1. Battistella G, Niederhauser J, Fornari E, Hippolyte L, Gronchi Perrin A, Lesca G, Forzano F, Hagmann P, Vingerhoets FJ, Draganski B, Maeder P, Jacquemont S. {{Brain structure in asymptomatic FMR1 premutation carriers at risk for fragile X-associated tremor/ataxia syndrome}}. {Neurobiology of aging}. 2013 Jan 5.
Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset movement disorder affecting FMR1 premutation carriers, is associated with cerebral and cerebellar lesions. The aim of this study was to test whether computational anatomy can detect similar patterns in asymptomatic FMR1 premutation carriers (mean age 46.7 years) with qualitatively normal -appearing grey and white matter on brain MRI. We used a multimodal imaging protocol to characterize brain anatomy by automated assessment of gray matter volume and white matter properties. Structural changes in the hippocampus and in the cerebellar motor network with decreased gray matter volume in lobule VI and white matter alterations of the corresponding afferent projections through the middle cerebellar peduncles are demonstrated. Diffuse subcortical white matter changes in both hemispheres, without corresponding gray matter alterations, are only identified through age x group interactions. We interpret the hippocampal fimbria and cerebellar changes as early alterations with a possible neurodevelopmental origin. In contrast, progression of the diffuse cerebral hemispheric white matter changes suggests a neurodegenerative process, leading to late-onset lesions, which may mark the imminent onset of FXTAS.
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2. Dovgopoly A, Mercado E, 3rd. {{A connectionist model of category learning by individuals with high-functioning autism spectrum disorder}}. {Cognitive, affective & behavioral neuroscience}. 2013 Jan 9.
Individuals with autism spectrum disorder (ASD) show atypical patterns of learning and generalization. We explored the possible impacts of autism-related neural abnormalities on perceptual category learning using a neural network model of visual cortical processing. When applied to experiments in which children or adults were trained to classify complex two-dimensional images, the model can account for atypical patterns of perceptual generalization. This is only possible, however, when individual differences in learning are taken into account. In particular, analyses performed with a self-organizing map suggested that individuals with high-functioning ASD show two distinct generalization patterns: one that is comparable to typical patterns, and a second in which there is almost no generalization. The model leads to novel predictions about how individuals will generalize when trained with simplified input sets and can explain why some researchers have failed to detect learning or generalization deficits in prior studies of category learning by individuals with autism. On the basis of these simulations, we propose that deficits in basic neural plasticity mechanisms may be sufficient to account for the atypical patterns of perceptual category learning and generalization associated with autism, but they do not account for why only a subset of individuals with autism would show such deficits. If variations in performance across subgroups reflect heterogeneous neural abnormalities, then future behavioral and neuroimaging studies of individuals with ASD will need to account for such disparities.
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3. Gadow KD, Devincent CJ, Siegal VI, Olvet DM, Kibria S, Kirsch SF, Hatchwell E. {{Allele-specific associations of 5-HTTLPR/rs25531 with ADHD and autism spectrum disorder}}. {Progress in neuro-psychopharmacology & biological psychiatry}. 2013 Jan 10;40:292-7.
BACKGROUND: The aims of the present study were to examine the association between a common serotonin transporter gene (SLC6A4) polymorphism 5-HTTLPR/rs25531 with severity of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) symptoms. METHODS: Mothers and teachers completed a validated DSM-IV-referenced rating scale for ADHD and ASD symptoms in 118 children with ASD. RESULTS: Analyses indicated that children with at least one copy of the S or L(G) allele obtained significantly more severe maternal ratings of hyperactivity (p=0.001; etap(2)=0.097) and impulsivity (p=0.027; etap(2)=0.044) but not inattention (p=0.061; etap(2)=0.032), controlling for ASD severity, than children homozygous for the L(A) allele. Conversely, mothers’ ratings indicated that children with L(A)/L(A) genotype had more severe ASD social deficits than S or L(G) allele carriers (p=0.003; etap(2)=0.081), controlling for ADHD symptom severity. Teachers’ ratings though consistent with mothers’ ratings of hyperactivity and social deficits were marginally significant (p=0.07/p=0.09). There was some evidence that the magnitude of parent-teacher agreement regarding symptom severity varied as a function of the child’s genotype. CONCLUSION: The 5-HTTLPR/rs25531 polymorphism or its correlates may modulate severity of ADHD and ASD symptoms in children with ASD, but in different ways. These tentative, hypothesis-generating findings require replication with larger independent samples.
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4. Hall J, Philip RC, Marwick K, Whalley HC, Romaniuk L, McIntosh AM, Santos I, Sprengelmeyer R, Johnstone EC, Stanfield AC, Young AW, Lawrie SM. {{Social cognition, the male brain and the autism spectrum}}. {PLoS One}. 2012;7(12):e49033.
