganti C, Bianchi FT, Hofer NT, Tuluc P, Obermair G, Defilippi P, Balzac F, Turco E, Bett GC, Rasmusson RL, Carbone E. Impaired chromaffin cells excitability and exocytosis in autistic Timothy syndrome TS2-neo mouse rescued by L-type calcium channel blockers. The Journal of physiology. 2019.

KEY POINTS SUMMARY : Tymothy syndrome (TS) is a multisystem disorder featuring cardiac arrhythmias, autism and adrenal gland dysfunction that originates from a de-novo point-mutation in the gene encoding Cav1.2 (CACNA1C) L-type channel. To study the role of Cav1.2 channel signals on autism, the autistic TS2-neo mouse has been generated bearing the G406R point-mutation associated with TS type-2. Using heterozygous TS2-neo mice, we report that the G406R mutation reduces the rate of inactivation and shifts leftward the activation and inactivation of L-type channels, causing marked increase of resting Ca(2+) -influx ("window" Ca(2+) -current). The increased "window current" causes marked reduction of NaV channel-density, switches normal tonic firing in abnormal burst firing, reduces mitochondria metabolism, induces cell swelling and decreases catecholamine release. Overnight incubations with nifedipine rescue NaV channel-density, the normal firing and the quantity of catecholamine released. We provide evidence that chromaffin cells malfunction derives from altered Cav1.2 channel-gatings. L-type voltage-gated calcium channels (Cav1) have a key role in long-term synaptic plasticity, sensory transduction, muscle contraction and hormone release. A point mutation in the gene encoding Cav1.2 (CACNA1C) causes Tymothy syndrome (TS), a multisystem disorder featuring cardiac arrhythmias, autism spectrum disorder (ASD) and adrenal gland dysfunction. In the more severe type-2 form (TS2), the missense mutation G406R is on exon 8 coding for the IS6-helix of Cav1.2 channel. The mutation causes reduced inactivation and induces autism. How this occurs and how Cav1.2 gating-changes alter cell excitability, neuronal firing and hormone release on molecular basis is still widely unknown. Here, using the TS2-neo mouse model of Timothy syndrome we show that the G406R mutation alters excitability and reduces secretory activity in adrenal chromaffin cells (CCs). Specifically, the TS2-mutation reduces the rate of voltage-dependent inactivation and shifts leftward the activation and steady state inactivation of L-type channels. This markedly increases the resting "window" Ca(2+) current that causes an increased percentage of CCs undergoing abnormal action potential (AP) burst firing, cell swelling, reduced mitochondrial metabolism and decreased catecholamine release. The increased "window Ca(2+) -current" causes also decreased NaV channel-density and increased steady-state inactivation that contribute to the increased abnormal burst firing. Overnight incubation with the L-type channel blocker nifedipine rescues the normal AP firing of CCs, the density of functioning NaV channels and their steady-state inactivation. We provide evidence that CCs malfunction derives from the altered Cav1.2 channel gating and that dihydropyridines are potential therapeutics for ASD. This article is protected by copyright. All rights reserved.

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4. Costa AP, Steffgen G, Vogele C. The Role of Alexithymia in Parent-Child Interaction and in the Emotional Ability of Children with Autism Spectrum Disorder. Autism Res. 2019.

Children with autism spectrum disorder (ASD) have more emotional difficulties than typically developing (TD) children. Of all the factors that impact children’s emotional development, parents, and the way they interact with their children, are of crucial importance. The present study compared the amount of parent-child interactions among 35 dyads of parents and their children with ASD and 41 dyads of parents and their TD children, aged between 3 and 13 years, during a frustration-eliciting situation. We further examined whether children’s alexithymia is linked to parent-child interactions and whether parent-child interactions are linked to children’s emotional difficulties. We found that parents of children with ASD interacted significantly less with their children than parents of TD children. This reduced interaction was better explained by children’s alexithymia than by children’s ASD diagnosis. Finally, parent-child interaction mediated the relationship between children’s ASD diagnosis and children’s emotion regulation ability, as well as some aspects of children’s emotional reactivity but only if not accounting for children’s alexithymia levels. Our results demonstrate the determinant role children’s alexithymia plays on parent-child interactions and on how these interactions are linked to children’s difficulties in emotion regulation and emotional reactivity. Results are discussed in light of how parent-child interactions and the emotional ability of children with ASD can be improved by targeting children’s alexithymia. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : In the present research, we found that parents of children with autism interact less with their children compared to parents of typically developing children. We also found that this decreased interaction is linked to children’s difficulties to recognize, describe, and distinguish emotions, a triad of difficulties known as alexithymia. Furthermore, parents’ interaction with their children explains emotional reactivity and emotion regulation problems in children with autism. However, if we take into consideration children’s alexithymia, then parents’ interaction with their children is not related to their children’s emotional difficulties in reactivity and regulation. Therefore, to improve the interaction between parents and their children with autism, and the emotional development of these children, we recommend interventions that teach children with autism how to recognize, describe, and distinguish emotions in themselves and others.

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5. Davlantis KS, Estes A, Dawson G, Rogers SJ. A novel method for measuring learning opportunities provided by parents to young children with autism spectrum disorder. Autism. 2019 : 1362361318817303.

