1. Andoh-Noda T, Inouye MO, Miyake K, Kubota T, Okano H, Akamatsu W. {{Modeling Rett syndrome using human induced pluripotent stem cells}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
Rett syndrome (RTT) is one of a group of neurodevelopmental disorders typically characterized by deficits in the X-linked gene MECP2 (methyl-CpG binding protein 2). The MECP2 gene encodes a multifunctional protein involved in transcriptional repression, transcriptional activation, chromatin remodeling, and RNA splicing. Genetic deletion of Mecp2 in mice revealed neuronal disabilities including RTT-like phenotypes and provided an excellent platform for understanding the pathogenesis of RTT. So far, there are no effective pharmacological treatments for RTT because the role of MECP2 in RTT is incompletely understood. Recently, human induced pluripotent stem cell (hiPSC) technologies have improved our knowledge of neurological and neurodevelopmental diseases including RTT because neurons derived from RTT-hiPSCs can be used for disease modeling to understand RTT phenotypes and to perform high throughput pharmaceutical drug screening. In this review, we provide an overview of RTT, including MeCP2 function and mouse models of RTT. In addition, we introduce recent advances in disease modeling of RTT using hiPSC-derived neural cells.
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2. Ha VS, Whittaker A. {{‘Closer to my world’: Children with autism spectrum disorder tell their stories through photovoice}}. {Glob Public Health};2016 (Apr 13):1-18.
One of the challenges in doing research with individuals with autism spectrum disorder (ASD) is the difficulty in communication. This study employed a modified form of photovoice with a group of young people with ASD in Hanoi, Vietnam, to provide a means of meaningful participation in research about their lives, experiences, and needs. We describe the process of conducting photovoice with nine children with ASD from June 2011 to May 2012, many of whom had limited verbal communication skills. More than 2100 photos were taken by children. Undertaking photovoice with children with ASD required some modification of the method. In particular we consider the difficulties in analysing and interpreting the photographs produced by children with ASD. Due to the ambiguities of the visual images produced we found content analysis of photographs alone was inadequate. There was a discrepancy between our initial interpretations of the photographs and our understandings derived from information from interviews with children, parents, carers, and our own observations. Our study points to the need to understand context through multiple methods and the potential of photovoice as a means to mediate communication and participation in research for groups with communication difficulties.
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3. Koshiba M, Karino G, Mimura K, Nakamura S, Yui K, Kunikata T, Yamanouchi H. {{Psycho-cognitive intervention for ASD from cross-species behavioral analyses of infants, chicks and common marmosets}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
Educational treatment to support social development of children with autism spectrum disorder (ASD) is an important topic in developmental psychiatry. However, it remains difficult to objectively quantify the socio-emotional development of ASD children. To address this problem, we developed a novel analytical method that assesses subjects’ complex behaviors using multivariate analysis, ‘Behavior Output analysis for Quantitative Emotional State Translation’ (BOUQUET). Here, we examine the potential for psycho-cognitive ASD therapy based on comparative evaluations of clinical (human) and experimental (animal) models. Our observations of ASD children (vs. their normally developing siblings) and the domestic chick in socio-sensory deprivation models show the importance of unimodal sensory stimulation, particularly important for tactile- and auditory-biased socialization. Identifying psycho-cognitive elements in early neural development, human newborn infants in neonatal intensive care unit (NICU) as well as a New World monkey, the common marmoset, also prompted us to focus on development of voluntary movement against gravity. In summary, striking behavioral similarities between children with ASD and domestic chicks’ socio-sensory deprivation models support the role of multimodal sensory-motor integration as a prerequisite step for normal development of socio-emotional and psycho-cognitive functions. Data obtained in the common marmoset model also suggest that switching from primitive anti-gravity reflexes to complex voluntary movement may be a critical milestone for psycho-cognitive development. Combining clinical findings with these animal models, and using multivariate integrative analyses, may facilitate the development of effective interventions to improve social functions in infants and in children with neurodevelopmental disorders.
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4. Kurita T, Kikuchi M, Yoshimura Y, Hiraishi H, Hasegawa C, Takahashi T, Hirosawa T, Furutani N, Higashida H, Ikeda T, Mutou K, Asada M, Minabe Y. {{Atypical Bilateral Brain Synchronization in the Early Stage of Human Voice Auditory Processing in Young Children with Autism}}. {PLoS One};2016;11(4):e0153077.
