Towards a new functional assessment of autistic dysfunction in children with developmental disorders: the Behaviour Function Inventory.

In order to assess particular disorders of psychological development and functioning in children with developmental disorders, we have developed a new tool, the Behaviour Function Inventory (BFI), based on 11 neurophysiological functions, disorders of which are considered to contribute to the core autistic syndrome. This article reports the reliability and validity study of this new scale. Factorial analysis computed on the 55 initial items identified six main dimensions which we characterized and labelled: interaction dysfunction, praxis dysfunction, auditory dysfunction, attention dysfunction, islet of ability and emotional dysfunction. Relationships between these six new variables and diagnostic subgroups, and chronological and developmental age, are discussed. The BFI offers precise information of the functional symptomatology of autism, showing clear evidence of some disordered areas of functioning. This new approach may provide valuable information in clinical research, especially for psychopathology and physiopathology studies.

[Latent imitation of human movements presented on a videoscopic screen, disclosed by electroencephalographic mapping in the spectator]. / Imitation latente de mouvements humains présentés sur écran vidéoscopique, mise en évidence par cartographie électro-encéphalographique chez le spectateur.

Trend to imitate human movement is studied here by EEG mapping. The effects of three kinds of situations are compared: a movement on a TV screen is presented to the subject; a movement is realized by the experimenter in front of the subject; the subject is asked to perform a movement. These three situations elicited important modifications in alpha 1 rhythms over the centroparietal area of the scalp. These results are discussed according to neurophysiological and neuropsychological data, including the possible role of frontal lobe in imitation. Preliminary experiments in psychopathology concern imitation disturbances in autistic children.

[Further clinical evaluations elicited by functional biological investigations in childhood autism]. / Evaluations cliniques complémentaires suscitées par des explorations biologiques fonctionnelles dans l'autisme de l'enfant.

As childhood autism is usually considered as a developmental disorder, complete assessment of each patient requires non only clinical examination but various biological investigations: EEG and evoked potentials recordings, biochemical dosages and sometimes, cerebral blood flow measures, molecular biologic explorations.... These investigations help to understand neurophysiological dysfunctionings which underly different autistic syndromes. It therefore seems necessary to develop quantified clinical tools which could allow closer matching between clinical evaluations and biological numerical data. These complementary evaluations must be both simple and quick to perform in medical practice, as they are added to an already heavy clinical examination. The main tools used in our bioclinical Department are described here. For each child, psychiatric, pediatric and neurological examination was performed. Different scales were progressively elaborated and validated to complete and precise behavioral parameters. Attention and perception were evaluated by a Behavior Summarized Evaluation (BSE) scale, association and imitation by appropriate scales, language by the Pre-Verbal Behavior Summarized Evaluation (PV-BSE) scale, early symptoms by the Infant Behavior Summarized Evaluation (t-BSE) scale. The main neurophysiological dysfunctionings were grouped in a Behavioral Functional Inventory (BFI). Clinical genetic data were scored in a summarized assessment carrying both on the antecedents and on the somatic abnormalities. The completed clinical data were gathered in a Quantified Multidimensional Assessment (QMA), with four axes: socialization, communication, cognition and neurological observation. These clinical evaluations provide behavioral details that can be integrated into a bioclinical database and give an objective approach to the heterogeneity of autism. They invite both clinicians and biologists to deepen the description of individual profiles which allow better understanding of physiopathological mechanisms in autistic children.

Validation of the Revised Behavior Summarized Evaluation Scale.

The Behavioral Summarized Evaluation scale (BSE), previously published and validated, was developed for the evaluation for the autistic behavior in developmentally disorder children. A revised version of this scale, the Revised Behavior Summarized Evaluation Scale (BSE-R) completed the 20-item BSE scale with the most relevant items extracted from a similar evaluation carried out with very young children. Thus 9 items were added to the original scale concerning nonverbal communication, emotional, and perception areas. This paper reports the reliability and validity studies of this new scale. In addition to confirming the previously published findings concerning the first version of the BSE, new items were extracted from the BSE-R content validity study. They involve fundamental functions such as intention and imitation which open new perspectives for a physiopathological approach to developmental disorders. The BSE-R is a useful tool for progressive recording of the evolution of patients both treated over long periods and included in short-term controlled therapeutic studies.

Temporal prominence of auditory evoked potentials (N1 wave) in 4-8-year-old children.

Cortical auditory evoked potentials (N1 wave) were studied in 24 adults (12 men, 12 women) and 20 children (12 boys, 8 girls; age: 4-8 years). In adults, this wave was recorded with maximal amplitude at frontocentral sites, peaking at about 100 ms poststimulation, whereas in children the auditory response displayed maximal amplitude at the midtemporal sites, with a positive wave at about 100 ms and a large negative wave at approximately 170 ms. Moreover, the modulatory effects of intensity on N1 amplitude were prominent at frontocentral sites in adults and at temporal sites in children. Frontocentral negative response was also recorded in children but was smaller in amplitude and longer in peak latency (around 140 ms) than in adults; responses were of greater amplitude at the frontal site than at the vertex before 6 years of age, whereas the reverse was more often found after this age. These data suggest great differences with age in the neural generators contributing to auditory evoked potentials recorded in the N1 latency range.