The aim of this study was to develop a measurement approach to assess the learning opportunities provided by parents to their young children with autism spectrum disorder during a free play task and to examine the relationship between learning opportunities and child performance on measures of cognition, autism spectrum disorder symptoms, and language. Participants were 91 children with autism spectrum disorder ages 12-24 months and their parents. Ordinary least squares regression was used. Results showed that children whose parents provided more learning opportunities had significantly higher cognitive scores and significantly higher vocabulary comprehension and production. The psychometric properties of the measurement approach were investigated and results indicated that it may be psychometrically sound.

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6. Demarquoy C, Demarquoy J. Autism and carnitine : A possible link. World journal of biological chemistry. 2019 ; 10(1) : 7-16.

Patients with autism spectrum disorders (ASD) present deficits in social interactions and communication, they also show limited and stereotypical patterns of behaviors and interests. The pathophysiological bases of ASD have not been defined yet. Many factors seem to be involved in the onset of this disorder. These include genetic and environmental factors, but autism is not linked to a single origin, only. Autism onset can be connected with various factors such as metabolic disorders : including carnitine deficiency. Carnitine is a derivative of two amino acid lysine and methionine. Carnitine is a cofactor for a large family of enzymes : the carnitine acyltransferases. Through their action these enzymes (and L-carnitine) are involved in energy production and metabolic homeostasis. Some people with autism (less than 20%) seem to have L-carnitine metabolism disorders and for these patients, a dietary supplementation with L-carnitine is beneficial. This review summarizes the available information on this topic.

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7. Deutsch SI, Raffaele CT. Understanding facial expressivity in autism spectrum disorder : An inside out review of the biological basis and clinical implications. Prog Neuropsychopharmacol Biol Psychiatry. 2019 ; 88 : 401-17.

Deficits in decoding and understanding facially expressed emotions occur commonly in persons with autism spectrum disorder (ASD), which contribute to the impairment of social communication that serves as one of its core diagnostic criteria. Research suggests that abnormalities of visual scanning of the face, activation of key nodes within the "social brain" by facially expressed emotions, functional connectivity within and between nodes of the "social brain", and transduction of specific neurotransmitter/neuromodulatory signals contribute to the pathogenesis of these deficits in at least some persons with ASD. Importantly, the etiologies of these deficits are heterogeneous and include genetic, immunologic, and inflammatory mechanisms, as well as in utero exposures to drugs and toxins. The manifestation and severity of these deficits can also be influenced by developmental age, IQ and genetic background. Consistent with the goals of the Special Issue, the current Review is intended to familiarize the readership with several of the leading neurobiological mechanisms proposed to underlie these deficits in decoding facially expressed emotions and stimulate interest in translational preclinical and clinical investigations, whose ultimate purpose is to attenuate their severity and, thereby, improve functional outcomes of persons with ASD.

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8. Ford TC, Abu-Akel A, Crewther DP. The association of excitation and inhibition signaling with the relative symptom expression of autism and psychosis-proneness : Implications for psychopharmacology. Prog Neuropsychopharmacol Biol Psychiatry. 2019 ; 88 : 235-42.

The underlying mechanisms of autism and schizophrenia are poorly understood, partly due to a lack of dimension-specific research. Aberrant excitatory and inhibitory neurotransmission are implicated in both conditions, particularly in social dysfunction. This study investigates the extent to which the degree of autistic tendency and psychosis-proneness exclusively and interactively predict excitatory and inhibitory neurotransmitter concentrations in the superior temporal cortex (STC). In 38 adults (18 male, 18-40years), we obtained autistic tendencies (Autism-Spectrum Quotient [AQ]) and psychosis-proneness scores (Schizotypal Personality Questionnaire [PP]) ; magnetic resonance spectroscopy (MRS) quantified glutamate and GABA+ concentrations from the STC. Results demonstrated a negative AQ/PP interaction with glutamate concentration for the left STC voxel, where PP increased with glutamate for average AQ, while AQ decreased with glutamate for average-high PP. There was a negative AQ/PP interaction with glutamate/GABA+ ratio for the right STC, AQ increasing with glutamate/GABA+ for low-average PP, while PP decreased with glutamate/GABA+ for high AQ. Consistent with animal studies, we also reveal that overall reduced glutamate/GABA+ ratio might be precipitated by increased right hemisphere GABA+ concentrations. These findings illustrate the importance of considering the concurrent effects of autism and psychosis dimensions on understanding the pathophysiological mechanisms implicated in either condition, and can advance psychopharmacological research into better treatment options for patients.

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9. Huang Y, Zhao Y, Ren Y, Yi Y, Li X, Gao Z, Zhan X, Yu J, Wang D, Liang S, Wu L. Identifying Genomic Variations in Monozygotic Twins Discordant for Autism Spectrum Disorder Using Whole-Genome Sequencing. Molecular therapy Nucleic acids. 2018 ; 14 : 204-11.

Autism spectrum disorder (ASD) presents a set of childhood neurodevelopmental disorders with impairments in social communication and restricted, repetitive, and stereotyped patterns of behavior. Here, based on the whole-genome sequencing (WGS) data of three monozygotic twins discordant for ASD, we explored multiple patient-specific genetic variations and prioritized a list of ASD risk genes. Our results identified DVMT (discordant variation in monozygotic twin) observed in at least two twin pairs, including 14,310 SNPs, 2,425 indels, and 16,735 CNVs, referring to a total of 2,174 genes, and 37 of these were covered by all three types of variations. Gene ontology (GO) enrichment analysis of biological processes for 2,174 genes showed that the majority of these genes were related to neurodevelopmental processes. In addition, functional network analysis showed that there was a strong functional relevance between 37 genes covered by all three types of variations. In conclusion, for the first time, we conducted a comprehensive scan of genomic differences between monozygotic twins discordant for ASD, providing researchers with in-depth directions. It may also provide effective strategies for clinical treatment of individuals affected by ASD.