Behavioral studies have shown that, at a population level, women perform better on tests of social cognition and empathy than men. Furthermore Autism Spectrum Disorders (ASDs), which are characterized by impairments in social functioning and empathy, occur more commonly in males than females. These findings have led to the hypothesis that differences in the functioning of the social brain between males and females contribute to the greater vulnerability of males to ASD and the suggestion that ASD may represent an extreme form of the male brain. Here we sought to investigate this hypothesis by determining: (i) whether males and females differ in social brain function, and (ii) whether any sex differences in social brain function are exaggerated in individuals with ASD. Using fMRI we show that males and females differ markedly in social brain function when making social decisions from faces (compared to simple sex judgements) especially when making decisions of an affective nature, with the greatest sex differences in social brain activation being in the inferior frontal cortex (IFC). We also demonstrate that this difference is exaggerated in individuals with ASD, who show an extreme male pattern of IFC function. These results show that males and females differ significantly in social brain function and support the view that sex differences in the social brain contribute to the greater vulnerability of males to ASDs.
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5. Jones L, Totsika V, Hastings RP, Petalas MA. {{Gender Differences When Parenting Children with Autism Spectrum Disorders: A Multilevel Modeling Approach}}. {J Autism Dev Disord}. 2013 Jan 10.
Parenting a child with autism may differentially affect mothers and fathers. Existing studies of mother-father differences often ignore the interdependence of data within families. We investigated gender differences within-families using multilevel linear modeling. Mothers and fathers of children with autism (161 couples) reported on their own well-being, and their child’s functioning. Mothers reported higher levels of distress compared with fathers, and child behavior problems predicted psychological distress for both mothers and fathers. We found little evidence of child functioning variables affecting mothers and fathers differently. Gender differences in the impact of child autism on parents appear to be robust. More family systems research is required to fully understand these gender differences and the implications for family support.
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6. Lauritsen MB. {{Autism spectrum disorders}}. {European child & adolescent psychiatry}. 2013 Jan 9.
The revision of the diagnostic criteria for ASD has been widely anticipated and is expected to be an important contribution to the refinement of the definition of ASD. In the upcoming DSM-5, several changes have been made compared to the previous diagnostic criteria. They include no emphasis on language delay and age of onset except that ASD is defined as a neurodevelopmental disorder with symptoms in early childhood although the disorder may first be diagnosed later in life. The three areas of impairments in ASD are reduced to two areas, namely a social-communication domain and a behavioral domain including fixated interests and repetitive behaviors. In addition, the clinical presentation of ASD in the individual is described in more detail in terms of clinical specifiers. In addition to reporting these changes in the classification, the major international guidelines are introduced and a brief description of good clinical practice of assessment and the overall principles of intervention is provided.
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7. Massand E, Bowler DM, Mottron L, Hosein A, Jemel B. {{ERP Correlates of Recognition Memory in Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2013 Jan 10.
Recognition memory in autism spectrum disorder (ASD) tends to be undiminished compared to that of typically developing (TD) individuals (Bowler et al. 2007), but it is still unknown whether memory in ASD relies on qualitatively similar or different neurophysiology. We sought to explore the neural activity underlying recognition by employing the old/new word repetition event-related potential effect. Behavioural recognition performance was comparable across both groups, and demonstrated superior recognition for low frequency over high frequency words. However, the ASD group showed a parietal rather than anterior onset (300-500 ms), and diminished right frontal old/new effects (800-1500 ms) relative to TD individuals. This study shows that undiminished recognition performance results from a pattern of differing functional neurophysiology in ASD.
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8. Qin M, Schmidt KC, Zametkin AJ, Bishu S, Horowitz LM, Burlin TV, Xia Z, Huang T, Quezado ZM, Smith CB. {{Altered cerebral protein synthesis in fragile X syndrome: studies in human subjects and knockout mice}}. {Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism}. 2013 Jan 9.
Dysregulated protein synthesis is thought to be a core phenotype of fragile X syndrome (FXS). In a mouse model (Fmr1 knockout (KO)) of FXS, rates of cerebral protein synthesis (rCPS) are increased in selective brain regions. We hypothesized that rCPS are also increased in FXS subjects. We measured rCPS with the L-[1-(11)C]leucine positron emission tomography (PET) method in whole brain and 10 regions in 15 FXS subjects who, because of their impairments, were studied under deep sedation with propofol. We compared results with those of 12 age-matched controls studied both awake and sedated. In controls, we found no differences in rCPS between awake and propofol sedation. Contrary to our hypothesis, FXS subjects under propofol sedation had reduced rCPS in whole brain, cerebellum, and cortex compared with sedated controls. To investigate whether propofol could have a disparate effect in FXS subjects masking usually elevated rCPS, we measured rCPS in C57Bl/6 wild-type (WT) and KO mice awake or under propofol sedation. Propofol decreased rCPS substantially in most regions examined in KO mice, but in WT mice caused few discrete changes. Propofol acts by decreasing neuronal activity either directly or by increasing inhibitory synaptic activity. Our results suggest that changes in synaptic signaling can correct increased rCPS in FXS.Journal of Cerebral Blood Flow & Metabolism advance online publication, 9 January 2013; doi:10.1038/jcbfm.2012.205.