Autism spectrum disorder (ASD) has been postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical interhemispheric circuitry. In the context of ASD, alterations in both peripheral and central auditory processes have also attracted a great deal of interest because these changes appear to represent pathophysiological processes; therefore, many prior studies have focused on atypical auditory responses in ASD. The auditory evoked field (AEF), recorded by magnetoencephalography, and the synchronization of these processes between right and left hemispheres was recently suggested to reflect various cognitive abilities in children. However, to date, no previous study has focused on AEF synchronization in ASD subjects. To assess global coordination across spatially distributed brain regions, the analysis of Omega complexity from multichannel neurophysiological data was proposed. Using Omega complexity analysis, we investigated the global coordination of AEFs in 3-8-year-old typically developing (TD) children (n = 50) and children with ASD (n = 50) in 50-ms time-windows. Children with ASD displayed significantly higher Omega complexities compared with TD children in the time-window of 0-50 ms, suggesting lower whole brain synchronization in the early stage of the P1m component. When we analyzed the left and right hemispheres separately, no significant differences in any time-windows were observed. These results suggest lower right-left hemispheric synchronization in children with ASD compared with TD children. Our study provides new evidence of aberrant neural synchronization in young children with ASD by investigating auditory evoked neural responses to the human voice.
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5. Liu H, Talalay P, Fahey JW. {{Biomarker-guided Strategy for Treatment of Autism Spectrum Disorder (ASD)}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
Autism spectrum disorder (ASD) is a complex, life-long neurodevelopmental disorder currently affecting an estimated 1 out of 68 among children aged 8 y in the United States. ASD has complex genetic and epigenetic features that lead to the phenotype and there is no single genetic marker for the diagnosis. Therefore, the diagnosis for ASD is phenotype-based with no validated or credible laboratory tests available. Evidence-based treatments for ASD are limited. There is no FDA approved medical therapy that addresses either core ASD symptoms or pathophysiological processes associated with ASD. We outline herein, several ASD-associated basic physiological pathways that can be regulated by the small molecule phytochemical sulforaphane, as an example of a druggable small molecule target for which much in vitro, pre-clinical, and clinical evidence already exists: (1) redox metabolism/oxidative stress, (2) mitochondrial dysfunction, (3) immune dysregulation/neuroinflammation, (4) febrile illness and the heat shock response, (5) synaptic dysfunction. Furthermore, we identify the biomarkers that can be used to assess the functioning of these pathways as well suggest how these biomarkers could guide novel treatment strategies to correct these biochemical abnormalities in order to improve core and associated symptoms of ASD.
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6. Oien RA, Siper P, Kolevzon A, Grodberg D. {{Detecting Autism Spectrum Disorder in Children With ADHD and Social Disability}}. {J Atten Disord};2016 (Apr 13)
OBJECTIVE: The social disability associated with ADHD often makes diagnostic and treatment decision making challenging. This protocol investigates the test performance of the Autism Mental Status Exam (AMSE) in detecting autism spectrum disorder (ASD) in a sample of 45 children with ADHD and ASD symptomatology. The AMSE is a brief ASD diagnostic assessment administered in the context of a clinical exam. METHOD: All participants received a developmental evaluation, including the AMSE, followed by independent gold standard diagnostic assessments including the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R). RESULTS: Receiver operating characteristics (ROC) curve analysis indicated strong sensitivity and specificity in this population. Optimal cutoff scores are provided. CONCLUSION: The AMSE holds promise as a brief ASD assessment tool for children with ADHD and ASD symptomatology and as a guide for treatment and referral decisions at the point of care.
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7. Okamoto Y, Ishitobi M, Wada Y, Kosaka H. {{The Potential of Nasal Oxytocin Administration for Remediation of Autism Spectrum Disorders}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
Administration of oxytocin has been proposed as a treatment for the core symptoms of autism spectrum disorder (ASD), including social-communicative deficit. Previous clinical trials have investigated the efficacy and safety of oxytocin intranasal single-dose and long-term administration for individuals with ASD. All studies suggest that single-dose and long-term administration are well tolerated, and no severe adverse events have been reported. However, the efficacy of long-term oxytocin administration is controversial. Some studies have reported significant improvement of the core symptoms of ASD by long-term oxytocin administration, while other studies showed no such improvement. To elucidate the factors influencing the efficacy of oxytocin administration, it is necessary to examine the effects of administration schedules (e.g., dosage amount, frequency per day) and participant characteristics (e.g., age, sex, intellectual ability). In addition to doubts about the efficacy of particular methods of administration, questions remain about the mechanism of action of intranasal oxytocin on the central nervous system. Examination of changes in the neural underpinnings of social behavior and simultaneous oxytocin levels in blood or cerebrospinal fluid could prove important in elucidating the pharmacokinetics of intranasal oxytocin administration, which could be essential for establishing optimal oxytocin treatments for individuals with ASD.