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10. Izuno T, Takagi S, Nakamurai M, Narushima K, Uchiyama T, Nishikawa T. [An Adolescent Case of ASD Presenting with Persistent Catatonia and Epileptic EEG Discharge]. Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica. 2016 ; 118(3) : 125-32.

A 26-year-old man developed a catatonic state after his grandmother’s death and the Great East Japan Earthquake. He was admitted to hospital because of the prolonged severe stupor. Electroencephalography (EEG) revealed focal (F3 electrode) and generalized epileptic abnormalities. He was administered antiepileptic agents and benzodiazepines, but his stupor did not improve in spite of a reduced frequency of epileptic EEG abnormalities. His clinical his- tory did not suggest any psychotic disorders. Thereafter, extensive physical examinations were performed, but an organic cause of the stupor was not determined. For about two years, he was unable to intake food without tubal feeding, have a conversation, or move spontaneously. One day, a generalized tonic-clonic seizure (GTC) occurred spontaneously for the first time in his life, and then his stupor markedly improved. Thereafter, he could eat food spontaneously, have a fluent conversation, and move actively. After his condition had improved, we asked his parents about his developmental history, clinical history, and present state. According to clini- cal interviews including the use of PARS (Pervasive Developmental Disorders Autism Society Japan Rating Scale), DISCO (Diagnostic Interview for Social and Communication Disorders), and WAIS-III (Wechsler Adult Intelligence Scale-third edition), he was diagnosed with autistic spectrum disorder (ASD) and mild intellectual disability. It was considered that his stupor had occurred secondary to ASD. Wing et al. reported that catatonia occurred in about 17% of ASD adolescents and young adults as a later complication. It is possible that this case, without any psychotic disorders and with ASD that has been undiagnosed until young adult, progress to such a severe and prolonged catatonic state. We report this case to show that severe catatonia is possible in adolescents and young adults during the carry-over period in ASD patients.

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11. Jang W, Kim Y, Han E, Park J, Chae H, Kwon A, Choi H, Kim J, Son JO, Lee SJ, Hong BY, Jang DH, Han JY, Lee JH, Kim SY, Lee IG, Sung IK, Moon Y, Kim M, Park JH. Chromosomal Microarray Analysis as a First-Tier Clinical Diagnostic Test in Patients With Developmental Delay/Intellectual Disability, Autism Spectrum Disorders, and Multiple Congenital Anomalies : A Prospective Multicenter Study in Korea. Annals of laboratory medicine. 2019 ; 39(3) : 299-310.

BACKGROUND : To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA). METHODS : We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results. RESULTS : A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected : 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients : IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively. CONCLUSIONS : Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.

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12. Jarmolowska B, Bukalo M, Fiedorowicz E, Cieslinska A, Kordulewska NK, Moszynska M, Swiatecki A, Kostyra E. Role of Milk-Derived Opioid Peptides and Proline Dipeptidyl Peptidase-4 in Autism Spectrum Disorders. Nutrients. 2019 ; 11(1).

Opioid peptides released during digestion of dietary proteins such as casein, were suggested to contribute to autism development, leading to the announcement of opioid excess hypothesis of autism. This paper examines role of enzyme proline dipeptidyl peptidase-4 (DPPIV ; EC 3.4.14.5) and it is exogenous substrate, beta-casomorphin-7 (BCM7) in autism etiology. Our study included measurements of DPPIV and BCM7 concentrations in serum and urine, which were analyzed with ELISA assays and activity of DPPIV was measured by colorimetric test. The effect of opioid peptides from hydrolysed bovine milk on DPPIV gene expression in peripheral blood mononuclear cells (PBMC) in autistic and healthy children was determined using the Real-Time PCR (Polymerase Chain Reaction) method. Our research included 51 healthy children and 86 children diagnosed with autism spectrum disorder (ASD, ICDF84). We determined that the concentration of BCM7 in serum was significantly, 1.6-fold, higher in the ASD group than in controls (p < 0.0001). Concentration of DPPIV was found to also be significantly higher in serum from ASD children compared to the control group (p < 0.01), while we did not notice significant difference in enzymatic activity of serum DPPIV between the two study groups. We confirmed correlation according to the gender between analyzed parameters. The inspiration for this study emanated from clinical experience of the daily diet role in relieving the symptoms of autism. Despite this, we have concluded that milk-derived opioid peptides and DPPIV are potentially factors in determining the pathogenesis of autism ; conducted studies are still limited and require further research.

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13. Kellerman AM, Schwichtenberg AJ, Tonnsen BL, Posada G, Lane SP. Dyadic interactions in children exhibiting the broader autism phenotype : Is the broader autism phenotype distinguishable from typical development ?. Autism Res. 2019.

