Catherine Barthélémy

X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the Neuroligin family

A large French family including members affected by nonspecific X-linked mental retardation, with or without autism or pervasive developmental disorder in affected male patients, has been found to have a 2-base-pair deletion in the Neuroligin 4 gene (NLGN4) located at Xp22.33. This mutation leads to a premature stop codon in the middle of the sequence of the normal protein and is thought to suppress the transmembrane domain and sequences important for the dimerization of neuroligins that are required for proper cell-cell interaction through binding to beta-neurexins. As the neuroligins are mostly enriched at excitatory synapses, these results suggest that a defect in synaptogenesis may lead to deficits in cognitive development and communication processes. The fact that the deletion was present in both autistic and nonautistic mentally retarded males suggests that the NLGN4 gene is not only involved in autism, as previously described, but also in mental retardation, indicating that some types of autistic disorder and mental retardation may have common genetic origins.

Abnormal cortical voice processing in autism

Impairments in social interaction are a key feature of autism and are associated with atypical social information processing. Here we report functional magnetic resonance imaging (fMRI) results showing that individuals with autism failed to activate superior temporal sulcus (STS) voice-selective regions in response to vocal sounds, whereas they showed a normal activation pattern in response to nonvocal sounds. These findings suggest abnormal cortical processing of socially relevant auditory information in autism.

Observation and execution of movement: similarities demonstrated by quantified electroencephalography

Quantified electroencephalography (qEEG) was used to compare cerebral electrical variations while human subjects (10 males and 10 females) were observing and executing finger movements and while they were resting. Video recording enabled elimination of subjects performing involuntary movements. EEGs were recorded from 14 sites in seven frequency bands: theta 1, theta 2, alpha 1, alpha, beta 1, beta 2 and beta 3. Analyses were performed on logarithmically transformed absolute spectral power values. Both observation and execution of finger movements involved a decrease in spectral power compared with resting. This decrease was significant only for the alpha 1 frequency band (7.5–10.5 Hz) and it involved nine of the 14 electrode locations (F7, F8, F4, T6, T5, C3, C4, P3 and P4). This indicates that the motor cortex and the frontal cortex are specifically activated by both observation and execution of finger movements. These results provide evidence that observation and execution of movement share the same cortical network.

Recurrent Rearrangements in Synaptic and Neurodevelopmental Genes and Shared Biologic Pathways in Schizophrenia, Autism, and Mental Retardation

CONTEXT Results of comparative genomic hybridization studies have suggested that rare copy number variations (CNVs) at numerous loci are involved in the cause of mental retardation, autism spectrum disorders, and schizophrenia. OBJECTIVES To provide an estimate of the collective frequency of a set of recurrent or overlapping CNVs in 3 different groups of cases compared with healthy control subjects and to assess whether each CNV is present in more than 1 clinical category. DESIGN Case-control study. SETTING Academic research. PARTICIPANTS We investigated 28 candidate loci previously identified by comparative genomic hybridization studies for gene dosage alteration in 247 cases with mental retardation, in 260 cases with autism spectrum disorders, in 236 cases with schizophrenia or schizoaffective disorder, and in 236 controls. MAIN OUTCOME MEASURES Collective and individual frequencies of the analyzed CNVs in cases compared with controls. RESULTS Recurrent or overlapping CNVs were found in cases at 39.3% of the selected loci. The collective frequency of CNVs at these loci is significantly increased in cases with autism, in cases with schizophrenia, and in cases with mental retardation compared with controls (P < .001, P = .01, and P = .001, respectively, Fisher exact test). Individual significance (P = .02 without correction for multiple testing) was reached for the association between autism and a 350-kilobase deletion located at 22q11 and spanning the PRODH and DGCR6 genes. CONCLUSIONS Weakly to moderately recurrent CNVs (transmitted or occurring de novo) seem to be causative or contributory factors for these diseases. Most of these CNVs (which contain genes involved in neurotransmission or in synapse formation and maintenance) are present in the 3 pathologic conditions (schizophrenia, autism, and mental retardation), supporting the existence of shared biologic pathways in these neurodevelopmental disorders.

Blockade by benzodiazepines of the selective high increase in dopamine turnover induced by stress in mesocortical dopaminergic neurons of the rat

The effects of electrical foot shock on the activity of the ascending dopaminergic neurons were estimated in the rat by measuring the changes in DOPAC and DA levels in discrete brain areas. DOPAC and DA levels were estimated with a radioenzymatic method in microdiscs of tissues punched out from serial frontal sections of the brain. A marked rise in the ratio of DOPAC/DA levels resulting from an increase of DOPAC and a decrease of DA levels was found in the cerebral frontal cortex at the end of a 20 min stress. The effect was less pronounced in stress of shorter duration from 3 to 10 min and was only related to a reduction of DA levels. Using the DOPAC/DA ratio as an index of the activity of the neurons, the mesocortical dopaminergic neurons were found to be selectively activated under stress since this ratio was increased in the frontal and cingular cortices but not in limbic structures such as the septum, the amygdala and the nucleus accumbens or in the striatum. Finally, pretreatment of the rats with diazepam (5 mg/kg i.p.) or chlordiazepoxide (10 mg/kg i.p.) prevented the increase in the DOPAC/DA ratio in the frontal cerebral cortex of rats submitted to the 20 min stress.

