1. Anagnostou E, Zwaigenbaum L, Szatmari P, Fombonne E, Fernandez BA, Woodbury-Smith M, Brian J, Bryson S, Smith IM, Drmic I, Buchanan JA, Roberts W, Scherer SW. {{Autism spectrum disorder: advances in evidence-based practice}}. {CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne}. 2014 Jan 13.
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2. Baker SM. {{Learning About Autism}}. {Global advances in health and medicine : improving healthcare outcomes worldwide}. 2013 Nov;2(6):38-46.
A medical essay written in 1923 pointed out the fallacy of blaming a chronic illness on the name of a disease. The focus of treatment should be the individual, not the disease. With a focus on options based on the individuality of each patient, I ask a simple two-part question: Does my patient need to avoid or be rid of substances and/or to be provided with substances that would favor nature’s impulse toward healing? In my academic training as a physician, I learned that a clinically effective stance favored an optimistic intent combined with the objective application of my skills-refined though the practice of listening, prescribing, and observing outcome. My understanding of autism has rested on a foundation of the individuality of every living thing, the rhythmicity of life, and the balance that characterizes healthy systems. The first autistic child I examined struck me with a nonverbal message: « I am in here; see me. » The recognition of the role of bacterial toxins amplified my notion that a general disorder of the microbiome underlies the loss of immune tolerance that accompanies the global state of sensitivity found in individuals in the autism spectrum. Depletion of organisms that have populated the human gut since before the dawn of our species arises as the most recent elevation of my learning curve.
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3. Baker SM. {{Scientific narratives in autism spectrum disorder}}. {Global advances in health and medicine : improving healthcare outcomes worldwide}. 2013 Nov;2(6):5.
Autism spectrum disorder (ASD) has increased in prevalence in the United States from one in 10 000 in the 1950s to one in 88 today. And in South Korea, the prevalence is now one in 44.(1) If the current rate of increase in the incidence of ASD continues, it could become the norm in children in 30 years. Scientific research continues to reveal potential connections between ASD and the gut microbiome or cancer gene mutations. It occurs in all socioeconomic and ethnic groups and is almost five times more common in boys than in girls. The costs to families and society is high-Medicaid costs for children with ASD are almost five times higher than for children without a diagnosis of ASD. And these costs do not begin to include those of intensive behavioral intervention.(2) Why is the prevalence of this condition increasing, and can a systems-oriented approach be used to resolve this pressing health challenge?
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4. Baker SM, Milivojevich A. {{Gender differences among children with autism spectrum disorder: differential symptom patterns}}. {Global advances in health and medicine : improving healthcare outcomes worldwide}. 2013 Nov;2(6):8-18.
The gender ratio among children in the autism spectrum of more than four boys to every girl is widely recognized. The authors present an analysis of gender differences among 79 482 symptoms and strengths in 1495 boys and 336 girls aged 2 to 18 years from parent-identified autistic children reported to a structurally novel anonymous parent-entered online database, Autism360. The data reveal differences that provide previously undetected clues to gender differences in immune and central nervous system and gastrointestinal functional disturbances. Together with published observations of male/female differences in inflammation, oxidative stress, and detoxication, these findings open doors to research focusing on gender physiology as clues to etiologic factors in autism. This study exemplifies a research method based on a large, detailed, patient-entered, structured data set in which patterns of individual illness and healing may answer collective questions about prevention and treatment.
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5. Bekele E, Crittendon J, Zheng Z, Swanson A, Weitlauf A, Warren Z, Sarkar N. {{Assessing the Utility of a Virtual Environment for Enhancing Facial Affect Recognition in Adolescents with Autism}}. {J Autism Dev Disord}. 2014 Jan 14.
Teenagers with autism spectrum disorder (ASD) and age-matched controls participated in a dynamic facial affect recognition task within a virtual reality (VR) environment. Participants identified the emotion of a facial expression displayed at varied levels of intensity by a computer generated avatar. The system assessed performance (i.e., accuracy, confidence ratings, response latency, and stimulus discrimination) as well as how participants used their gaze to process facial information using an eye tracker. Participants in both groups were similarly accurate at basic facial affect recognition at varied levels of intensity. Despite similar performance characteristics, ASD participants endorsed lower confidence in their responses and substantial variation in gaze patterns in absence of perceptual discrimination deficits. These results add support to the hypothesis that deficits in emotion and face recognition for individuals with ASD are related to fundamental differences in information processing. We discuss implications of this finding in a VR environment with regards to potential future applications and paradigms targeting not just enhanced performance, but enhanced social information processing within intelligent systems capable of adaptation to individual processing differences.
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6. Bitsika V, Sharpley CF, Sweeney JA, McFarlane JR. {{HPA and SAM axis responses as correlates of self- vs parental ratings of anxiety in boys with an Autistic Disorder}}. {Physiology & behavior}. 2014 Jan 9.
Anxiety and Autistic Disorder (AD) are both neurological conditions and both disorders share some features that make it difficult to precisely allocate specific symptoms to each disorder. HPA and SAM axis activity have been conclusively associated with anxiety, and may provide a method of validating anxiety rating scale assessments given by parents and their children with AD about those children. Data from HPA axis (salivary cortisol) and SAM axis (salivary alpha amylase) responses were collected from a sample of 32 high-functioning boys (M age=11yr) with an Autistic Disorder (AD) and were compared with the boys’ and their mothers’ ratings of the boys’ anxiety. There was a significant difference between the self-ratings given by the boys and ratings given about them by their mothers. Further, only the boys’ self-ratings of their anxiety significantly predicted the HPA axis responses and neither were significantly related to SAM axis responses. Some boys showed cortisol responses which were similar to that previously reported in children who had suffered chronic and severe anxiety arising from stressful social interactions. As well as suggesting that some boys with an AD can provide valid self-assessments of their anxiety, these data also point to the presence of very high levels of chronic HPA-axis arousal and consequent chronic anxiety in these boys.