In families raising a child with an autism spectrum disorder (ASD), infant siblings are at elevated risk for ASD and other developmental concerns, including elements of the broader autism phenotype (BAP). Typically, the BAP is indexed using standardized developmental assessments ; however, these measures do not capture a number of social difficulties commonly associated with the BAP. The present study aims to expand our developmental understanding of the BAP by comparing children exhibiting the BAP to their typically developing peers on, (a) standardized measures of development, and (b) social behaviors exhibited during dyadic play interactions. As part of a prospective study, dyads were recruited from families with at least one older child with ASD (high-risk, n = 36), and families with no history of ASD (low-risk, n = 38). During laboratory visits at 12, 15, 18, and 24 months of age, infants completed a series of standardized assessments and a mother-child play interaction. Dyadic play interactions were micro-analytically coded for gaze, positive affect, and vocalizations to create theory-driven composites to index dyadic synchrony and responsiveness. Videos were also coded with an existing rating scheme for joint engagement and child responsiveness. Multilevel models revealed significant group differences on select constructs within the first 2 years. Language and cognitive differences emerged by 24 months of age, whereas dyadic differences were evident as early as 15 months. Recognizing the increasing demand for elevated-risk interventions, these findings highlight several social constructs through which interventions may identify risk and promote optimal development. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : In families raising children with an autism spectrum disorder (ASD), younger siblings are at an increased risk for social and developmental difficulties that characterize a "broader autism phenotype." The present study explored the emergence of social, language, and cognitive differences in the first 2 years of life. Social differences were evident as early as 15 months of age for several play-based measures, and language and cognitive differences emerged by 24 months of age. For infant siblings of children with ASD, some of the earliest behavioral marks for subclinical features of ASD are evident within the first 2 years of life.

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14. Krupa M, Boominathan P, Ramanan PV, Sebastian S. Relationship Between Screen Time and Mother-Child Reciprocal Interaction in Typically Developing Children and Children with Autism Spectrum Disorders. Indian journal of pediatrics. 2019.

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15. Kuschefski M, Falter-Wagner CM, Bente G, Vogeley K, Georgescu AL. Inferring power and dominance from dyadic nonverbal interactions in autism spectrum disorder. Autism Res. 2019.

Research studies to date have revealed conflicting results with respect to the processing of nonverbal cues from social interactions in autism spectrum disorder (ASD). Therefore, the aim of the present study was to investigate the contribution of two important factors for the perception of dyadic social interactions, namely (a) the movement contingency and (b) the spatial context. To this end, 26 adult participants with ASD and 26 age-, sex-, and IQ-matched typically developed control participants observed animations presenting nonverbal interactions between two human virtual characters enacting power relationships. We manipulated (a) movement contingency by exchanging one of the two original agents with an agent from another dyad and (b) spatial context by changing agents’ spatial orientation to a back-to-back position. Participants were asked to rate dominance and submissiveness of these agents. Results showed that the movement contingency manipulation affected accuracy and consistency of power perception and that the spatial context manipulation slowed down reaction times comparably in both groups. With regard to group differences, individuals with ASD were found to judge power relationships slower compared to control participants, potentially suggesting a more explicit processing style in ASD. Furthermore, the spatial context manipulation slowed down the reaction times more in the contingent compared to the non-contingent conditions only in the ASD group. These findings contribute to the ongoing debate whether individuals with ASD have difficulties in understanding nonverbal cues in a dyadic context by suggesting that they do so in more subtle ways than previously investigated. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : This study shows that the ability and speed of judging who is dominant in a social interaction depends on two factors : (a) whether their movements are matched and (b) whether they are facing each other or not. This is similarly the case for participants with and without autism. Interestingly, however, individuals with autism seem to judge generally slower, suggesting a more explicit processing style. The two factors seem to interact, suggesting that nonverbal processing difficulties are subtler than previously thought.

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16. Maximo JO, Kana RK. Aberrant "deep connectivity" in autism : A cortico-subcortical functional connectivity magnetic resonance imaging study. Autism Res. 2019.

The number of studies examining functional brain networks in Autism Spectrum Disorder (ASD) has risen over the last decade and has characterized ASD as a disorder of altered brain connectivity. However, these studies have focused largely on cortical structures, and only a few studies have examined cortico-subcortical connectivity in regions like thalamus and basal ganglia in ASD. The goal of this study was to characterize the functional connectivity between cortex and subcortical regions in ASD using the Autism Brain Imaging Data Exchange (ABIDE-II). Resting-state functional magnetic resonance imaging data were used from 168 typically developing (TD) and 138 ASD participants across different sites from the ABIDE II dataset. Functional connectivity of basal ganglia and thalamus to unimodal and supramodal networks was examined in this study. Overconnectivity (ASD > TD) was found between unimodal (except for medial visual network) and subcortical regions, and underconnectivity (TD > ASD) was found between supramodal (except for default mode and dorsal attention networks) and subcortical regions ; positive correlations between ASD phenotype and unimodal-subcortical connectivity were found and negative ones with supramodal-subcortical connectivity. These findings suggest that brain networks heavily involved in sensory processing had higher connectivity with subcortical regions, whereas those involved in higher-order thinking showed decreased connectivity in ASD. In addition, brain-behavior correlations indicated a relationship between ASD phenotype and connectivity. Thus, differences in cortico-subcortical connectivity may have a significant impact on basic and higher-order cognitive processes in ASD. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : This study focused on examining the functional connectivity (synchronization of brain activity across regions) of two types of brain networks (unimodal and supramodal) with subcortical areas (thalamus and basal ganglia) in children, adolescents, and adults with autism spectrum disorder (ASD) and how this relates to ASD phenotype. ASD participants showed overconnectivity in unimodal networks and underconnectivity in supramodal networks. These findings provide new insights into cortico-subcortical connections between basic sensory and high-order cognitive processes.