Serotonin and autism: biochemical and molecular biology features.

Whole blood and urinary levels of serotonin (5-hydroxytryptamine; 5-HT) and the derivative urinary 5-hydroxyindoleacetic acid (5-HIAA) were measured in normal and autistic subjects. An association was tested between autism and a marker coding for the 5-HT2A serotonergic receptor gene. Significant group (high urinary 5-HT and low whole blood 5-HT in autism) and age effects (urinary 5-HT decrease with age) were found. Moreover, whole blood 5-HT levels were correlated with clinical state. No differences in allele and genotype frequencies for the 5-HT2A receptor marker were found in this autistic population compared with age-matched healthy students.

X chromosome and infantile autism.

Family studies and epidemiologic data in autism show the involvement of genetic factors in the etiology of this syndrome. The frequent association of X chromosome with mental retardation and behavior disturbances raises the question of its implication in the etiology of autism. Several markers of X chromosome were tested in autistic and control populations by association study. The autistic population was submitted to an extensive clinical examination. For the DXS287 marker, chi 2 analysis showed a different allele distribution between control and patient groups. This difference was enhanced when children with the most severe autistic behaviors and the least serious cognitive disorders were selected for statistical comparison. To our knowledge, this is the first association study described using markers of X chromosome in infantile autism. These preliminary results encourage our research on this chromosome, which could be considered as a significant genetic component of the multifactorial etiology of autism.

Neuropathological study of a case of autistic syndrome with severe mental retardation.

Infantile autism is a syndrome of unknown aetiology and unknown neuro-anatomic substrate. The authors report a histological study of the brain of a well-documented 16-year-old female with autistic syndrome and severe mental retardation, using direct microscopic examination of the whole brain. The major findings are low brain weight, a thin corpus callosum and ventricular dilatation. No abnormalities were found in the hippocampus or cerebellum. Excessive axonal elimination during brain development is hypothesized. The relations of hypothetical developmental events with the clinical features of autistic syndrome are discussed.

Quantified multidimensional assessment of autism and other pervasive developmental disorders. Application for bioclinical research.

A large number of investigation techniques are used to establish the relationships between the clinical and biological data which are necessary for physiopathological analysis in the field of developmental disorders. It therefore seemed necessary to develop a quantified grouping system, based on developmental assessments, which could allow closer matching between clinical evaluations and biological numerical data. Two hundred and two subjects presenting developmental disorders (autistic disorder, pervasive developmental disorder not otherwise specified and mental retardation) were examined. For each child, a quantification of autistic behaviour, intellectual impairment, neurological signs and language and communication disorders was performed. A cluster analysis of these quantified data elicited four subgroups according to the scores obtained in these four different areas. We showed the value of this approach by applying it to one of the studies of monoamines routinely examined in childhood autism--dopamine and HVA, its main urinary derivative. Moreover, this method revealed a subgroup within the total population which was independent of nosographic classification and which had a particular clinical and biochemical profile. Other applications could follow, for example in the fields of neurophysiology, cerebral imaging, molecular biology and genetics.

Association study with two markers of a human homeogene in infantile autism.

Epidemiological data and family studies in autism show that there is a genetic susceptibility factor in the aetiology of this syndrome. We carried out an association study in infantile autism. Two markers of the homeogene EN2 involved in cerebellar development were tested in a population of 100 autistic children and in a population of 100 control children. With the MP4 probe showing a PvuII polymorphism, significant differences in the allele frequencies between the two populations were found (chi 2 = 7.99, df = 1, p < 0.01). With the MP5 probe showing an SstI polymorphism, no difference appeared (chi 2 = 1.17, not significant). Several clinical examinations allowed us to characterise the autistic children. Most of them had high scores for autistic behaviour and language disorders but low scores for neurological syndromes. Two children had a significant family history and six children had confirmed syndromes or diseases of genetic origin. Discriminant analysis between clinical and molecular data did not give significant results. These preliminary results must be supported by further analyses of this gene and by studies of its potential involvement in the pathophysiology of the autistic syndrome.

Delayed maturation of the frontal cortex in childhood autism.

OBJECTIVE: The authors investigated the metabolic maturation of the frontal cortex in pre-school autistic children. METHOD: Regional cerebral blood flow (CBF) in five children with primary autism diagnosed according to the DSM-III-R criteria was studied longitudinally. Regional CBF in each of the autistic children was measured with single photon emission computed tomography twice during their development: at the age of 3-4 years and 3 years later. At each stage, the autistic children were compared to an age-matched comparison group of five nonautistic children with normal development. RESULTS: A transient frontal hypoperfusion was found in the autistic children at ages 3-4 years; this corresponded to the pattern of perfusion observed in much younger normal children. By the ages of 6-7, the autistic children's frontal perfusion had attained normal values. CONCLUSIONS: Since CBF patterns in children are related to maturational changes in brain function, these results indicate a delayed frontal maturation in childhood autism. Such a delayed brain maturational process is consistent with the clinical data and cognitive performance of autistic children.

