Le numéro de septembre 2014 du Journal of Neural Transmission est consacré à la neurobiologie de l’autisme.

1. Freitag C, Konrad K. Autism spectrum disorder : underlying neurobiology. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1077-9.

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2. Chiocchetti A, Bour H, Freitag C. Glutamatergic candidate genes in autism spectrum disorder : an overview. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1081-106.

Autism spectrum disorders (ASD) are neurodevelopmental disorders with early onset in childhood. Most of the risk for ASD can be explained by genetic variants that act in interaction with biological environmental risk factors. However, the architecture of the genetic components is still unclear. Genetic studies and subsequent systems biological approaches described converging functional effects of identified genes towards pathways relevant for neuronal signalling. Mouse models suggest an aberrant synaptic plasticity at the neuropathological level, which is believed to be conferred by dysregulation of long-term potentiation or depression of neuronal connections. A central pathway regulating these mechanisms is glutamatergic signalling. Here, we hypothesized that susceptibility genes for ASD are enriched for components of this pathway. To further understand the impact of ASD risk genes on the glutamatergic pathway, we performed a systematic review using the literature database “pubmed” and the “AutismKB” knowledgebase. We provide an overview of the glutamatergic system in typical brain function and development, and summarize findings from linkage, association, copy number variants, and sequencing studies in ASD to provide a comprehensive picture of the glutamatergic landscape of ASD genetics. Genetic variants associated with ASD were enriched in glutamatergic pathways, affecting receptor signalling, metabolism and transport. Furthermore, in genetically modified mouse models for ASD, pharmacological compounds acting on ionotropic or metabotropic receptor activity are able to rescue ASD reminscent phenotypes. We conclude that glutamatergic genetic risk factors for ASD show a complex pattern and further studies are needed to fully understand its mechanisms, before translation of findings into clinical applications and individualized treatment approaches will be possible.

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3. Waltes R, Gfesser J, Haslinger D, Schneider-Momm K, Biscaldi M, Voran A, Freitag C, Chiocchetti A. Common EIF4E variants modulate risk for autism spectrum disorders in the high-functioning range. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1107-16.

The genetic architecture of Autism Spectrum Disorders (ASD) is complex. Common genetic variation has especially been related to high-functioning ASD. In addition, some studies favoured analysis of strictly diagnosed autism individuals, which resulted in more robust findings than the combined analysis of all spectrum individuals. Functional variants modulating EIF4E expression have previously been indicated as risk factors for ASD. Pharmacological modulation of glutamate receptors which regulate EIF4E activity resulted in reduced repetitive behaviours in human and animal studies. Based on these findings, we tested common EIF4E variants for association with overall ASD, with strict autism and with the strict high-functioning autism (strict HFA) subgroup, and their effect on repetitive and/or stereotypic behaviour. We observed over-transmission of rs13109000G in the strict HFA and the strict autism cohort but not in the larger ASD cohort. We report protective effects for the minor allele of rs4699369T on stereotyped and ritualized behaviour in the overall ASD cohort, the strict autism but not in the strict HFA group. In addition, a protective role for rs4699369T and a risk effect of rs12498533G on hand and finger mannerisms was observed. These results need to be replicated in larger ASD and strict autism samples. The predicted impact on transcription through the ASD associated EIF4E variants rs4699369T and rs12498533G as well as the association of the EIF4E interaction partners FMRP and CYFIP1 with ASD point to an mRNA mediated pathomechanism for ASD.

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4. Taurines R, Segura M, Schecklmann M, Albantakis L, Grünblatt E, Walitza S, Jans T, Lyttwin B, Haberhausen M, Theisen F, Martin B, Briegel W, Thome J, Schwenck C, Romanos M, Gerlach M. Altered peripheral BDNF mRNA expression and BDNF protein concentrations in blood of children and adolescents with autism spectrum disorder. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1117-28.