Perception of motion and qEEG activity in human adults.

This study was designed to relate visual perception of motion to cortical activity, by evaluation of the association of quantified electroencephalogram (qEEG) parameters with a video film projection. The EEG was recorded from 14 sites according to the International 10-20 system and a common average reference was used. Forty right-handed volunteers (mean age = 24 years) were examined. The video film consisted of 20 s sequences showing still shots and moving shots with human movements or object movements. The EEG was then subjected to spectral analysis; the spectral powers for the theta, alpha and beta bands were calculated for 14 s epochs and compared with sequences of the video film. All analyses were based on logarithmically transformed absolute spectral power values. The power values of each frequency band were analysed in a 3-way repeated measure ANOVA (Hemisphere x Electrode x Sequence). The results were represented by EEG cartography. Significant decreases in the alpha 1, beta 1 and beta 2 power values of EEG in centro-parietal regions of both hemispheres were shown during perception of human motion sequences. This suggests participation of the sensorimotor cortex during visual observation of human motion.

Hypersensitivity to acoustic change in children with autism: electrophysiological evidence of left frontal cortex dysfunctioning.

Exaggerated reactions to even small changes in the environment and abnormal behaviors in response to auditory stimuli are frequently observed in children with autism (CWA). Brain mechanisms involved in the automatic detection of auditory frequency change were studied using scalp potential and scalp current density (SCD) mapping of mismatch negativity (MMN) in 15 CWA matched with 15 healthy children. Compared with the response in controls, MMN recorded at the Fz site in CWA showed significantly shorter latency and was followed by a P3a wave. Mapping of potentials indicated significant intergroup differences. Moreover, SCD mapping demonstrated the dynamics of the different MMN generators: Although temporal component was evidenced bilaterally in both groups, it occurred earlier on the left hemisphere in CWA, preceded by an abnormal early left frontal component. The electrophysiological pattern reported here emphasized a left frontal cortex dysfunctioning that might also be implicated in cognitive and behavioral impairment characteristic, of this complex neurodevelopmental disorder.

Motor control and children with autism: deficit of anticipatory function?

This study aims at investigating how do anticipatory postural adjustments develop in children with autism, during a bimanual load-lifting task that required maintaining the stabilisation of the forearm despite imposed or voluntary unloading. Elbow angle and electromyographic were recorded on the child forearm supporting the load. The forearm stabilisation was as good in children with autism as in the control group. However, in children with autism, the latencies for both kinematics and muscular events indicated an increase of the duration of unloading. These results indicate the use of a feedback rather than a feed-forward mode of control. Impairments in both the building of internal representations and the mastering of timing parameters, could explain the deficient postural anticipation reported in children with autism.

Auditory associative cortex dysfunction in children with autism: evidence from late auditory evoked potentials (N1 wave–T complex)

OBJECTIVES Auditory processing at the cortical level was investigated with late auditory evoked potentials (N1 wave-T complex) in 4-8-year-old autistic children with mental retardation and compared to both age-matched normal and mentally retarded children (16 children in each group). METHODS Two negative peaks which occurred in the 80-200 ms latency range were analyzed according to stimulus intensity level (50 to 80 dB SPL): the first culminated at fronto-central sites (N1b) and the second at bitemporal sites (N1c, equivalent to Tb of the T complex). The latter wave was the most prominent and reliable response in normal children at this age. RESULTS Our results in autistic children indicated abnormalities of this wave with markedly smaller amplitude at bitemporal sites and pronounced peak latency delay (around 20 ms). Moreover, in both reference groups the intensity effect was found on both sides whereas in autistic children it was absent on the left side but present on the right. CONCLUSION These findings in autistic children showing very disturbed verbal communication argue for dysfunction in brain areas involved in N1c generation i.e., the auditory associative cortex in the lateral part of the superior temporal gyrus, with more specific left side defects when auditory stimulus have to be processed.

Maturation of frontal and temporal components of mismatch negativity (MMN) in children.

The mismatch negativity (MMN) response of auditory ERPs in adults appears to result from several overlapping components involving both frontal and temporal brain areas. Our aim was to test whether a similar configuration could be observed in children, and to examine the maturation rates of the different components. MMN (standard tones: 1000 Hz, deviants: 1100 Hz) was recorded from 28 scalp electrodes in 24 healthy children aged from 5 to 10 and in eight adults for comparison. Scalp current density analysis revealed both temporal and frontal components in children of all ages as well as in adults. Moreover the amplitudes of the temporal components were significantly greater in children than in adults, whereas the frontal components were similar at all ages. The results strongly suggest that MMN is mediated by at least two separate neural systems, and that the frontal system matures earlier than the sensory-specific system.