On the nature of the speech perception deficits in children with autism spectrum disorders.

Previous studies have claimed to show deficits in the perception of speech sounds in autism spectrum disorders (ASD). The aim of the current study was to clarify the nature of such deficits. Children with ASD might only exhibit a lesser amount of precision in the perception of phoneme categories (CPR deficit). However, these children might further present an allophonic mode of speech perception, similar to the one evidenced in dyslexia, characterised by enhanced discrimination of acoustic differences within phoneme categories. Allophonic perception usually gives rise to a categorical perception (CP) deficit, characterised by a weaker coherence between discrimination and identification of speech sounds. The perceptual performance of ASD children was compared to that of control children of the same chronological age. Identification and discrimination data were collected for continua of natural vowels, synthetic vowels, and synthetic consonants. Results confirmed that children with ASD exhibit a CPR deficit for the three stimulus continua. These children further exhibited a trend toward allophonic perception that was, however, not accompanied by the usual CP deficit. These findings confirm that the commonly found CPR deficit is also present in ASD. Whether children with ASD also present allophonic perception requires further investigations.

Social cognition and the superior temporal sulcus: implications in autism.

The most common clinical sign of autism spectrum disorders (ASD) is social interaction impairment, which is associated with communication deficits and stereotyped behaviors. Based on brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. These abnormalities are characterized by decreased grey matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomofunctional anomalies occurring early across brain development could constitute the first step in the cascade of neural dysfunctions underlying autism. It is known that STS is highly implicated on social perception processing, from perception of biological movements, such as body movements or eye gaze, to more complex social cognition processes. Among the impairments that can be described in social perception processing, eye gaze perception is particularly relevant in autism. Gaze abnormalities can now be objectively measured using eye-tracking methodology. In the present work, we will review recent data on STS contributions to normal social cognition and its implication in autism, with particular focus on eye gaze perception.

[Brain imaging of infantile autism]. / Imagerie cérébrale dans l'autisme infantile.

Understanding of brain structural anomalies seen in children with autism has considerably progressed since the apparition of MRI and functional imaging. All the results are converging toward the description of anatomical and functional anomalies in the regions of the so-called "social brain". Statistical analyses show diminution of gray matter in the region of the superior temporal sulcus (STS). Functional studies with PET shows a diminution of brain blood flow at rest in the same region. Brain activation studies show absence of activation of the specialized region in processing human voice and hypoactivation of "social brain" regions in complex tasks of social cognition. At last, abnormal connectivity between the frontal and temporal regions has been showed. Those regions are implicated in processing sensorial inputs necessary for normal social life. All those anomalies could be responsible of the abnormal social behaviour pattern of children with autism.

Histone deacetylase inhibitors suppress interleukin-1beta-induced nitric oxide and prostaglandin E2 production in human chondrocytes.

OBJECTIVE: Overproduction of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) plays an important role in the pathogenesis of osteoarthritis (OA). In the present study, we determined the effect of trichostatin A (TSA) and butyric acid (BA), two histone deacetylase (HDAC) inhibitors, on NO and PGE(2) synthesis, inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 expression, and nuclear factor (NF)-kappaB DNA-binding activity, in interleukin-1beta (IL-1)-stimulated human OA chondrocytes, and on IL-1-induced proteoglycan degradation in cartilage explants. METHODS: Chondrocytes were stimulated with IL-1 in the absence or presence of increasing concentrations of TSA or BA. The production of NO and PGE(2) was evaluated using Griess reagent and an enzyme immunoassay, respectively. The expression of iNOS and COX-2 proteins and mRNAs was evaluated using Western blotting and real-time reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Proteoglycan degradation was measured with dimethymethylene blue assay. Electrophoretic mobility shift assay (EMSA) was utilized to analyze the DNA-binding activity of NF-kappaB. RESULTS: HDAC inhibition with TSA or BA resulted in a dose-dependent inhibition of IL-1-induced NO and PGE(2) production. IL-17- and tumor necrosis factor-alpha (TNF-alpha)-induced NO and PGE(2) production was also inhibited by TSA and BA. This inhibition correlated with the suppression of iNOS and COX-2 protein and mRNA expression. TSA and BA also prevented IL-1-induced proteoglycan release from cartilage explants. Finally, we demonstrate that the DNA-binding activity of NF-kappaB, was induced by IL-1, but was not affected by treatment with HDAC inhibitors. CONCLUSIONS: These data indicate that HDAC inhibitors suppressed IL-1-induced NO and PGE(2) synthesis, iNOS and COX-2 expression, as well as proteoglycan degradation. The suppressive effect of HDAC inhibitors is not due to impaired DNA-binding activity of NF-kappaB. These findings also suggest that HDAC inhibitors may be of potential therapeutic value in the treatment of OA.

Abnormal melatonin synthesis in autism spectrum disorders.

Melatonin is produced in the dark by the pineal gland and is a key regulator of circadian and seasonal rhythms. A low melatonin level has been reported in individuals with autism spectrum disorders (ASD), but the underlying cause of this deficit was unknown. The ASMT gene, encoding the last enzyme of melatonin synthesis, is located on the pseudo-autosomal region 1 of the sex chromosomes, deleted in several individuals with ASD. In this study, we sequenced all ASMT exons and promoters in individuals with ASD (n=250) and compared the allelic frequencies with controls (n=255). Non-conservative variations of ASMT were identified, including a splicing mutation present in two families with ASD, but not in controls. Two polymorphisms located in the promoter (rs4446909 and rs5989681) were more frequent in ASD compared to controls (P=0.0006) and were associated with a dramatic decrease in ASMT transcripts in blood cell lines (P=2 x 10(-10)). Biochemical analyses performed on blood platelets and/or cultured cells revealed a highly significant decrease in ASMT activity (P=2 x 10(-12)) and melatonin level (P=3 x 10(-11)) in individuals with ASD. These results indicate that a low melatonin level, caused by a primary deficit in ASMT activity, is a risk factor for ASD. They also support ASMT as a susceptibility gene for ASD and highlight the crucial role of melatonin in human cognition and behavior.