Findings from molecular genetic studies and analyses of postmortem and peripheral tissue led to the hypothesis that neurotrophins—as crucial moderators of neuroplasticity—impact on the pathophysiology of autism spectrum disorder (ASD). The study projects aimed to complement former results on the role of brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family with fundamental impact on brain development and function. The purpose of this work was to investigate peripheral BDNF mRNA expression and BDNF protein concentrations in ASD as potential surrogates for the effects observed in the central nervous system. In a BDNF protein quantification study, serum concentrations were analyzed using Enzyme-Linked Immunosorbent Assays in 24 male patients with ASD, all with an IQ > 70 (age 13.9 ± 3.0 years) and 20 age- and gender-matched healthy control subjects (age 14.4 ± 2.1 years ; p = 0.522). In a further independent project, a BDNF mRNA expression analysis, mRNA levels from total blood were assessed by quantitative real-time polymerase chain reaction in a sample of 16 male ASD patients (age 10.8 ± 2.2), 15 age- and gender-matched healthy controls (age 12.1 ± 2.2) and 15 patients with attention deficit hyperactivity disorder as a clinical control group (age 11.8 ± 2.2 ; p = 0.207). In the protein quantification project, significantly decreased BDNF serum concentrations were found in ASD cases compared to healthy control children (t = −2.123, df = 42, p < 0.05). Analysis of covariance (ANCOVA) revealed this result in accordance with significant reductions in BDNF mRNA expression in ASD, observed in the mRNA expression study (F = 3.65 ; df = 2.43 ; p < 0.05) ; neither age nor IQ confounded the result, as indicated by ANCOVA (F = 3.961 ; df = 2.41 ; p < 0.05, η 2 = 0.162). Our study projects supported the notion that neurotrophins are involved in the pathophysiology of ASD. Further studies may eventually contribute to the identification of distinct peripheral mRNA expression and protein concentration patterns possibly supporting diagnostic and therapeutic processes.

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5. Luckhardt C, Jarczok TA, Bender S. Elucidating the neurophysiological underpinnings of autism spectrum disorder : new developments. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1129-44.

The study of neurophysiological approaches together with rare and common risk factors for Autism Spectrum Disorder (ASD) allows elucidating the specific underlying neurobiology of ASD. Whereas most neurophysiologically based research in ASD to date has focussed on case–control differences based on the DSM- or ICD-based categorical ASD diagnosis, more recent studies have aimed at studying genetically and/or neurophysiologically defined homogeneous ASD subgroups for specific neuronal biomarkers. This review addresses the neurophysiological investigation of ASD by evoked and event-related potentials, by EEG/MEG connectivity measures such as coherence, and transcranial magnetic stimulation. As an example of classical neurophysiological studies in ASD, we report event-related potential studies which have illustrated which brain areas and processing stages are affected in the visual perception of socially relevant stimuli. However, a paradigm shift has taken place in recent years focussing on how these findings can be tracked down to basic neuronal functions such as deficits in cortico-cortical connectivity and the interaction between brain areas. Disconnectivity, for example, can again be related to genetically induced shifts in the excitation/inhibition balance. Genetic causes of ASD may be grouped by their effects on the brain’s system level to identify ASD subgroups which respond differentially to therapeutic interventions.

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6. Ambrosino S, Bos DJ, van Raalten TR, Kobussen NA, van Belle J, Oranje B, Durston S. Functional connectivity during cognitive control in children with autism spectrum disorder : an independent component analysis. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1145-55.

Restrictive and repetitive behavior in autism may be related to deficits in cognitive control. Here, we aimed to assess functional connectivity during a cognitive control task and compare brain network activity and connectivity in children with autism spectrum disorders (ASD) and typically developing children using a multivariate data-driven approach. 19 high-functioning boys with ASD and 19 age-matched typically developing boys were included in this study. Functional magnetic resonance imaging was performed at 3T during the performance of a cognitive control task (go/no-go paradigm). Functional networks were identified using independent component analysis. Network activity and connectivity was compared between groups and correlated with clinical measures of rigid behavior using multivariate analysis of covariance. We found no differences between the groups in task performance or in network activity. Power analysis indicated that, if this were a real difference, it would require nearly 800 subjects to show group differences in network activity using this paradigm. Neither were there correlations between network activity and rigid behavior. Our data do not provide support for the presence of deficits in cognitive control in children with ASD, or the functional networks supporting this ability.

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7. Ecker C, Shahidiani A, Feng Y, Daly E, Murphy C, D’Almeida V, Deoni S, Williams SC, Gillan N, Gudbrandsen M, Wichers R, Andrews D, Van Hemert L, Murphy DGM. The effect of age, diagnosis, and their interaction on vertex-based measures of cortical thickness and surface area in autism spectrum disorder. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1157-70.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is accompanied by an atypical development of brain maturation. So far, brain development has mainly been studied during early childhood in ASD, and using measures of total or lobular brain volume. However, cortical volumetric measures are a product of two distinct biological neuroanatomical features, cortical thickness, and surface area, which most likely also have different neurodevelopmental trajectories in ASD. Here, we therefore examined age-related differences in cortical thickness and surface area in a cross-sectional sample of 77 male individuals with ASD ranging from 7 to 25 years of age, and 77 male neurotypical controls matched for age and FSIQ. Surface-based measures were analyzed using a general linear model (GLM) including linear, quadratic, and cubic age terms, as well as their interactions with the main effect of group. When controlling for the effects of age, individuals with ASD had spatially distributed reductions in cortical thickness relative to controls, particularly in fronto-temporal regions, and also showed significantly reduced surface area in the prefrontal cortex and the anterior temporal lobe. We also observed significant group × age interactions for both measures. However, while cortical thickness was best predicted by a quadratic age term, the neurodevelopmental trajectory for measures of surface area was mostly linear. Our findings suggest that ASD is accompanied by age-related and region-specific reductions in cortical thickness and surface area during childhood and early adulthood. Thus, differences in the neurodevelopmental trajectory of maturation for both measures need to be taken into account when interpreting between-group differences overall.