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7. Camarata S. {{Validity of early identification and early intervention in autism spectrum disorders: Future directions}}. {International journal of speech-language pathology}. 2014 Feb;16(1):61-8.
Abstract The papers on early identification and early intervention for autism spectrum disorders (ASD) in this scientific forum (published in volume 16(1) International Journal of Speech-Language Pathology) raise many important points, including describing the substantial progress made to date as well as analyses of current gaps and weaknesses in the existing evidence base. It is humbling to see the collective expertise of the distinguished authors contributing to this scientific forum including interdisciplinary perspectives and it is not surprising that there is ongoing debate on this important topic. In addition to discussing the points raised by these authors, this paper considers the implications of the new diagnostic criteria for ASD and for social communication disorder (SCD) in the Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) in the US. Differential diagnosis of ASD and SCD will be paramount in testing early intervention for ASD and the expertise of speech-language pathologists in identifying SCD in infants and toddlers will be a central feature of discovery for both early identification and for early intervention in the decades to come. Finally, a biomedical example on testing early intervention on a spectrum disorder, derived from diabetes, is presented to illustrate both the promise and the pitfalls in testing interventions in the absence of well-validated assessment and intervention paradigms.
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8. Camarata S. {{Early identification and early intervention in autism spectrum disorders: Accurate and effective?}}. {International journal of speech-language pathology}. 2014 Feb;16(1):1-10.
Abstract Over the past decade, there has been increased interest in identifying autism and autism spectrum disorder (ASD) in toddlers. Although there is a strong rationale for identifying ASD early and delivering effective intervention, a recent report in the journal Pediatrics raises important questions about the scientific evidence currently available supporting early intervention. In addition, the British National Health Service (NHS) has not adopted universal screening for autism, even though the American (US) Academy of Pediatrics endorsed a recommendation that all toddlers be screened for ASD by the age of 24 months (in 2007). The goal of this initiative is to identify and, where indicated, provide early intervention for autism and ASD. Although it is inarguable that this is a worthwhile and laudable goal, the systematic study of this goal is confounded by the inherent difficulty in reliably identifying autism in 24-month-old toddlers. It is challenging to demonstrate intervention effects in the absence of randomly assigned control groups in an increasingly heterogeneous ASD population. The purpose of this paper is to examine the current literature on early identification and early intervention in autism and ASD and to provide a framework for examining these issues.
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9. Cavalari RN, Donovick PJ. {{Agenesis of the corpus callosum: symptoms consistent with developmental disability in two siblings}}. {Neurocase}. 2014 Jan 13.
Agenesis of the corpus callosum (AgCC) is a congenital disorder that disrupts the development of neurological structures connecting the right and left hemispheres of the brain. In addition to neurological symptoms, many individuals with AgCC demonstrate marked deficits in social, communication, and adaptive skills. This paper presents two case studies of congenital AgCC in siblings with socioemotional and behavioral symptoms consistent with developmental disability, but with notably different symptom presentations and clinical needs. Conclusions from these cases suggest that unique symptom profiles of individuals with AgCC warrant careful consideration for referral to appropriate academic and habilitative services.
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10. Charman T. {{Early identification and intervention in autism spectrum disorders: Some progress but not as much as we hoped}}. {International journal of speech-language pathology}. 2014 Feb;16(1):15-8.
Abstract Camarata’s (2014) review summarizes the progress that has been made in the field of early identification and early intervention in autism spectrum disorders (ASD) over the past few decades, but also provides a salutary reminder that much still needs to be done. Whilst it is possible to prospectively identify cases of ASD using screening instruments; it is critical that those using such screens in clinical practice understand how to interpret data from published studies and consider how screening information is communicated to parents. After several decades when few randomized controlled trials of early intervention in ASD were conducted, the last decade has seen an explosion of new studies. Despite initial optimism, as more trials are published they have highlighted the limits of, and challenges to, early intervention in ASD. Given the complex nature of ASD these sobering lessons are perhaps not surprising. Rather than promote despondency, they need to inspire and inform the next decade of clinical research to move the field forward to the benefit of young children with ASD and those who care for them.
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11. Compart PJ. {{The Pathophysiology of Autism}}. {Global advances in health and medicine : improving healthcare outcomes worldwide}. 2013 Nov;2(6):32-7.
Autism has been classically defined by its behavioral symptoms. Traditional medical research has focused on genetic or intrinsic brain-based causes of autism. While both of these are important, additional research has focused on the underlying disordered biochemistry seen in many individuals with autism. Many of these biomedical factors are amenable to treatment. This article will review the main pathophysiologic factors seen in individuals with autism spectrum disorders.
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12. Cukier HN, Dueker ND, Slifer SH, Lee JM, Whitehead PL, Lalanne E, Leyva N, Konidari I, Gentry RC, Hulme WF, Van Booven D, Mayo V, Hofmann NK, Schmidt MA, Martin ER, Haines JL, Cuccaro ML, Gilbert JR, Pericak-Vance MA. {{Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders}}. {Molecular autism}. 2014 Jan 10;5(1):1.
BACKGROUND: Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. METHODS: To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. RESULTS: We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P = 8.55 x 10-5). CONCLUSIONS: By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases.