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9. Robertson RE, Wehby JH, King SM. {{Increased parent reinforcement of spontaneous requests in children with autism spectrum disorder: Effects on problem behavior}}. {Research in developmental disabilities}. 2013 Jan 5;34(3):1069-82.
Previous studies of response classes in individuals with developmental disabilities (DD) and problem behavior have shown that mild problem behavior, precursor behavior, and mands or requests can occur as functionally equivalent to severe problem behavior in some individuals. Furthermore, participants in some studies chose to use functionally equivalent alternatives over severe problem behavior to produce the maintaining reinforcer. The present study added to this literature by having parents reinforce spontaneous requests functionally equivalent to problem behavior in their children with autism at home. First, parent-implemented functional analyses identified conditions associated with increased problem behavior and requests in two children with autism. Then, parents provided the maintaining reinforcer contingent on problem behavior alone or both problem behavior and requests in a withdrawal design. The treatment analysis indicated that the same reinforcer maintained child requests and problem behavior. In addition, when parents reinforced both requests and problem behavior, child participants demonstrated a preference for requests, thereby decreasing problem behavior. Implications of this relation for function-based treatment of problem behavior in children with autism are discussed.
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10. Shaw TA, Langdon R, Porter MA. {{Hyper-reactivity in Fragile X Syndrome Females: Generalized or Specific to Socially-salient Stimuli? A Skin Conductance Study}}. {International journal of psychophysiology : official journal of the International Organization of Psychophysiology}. 2013 Jan 5.
Fragile X syndrome (FXS) is characterized by hyper-reactivity, autistic tendencies and social anxiety. It has been hypothesized that the FXS social phenotype is secondary to a generalized hyper-reactivity that leads to social avoidance. No study, however, has investigated whether hyperarousal in FXS is generalized or more specific to socially salient information. We recorded skin conductance responses (SCRs) while females with FXS, as well as chronological age- (CA-) and mental age- (MA-) matched controls, viewed two sets of visual images: direct-gaze emotional faces and affectively arousing scenes. Explicit emotion recognition and subjective ratings of emotions aroused by images were also recorded. Overall, females with FXS displayed hyper-reactivity only when viewing the more socially salient stimuli (emotional faces), compared to CA-matched controls, but not MA-matched controls. Moreover, females with FXS also displayed atypical emotion recognition abilities and subjective ratings of their own emotional states. These findings suggest that any hyper-reactivity observed in FXS may be more specific to socially salient stimuli, rather than generalized.
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11. Yang Q, Feng B, Zhang K, Guo YY, Liu SB, Wu YM, Li XQ, Zhao MG. {{Excessive astrocyte-derived neurotrophin-3 contributes to the abnormal neuronal dendritic development in a mouse model of fragile x syndrome}}. {PLoS genetics}. 2012 Dec;8(12):e1003172.
Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest a role of astrocytes in neuronal development. However, the mechanisms involved in the regulation process of astrocytes from FXS remain unclear. In this study, we found that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse which lacks FMRP expression, inhibited the proper elaboration of dendritic processes of neurons in vitro. Furthermore, astrocytic conditioned medium (ACM) from KO astrocytes inhibited proper dendritic growth of both wild-type (WT) and KO neurons. Inducing expression of FMRP by transfection of FMRP vectors in KO astrocytes restored dendritic morphology and levels of synaptic proteins. Further experiments revealed elevated levels of the neurotrophin-3 (NT-3) in KO ACM and the prefrontal cortex of Fmr1 KO mice. However, the levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were normal. FMRP has multiple RNA-binding motifs and is involved in translational regulation. RNA-binding protein immunoprecipitation (RIP) showed the NT-3 mRNA interacted with FMRP in WT astrocytes. Addition of high concentrations of exogenous NT-3 to culture medium reduced the dendrites of neurons and synaptic protein levels, whereas these measures were ameliorated by neutralizing antibody to NT-3 or knockdown of NT-3 expression in KO astrocytes through short hairpin RNAs (shRNAs). Prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA infected KO astrocytes rescued the deficit of trace fear memory in KO mice, concomitantly decreased the NT-3 levels in the prefrontal cortex. This study indicates that excessive NT-3 from astrocytes contributes to the abnormal neuronal dendritic development and that astrocytes could be a potential therapeutic target for FXS.