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17. McVey AJ. The neurobiological presentation of anxiety in autism spectrum disorder : A systematic review. Autism Res. 2019.

Anxiety is common among people with autism and is associated with unique and additive challenges. Anxiety is thought to have neurobiological components, and measures of arousal in typical development have long been studied. Recently, neurobiological measures of anxiety in autism have begun to receive empirical evaluation, but results have not yet been examined together. This systematic review, therefore, summarizes the state of the research of the neurobiology of anxiety in autism. Studies published between 1999 and June 2017 were reviewed. Results across measures of arousal point to inconsistencies in results and a lack of synthesis in the literature. Considerations regarding these inconsistencies are discussed, recommendations for future studies are offered, and clinical implications for this work are presented. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : Anxiety is common among people with autism. Because anxiety has been linked with a variety of differences in physiological (bodily) and neurophysiological (brain) functioning in people without autism, research has begun to examine these processes in autism as well. This literature, however, has not yet been examined as a whole. Therefore, this paper begins to address that gap to provide the field with a better understanding of how anxiety affects people with autism and discusses implications for future research and clinical practice.

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18. Minakova E, Lang J, Medel-Matus JS, Gould GG, Reynolds A, Shin D, Mazarati A, Sankar R. Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism. PLoS One. 2019 ; 14(1) : e0210389.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism.

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19. Monz BU, Houghton R, Law K, Loss G. Treatment patterns in children with autism in the United States. Autism Res. 2019.

Children with autism receive different types of non-drug treatments. We aimed to describe caregiver-reported pattern of care and its variability by geography and healthcare coverage in a US-wide sample of children aged 3-17 years. We recruited caregivers from the Simons Foundation Powering Autism Research for Knowledge (SPARK) cohort. Two online questionnaires (non-drug treatment, Autism Impact Measure) were completed in September/October 2017. Primary outcome measures were caregiver-reported types and intensities of treatments (behavioral, developmental/relationship, speech and language (SLT), occupational, psychological, "other" ; parent/caregiver training) in the previous 12 months. Main explanatory variables were geography and type of healthcare coverage. We investigated associations between the type/intensity of treatments and geography (metropolitan/nonmetropolitan) or coverage (Medicaid vs privately insured by employer) using regression analysis. Caregivers (n = 5,122) were mainly mothers (92.1%) with mean (SD) age of 39.0 (7.3) years. Mean child age was 9.1 (3.9) years ; mostly males (80.0%). Almost all children received at least one intervention (96.0%). Eighty percent received SLT or occupational therapy, while 52.0% received both. Behavioral therapy and SLT were significantly more frequent and more intense in metropolitan than in nonmetropolitan areas. No consistently significant associations were seen between healthcare coverage and frequency or intensity of interventions. At least one barrier such as "waiting list" and "no coverage" was reported by 44.8%. In conclusion, in children sampled from SPARK, we observed differences between metropolitan and nonmetropolitan areas, while we did not find significant differences between those privately insured versus Medicaid. Autism Research 2019. (c) 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY : The American Academy of Child and Adolescent Psychiatry recommends the use of multiple treatment modalities in autism spectrum disorder (ASD). We wanted to understand what types of treatment children (aged 3-17 years) with ASD receive in the United States, how and where the treatments take place and for how long. We invited caregivers from Simons Foundation Powering Autism Research for Knowledge ("SPARK ," https://sparkforautism.org/) to complete the study questions online. Participants reported on utilization of conventional, non-drug treatments for ASD, including behavioral interventions, developmental/relationship interventions, speech and language therapy (SLT), occupational therapy, psychological therapy, and parent/caregiver training. People that completed the study (n = 5,122) were primarily mothers of the child with ASD (92%) ; most of the children were boys (80%). The ASD care for the child was mostly coordinating by the mother. Almost all children received at least some type of non-drug therapies (96%), most often SLT and/or occupational therapy, mainly provided in school. Behavioral therapy was most often received in public school in rural areas, while at home in urban areas. We saw less use of behavioral therapy and SLT in rural areas, but overall comparable use between children covered by Medicaid and those covered by private insurance. Almost half the caregivers reported at least one barrier to treatment, such as "waiting list" and "no coverage." More than half said that their child benefited "much" or "very much" from the therapies received. While overall non-drug treatment rates for children with ASD were high in the United States in our study, differences existed depending on where the family lives ; not only regarding the type of therapy, but also where it takes place.

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20. Munesue T, Minabe Y. [The Possible Role of Oxytocin in Autism Spectrum Disorder]. Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica. 2016 ; 118(6) : 399-409.