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13. Damiani JM, Sweet BV, Sohoni P. {{Melatonin: An option for managing sleep disorders in children with autism spectrum disorder}}. {American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists}. 2014 Jan 15;71(2):95-101.
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14. Das DK, Jadhav V, Ghattargi V, Udani V. {{Novel mutation in Forkhead box G1 (FOXG1) gene in an Indian patient with Rett syndrome}}. {Gene}. 2014 Jan 9.
Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by the progressive loss of intellectual functioning, fine and gross motor skills and communicative abilities, deceleration of head growth, and the development of stereotypic hand movements, occurring after a period of normal development. The classic form of RTT involves mutation in MECP2 while the involvement of CDKL5 and FOXG1 genes has been identified in atypical RTT phenotype. FOXG1 gene encodes for a fork-head box protein G1, a transcription factor acting primarily as transcriptional repressor through DNA binding in the embryonic telencephalon as well as a number of other neurodevelopmental processes. In this report we have described the molecular analysis of FOXG1 gene in Indian patients with Rett syndrome. FOXG1 gene mutation analysis was done in a cohort of 34 MECP2/CDKL5 mutation negative RTT patients. We have identified a novel mutation (p. D263VfsX190) in FOXG1 gene in a patient with congenital variant of Rett syndrome. This mutation resulted into a frameshift, thereby causing an alteration in the reading frames of the entire coding sequence downstream of the mutation. The start position of the frameshift (Asp263) and amino acid towards the carboxyl terminal end of the protein was found to be well conserved across species using multiple sequence alignment. Since the mutation is located at forkhead binding domain, the resultant mutation disrupts the secondary structure of the protein making it non-functional. This is the first report from India showing mutation in FOXG1 gene in Rett syndrome.
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15. Deth RC. {{Autism: a redox/methylation disorder}}. {Global advances in health and medicine : improving healthcare outcomes worldwide}. 2013 Nov;2(6):68-73.
While autism is still a mysterious developmental disorder, expansion of research efforts over the past 10 to 15 years has yielded a number of important clues implicating both genetic and environmental factors. We can now assert with a measure of confidence that contemporary autism reflects the combined impact of multiple environmental factors on the processes that regulate development in genetically vulnerable individuals. Since epigenetic regulation of gene expression is acknowledged as the most critical factor in development and DNA methylation (the addition of a carbon atom at discrete locations) is the fundamental event for epigenetic regulation, dysfunctional methylation can be considered as a likely cause of autism. Since methylation activity is highly sensitive to oxidative stress (an abnormal redox state) and many environmental factors promote oxidative stress, we have proposed a redox/methylation hypothesis for autism causation. The narrative herein describes the evolution of this hypothesis, which is essentially a series of linked discoveries about how the brain uniquely relies on oxidation and methylation to guide its development and to carry out its cognitive functions.
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16. Ecker C, Murphy D. {{Neuroimaging in autism-from basic science to translational research}}. {Nature reviews Neurology}. 2014 Jan 14.
Over the past decade, human neuroimaging studies have provided invaluable insights into the neural substrates that underlie autism spectrum disorder (ASD). Although observations from multiple neuroimaging approaches converge in suggesting that changes in brain structure, functioning and connectivity are associated with ASD, the neurobiology of this disorder is complex, and considerable aetiological and phenotypic heterogeneity exists among individuals on the autism spectrum. Characterization of the neurobiological alterations that underlie ASD and development of novel pharmacotherapies for ASD, therefore, requires multidisciplinary collaboration. Consequently, pressure is growing to combine neuroimaging data with information provided by other disciplines to translate research findings into clinically useful biomarkers. So far, however, neuroimaging studies in patients with ASD have mainly been conducted in isolation, and the low specificity of neuroimaging measures has hindered the development of biomarkers that could aid clinical trials and/or facilitate patient identification. Novel approaches to acquiring and analysing data on brain characteristics are currently being developed to overcome these inherent limitations, and to integrate neuroimaging into translational research. Here, we discuss promising new studies of cortical pathology in patients with ASD, and outline how the novel insights thereby obtained could inform diagnosis and treatment of ASD in the future.
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17. Edmonson C, Ziats MN, Rennert OM. {{Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum}}. {Molecular autism}. 2014 Jan 10;5(1):3.
BACKGROUND: The cellular mechanism(s) underlying autism spectrum disorders (ASDs) are not completely understood, but ASDs are thought to ultimately result from disrupted synaptogenesis. However, studies have also shown that glial cell numbers and function are abnormal in post-mortem brain tissue from autistic patients. Direct assessment of glial cells in post-mortem human brain tissue is technically challenging, limiting glial research in human ASD studies. Therefore, we attempted to determine if glial cell-type specific markers may be altered in autistic brain tissue in a manner that is consistent with known cellular findings, such that they could serve as a proxy for glial cell numbers and/or activation patterns. METHODS: We assessed the relative expression of five glial-specific markers and two neuron-specific markers via qRT-PCR. We studied tissue samples from the prefrontal cortex (PFC) and cerebellum of nine post-mortem autistic brain samples and nine neurologically-normal controls. Relative fold-change in gene expression was determined using the DeltaDeltaCt method normalized to housekeeping gene beta-actin, with a two-tailed Student’s t-test P <0.05 between groups considered as significant. RESULTS: Both astrocyte- and microglial-specific markers were significantly more highly expressed in autistic PFC as compared to matched controls, while in the cerebellum only astrocyte markers were elevated in autistic samples. In contrast, neuron-specific markers showed significantly lower expression in both the PFC and cerebellum of autistic patients as compared to controls. CONCLUSIONS: These results are in line with previous findings showing increased glial cell numbers and up-regulation of glial cell gene expression in autistic post-mortem brain tissue, particularly in the PFC, as well as decreased number of neurons in both the PFC and cerebellum of autistic patients. The concordance of these results with cell-level studies in post-mortem autistic brain tissue suggests that expression of glial cell-type specific markers may serve as a useful alternative to traditional cellular characterization methods, especially when appropriately-preserved post-mortem tissue is lacking. Additionally, these results demonstrate abnormal glial-specific gene expression in autistic brains, supporting previous studies that have observed altered glial cell numbers or activation patterns in ASDs. Future work should directly assess the correlation between cell-type specific marker levels and cell number and activation patterns.