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8. Sato A. {{mTOR, a potential target to treat autism spectrum disorder}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
Mammalian target of rapamycin (mTOR) is a key regulator in various cellular processes, including cell growth, gene expression, and synaptic functions. Autism spectrum disorder (ASD) is frequently accompanied by monogenic disorders, such as tuberous sclerosis complex, phosphatase and tensin homolog tumor hamartoma syndrome, neurofibromatosis 1, and fragile X syndrome, in which mTOR is hyperactive. Mutations in the genes involved in the mTOR-mediated signaling pathway have been identified in some cases of syndromic ASD. Evidences indicate a pathogenic role for hyperactive mTOR-mediated signaling in ASD associated with these monogenic disorders, and mTOR inhibitors are a potential pharmacotherapy for ASD. Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactive mTOR-mediated signaling. In this review, the relationship between mTOR and ASD is discussed.
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9. Singh K, Zimmerman AW. {{Sulforaphane treatment of young men with Autism Spectrum Disorder}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders that begin in early childhood. They are characterized by differences in behavior and delays in communication and affect at least 1% of children. Observational studies have now confirmed that behaviors of a substantial percentage of children with autism tend to improve with the onset of febrile illness, which might be the downstream effects of altered metabolic pathways involving increased expression of heat shock proteins (HSP) and cellular stress responses. Sulforaphane, a phytochemical derived from a number of cruciferous vegetables, most notably broccoli sprouts, has metabolic effects that in some ways resemble that of fever. This review paper discusses this « fever effect » and the intracellular effects of sulforaphane as well as the results of our recent clinical trial of sulforaphane in young adults with autism. The accompanying review by Liu et al describes the cellular actions of sulforaphane and potential biomarkers in the study of ASD.
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10. Wake R, Miyaoka T, Furuya M, Hashioka S, Horiguchi J. {{Effects of yokusankan, a Japanese kampo medicine, for symptoms associated autism spectrum disorder}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
Autism spectrum disorder (ASD) is a neuropsychiatric syndrome characterized by deficits in social interaction, qualitative impairments in communication, and restricted, repetitive, and stereotyped patterns of behavior, interests, or activities. All ASDs have a qualitative impairment in social relatedness. However, many individuals with ASDs have interfering symptoms, including irritability (aggression, self-injurious behavior, and severe tantrums). Behavioral therapy is often helpful in decreasing these behaviors. However, adjunctive medications are sometimes needed owing to the intensity and severity of irritability. Numerous medications have been tested on patients with ASD although many of these medications have been demonstrated to be useful, no clear main treatment for ASD has emerged. Despite the efficacy of some of the medicines, acceptability and side effects have proven to be barriers to their use. Yokukansan (YKS), a traditional Japanese medicine, is composed of seven kinds of dried herbs. It is widely prescribed in clinical situation for treating psychiatric disorders by acting on mainly glutamatergic and serotonergic nervous system. Recent studies indicate that YKS may be safe and useful in treating behavioral and psychological symptoms in dementia patients. In this review, we introduce the ameliorative effects of YKS on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS) and Asperger’s disorder in the open-label studies, suggesting that YKS is effective and well tolerated for the treatment of severe irritability/agitation and hyperactivity/noncompliance in subjects with ASD. In addition, various mechanisms include serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects which are thought to be involved in the mechanisms underlying the efficacy of YKS.
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11. Wang J, Li L, Shao SS, He Z, Chen YL, Kong R, Zhang XH, Gong JH, Song RR. {{Association analysis of genetic variant of rs13331 in PSD95 gene with autism spectrum disorders: A case-control study in a Chinese population}}. {J Huazhong Univ Sci Technolog Med Sci};2016 (Apr);36(2):285-288.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by high heritability. Recently, autism, the most profound form of ASD, has been increasingly attributed to synaptic abnormalities. Postsynaptic density 95 (PSD95), encoding PSD protein-95, was found essential for synaptic formation, maturation and plasticity at a PSD of excitatory synapse. It is possibly a crucial candidate gene for the pathogenesis of ASD. To identify the relationship between the rs13331 of PSD95 gene and ASD, we performed a case-control study in 212 patients and 636 controls in a Chinese population by using a polymerase chain reaction-restriction fragment length polymerase (PCR-RFLP) assay. The results showed that in genetic analysis of the heterozygous model, an association between the T allele of the rs13331 and ASD was found in the dominant model (OR=1.709, 95% CI 1.227-2.382, P=0.002) and the additive model (OR=1.409, 95% CI=1.104-1.800, P=0.006). Our data indicate that the genetic mutation C>T at the rs13331 in the PSD95 gene is strikingly associated with an increased risk of ASD.
