A strategic plan to identify key neurophysiological mechanisms and brain circuits in autism.

Autism and Autism Spectrum Disorder (ASD) cover a large variety of clinical profiles which share two main dimensions: social and communication impairment and repetitive behaviors or restricted interests, which are present during childhood. There is now no doubt that genetic factors are a major component in the etiology of autism but precise physiopathological pathways are still being investigated. Furthermore, developmental trajectories combined with compensatory mechanisms will lead to various clinical and neurophysiological profiles which together constitute this Autism Spectrum Disorder. To better understand the pathophysiology of autism, comprehension of key neurophysiological mechanisms and brain circuits underlying the different bioclinical profiles is thus crucial. To achieve this goal we propose a strategy which investigates different levels of information processing from sensory perception to complex cognitive processing, taking into account the complexity of the stimulus and whether it is social or non-social in nature. In order to identify different developmental trajectories and to take into account compensatory mechanisms, we further propose that such protocols should be carried out in individuals from childhood to adulthood representing a wide variety of clinical forms.

Exploration of core features of a human face by healthy and autistic adults analyzed by visual scanning.

Autism is a neurodevelopmental disorder characterized by disorders in social interaction and emotional reciprocity which can be explained by impairments of the ability to understand the mental states of others ("theory of mind") and recognition of facial expressions. These impairments may be related to the difficulties with face recognition characteristic of this disorder. Face perception plays a critical role in the development of social interaction and understanding of the internal emotional state of others. It depends on initial oculomotor exploration. The aim of this study was to quantify ocular behaviour in 11 adults with autism and 23 healthy subjects (15-35 years) while exploring neutral faces and faces expressing an emotion using an eye tracking method. The strategy used to explore faces was also studied. All subjects spent significantly more time on the eye region than on the rest of the face. However, subjects with autism spent less time on the eye region than healthy subjects. The latter used a strategy based on their own eye dominance when exploring faces. All healthy subjects significantly began their exploration of a face by looking at the eye in the contralateral visual field to their dominant eye. This strategy seemed to be impaired in patients with autism. To conclude, these results contrast with earlier reports regarding the lack of interest in the eye region in patients with autism, and demonstrate for the first time that perception of the face is dependent on eye dominance.

Impaired cortical activation in autistic children: is the mirror neuron system involved?

The inability to imitate becomes obvious early in autistic children and seems to contribute to learning delay and to disorders of communication and contact. Posture, motility and imitation disorders in autistic syndrome might be the consequence of an abnormality of sensori-motor integration, related to the visual perception of movement, and could reflect impairment of the mirror neuron system (MNS). We compared EEG activity during the observation of videos showing actions or still scenes in 14 right-handed autistic children and 14 right-handed, age- and gender-matched control children (3 girls and 11 boys, aged 5 years 3 months-7 years 11 months). We showed desynchronisation of the EEG in the motor cerebral cortex and the frontal and temporal areas during observation of human actions in the group of healthy children. No such desynchronisation was found in autistic children. Moreover, inversion of the pattern of hemispheric activation was found in autistic children, with increased cortical activity in the right hemisphere in the posterior region, including the centro-parietal and temporo-occipital sites. These results are in agreement with the hypothesis of impairment of the mirror neuron system in autistic disorder.

Evaluation of protective effect of DNA vaccination with genes encoding antigens GRA4 and SAG1 associated with GM-CSF plasmid, against acute, chronical and congenital toxoplasmosis in mice.

To develop a multiantigenic vaccine against toxoplasmosis, two Toxoplasma gondii antigens, SAG1 and GRA4 selected on the basis of previous immunological and immunization studies, were chosen. We showed that DNA-based immunization with plasmids expressing GRA4 (pGRA4) or SAG1 (pSAG1mut) reduced mortality of susceptible C57BL/6 mice upon oral challenge with cysts of the 76K type II strain (62% survival). Immunization with pGRA4 and pSAG1mut, enhanced the protection (75% survival). This protection was further increased by co-inoculation with a plasmid encoding the granulocyte-macrophage colony-stimulating factor (GM-CSF) (87% survival). This latter DNA cocktail provided significant protection of less susceptible outbred Swiss OF1 mice against the development of cerebral cysts. A significantly higher survival of newborns from immunized outbred mice exposed to infection during gestation was observed (4.25+/-3.77 live pups/litter) in comparison to non-immunized mice (1.08+/-2.15 live pups/litter) without preventing parasite vertical transmission. Analysis of the immune response showed that protected animals developed a specific humoral and cellular Th1 response to native T. gondii SAG1 and GRA4 antigens. Our data demonstrated that protection was improved by associating antigens (SAG1 and GRA4) and cytokine (GM-CSF) for further development of a multiantigenic vaccine against toxoplasmosis.