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18. Goldknopf EJ. {{Atypical resource allocation may contribute to many aspects of autism}}. {Frontiers in integrative neuroscience}. 2013;7:82.
Based on a review of the literature and on reports by people with autism, this paper suggests that atypical resource allocation is a factor that contributes to many aspects of autism spectrum conditions, including difficulties with language and social cognition, atypical sensory and attentional experiences, executive and motor challenges, and perceptual and conceptual strengths and weaknesses. Drawing upon resource theoretical approaches that suggest that perception, cognition, and action draw upon multiple pools of resources, the approach hypothesizes that compared with resources in typical cognition, resources in autism are narrowed or reduced, especially in people with strong sensory symptoms. In narrowed attention, resources are restricted to smaller areas and to fewer modalities, stages of processing, and cognitive processes than in typical cognition; narrowed resources may be more intense than in typical cognition. In reduced attentional capacity, overall resources are reduced; resources may be restricted to fewer modalities, stages of processing, and cognitive processes than in typical cognition, or the amount of resources allocated to each area or process may be reduced. Possible neural bases of the hypothesized atypical resource allocation, relations to other approaches, limitations, and tests of the hypotheses are discussed.
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19. James SJ. {{Autism and Folate-dependent One-carbon Metabolism: Serendipity and Critical Branch-point Decisions in Science}}. {Global advances in health and medicine : improving healthcare outcomes worldwide}. 2013 Nov;2(6):48-51.
Folate-dependent one-carbon metabolism is present in every cell of the body. It represents a central systems biology hub that reverberates into countless other pathways with more specialized roles in specialized cell types throughout the body. I have spent 25 years of research on this core biochemical pathway with several unanticipated iterations that led me from Down syndrome to congenital heart defects to leukemia and finally to autism about 12 years ago. Figure 1 provides an overview of the three interdependent pathways involved in folate-dependent methionine « transmethylation » and « transsulfuration. » Methionine is necessary for the synthesis of S-adenosylmethionine (SAM), the major methyl donor for all cellular methylation reactions. It is also the major precursor for cysteine, the rate-limiting amino acid for glutathione synthesis linking transmethylation and transsulfuration pathways. Methionine levels can be negatively affected by genetic and environmental factors that reduce folate availability and/or oxidative inhibition of the methionine synthase enzyme. Because these three metabolic pathways are mutually interdependent, genetic or environmental perturbation of folate or methionine metabolism will indirectly impact glutathione synthesis, and conversely, alterations in glutathione synthesis will alter flux through pathways of folate and methionine metabolism. This interdependency translates into broader impact on essential cellular functions.
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20. Kleijer KT, Schmeisser MJ, Krueger DD, Boeckers TM, Scheiffele P, Bourgeron T, Brose N, Burbach JP. {{Neurobiology of autism gene products: towards pathogenesis and drug targets}}. {Psychopharmacology}. 2014 Jan 14.
RATIONALE: The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets. OBJECTIVE: The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms. METHOD: Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions. RESULTS: The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity. CONCLUSIONS: ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.
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21. Kronenberg LM, Goossens PJ, van Etten DM, van Achterberg T, van den Brink W. {{Need for Care and Life Satisfaction in Adult Substance Use Disorder Patients With and Without Attention Deficit Hyperactivity Disorder (ADHD) or Autism Spectrum Disorder (ASD)}}. {Perspectives in psychiatric care}. 2014 Jan 10.
PURPOSE: To identify care needs of adult substance use disorder (SUD) patients with and without co-occurring attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). DESIGN AND METHODS: An exploratory study using the European Addiction Severity Index, the Camberwell Assessment of Needs, and the Manchester Short Assessment of Quality of Life to assess and compare care needs and perceived quality of life. FINDINGS: All patients are dissatisfied with parts of their existence. SUD patients have fewer care needs than SUD patients with co-occurring ADHD or ASD. The SUD and SUD + ADHD groups report needs in similar domains. The SUD + ASD group shows a greater number of and more extensive care needs. PRACTICE IMPLICATIONS: Differences in the care needs of adult SUD patients with and without ADHD or ASD should be taken into account when developing evidence-based nursing care interventions.
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22. Macfabe D. {{Autism: metabolism, mitochondria, and the microbiome}}. {Global advances in health and medicine : improving healthcare outcomes worldwide}. 2013 Nov;2(6):52-66.