[Is age at onset associated with executive dysfunction in obsessive-compulsive disorder?]. / Fonctions exécutives dans le trouble obsessionnel compulsif: effet de l'âge de début des troubles.

In obsessive-compulsive disorder (OCD), clinical, neurobiological and genetic differences have been reported according to age at onset (AAO). Given the importance of identifying homogeneous subtypes in complex hete-rogeneous disorders such as OCD, it would be particularly useful to identify a specific cognitive profile associated with early-onset OCD. Although impaired cognition has repea-tedly been demonstrated in OCD patients, discrepancies between studies have hampered the identification of a precise cognitive dysfunction. Executive dysfunction has often been reported, but findings have not always been replicated. The aim of this study was to assess executive functions in 30 patients according to their AAO. The sample consisted of 15 early-onset and 15 late-onset OCD patients and 22 normal controls, matched for age, sex and socio-economic status. Various aspects of executive function were assessed with five neuropsychological tests: Tower of London, Trail Making Test, Verbal Fluency, Design Fluency and Association Fluen-cy. The 30 OCD patients obtained lower total scores than the controls in the Tower of London test and association fluen-cy task (p<0.05 and p<0.001, respectively). Impairments were more marked for the early-onset group, with no effect of gender or age at interview. Deficits in specific aspects of frontal lobe function were found in the OCD group and were particularly pronounced within the early-onset group. These findings confirm clinical data suggesting that OCD patients can be subtyped according to age at onset and that OCD patients present unusual cognitive characteristics. They also support the hypothesis that early-onset OCD might be a rele-vant subgroup characterised both by a particular clinical profile and by specific cognitive characteristics.

Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study.

The underlying neurobiology of autism, a severe pervasive developmental disorder, remains unknown. Few neocortical brain MRI abnormalities have been reported. Using rest functional brain imaging, two independent studies have described localized bilateral temporal hypoperfusion in children with primary autism. In order to search for convergent evidence of anatomical abnormalities in autistic children, we performed an anatomical MRI study using optimized whole-brain voxel-based morphometry (VBM). High-resolution 3-D T1-weighted MRI data sets were acquired in 21 children with primary autism (mean age 9.3 +/- 2.2 years) and 12 healthy control children (mean age 10.8 +/- 2.7 years). By comparing autistic children to normal children, we found bilaterally significant decreases of grey matter concentration located in superior temporal sulcus (STS) (P < 0.05 corrected, after small volume correction; SVC). Children with autism were also found to have a decrease of white matter concentration located in the right temporal pole and in cerebellum (P < 0.05, corrected) compared to normal children. These results suggest that autism is associated with bilateral anatomical abnormalities localized in the STS and are remarkably consistent with functional hypoperfusion previously reported in children with autism. The multimodal STS areas are involved in highest level of cortical integration of both sensory and limbic information. Moreover, the STS is now recognized as a key cortical area of the "social brain" and is implicated in social perceptual skills that are characteristically impaired in autism. Therefore, the convergent anatomical and functional temporal abnormalities observed in autism may be important in the understanding of brain behavior relationships in this severe developmental disorder.

[Bitemporal lobe dysfonction in infantile autism: positron emission tomography study]. / Dysfonctionnement bitemporal dans l'autisme infantile: étude en tomographie par émission de positons.

PURPOSE: Childhood autism is a severe developmental disorder that impairs the acquisition of some of the most important skills in human life. Progress in understanding the neural basis of childhood autism requires clear and reliable data indicating specific neuroanatomical or neurophysiological abnormalities. The purpose of the present study was to research localized brain dysfunction in autistic children using functional brain imaging. PATIENTS AND METHODS: Regional cerebral blood flow (rCBF) was measured with positron emission tomography (PET) in 21 primary autistic children and 10 age-matched non autistic children. RESULTS: A statistical parametric analysis of rCBF images revealed significant bilateral temporal hypoperfusion in the associative auditory cortex (superior temporal gyrus) and in the multimodal cortex (superior temporal sulcus) in the autistic group (p<0.001). In addition, temporal hypoperfusion was detected individually in 77% of autistic children. CONCLUSION: These findings provide robust evidence of well localized functional abnormalities in autistic children located in the superior temporal lobe. Such localized abnormalities were not detected with the low resolution PET camera,. This study suggests that high resolution PET camera combined with statistical parametric mapping is useful to understand developmental disorders.

Opiate antagonists in children and adolescents.

Naltrexone a pure opioid antagonist, well tolerated in young patients, has been found to be an interesting treatment in some disorders in children and adolescents. Naltrexone has been first tried in mental retardation and autism disorders in children and adolescents. Symptoms like self-injury behaviours, hyperactivity, stereotyped and ritualistic conducts appear to be improved in a subgroup of children with the opiate antagonist. But new controlled studies still need to be done before recommending naltrexone in autism. Preliminary results in the treatment of alcoholic adolescents seem to support the efficacy of naltrexone on abstinence when combined with a supportive psychotherapy. In adults, results found with the use of naltrexone in eating disorders are different, when considering the duration and the dosage of the treatment and the kind of eating disorder (bulimia, binge eating or anorexia nervosa). Studies in children and adolescents are needed before proposing naltrexone in eating disorders. We resumed here the results found with this treatment in these indications.