Catecholaminergic metabolism and autism.

The authors determined levels of dopamine (DA) and its derivatives homovanillic acid (HVA), 3-4 dihydroxyphenylacetic acid (DOPAC), 3 methoxytyramine and norepinephrine + epinephrine (NE + E) in the urine, and DA, E and NE in the whole blood of 50 autistic children aged between 1 year 11 months and 16 years. An association was tested for between markers coding for the enzymes and D3 dopaminergic receptor genes implicated in the monoaminergic pathway and autism, using restriction fragment-length polymorphism. There were significant modifications of catecholamine metabolites, but no difference for allele frequencies of the genes coding for tyrosine hydroxylase, dopamine beta hydroxylase and DRD3 in this population compared with a healthy school population matched for chronological age. However, some of the data encourage a more complete study of chromosome 11.

Cognitive and social dysfunction in childhood autism: a neuropsychological and physiological approach.

A neurophysiological approach to developmental studies of childhood autism has revealed major cognitive and sensori-motor disturbances which are associated with impairment in social relationships. This new approach suggests the existence of underlying cerebral dysfunction, signs of which are revealed by functional exploration and cerebral imaging.

[Childhood autism: a relating deficiency due to a developmental disorder of the central nervous system]. / L'autisme de l'enfant: une déficience relationnelle liée à un trouble du développement du système nerveux central.

Childhood autism with its difficulties in relating to others has been for a long time imputed to conscious or unconscious educative errors of the mother. Clinical and biological data can be opposed to this conception. Familial movies analysis exhibits early disorders in attention, perception, intention, limitation and muscular tone. Later, recording of cerebral reactivity to auditory stimulations confirms deficiencies in attention, perception, association ... and shows a diminution of the responses in the left hemisphere. Abnormalities in the development of the cerebellum are also described. Modifications of main neurotransmitters as Dopamine and Serotonin and their derivatives are often present. A recent study of the genes which control enzymes regulating metabolism of these transmitters does not show evident modifications by polymorphism analysis. On the contrary a peculiarity in the Harvey-RAS gene allows to differentiate in a significant way an autistic and a normal group. This gene is involved in the regulation of growth factor and/or differentiation of neural cells. These observations support the hypothesis considering autism as a relating deficiency due to a developmental disorder of central nervous system.

[Scales and questionnaires for the evaluation of behavior disorders in children]. / Echelles et questionnaires d'évaluation des troubles du comportement chez l'enfant.

The need for quantitative clinical evaluation tools for use in child psychiatry is obvious. Behavior rating scales are useful for comparing clinical and laboratory data, monitoring the effects of treatments, and enhancing communication between clinicians and investigators. The methodological principles used to construct and validate such tools are described. This approach is of benefit in most psychiatric disorders of children and adolescents. The questionnaires and scales most widely used throughout the world and available in French are reviewed. The advantages and drawbacks of evaluation scales in everyday practice and in research are discussed, with the BSE-A scale (Behavior Summarized Evaluation of Austism) as an example.

Possible association of c-Harvey-Ras-1 (HRAS-1) marker with autism.

We tested for an association between autism and genes coding for enzymes involved in monoaminergic metabolism and for a linked marker, c-Harvey-Ras-1 (HRAS 1), using restriction fragment length polymorphisms. We did not find evidence of an association between autism and genes coding for tyrosine hydroxylase, dopamine-beta-hydroxylase (DBH), and tryptophan hydroxylase. However, we report a positive association between autism and the locus containing the gene for HRAS-1.

Auditory stimulus intensity responses and frontal midline theta rhythm.

The influence of stimulus intensity on the N1 component of auditory evoked potentials recorded at fronto-central sites was investigated in respect to the spectral components of the EEG recorded at Cz, Fz and Oz. The study was performed on 14 healthy adult subjects. The only EEG frequency bandwidth that was strongly correlated with the N1 amplitude-intensity slope was the theta rhythm, particularly the 5-7 Hz frequencies recorded at Cz and Fz. This frequency bandwidth corresponds to the previously described frontal midline theta rhythm related to performance of tests that require continuous concentration of attention. Our results show that the steeper the slope, the greater the amount of Fm theta. This suggests that the interindividual differences in the N1 amplitude/intensity slope could be related to interindividual differences in attentional readiness toward the auditory stimuli, even when delivered in "passive" conditions.

Theoretical aspects of the study of benzodiazepine receptors in infantile autism.

This paper is part of a special section on 'psychopharmacotherapy in children' and focuses on benzodiazepine receptors in autism. Infantile autism in an early and pervasive developmental disorder described by Kanner in 1943. Anatomical, pathological and magnetic resonance imaging studies have indicated changes in the cerebellum and hippocampus of autistic subjects. Given the numerical importance and diffuse benzodiazepine receptors, their study by functional brain imaging methods in vivo could be value in cases of infantile autism as a gauge of neuronal potentiality. The main data concerning benzodiazepine complex are presented. The relations between these data and the neurophysiological hypotheses of autism are discussed.