New approaches are needed to examine the diverse symptoms and comorbidities of the growing family of neurodevelopmental disorders known as autism spectrum disorder (ASD). ASD originally was thought to be a static, inheritable neurodevelopmental disorder, and our understanding of it is undergoing a major shift. It is emerging as a dynamic system of metabolic and immune anomalies involving many organ systems, including the brain, and environmental exposure. The initial detailed observation and inquiry of patients with ASD and related conditions and the histories of their caregivers and families have been invaluable. How gastrointestinal (GI) factors are related to ASD is not yet clear. Nevertheless, many patients with ASD have a history of previous antibiotic exposure or hospitalization, GI symptoms, abnormal food cravings, and unique intestinal bacterial populations, which have been proposed to relate to variable symptom severity. In addition to traditional scientific inquiry, detailed clinical observation and recording of exacerbations, remissions, and comorbidities are needed. This article reviews the role that enteric short-chain fatty acids, particularly propionic (also called propanoic) acid, produced from ASD-associated GI bacteria, may play in the etiology of some forms of ASD. Human populations that are partial metabolizers of propionic acid are more common than previously thought. The results from pre-clinical laboratory studies show that propionic acid-treated rats display ASD-like repetitive, perseverative, and antisocial behaviors and seizure. Neurochemical changes, consistent and predictive with findings in ASD patients, including neuroinflammation, increased oxidative stress, mitochondrial dysfunction, glutathione depletion, and altered phospholipid/acylcarnitine profiles, have been observed. Propionic acid has bioactive effects on (1) neurotransmitter systems, (2) intracellular acidification and calcium release, (3) fatty acid metabolism, (4) gap junction gating, (5) immune function, and (6) alteration of gene expression that warrant further exploration. Traditional scientific experimentation is needed to verify the hypothesis that enteric short-chain fatty acids may be a potential environmental trigger in some forms of ASD. Novel collaborative developments in systems biology, particularly examining the role of the microbiome and its effects on host metabolism, immune and mitochondrial function, and gene expression, hold great promise in ASD.
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23. Maramara LA, He W, Ming X. {{Pre- and Perinatal Risk Factors for Autism Spectrum Disorder in a New Jersey Cohort}}. {Journal of child neurology}. 2014 Jan 10.
This study evaluated the prevalence of pre- and perinatal risk factors in a cohort of children with autism spectrum disorders compared with the New Jersey population. Our cohort included 268 individuals with an autism spectrum disorder. Birth histories were obtained by a self-administered questionnaire. The autism spectrum disorders cohort rates of 7 perinatal risk factors were significantly higher than New Jersey state rates: mother’s age 35 years or older, low birth weight, multiple gestation, prematurity, vaginal bleeding, prolonged labor, and hypoxia. Analysis of clustering of risk factors in the cohort showed no significant differences across maternal and paternal age groups. Older mothers in the cohort had a higher risk of infant hypoxia. Multiple risk factors during pregnancy appear to be associated with a higher risk of autism spectrum disorders in offspring, supporting the hypothesis that environmental influences in conjunction with genetics contribute to the causes of autism spectrum disorders.
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24. Mateu-Huertas E, Rodriguez-Revenga L, Alvarez-Mora MI, Madrigal I, Willemsen R, Mila M, Marti E, Estivill X. {{Blood expression profiles of fragile X premutation carriers identify candidate genes involved in neurodegenerative and infertility phenotypes}}. {Neurobiology of disease}. 2014 Jan 10.
Male premutation carriers presenting between 55-200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5′- UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.
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25. McDuffie A, Thurman AJ, Hagerman RJ, Abbeduto L. {{Symptoms of Autism in Males with Fragile X Syndrome: A Comparison to Nonsyndromic ASD Using Current ADI-R Scores}}. {J Autism Dev Disord}. 2014 Jan 11.
Symptoms of autism are frequent in males with fragile X syndrome (FXS), but it is not clear whether symptom profiles differ from those of nonsyndromic ASD. Using individual item scores from the Autism Diagnostic Inventory-Revised, we examined which current symptoms of autism differed in boys with FXS relative to same-aged boys diagnosed with nonsyndromic ASD. In addition, different subsamples of participants were matched on autism diagnostic status and severity of autism symptoms. Between-group comparisons revealed that boys with FXS showed significantly less impairment in Social Smiling than did age-, diagnostic-, and severity-matched boys with nonsyndromic ASD. Severity-matched boys with FXS showed more impairment in complex mannerisms than did boys with nonsyndromic ASD. Behavioral differences between FXS and nonsyndromic ASD may be of theoretical importance in understanding the causes and correlates of ASD in FXS and in developing and implementing appropriate treatments.
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26. Nguyen M, Roth A, Kyzar EJ, Poudel MK, Wong K, Stewart AM, Kalueff AV. {{Decoding the contribution of dopaminergic genes and pathways to autism spectrum disorder (ASD)}}. {Neurochemistry international}. 2014 Jan 9.
Autism spectrum disorder (ASD) is a debilitating brain illness causing social deficits, delayed development and repetitive behaviors. ASD is a heritable neurodevelopmental disorder with poorly understood and complex etiology. The central dopaminergic system is strongly implicated in ASD pathogenesis. Genes encoding various elements of this system (including dopamine receptors, the dopamine transporter or enzymes of synthesis and catabolism) have been linked to ASD. Here, we comprehensively evaluate known molecular interactors of dopaminergic genes, and identify their potential molecular partners within up/down-steam signaling pathways associated with dopamine. These in-silico analyses allowed us to construct a map of molecular pathways, regulated by dopamine and involved in ASD. Clustering these pathways reveals groups of genes associated with dopamine metabolism, encoding proteins that control dopamine neurotransmission, cytoskeletal processes, synaptic release, Ca2+ signaling, as well as the adenosine, glutamatergic and gamma-aminobutyric systems. Overall, our analyses emphasize the important role of the dopaminergic system in ASD, and implicate several cellular signaling processes in its pathogenesis.
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27. Niederberger C. {{Re: Autism and Mental Retardation among Offspring Born after In Vitro Fertilization}}. {The Journal of urology}. 2014 Feb;191(2):433-5.