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12. Weiss JA, Ting V, Perry A. {{Psychosocial correlates of psychiatric diagnoses and maladaptive behaviour in youth with severe developmental disability}}. {J Intellect Disabil Res};2016 (Apr 13)
BACKGROUND: We know little about the correlates of mental health problems in youth with severe and profound intellectual disability (ID), as most research includes these youth within larger samples that include greater proportions of mild and moderate disability. The purpose of the current study was to identify the child, family and psychosocial characteristics that were associated with the presence of psychiatric diagnoses and maladaptive behaviour in youth with severe ID. METHODS: Participants were 141 parents of youth with severe or profound levels of ID, 4 to 18 years of age. The mean age of children was 11.04 years (SD = 3.38), with 68% male and 39% with autism spectrum disorder (ASD). Parents completed a primarily online survey of child and family characteristics, negative life events, family quality of life and their own mental health. RESULTS: Logistic regression analyses revealed that youth with a psychiatric diagnosis had higher levels of adaptive behaviour and experienced more negative life events than youth without psychiatric diagnosis, while the presence of clinically significant maladaptive behaviour was related to higher levels of adaptive behaviour, parents’ mental health problems and lower family quality of life. Child age, gender, ASD status and financial hardship were not related to either outcome variable. CONCLUSIONS: Youth with severe and profound ID who experience psychosocial stressors are more likely reported to have mental health problems than youth without such stressors. It is likely that a combination of child and family based interventions, along with with policies that address larger systemic issues of social adversity, are needed to promote mental health and treat psychopathology when it arises.
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13. Wong S, Giulivi C. {{Autism, mitochondria and polybrominated diphenyl ether exposure}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
BACKGROUND: Autism spectrum disorders (ASD) are a growing concern with more than 1 in every 68 children affected in the United States by age 8. Limited scientific advances have been made regarding the etiology of autism, with general agreement that both genetic and environmental factors contribute to this disorder. OBJECTIVE: To explore the link between exposure to PBDE, mitochondrial dysfunction and autism risk. RESULTS: Perinatal exposures to PBDEs may contribute to the etiology or morbidity of ASD including mitochondrial dysfunction based on (i) their increased environmental abundance and human exposures, (ii) their activity towards implicated in neuronal development and synaptic plasticity including mitochondria, and (iii) their bioaccumulation in mitochondria. CONCLUSIONS: In this review, we propose that PBDE, and possibly other environmental exposures, during child development can induce or compound mitochondrial dysfunction, which in conjunction with a dysregulated antioxidant response, increase a child’s susceptibility of autism.
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14. Yui K, Kawasaki Y, Yamada H, Ogawa S. {{Oxidative Stress and Nitric Oxide in Autism Spectrum Disorder and Other Neuropsychiatric Disorders}}. {CNS Neurol Disord Drug Targets};2016 (Apr 13)
The etiology of autism spectrum disorder (ASD) remains unclear; however, the toxic environmental exposure to oxidative stress has been suggested to play an important role in its pathogenesis. A loss of balance between oxidative stress and antioxidant capacity produces an excess of reactive nitrogen species (RNS) such as nitric oxide (NO). Polyunsaturated fatty acids (PUFAs), particularly arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid, are closely related to NO and NO synthase. In the pathophysiology of ASD, NO is related to the activity of primary PUFAs. NO modulates short- and long-term synaptic plasticity and plays essential roles in the regulation of a wide range of physiological processes including neurotransmission. NO affects the function of reactive oxygen species (ROS) in the local cellular milieu, in which biological antioxidants are present. NO plays a double role in the organism showing both neuroprotective and neurotoxic effects. Redox imbalance leads to the activation of the neurotoxic pathway, suggesting a crossroads for the neurotoxic or neuroprotective effects of NO. Furthermore, the dual role of NO could depend on the adaptive functions of the antioxidant capacity and oxidative stress-related ROS/RNS as the disease progresses. Increased concentrations of arachidonic acid promote neuronal survival, and the dysregulation of the NO system plays an important role in the pathophysiology of bipolar disorder and recurrent depressive disorders. Therefore, the NO system could provide useful drug targets for these diseases. NO and NO donors also show therapeutic potential for Alzheimer’s disease and schizophrenia with refractory symptoms and cognitive dysfunction.