The core symptoms of autism spectrum disorder (ASD) comprise impairments of social communication and social interactions as well as restricted and repetitive patterns of interests and activities. No definitive treatments for these core symptoms currently exist. Oxytocin, a highly conserved peptide, has been suggested to moderate inter-individual relationships based on the results of many vertebrate studies. Recently, oxytocin has received a great deal of attention as a promising candidate for the treatment of ASD. Here, we review studies on the role of oxytocin in ASD. Numerous randomized controlled trials (RCTs) have shown single- dose oxytocin administration to have significantly favorable effects compared with placebo for both neuro-typical individuals and individuals with ASD. Furthermore, extended administra- tion of oxytocin was associated with effects that significantly exceeded those of a placebo in three of five published RCTs for ASD. Moreover, approximately 20 RCTs investigating whether oxytocin is favorable for ASD participants are in progress, according to clinical trial registries certified by the World Health Organization. The results of these RCTs may elucidate the issues regarding favorable and adverse effects, appropriate doses and treatment durations, participant selection, and specifically how to assess the changes in impairments of social com- munication and social interactions. In addition, it is necessary to consider which version of the Diagnostic and Statistical Manual of Mental Disorders (DSM) is used for the diagnosis of ASD in each RCT because the range of individuals diagnosed with ASD has become gradually nar- rower with each DSM revision, i. e., the Fourth Edition, the Fourth Edition Text Revision, and the Fifth Edition.

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21. Nadeem A, Ahmad SF, Attia SM, Al-Ayadhi LY, Al-Harbi NO, Bakheet SA. Dysregulated enzymatic antioxidant network in peripheral neutrophils and monocytes in children with autism. Prog Neuropsychopharmacol Biol Psychiatry. 2019 ; 88 : 352-9.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder where immune cells play an important role. Oxidants and pro-inflammatory cytokines generated by innate immune cells have been implicated in the pathogenesis of ASD. Many previous reports have shown the role of various enzymatic antioxidants in the plasma/red blood cells of ASD subjects, however no study so far has evaluated them in peripheral immune cells of innate origin (neutrophils and monocytes) in ASD patients and typically developing control (TDC) children. With this background, our study explored the expression and activities of major enzymatic antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) in peripheral neutrophils and monocytes of TDC/ASD subjects. Our data show that expression and activity of SOD is increased in ASD subjects as compared to TDC children in neutrophils and monocytes. On the other hand, GPx/GR activity is either reduced/unaltered in neutrophils and monocytes of ASD subjects as compared to TDC children. Increased SOD expression is associated with upregulated expression of nitrotyrosine (a marker of oxidant damage) in both innate immune cells of ASD subjects. Our study suggests that despite adaptive antioxidant response, there is an increased oxidative burden in peripheral neutrophils and monocytes of ASD subjects. This suggests that dysregulated enzymatic antioxidant network in peripheral innate immune cells could play a significant role in the pathogenesis of autism.

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22. Ogino K, Takahashi H, Nakamura T, Kim J, Kikuchi H, Nakahachi T, Ebishima K, Yoshiuchi K, Ando T, Sumiyoshi T, Stickley A, Yamamoto Y, Kamio Y. Negatively Skewed Locomotor Activity Is Related to Autistic Traits and Behavioral Problems in Typically Developing Children and Those With Autism Spectrum Disorders. Front Hum Neurosci. 2018 ; 12 : 518.

An important objective for researchers and clinicians is to gain a better understanding of the factors that underlie autism spectrum disorders (ASDs). It is possible that investigating objective and quantitative behavioral phenotypes and their relationship to clinical characteristics, such as autistic traits and other emotional/behavioral problems, might facilitate this process. Given this, in the current study we examined the link between locomotor dynamics and clinical characteristics, including autistic traits and emotional/behavioral problems, in children with ASD (n = 14) and typically developing (TD) children (n = 13). A watch-type actigraph was used to continuously measure locomotor activity which was assessed in terms of mean activity levels and the skewness of activity. Parents assessed quantitative autistic traits using the Japanese version of the Social Responsiveness Scale (SRS) and emotional and behavioral problems using the Japanese version of the Strengths and Difficulties Questionnaire (SDQ). Results showed that among all children, all-day activity was more negatively skewed, suggesting sporadic large all-day "troughs" in activity and was significantly correlated with the SRS social awareness subscale score (rho = -0.446, p = 0.038). In addition, the more negatively skewed daytime locomotor activity was associated with the SDQ Hyperactivity Inattention subscale score (rho = -0.493, p = 0.020). The results of this study indicate that investigating locomotor dynamics may provide one way to increase understanding of the neurophysiological mechanisms underlying the clinical characteristics of ASD.

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23. Qiu S, Li Y, Bai Y, Shi J, Cui H, Gu Y, Ren Y, Zhao Q, Zhang K, Lu M, Wang Y, Li Y, Zhong W, Zhu X, Liu Y, Cheng Y, Qiao Y, Liu Y. SHANK1 polymorphisms and SNP-SNP interactions among SHANK family : A possible cue for recognition to autism spectrum disorder in infant age. Autism Res. 2019.