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28. Rose S, Frye RE, Slattery J, Wynne R, Tippett M, Pavliv O, Melnyk S, James SJ. {{Oxidative stress induces mitochondrial dysfunction in a subset of autism lymphoblastoid cell lines in a well-matched case control cohort}}. {PloS one}. 2014;9(1):e85436.
There is increasing recognition that mitochondrial dysfunction is associated with the autism spectrum disorders. However, little attention has been given to the etiology of mitochondrial dysfunction or how mitochondrial abnormalities might interact with other physiological disturbances associated with autism, such as oxidative stress. In the current study we used respirometry to examine reserve capacity, a measure of the mitochondrial ability to respond to physiological stress, in lymphoblastoid cell lines (LCLs) derived from children with autistic disorder (AD) as well as age and gender-matched control LCLs. We demonstrate, for the first time, that LCLs derived from children with AD have an abnormal mitochondrial reserve capacity before and after exposure to increasingly higher concentrations of 2,3-dimethoxy-1,4-napthoquinone (DMNQ), an agent that increases intracellular reactive oxygen species (ROS). Specifically, the AD LCLs exhibit a higher reserve capacity at baseline and a sharper depletion of reserve capacity when ROS exposure is increased, as compared to control LCLs. Detailed investigation indicated that reserve capacity abnormalities seen in AD LCLs were the result of higher ATP-linked respiration and maximal respiratory capacity at baseline combined with a marked increase in proton leak respiration as ROS was increased. We further demonstrate that these reserve capacity abnormalities are driven by a subgroup of eight (32%) of 25 AD LCLs. Additional investigation of this subgroup of AD LCLs with reserve capacity abnormalities revealed that it demonstrated a greater reliance on glycolysis and on uncoupling protein 2 to regulate oxidative stress at the inner mitochondria membrane. This study suggests that a significant subgroup of AD children may have alterations in mitochondrial function which could render them more vulnerable to a pro-oxidant microenvironment derived from intrinsic and extrinsic sources of ROS such as immune activation and pro-oxidant environmental toxicants. These findings are consistent with the notion that AD is caused by a combination of genetic and environmental factors.
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29. Segal NL. {{Stolen Twin: Fascination and Curiosity/Twin Research Reports: Evolution of Sleep Length; Dental Treatment of Craniopagus Twins; Cryopreserved Double Embryo Transfer; Gender Options in Multiple Pregnancy/Current Events: Appendectomy in One Twin; Autistic Twin Marathon Runners; 3D Facial Recognition; Twin Biathletes}}. {Twin research and human genetics : the official journal of the International Society for Twin Studies}. 2014 Jan 14:1-6.
The story of her allegedly stolen twin brother in Armenia is recounted by a ‘singleton twin’ living in the United States. The behavioral consequences and societal implications of this loss are considered. This case is followed by twin research reports on the evolution of sleep length, dental treatment of craniopagus conjoined twins, cryopreserved double embryo transfer (DET), and gender options in multiple pregnancy. Current events include the diagnosis of appendectomy in one identical twin, the accomplishments of autistic twin marathon runners, the power of three-dimensional (3D) facial recognition, and the goals of twin biathletes heading to the 2014 Sochi Olympics in Russia.
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30. Sterling L, Renno P, Storch EA, Ehrenreich-May J, Lewin AB, Arnold E, Lin E, Wood J. {{Validity of the Revised Children’s Anxiety and Depression Scale for youth with autism spectrum disorders}}. {Autism}. 2014 Jan 13.
High rates of anxiety and depression are reported among youth with autism spectrum disorders. These conditions are generally assessed using measures validated for typically developing youth. Few studies have investigated their validity for autism spectrum disorders, which is crucial for accurate assessment and the provision of proper treatment. The Revised Children’s Anxiety and Depression Scale was evaluated with 67 youth with autism spectrum disorders to examine its utility in measuring anxiety and depression in this population. Parents and children (aged 11-15 years) referred to a multisite intervention study completed the Pediatric Anxiety Rating Scale, Multidimensional Anxiety Scale for Children, Anxiety Disorders Interview Schedule, Child Behavior Checklist, and Revised Children’s Anxiety and Depression Scale. Results suggest acceptable internal consistency of the Revised Children’s Anxiety and Depression Scale. Modest convergent validity was found among the Revised Children’s Anxiety and Depression Scale and other standardized measures of anxiety and depression. There were stronger correlations between Revised Children’s Anxiety and Depression Scale Total scores and subscales of measures expected to correlate significantly than those not expected to correlate. One exception was a significant association between the Revised Children’s Anxiety and Depression Scale and Child Behavior Checklist Attention subscale, calling into question the divergent validity in separating anxiety from attention problems. Overall, results suggest preliminary support for the Revised Children’s Anxiety and Depression Scale in youth with high-functioning autism spectrum disorders.
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31. Swettenham J, Remington A, Murphy P, Feuerstein M, Grim K, Lavie N. {{Seeing the Unseen: Autism Involves Reduced Susceptibility to Inattentional Blindness}}. {Neuropsychology}. 2014 Jan 13.