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8. Greimel E, Schulte-Rüther M, Kamp-Becker I, Remschmidt H, Herpertz-Dahlmann B, Konrad K. Impairment in face processing in autism spectrum disorder : a developmental perspective. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1171-81.

Findings on face identity and facial emotion recognition in autism spectrum disorder (ASD) are inconclusive. Moreover, little is known about the developmental trajectory of face processing skills in ASD. Taking a developmental perspective, the aim of this study was to extend previous findings on face processing skills in a sample of adolescents and adults with ASD. N = 38 adolescents and adults (13–49 years) with high-functioning ASD and n = 37 typically developing (TD) control subjects matched for age and IQ participated in the study. Moreover, n = 18 TD children between the ages of 8 and 12 were included to address the question whether face processing skills in ASD follow a delayed developmental pattern. Face processing skills were assessed using computerized tasks of face identity recognition (FR) and identification of facial emotions (IFE). ASD subjects showed impaired performance on several parameters of the FR and IFE task compared to TD control adolescents and adults. Whereas TD adolescents and adults outperformed TD children in both tasks, performance in ASD adolescents and adults was similar to the group of TD children. Within the groups of ASD and control adolescents and adults, no age-related changes in performance were found. Our findings corroborate and extend previous studies showing that ASD is characterised by broad impairments in the ability to process faces. These impairments seem to reflect a developmentally delayed pattern that remains stable throughout adolescence and adulthood.

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9. de Vries M, Geurts H. Beyond individual differences : are working memory and inhibition informative specifiers within ASD ?. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1183-98.

Findings on working memory (WM) and inhibition in children with autism spectrum disorders (ASD) are contradictory and earlier studies largely ignored individual differences. As WM and inhibition seem to be related, children who experience WM deficits might also experience inhibition deficits. Moreover, these children possibly form a distinct subgroup, differing on other variables, such as cognitive functioning, symptom severity, behavior, and attention deficit hyperactivity disorder (ADHD) characteristics. We studied a large sample of children with and without ASD (8–12 years, IQ > 80) with classic experimental tasks (n-back task, ASD n = 77, control n = 45 ; stop task, ASD n = 74, control n = 43), and explored individual differences. The ASD group made more errors on the n-back task with increasing WM load, and had longer stop signal reaction times on the stop task when compared with controls. However, only 6 % of the ASD group showed both WM and inhibition deficits, and 71 % showed no deficits. Parents of children with WM and/or inhibition deficits tended to report more conduct problems on the disruptive behavior disorder rating scale. ADHD characteristics did not influence performance. Some children used medication during testing, which seemingly influenced stop task performance, but excluding these data did not change the main findings. Large individual differences in cognitive functioning are present, even within children with ASD with average or above average intelligence. However, whether individual differences in specific cognitive domains, such as WM and inhibition are as informative as individual differences in diagnosis, comorbidity, and general cognitive functioning, calls for future research.

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10. Pankert A, Pankert K, Herpertz-Dahlmann B, Konrad K, Kohls G. Responsivity to familiar versus unfamiliar social reward in children with autism. Journal of Neural Transmission. 2014 2014/09/01 ;121(9):1199-210.

In autism spectrum disorders (ASD), social motivation theories suggest that the core social communication problems seen in children with ASD arise from diminished responsiveness to social reward. Although clinical and experimental data support these theories, the extent to which the reward deficit in ASD is unique for social rewards remains unclear. With the present investigation, we aimed to provide insight into the degree to which sociality as well as familiarity of reward incentives impact motivated goal-directed behavior in children with ASD. To do so, we directly compared the influence of familiar versus unfamiliar social reward relative to nonsocial, monetary reward in children with ASD relative to age- and IQ-matched typically developing controls (TDC) using a visual and auditory incentive go/nogo task with reward contingencies for successful response inhibitions. We found that children with ASD responded stronger to visual familiar and unfamiliar social reward as well as to nonsocial, monetary reward than TDC. While the present data are at odds with predictions made by social motivation theories, individual variations beyond clinical diagnosis, such as reward exposure across various social settings, help explain the pattern of results. The findings of this study stress the necessity for additional research on intra-individual as well as environmental factors that contribute to social reward responsiveness in individuals with ASD versus other neuropsychiatric disorders such as ADHD or conduct disorder.

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