Autism spectrum disorder (ASD) is a serious lifelong neurodevelopmental disorder. ASD is diagnosed for children at the age of two. ASD diagnosis, as early as possible, lays the foundation for treatment and much better prognosis. Notably, gene-based test is an inherent method to recognize the potential infants with ASD before the age of two. To investigate whether SHANK family contributes to ASD prediction, on the basis of our previous studies of SHANK2 and SHANK3, we further investigated associations between SHANK1 polymorphisms and ASD risk as well as SNP-SNP interactions among SHANK family. We enrolled 470 subjects (229 cases and 241 healthy controls) who were northeast Chinese Han. Four tag SNPs (rs73042561, rs3745521, rs4801846, and rs12461427) of SHANK1 were selected and genotyped. We used the SNPStats online analysis program to assess the associations between the four SNPs and ASD risk. The SNP-SNP interactions among SHANK family were analyzed using multifactor dimensionality reduction method. We found that the four SHANK1 SNPs were not associated with ASD risk in northeast Chinese Han population. There existed a strong synergistic interaction between rs11236697 [SHANK2] and rs74336682 [SHANK2], and moderate synergistic interactions (rs74336682 [SHANK2]-rs73042561 [SHANK1], rs11236697 [SHANK2]-rs77716438 [SHANK2], and rs11236697 [SHANK2]-rs75357229 [SHANK2]). These SHANK1 variants may not affect the susceptibility to ASD in Chinese Han population. SNP-SNP interactions in SHANK family may confer ASD risk. Autism Research 2019. (c) 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY : ASD is a serious lifelong neurodevelopmental disorder with strong genetic components. We investigated associations between SHANK1 polymorphisms and ASD risk as well as SNP-SNP interactions among SHANK family. Our results indicated that there exists no association between SHANK1 SNPs and ASD, and SNP-SNP interactions in SHANK family may confer ASD risk in the Northeast Han Chinese population. Future studies are needed to test more SHANK family SNPs in a large sample to demonstrate the associations.

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24. Rodriguez G, Hartley SL, Bolt D. Transactional Relations Between Parenting Stress and Child Autism Symptoms and Behavior Problems. J Autism Dev Disord. 2019.

Parents of children with autism spectrum disorder report elevated parenting stress. The current study examined bidirectional effects between parenting stress and three domains of child functioning (ASD symptoms, internalizing behavior problems, and externalizing behavior problems) across four time points in 188 families of children with ASD (ages 5-12 years). Mother and father reports of parenting stress and child functioning were used in cross-lag models to examine bidirectional associations between parenting stress and child functioning. Results indicated parent-driven effects for child internalizing behavior problems, while child externalizing behavior problems and ASD symptoms evidenced both parent-driven and child-driven effects, in different ways for mothers versus fathers. Overall, findings have important implications for interventions for families of children with ASD.

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25. Sanctuary MR, Kain JN, Chen SY, Kalanetra K, Lemay DG, Rose DR, Yang HT, Tancredi DJ, German JB, Slupsky CM, Ashwood P, Mills DA, Smilowitz JT, Angkustsiri K. Pilot study of probiotic/colostrum supplementation on gut function in children with autism and gastrointestinal symptoms. PLoS One. 2019 ; 14(1) : e0210064.

Over half of all children with autism spectrum disorders (ASD) have gastrointestinal (GI) co-morbidities including chronic constipation, diarrhea, and irritable bowel syndrome. The severity of these symptoms has been correlated with the degree of GI microbial dysbiosis. The study objective was to assess tolerability of a probiotic (Bifidobacterium infantis) in combination with a bovine colostrum product (BCP) as a source of prebiotic oligosaccharides and to evaluate GI, microbiome and immune factors in children with ASD and GI co-morbidities. This pilot study is a randomized, double blind, controlled trial of combination treatment (BCP + B. infantis) vs. BCP alone in a cross-over study in children ages 2-11 with ASD and GI co-morbidities (n = 8). This 12-week study included 5 weeks of probiotic-prebiotic supplementation, followed by a two-week washout period, and 5 weeks of prebiotic only supplementation. The primary outcome of tolerability was assessed using validated questionnaires of GI function and atypical behaviors, along with side effects. Results suggest that the combination treatment is well-tolerated in this cohort. The most common side effect was mild gassiness. Some participants on both treatments saw a reduction in the frequency of certain GI symptoms, as well as reduced occurrence of particular aberrant behaviors. Improvement may be explained by a reduction in IL-13 and TNF-alpha production in some participants. Although limited conclusions can be drawn from this small pilot study, the results support the need for further research into the efficacy of these treatments.

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26. Vianna P, Gomes JDA, Boquett JA, Fraga LR, Schuch JB, Vianna FSL, Schuler-Faccini L. Zika Virus as a Possible Risk Factor for Autism Spectrum Disorder : Neuroimmunological Aspects. Neuroimmunomodulation. 2019 : 1-8.

The recent outbreak of the Zika virus (ZIKV) and the discovery that perinatal Zika exposure can lead to the Congenital Zika Syndrome has promoted a call for prevention measures. Due to the increased number of babies born with microcephaly, structural brain abnormalities, and neurological alterations in regions affected by ZIKV, investigations were carried out in order to better understand this process. The maternal immune system directly influences the fetal central nervous system, and complications during pregnancy have been associated with neurodevelopmental disorders. Autism spectrum disorder (ASD), a neurodevelopmental disorder commonly manifested in the first years of life, is a disease with multifactorial etiology and is manifested typically by social and communication impairments, as well as stereotyped behaviors. Brain abnormalities, including both anatomically and functionally, can be observed in this disorder, suggesting delays in neuronal maturation and altered brain connectivity. It is known that some viral congenital infections, such as rubella, and cytomegalovirus can interfere with brain development, being associated with brain calcification, microcephaly, and ASD. Here, we reviewed a range of studies evaluating the aspects concerning brain development, immunological status during pregnancy, and neuroimmunomodulation in congenital viral infections, and we discuss if the fetal brain infection caused by ZIKV could predispose to ASD. Finally, we suggest a mechanism encompassing neurological and immunological pathways that could play a role in the development of ASD in infants after ZIKV infection in pregnancy.