Objective: Attention research in individuals with autism spectrum disorder (ASD) has produced conflicting results. Some findings demonstrate greater distractibility while others suggest superior focused attention. Applying Lavie’s load theory of attention to account for this discrepancy led us to hypothesize increased perceptual capacity in ASD. Preliminary support for our hypothesis has so far been found for adults with ASD with reaction time (RT) and signal detection sensitivity measures. Here we test the novel prediction we derived from this hypothesis that children with ASD should have lower rates of inattentional blindness than controls. Method: Twenty-four children with ASD (mean age = 10 years 10 months) and 39 typically developing children (age and IQ matched) took part in the study. We assessed the effects of perceptual load on the rates of inattentional blindness in each group. Participants performing a line discrimination task in either a high load or low load condition were presented with an unexpected extra stimulus on a critical trial. Performance on the line judgment task and rates of detection and stimulus identification were recorded. Results: Overall rates of detection and identification were higher in the ASD group than in the controls. Moreover, whereas both detection and identification rates were significantly lower in the high (compared with low) load conditions for the controls, these were unaffected by load in the ASD group. Conclusion: Reduced inattentional blindness rates under load in ASD suggests higher perceptual capacity is a core feature, present from childhood and leading to superior performance in various measures of perception and attention. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
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32. Usuda J, Ishizumi T, Inoue T, Takeuchi S, Iijima Y, Ibi T. {{Photodynamic Diagnosis (PDD) for Central Type Lung Cancers}}. {Journal of Nippon Medical School = Nippon Ika Daigaku zasshi}. 2013;80(6):402-3.
33. Webb SJ, Jones EJ, Kelly J, Dawson G. {{The motivation for very early intervention for infants at high risk for autism spectrum disorders}}. {International journal of speech-language pathology}. 2014 Feb;16(1):36-42.
Abstract The first Autism Research Matrix (IACC, 2003) listed the identification of behavioural and biological markers of risk for autism as a top priority. This emphasis was based on the hypothesis that intervention with infants at-risk, at an early age when the brain is developing and before core autism symptoms have emerged, could significantly alter the developmental trajectory of children at risk for the disorder and impact long-range outcome. Research has provided support for specific models of early autism intervention (e.g., Early Start Denver Model) for improving outcomes in young children with autism, based on both behavioural and brain activity measures. Although great strides have been made in ability to identify risk markers for autism in younger infant/toddler samples, how and when to intervene during the prodromal state remains a critical question. Emerging evidence suggests that abnormal brain circuitry in autism precedes altered social behaviours; thus, an intervention designed to promote early social engagement and reciprocity potentially could steer brain development back toward the normal trajectory and remit or reduce the expression of symptoms.
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34. Williams EC, Zhong X, Mohamed A, Li R, Liu Y, Dong Q, Ananiev GE, Mok JC, Lin BR, Chiao C, Cherney R, Li H, Zhang SC, Chang Q. {{Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild type neurons}}. {Human molecular genetics}. 2014 Jan 12.
The disease mechanism of Rett syndrome (RTT) is not well understood. Studies in RTT mouse models have suggested a non-cell autonomous role for astrocytes in RTT pathogenesis. However, it is not clear whether this is also true for human RTT astrocytes. To establish an in vitro human RTT model, we previously generated isogenic induced pluripotent stem cell (iPSC) lines from several RTT patients carrying different disease-causing mutations. Here we show that these RTT iPSC lines can be efficiently differentiated into astroglial progenitors and glial fibrillary acidic protein expressing (GFAP+) astrocytes that maintain isogenic status, that mutant RTT astrocytes carrying three different RTT mutations and their conditioned media have adverse effects on the morphology and function of wild type neurons, and that the glial effect on neuronal morphology is independent of the intrinsic neuronal deficit in mutant neurons. Moreover, we show that both Insulin-like Growth Factor 1 (IGF-1) and GPE are able to partially rescue the neuronal deficits caused by mutant RTT astrocytes. Our findings confirm the critical glial contribution to RTT pathology, reveal potential cellular targets of IGF-1 therapy, and further validate patient-specific iPSCs and their derivatives as valuable tools to study RTT disease mechanism.
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35. Xiao Z, Qiu T, Ke X, Xiao X, Xiao T, Liang F, Zou B, Huang H, Fang H, Chu K, Zhang J, Liu Y. {{Autism Spectrum Disorder as Early Neurodevelopmental Disorder: Evidence from the Brain Imaging Abnormalities in 2-3 Years Old Toddlers}}. {J Autism Dev Disord}. 2014 Jan 14.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships in adolescents and adults with ASD, literature is still limited in information about the neurobiology of ASD in the early age of life. Brain images of 50 toddlers with ASD and 28 age, gender, and developmental quotient matched toddlers with developmental delay (DD) (control group) between ages 2 and 3 years were captured using combined magnetic resonance-based structural imaging and diffusion tensor imaging (DTI). Structural magnetic resonance imaging was applied to assess overall gray matter (GM) and white matter (WM) volumes, and regional alterations were assessed by voxel-based morphometry. DTI was used to investigate the white matter tract integrity. Compared with DD, significant increases were observed in ASD, primarily in global GM and WM volumes and in right superior temporal gyrus regional GM and WM volumes. Higher fractional anisotropy value was also observed in the corpus callosum, posterior cingulate cortex, and limbic lobes of ASD. The converging findings of structural and white matter abnormalities in ASD suggest that alterations in neural-anatomy of different brain regions may be involved in behavioral and cognitive deficits associated with ASD, especially in an early age of 2-3 years old toddlers.
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36. Yang P, Chang CL. {{Glutamate-Mediated Signaling and Autism Spectrum Disorders: Emerging Treatment Targets}}. {Current pharmaceutical design}. 2014 Jan 10.