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27. Wang R, Tan J, Guo J, Zheng Y, Han Q, So KF, Yu J, Zhang L. Aberrant Development and Synaptic Transmission of Cerebellar Cortex in a VPA Induced Mouse Autism Model. Frontiers in cellular neuroscience. 2018 ; 12 : 500.

Autistic spectral disorder (ASD) is a prevalent neurodevelopmental disease that affects multiple brain regions. Both clinical and animal studies have revealed the possible involvement of the cerebellum in ASD pathology. In this study, we generated a rodent ASD model through a single prenatal administration of valproic acid (VPA) into pregnant mice, followed by cerebellar morphological and functional studies of the offspring. Behavioral studies showed that VPA exposure led to retardation of critical motor reflexes in juveniles and impaired learning in a tone-conditioned complex motor task in adults. These behavioral phenotypes were associated with premature migration and excess apoptosis of the granular cell (GC) precursor in the cerebellar cortex during the early postnatal period, and the decreased cell density and impaired dendritic arborization of the Purkinje neurons. On acute cerebellar slices, suppressed synaptic transmission of the Purkinje cells were reported in the VPA-treated mice. In summary, converging evidence from anatomical, electrophysiological and behavioral abnormalities in the VPA-treated mice suggest cerebellar pathology in ASD and indicate the potential values of motor dysfunction in the early diagnosis of ASD.

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28. Wang Y, Xiao Y, Li Y, Chu K, Feng M, Li C, Qiu N, Weng J, Ke X. Exploring the relationship between fairness and ’brain types’ in children with high-functioning autism spectrum disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2019 ; 88 : 151-8.

BACKGROUND : Existing research typically focuses on only one domain of cognition with regard to fairness-theory of mind or executive function. However, children with High-functioning autism spectrum disorder (HF-ASD) are cognitively impaired in both domains. Moreover, little is known about fairness characteristics in children with HF-ASD in relation to both domains of cognition. METHODS : Thirty children with HF-ASD as well as 39 children with typical development (TD) were evaluated in this study. We investigated the development of children’s fairness characteristics as a responder in a mini ultimatum game (UG). The different ’brain types,’ i.e., with or without HF-ASD, were evaluated using the Empathy Questionnaire-Systemizing Questionnaire (E/SC-Q). Furthermore, we explored the relationship between fairness and brain types using Pearson correlation analyses. RESULTS : Children in the HF-ASD group were more likely to accept unfair offers than were children in the TD group (chi(2)=17.513, p=.025). In the HF-ASD group, the acceptance rate of unfair offers was correlated with the discrepancy score (r=0.363, p=.048), while there were no significant correlations in the TD group. In HF-ASD group, compared with Type S, acceptance rate of unfair offer was significant higher in Extreme Type S ’brain type’ (F=28.584, p<.001). While dividing TD participants by ’brain type’, there was no significant difference in acceptance rate of unfair offer among five difference ’brain types’ (F=1.131, p=.358). Stepwise regression revealed that Extreme Type S positively predicted acceptance of unfair offers (F [1, 68]=8.695, p<.001). DISCUSSION : Our findings show that children with HF-ASD were more likely to accept an unfair offer ; in particular, the more unbalanced the development of empathy and systemizing was, the more significant the unfairness preference observed. Extreme Type S positively predicted the acceptance of unfair offers by children with HF-ASD. REGISTRATION OF CLINICAL TRIALS : World Health Organization class I registered international clinical trial platform, ChiCTR-ROC-17012877.

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29. Wisniowiecka-Kowalnik B, Nowakowska BA. Genetics and epigenetics of autism spectrum disorder-current evidence in the field. Journal of applied genetics. 2019.

Autism spectrum disorders (ASD) is a heterogenous group of neurodevelopmental disorders characterized by problems in social interaction and communication as well as the presence of repetitive and stereotyped behavior. It is estimated that the prevalence of ASD is 1-2% in the general population with the average male to female ratio 4-5:1. Although the causes of ASD remain largely unknown, the studies have shown that both genetic and environmental factors play an important role in the etiology of these disorders. Array comparative genomic hybridization and whole exome/genome sequencing studies identified common and rare copy number or single nucleotide variants in genes encoding proteins involved in brain development, which play an important role in neuron and synapse formation and function. The genetic etiology is recognized in 25-35% of patients with ASD. In this article, we review the current state of knowledge about the genetic etiology of ASD and also propose a diagnostic algorithm for patients.

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30. Yamamuro K. [The Pharmacotherapy of Autism Spectrum Disorder with ADHD Symptoms]. Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica. 2016 ; 118(6) : 391-8.

Diagnostic and treatment guidelines for childhood attention deficit/hyperactivity disorder (ADHD) were first released in Japan in 2003. Since then, there has been numerous changes in how ADHD is treated, such as the approval of slow-release methylphenidate and atomoxetine for use from childhood to adulthood. Demand regarding adult ADHD has also risen, as the symptoms of ADHD can persist into adulthood, and due to problems with high prevalence rates and comorbidities. Moreover, the DSM-5 recognized the coexistence of ADHD and autis- tic spectrum disorder (ASD), which further raised the level of concern. Yet at present, treat- ment guidelines have not been established for ASD with ADHD symptoms, so it is hoped such guidelines will be created quickly. This article provides a brief summary of recent findings on pharmacological therapy for ASD with ADHD symptoms.

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