Autism spectrum disorders (ASD) are developmental disorders which are characterized by deficits in reciprocal social interactions and communication, as well as the presence of impairing repetitive behaviors and restricted interests. Prior work examining human pathology, model systems and genetic studies have led to the current conceptualization of ASD as disorder of synaptic formation and functioning (a « synapsopathy »). In this regard, glutamate, the major excitatory neurotransmitter in central nervous system synaptic transmission with roles in learning, memory and synaptic plasticity, is hypothesized to play an important role in the pathophysiology of ASD. Molecules targeting glutamate signaling have been suggested to possess therapeutic potential for ASD treatment. This review focuses on the role of glutamate receptors structure and function, describes synaptic cell-adhesion molecule pathways related to glutamate and/or ASD, introduces a rare disease approach in the novel drug development of ASD treatment, and report glutamate-related clinical trials. We will also present the promising techniques of human-induced pluripotent stem cells, which may afford researchers the ability to study the relationships between clinical phenotype, cellular responses and glutamate involvement in ASD.
37. Yudkin D, Hayward B, Aladjem MI, Kumari D, Usdin K. {{Chromosome fragility and the abnormal replication of the FMR1 locus in Fragile X syndrome}}. {Human molecular genetics}. 2014 Jan 12.
Fragile X Syndrome (FXS) is a learning disability seen in individuals who have >200 CGG*CCG-repeats in the 5′ untranslated region of the X-linked FMR1 gene. Such alleles are associated with a fragile site, FRAXA, a gap or constriction in the chromosome that is coincident with the repeat and is induced by folate-stress or thymidylate synthase inhibitors like fluorodeoxyuridine (FdU). The molecular basis of the chromosome fragility is unknown. Previous work has suggested that the stable intrastrand structures formed by the repeat may be responsible, perhaps via their ability to block DNA synthesis. We have examined the replication dynamics of normal and FXS cells with and without FdU. We show here that an intrinsic problem with DNA replication exists in the FMR1 gene of individuals with FXS even in the absence of FdU. Our data suggests a model for chromosome fragility in FXS in which the repeat impairs replication from an origin of replication (ORI) immediately adjacent to the repeat. The fact that the replication problem occurs even in the absence of FdU suggests that this phenomenon may have in vivo consequences, including perhaps accounting for the loss of the X chromosome containing the fragile site that causes Turner syndrome (45, X0) in female carriers of such alleles. Our data on FRAXA may also be germane for the other FdU-inducible fragile sites in humans, that we show here share many common features with FRAXA.
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38. Zalla T, Sperduti M. {{The amygdala and the relevance detection theory of autism: an evolutionary perspective}}. {Frontiers in human neuroscience}. 2013;7:894.
In the last few decades there has been increasing interest in the role of the amygdala in psychiatric disorders and, in particular, in its contribution to the socio-emotional impairments in autism spectrum disorders (ASDs). Given that the amygdala is a component structure of the « social brain, » several theoretical explanations compatible with amygdala dysfunction have been proposed to account for socio-emotional impairments in ASDs, including abnormal eye contact, gaze monitoring, face processing, mental state understanding, and empathy. Nevertheless, many theoretical accounts, based on the Amygdala Theory of Autism, fail to elucidate the complex pattern of impairments observed in this population, which extends beyond the social domain. As posited by the Relevance Detector theory (Sander et al., 2003), the human amygdala is a critical component of a brain circuit involved in the appraisal of self-relevant events that include, but are not restricted to, social stimuli. Here, we propose that the behavioral and social-emotional features of ASDs may be better understood in terms of a disruption in a « Relevance Detector Network » affecting the processing of stimuli that are relevant for the organism’s self-regulating functions. In the present review, we will first summarize the main literature supporting the involvement of the amygdala in socio-emotional disturbances in ASDs. Next, we will present a revised version of the Amygdala Relevance Detector hypothesis and we will show that this theoretical framework can provide a better understanding of the heterogeneity of the impairments and symptomatology of ASDs. Finally, we will discuss some predictions of our model, and suggest new directions in the investigation of the role of the amygdala within the more generally disrupted cortical connectivity framework as a model of neural organization of the autistic brain.
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39. Zander E, Sturm H, Bolte S. {{The added value of the combined use of the Autism Diagnostic Interview-Revised and the Autism Diagnostic Observation Schedule: Diagnostic validity in a clinical Swedish sample of toddlers and young preschoolers}}. {Autism}. 2014 Jan 10.
The diagnostic validity of the new research algorithms of the Autism Diagnostic Interview-Revised and the revised algorithms of the Autism Diagnostic Observation Schedule was examined in a clinical sample of children aged 18-47 months. Validity was determined for each instrument separately and their combination against a clinical consensus diagnosis. A total of N = 268 children (n = 171 with autism spectrum disorder) were assessed. The new Autism Diagnostic Interview-Revised algorithms (research cutoff) gave excellent specificities (91%-96%) but low sensitivities (44%-52%). Applying adjusted cutoffs (lower than recommended based on receiver operating characteristics) yielded a better balance between sensitivity (77%-82%) and specificity (60%-62%). Findings for the Autism Diagnostic Observation Schedule were consistent with previous studies showing high sensitivity (94%-100%) and alongside lower specificity (52%-76%) when using the autism spectrum cutoff, but better balanced sensitivity (81%-94%) and specificity (81%-83%) when using the autism cutoff. A combination of both the Autism Diagnostic Interview-Revised (with adjusted cutoff) and the Autism Diagnostic Observation Schedule (autism spectrum cutoff) yielded balanced sensitivity (77%-80%) and specificity (87%-90%). Results favor a combined usage of the Autism Diagnostic Interview-Revised and Autism Diagnostic Observation Schedule in young children with unclear developmental problems, including suspicion of autism spectrum disorder. Evaluated separately, the Autism Diagnostic Observation Schedule (cutoff for autism) provides a better diagnostic accuracy than the Autism Diagnostic Interview-Revised.
